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Ju Y.,PLA Fourth Military Medical University | Xiao B.,Xian Hospital Of Traditional Chinese Medicine
African Health Sciences | Year: 2016

Background: Xiang Fu (Cyperus rotundus L) enters the liver, spleen and triple warmer meridians, and has qi stagnation-removing, qi circulation-promoting, menstruation-regulating and pain-relieving effects. Besides, it can improve ovarian function, and has hypolipidemic, hypoglycemic and neuroprotective actions. Objectives: To study the biflavone constituents in Cyperus rotundus L and to investigate the effect and mechanism of amentoflavone on inhibition of uterine tumors. Modern chromatographic techniques were applied for isolation and purification of compounds, which were then structurally elucidated based on their physicochemical properties and spectral data. Methods: Female SD rats were injected with diethylstilbestrol and progesterone to establish the pathological model of uterine fibroids. The rats were then randomly divided into amentoflavone high-, medium- and low-dose groups, mifepristone group, model group and blank control group (n=10 in each group), and these administered for six consecutive weeks. 24 h after the last administration, the rats were sacrificed, changes in uterine coefficient were observed, and morphological features of apoptotic cells in uterine smooth muscle tissues were detected. Afterwards, serum estradiol and progesterone levels were determined by radioimmunoassay, as well as NOS level in uterine fibroid tissue homogenates. Pro- and anti-apoptotic genes Bcl-2 and Bax were determined by immunohistochemical assay. Results: Four biflavone constituents were isolated and obtained. Amentoflavone could markedly reduce the uterine coefficient in model rats, lower serum estrogen levels in rats with uterine fibroids, improve the pathological conditions of uterine tissues, markedly reduce the number of Bcl-2- and Bax-positive dots in smooth muscles, and significantly inhibit the tumor-like proliferation in model rats (P<0.01), which were most obvious in the amentoflavone high-dose group. Conclusion: It concludes that amentoflavone has a significant inhibitory effect on uterine tumors in rats. Its mechanism may be by elevating Bax protein expression, down-regulating Bcl-2 expression, forming homodimers Bax/Bax, and reducing plasma estradiol and progesterone to promote apoptosis of uterine fibroid cells. © 2016, Makerere University, Medical School. All rights reserved.


Zheng L.-Q.,Chinese PLA General Hospital | Zheng L.-Q.,251st Hospital of Chinese PLA | Chi S.-M.,PLA Fourth Military Medical University | Li C.-X.,Chinese PLA General Hospital
Bioscience Reports | Year: 2017

Rab23 has been proven to play a role in membrane trafficking and protein transport in eukaryotic cells. Rab23 is also a negative regulator of the Sonic hedgehog (Shh) signaling pathway in an indirect way. The nonsense mutation and loss of protein of Rab23 has been associated with neural tube defect in mice and aberrant expression in various diseases in human such as neural system, breast, visceral, and cutaneous tumor. In addition, Rab23 may play joint roles in autophagosome formation during anti-infection process against Group A streptococcus. In this review, we give a brief review on the functions of Rab23, summarize the involvement of Rab23 in genetic research, membrane trafficking, and potential autophagy pathway, especially focus on tumor promotion, disease pathogenesis, and discuss the possible underlying mechanisms that are regulated by Rab23. © 2017 The Author(s).


Zhao D.,PLA Fourth Military Medical University | Yang J.,PLA Fourth Military Medical University | Yang L.,Xian Childrens Hospital
Oxidative medicine and cellular longevity | Year: 2017

Diabetes mellitus (DM) displays a high morbidity. The diabetic heart is susceptible to myocardial ischemia/reperfusion (MI/R) injury. Impaired activation of prosurvival pathways, endoplasmic reticulum (ER) stress, increased basal oxidative state, and decreased antioxidant defense and autophagy may render diabetic hearts more vulnerable to MI/R injury. Oxidative stress and mTOR signaling crucially regulate cardiometabolism, affecting MI/R injury under diabetes. Producing reactive oxygen species (ROS) and reactive nitrogen species (RNS), uncoupling nitric oxide synthase (NOS), and disturbing the mitochondrial quality control may be three major mechanisms of oxidative stress. mTOR signaling presents both cardioprotective and cardiotoxic effects on the diabetic heart, which interplays with oxidative stress directly or indirectly. Antihyperglycemic agent metformin and newly found free radicals scavengers, Sirt1 and CTRP9, may serve as promising pharmacological therapeutic targets. In this review, we will focus on the role of oxidative stress and mTOR signaling in the pathophysiology of MI/R injury in diabetes and discuss potential mechanisms and their interactions in an effort to provide some evidence for cardiometabolic targeted therapies for ischemic heart disease (IHD).


Ma L.-N.,Shaanxi Normal University | Liu S.,PLA Fourth Military Medical University
Advances in Intelligent Systems and Computing | Year: 2017

In this paper, we introduce the concept of p-relative degrees of activation, and a p-R0 type triple Imethod for interval valued fuzzy reasoning model is proposed which is proved to be continuous. Furthermore, we showed that this method has a good transmissible performance for approximate errors. © Springer International Publishing Switzerland 2017.


Liu M.-D.,PLA Fourth Military Medical University
Chinese journal of traumatology = Zhonghua chuang shang za zhi | Year: 2014

OBJECTIVE: To determine the changes of serum Tau protein, glial fibrillary acidic protein (GFAP), tumor necrosis factor alpha (TNF-α), and malonaldehyde (MDA) in rats after blast-related traumatic brain injury (BTBI) and to provide relative information for further studies on BTBI mechanism and seek specific biomarkers for BTBI.METHODS: Ninety male Sprague-Dawley rats were randomly assigned into three groups: control group, moderate blast injury group, and severe blast injury group (n=30 for each). Rats in the moderate and severe blast injury groups were respectively exposed to corresponding levels of BTBI. After explosion, serum levels of Tau, GFAP, TNF-α, and MDA in each group were determined by Elisa assay at different time points after injury (8 h, 24 h, 3 d, and 6 d). The extent of brain damage was detected by Nissl staining and TUNEL assay.RESULTS: Serum levels of Tau and GFAP rapidly increased and reached the peak at 24 h after either moderate or severe blast injury. All the values were significantly higher than control group at all time points (P<0.05). Serum TNF-α level of both injury groups peaked at 8 h after BTBI and stayed significantly higher than control group at all time points (P<0.05). Serum MDA of two injury groups began to significantly increase at 3 d and the level stayed significantly higher than control group until 6 d (P<0.05). Moreover, unlike the other biomarkers, serum MDA of severe blast injury group was significantly higher than moderate blast injury group at 6 d (P<0.05).CONCLUSION: The changes of serum Tau, GFAP, and TNF-α showed a good sensitivity at the acute phase after BTBI (within 24 h). However, their specificity and correlation with the extent of injury were limited in this experiment. Moreover, although the change of serum MDA showed a poor sensitivity and specificity to the diagnosis of BTBI during the first few days, it can reflect the injury degree at 6 d after injury. Therefore, further studies are needed to improve the methods of detecting more serum markers and investigate the significance of multiple markers in diagnosing BTBI.


Dong B.-W.,Xian Yang Central Hospital | Jin X.-H.,PLA Fourth Military Medical University | Yan C.-Y.,Xian Health Management Service Center | Yang T.,PLA Fourth Military Medical University | And 2 more authors.
FEBS Letters | Year: 2017

Members of the Drosophila behavior/human splicing protein family, including splicing factor proline/glutamine rich (SFPQ), non-POU domain-containing octamer-binding protein (NONO), and paraspeckle protein component 1 (PSPC1), are abundantly expressed in testicular Sertoli cells (SCs), but their roles remain obscure. Here, we show that treatment with mono-(2-ethylhexyl) phthalate (MEHP), a well-known SC toxicant, selectively stimulates the expression levels of NONO and PSPC1. Simultaneous inhibition of NONO and PSPC1 expression in SCs enhances MEHP-induced oxidative stress and potentiates SC death. Mechanistically, NONO and PSPC1 transcriptionally activate aldehyde dehydrogenase 1 (Aldh1a1), by synergistically binding to the distinct CCGGAGTC sequence in the Aldh1a1 promoter. Together, the NONO/PSPC1-ALDH1A1 cascade may serve as an indispensable defense mechanism against MEHP insult in SCs. © 2017 Federation of European Biochemical Societies


Shang R.,PLA Fourth Military Medical University | Pu M.,PLA Fourth Military Medical University | Li Y.,PLA Fourth Military Medical University | Wang D.,PLA Fourth Military Medical University
Oncology Reports | Year: 2017

The Forkhead box M1 (FOXM1) transcription factor plays crucial roles in the initiation and progression of various malignancies, including hepatocellular carcinoma (HCC). However, the mechanism by which FOXM1 regulates cancer metabolism remains unclear. In the present study, overexpression and RNA interference (RNAi) approaches were used to investigate the role of FOXM1 in the regulation of glycolysis in vitro. Luciferase reporter assays were used to explore the transcriptional regulation of the glucose transporter 1 (GLUT1) promoter by FOXM1. Then, immunohistochemical staining was used to examine the expression of FOXM1 and GLUT1 in 100 paired HCC and adjacent non-cancerous liver tissues. Chi-square test and logistic regression analysis were performed to evaluate the association between FOXM1 and GLUT1 expression with clinicopathological characteristics. Our data showed that FOXM1 promoted glycolysis in the HCC cells. FOXM1 knockdown significantly reduced the expression of GLUT1 among key glycolysis-related molecules in the different HCC cell lines. Glucose uptake and lactate production assay showed that FOXM1 positively regulated glycolysis based on GLUT1 expression. Moreover, FOXM1 overexpression increased and knockdown decreased GLUT1 expression. Luciferase reporter assays showed that the-206 to-199 bp region of the GLUT1 promoter is important for FOXM1 to enhance GLUT1 promoter activity. The results of the IHC analysis showed that the protein expression of FOXM1 and GLUT1 was closely related to the tumor histological grade and TNM stage. In addition, GLUT1 expression was also related to microvascular invasion. In conclusion, overexpression of FOXM1 and GLUT1 may play critical roles in HCC. FOXM1 promotes HCC glycolysis by transactivating GLUT1 expression.


Li R.,PLA Fourth Military Medical University
Zhonghua yi xue za zhi | Year: 2016

OBJECTIVE: This study was designed to observe the antioxidant effects of hyperbaric oxygen (HBO) on brains of rats after acute carbon monoxide (CO) poisoning.METHODS: Sixty-six Sprague-Dawley (SD) male rats were divided into three groups including control group, CO group and HBO group.Morris water maze experiments were used for monitoring cognitive function.Antioxidant capacities were evaluated by detecting T-AOC, GSH-PX, GR and CAT activities in the brain.RESULTS: Compared with the control group (45±17, 43±14, 35±12, 34±11, 29±13) s and the HBO group (40±10, 39±6, 35±9, 31±11, 21±10) s, the CO group (57±5, 54±8, 52±8, 52±10, 46±8) s had the longer escape latency (P<0.05). Compared with the control group (51±6) s and the HBO group(40±10) s, the CO group (8±5) s had the shorter swimming time in I quadrant (P<0.05). Compared with the control group (1.25±0.40) U/mg and the HBO group(0.97±0.31, 0.97±0.39, 1.45±0.15, 1.40±0.25, 1.20±0.20) U/mg, the CO group (0.68±0.09, 0.45±0.17, 0.71±0.18, 0.69±0.29, 0.48±0.29) U/mg had the lower T-AOC activity of brain tissue.The GSH-PX activity (42±13, 106±46, 197±49, 173±42, 429±58) U/mg in the CO group decreased compared with the control group (182±53) U/mg and the HBO group (203±63, 325±86, 389±29, 385±100, 453±32) U/mg.GR activity (4.3±0.7, 2.6±0.5, 3.0±1.2, 1.8±0.8, 3.2±1.9) U/mg in the CO group decreased compared with the control group(14.5±3.0) U/mg and the HBO group (13.9±3.3, 4.3±1.0, 3.9±0.7, 4.8±0.9, 4.6±0.9) U/mg.CAT activity (1.6±0.8, 4.3±1.6, 3.9±1.0, 8.5±2.6, 5.4±1.7) U/mg in the CO group decreased compared with the control group(5.2±1.3) U/mg and the HBO group (5.2±2.2, 8.8±2.8, 5.3±1.0, 9.2±2.1, 14.1±3.8) U/mg.CONCLUSIONS: HBO can improve the behavior of rats after acute CO poisoning.The antioxidant capacity in rat brain tissue after acute CO poisoning decreases, while after the HBO therapy, the antioxidant capacity in rat brain tissue can increase.


Wang K.,PLA Fourth Military Medical University | Chang Q.,150 Hospital of PLA | Li H.-L.,150 Hospital of PLA
Medical Journal of Chinese People's Liberation Army | Year: 2017

Objective To analyze risk factors for grenade throwing fractures and put forward corresponding preventive measures for the fractures during the military training in recruits, so as to reduce the happen in the military training. Methods The research is case-control study. The trial group and the control group (39 patients each) were followed up and investigated. The investigation indicators included height, body mass index (BMI), whether drinking carbonated beverage frequently, literacy, osteoporosis, throwing training score, throwing posture, warm-up sufficiently, region, whether attend often physical exercise before recruitment, exercise strength, and weather factor. Results There were significant differences in the warm-up sufficiency, attending physical exercise before recruitment, exercise intensity, throwing posture, weather factor between trial group and the control group in recruits. The logistic regression analysis showed that the lack of physical exercise before recruitment, strong exercise intensity, nonstandard throwing posture were the risk factors in grenade throwing fractures in recruits. Conclusion Sufficient warm-up, avoiding exhausted exercise and assault exercise, strict training in accordance with the standard throwing posture, regular participation in physical exercise before recruitment and training in warm season are effective methods for preventing grenade throwing fractures in recruits. © 2017, People's Military Medical Press. All rights reserved.


Wu N.,Xianyang Central Hospital | Jin L.,PLA Fourth Military Medical University | Wang G.,PLA Fourth Military Medical University
Clinical Laboratory | Year: 2017

Background: Epidermolysis bullosa pruriginosa (DEB-Pr) is a rare disease caused by mutations in the collagen, type VII, alpha 1 (COL7A1) gene. Here, we identified a novel COL7A1 mutation in a Chinese family with DEB-Pr. Methods: Blood samples were obtained from 4 affected individuals of the 16-member family for isolation of genomic DNA. The COL7A1 exons were then amplified using PCR for direct sequencing. Two unaffected family members and 50 healthy controls were also enrolled for a comparison of genetic polymorphisms. Results: We identified a novel mutation, exon 110 c.8111G>A, P.GIy2704Glu (GGA>GAA), in all 4 affected individuals but not in the unaffected family members or healthy controls. Conclusions: A glycine substitution specific to COL7A1, exon 110 c.8111G>A, P.GIy2704Glu (GGA>GAA), was identified in a Chinese family with DEB-Pr.


Gangadharan V.,University of Heidelberg | Wang X.,PLA Fourth Military Medical University | Wang X.,Yan'an University | Luo C.,PLA Fourth Military Medical University
Molecular Pain | Year: 2017

Chronic pain represents a frequent and poorly understood public health issue. Numerous studies have documented the key significance of plastic changes along the somatosensory pain pathways in chronic pain states. Our recent study demonstrated that the cGMP-dependent protein kinase I (PKG-I) specifically localized in nociceptors constitutes a key mediator of hyperexcitability of primary sensory neurons and spinal synaptic plasticity after inflammation. However, whether PKG-I in nociceptors further affects the cortical plasticity in the ascending pain pathways under pathological states has remained elusive. The immediate early gene c-fos and phosphorylated ERK1/2 (pERK1/2) are considered reliable indicators for the neuronal activation status and it permits a comprehensive and large-scale observation of nociceptive neuronal activity along the ascending pain pathways subjected to tissue injury. In the present study, we systemically demonstrated that peripheral injury in PKG-Ifl/fl mice produced a significant upregulation of c-Fos or pERK1/2 over from the periphery to the cortex along the pain pathways, including dorsal root ganglion (DRG), spinal dorsal horn, ventral posterolateral thalamus (VPL), primary somatosensory hindlimb cortex (S1HL), anterior cingulate cortex (ACC), basolateral amygdale, periaqueductal grey (PAG) and parabrachial nuecleus (PBN). In contrast, very few cells in the above regions showed c-Fos or pERK1/2 induction in nociceptor specific knockout mice lacking PKG-I (SNS-PKG-I-/- mice). Our results indicate that PKG-I expressed in nociceptors is not only a key determinant of DRG hyperexcitability and spinal synaptic plasticity, but also an important modulator of cortical neuronal activity in pathological pain states and represent what we believe to be novel targets in the periphery for pain therapeutics. © 2017, SAGE Publications Inc. All rights reserved.


Wu J.B.,Cedars Sinai Medical Center | Wu J.B.,Washington State University | Yin L.,Cedars Sinai Medical Center | Shi C.,Cedars Sinai Medical Center | And 15 more authors.
Cancer Cell | Year: 2017

Metastasis is a predominant cause of death for prostate cancer (PCa) patients; however, the underlying mechanisms are poorly understood. We report that monoamine oxidase A (MAOA) is a clinically and functionally important mediator of PCa bone and visceral metastases, activating paracrine Shh signaling in tumor-stromal interactions. MAOA provides tumor cell growth advantages in the bone microenvironment by stimulating interleukin-6 (IL6) release from osteoblasts, and triggers skeletal colonization by activating osteoclastogenesis through osteoblast production of RANKL and IL6. MAOA inhibitor treatment effectively reduces metastasis and prolongs mouse survival by disengaging the Shh-IL6-RANKL signaling network in stromal cells in the tumor microenvironment. These findings provide a rationale for targeting MAOA and its associated molecules to treat PCa metastasis. © 2017 Elsevier Inc.


Gu X.,PLA Fourth Military Medical University | Gao Y.,Peoples Hospital of BaoJi City | Mu D.-G.,PLA Fourth Military Medical University | Fu E.-Q.,PLA Fourth Military Medical University
Experimental Cell Research | Year: 2017

Autophagy plays a pivotal role in activating the antimicrobial host defense against Mycobacterium tuberculosis (M.tb.). The emerging roles of microRNAs (miRNAs) in regulating immune responses have attracted increasing attention in recent years. Appreciating the potential of host-directed therapies designed to control autophagy during mycobacterial infection, we focused on the influence of miR-23a-5p on the activation of macrophage autophagy during M.tb. infection in bone marrow-derived macrophages (BMDMs) and murine RAW264.7 cells. Here, we demonstrated that M.tb.-infection of macrophages lead to markedly enhanced expression of miR-23a-5p in a time- and dose-dependent manner. Furthermore, forced expression of miR-23a-5p accelerated the survival rate of intracellular mycobacteria, while transfection with miR-23a-5p inhibitors attenuated mycobacterial survival. More importantly, overexpression of miR-23a-5p dramatically prevented M.tb.-induced activation of autophagy in macrophages, whereas inhibitors of miR-23a-5p remarkably accelerated M.tb.-induced autophagy. Mechanistically, miR-23a-5p is able to modulate TLR2/MyD88/NF-κB signaling activity by targeting TLR2 in RAW264.7 cells in response to M.tb.-infection. Collectively, these findings demonstrated that miR-23a-5p modulated the innate host defense by promoting mycobacteria survival and inhibiting the activation of autophagy against M.tb. through TLR2/MyD88/NF-κB pathway by targeting TLR2, which may provide a promising therapeutic target for tuberculosis. © 2017.


Liu B.,PLA Fourth Military Medical University | Zhang Z.,Samsung
Proceedings - 2016 IEEE Biomedical Circuits and Systems Conference, BioCAS 2016 | Year: 2016

Compressed sensing (CS) has been used as an efficient, low-energy data compressor for the telemonitoring of physiological signals such as ECG or EEG. However, the performance of these applications is often assessed by the quality of signal recovery such as Percentage Root-mean square Difference (PRD). In this paper, (1) we show that the metric of signal recovery quality such as PRD is not adequate for CS based compressor, especially when failing to regard the sampling rate of raw signals. (2) we analyze the distortion of CS on EEG telemonitoring for the epileptic, where the performance is evaluated using different sampling rates and the quality is assessed by epileptic seizure classification accuracy. We aim to establish a task-oriented protocol for correctly applying CS as a data compressor on EEG and other physiological signals. © 2016 IEEE.


Zhao L.,PLA Fourth Military Medical University | Chang D.W.,University of Houston | Gong Y.,University of Houston | Eng C.,University of Houston | Wu X.,University of Houston
DNA Repair | Year: 2017

The detection of γ-H2AX focus is one of the most sensitive ways to monitor DNA double-strand breaks (DSBs). Although changes in γ-H2AX activity have been studied in tumor cells in colorectal cancer (CRC), changes in peripheral blood lymphocytes (PBLs) have not been examined previously. We hypothesize that higher levels of irradiation-induced γ-H2AX in PBLs may be associated with an elevated risk of colorectal cancer (CRC). In a case-control study, the baseline and ionizing radiation (IR)-induced γ-H2AX levels in PBLs from frequency-matched 320 untreated CRC patients and 320 controls were detected by a laser scanning cytometer-based immunocytochemical method. We used unconditional multivariable logistic regression to evaluate CRC risk by using the ratio of IR-induced γ-H2AX to the baseline levels with adjustment of age, sex and smoking status. We found CRC cases had significantly higher γ-H2AX ratio (1.5 vs. 1.41, P< 0.0001) compared with controls. When using the median γ-H2AX ratio of controls as a cutoff point, we found higher γ-H2AX ratio was significantly associated with an increased risk of CRC (OR = 6.72, 95% CI = 4.54-9.94). Quartile analyses also showed significant dose-response relationship between higher γ-H2AX ratio and increased risk of CRC (P for trend. <. 0.0001). Age, sex, BMI and smoking status also influenced the association of γ-H2AX ratio with CRC risk; however, no interactions with γ-H2AX ratio were observed. These results support the premise that DSBs in peripheral blood as measured by γ-H2AX level might represent an intermediate phenotype to assess the risk of CRC. Future prospective studies are necessary to confirm our findings in independent populations. © 2017.


Han D.,Chinese PLA General Hospital | Han D.,PLA Fourth Military Medical University | Gao Q.,Academy of Military Medical science | Cao F.,Chinese PLA General Hospital | Cao F.,PLA Fourth Military Medical University
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2017

Long noncoding RNAs (lncRNAs) represent a category of noncoding RNAs with the potential for genetic and epigenetic regulations. As important regulators of gene expression, increasing evidence has proven that lncRNAs play a significant regulatory role in various cardiovascular pathologies. In particular, lncRNAs have been proved to be participating in gene regulatory mechanisms involved in heart growth and development that can be exploited to repair the injured adult heart. Furthermore, lncRNAs have been revealed as possible therapeutic targets for heart failure with different causes and in different stages. In the journey from a healthy heart to heart failure, lncRNAs have been shown to participate in almost every landmark of heart failure pathogenesis including ischemic injury, cardiac hypertrophy, and cardiac fibrosis. Furthermore, the manipulation of lncRNAs palliates the progression of heart failure by attenuating ischemic heart injury, cardiac hypertrophy and cardiac fibrosis, as well as facilitating heart regeneration and therapeutic angiogenesis. This review will highlight recent updates regarding the involvement of lncRNAs in cardiac hypertrophy and heart failure and their potential as novel therapeutic targets. This article is part of a Special Issue entitled: Genetic and epigenetic control of heart failure - edited by Jun Ren & Megan Yingmei Zhang. © 2017 Elsevier B.V.


Liu Z.,Zhejiang University of Technology | Liu Z.,PLA Fourth Military Medical University | Fu Z.,Zhejiang University of Technology | Jin Y.,Zhejiang University of Technology
Chemosphere | Year: 2017

Atrazine (ATZ) and its main metabolites, i.e., diaminochlorotriazine (DACT), deisopropylatrazine (DIP), and deethylatrazine (DE), have been widely detected in surface water around the world. In the present study, to determine their immunotoxic effects, zebrafish during the early developmental stage were exposed to ATZ and its main metabolites at environmental concentrations (30, 100, 300 μg L−1). It was observed that ATZ, DACT, DIP and DE selectively induced the transcription of immunotoxic related genes including Tnfα, Il-1β, Il-6, Il-8, Cxcl-clc and Cc-chem in larval zebrafish. Pretreatment with ATZ and its metabolites also changed the immune response of larval zebrafish to LPS and E. coli challenge, which was indicated by the alternation in the mRNA levels of some cytokines. In addition, 300 μg L−1 ATZ and DACT exposure could also increase the release of tryptase into water, indicating that they increased the anaphylactoid reaction in the larval zebrafish. According to these results, both of ATZ and its metabolites exposure could cause the immunotoxicity in larval zebrafish. Thus, we thought that the ecological risks of the metabolites of ATZ on aquatic organisms could not be ignored. © 2016 Elsevier Ltd


Yu Y.-Q.,University of Washington | Yu Y.-Q.,PLA Fourth Military Medical University | Barry D.M.,University of Washington | Hao Y.,University of Washington | And 4 more authors.
Science | Year: 2017

Socially contagious itch is ubiquitous in human society, but whether it exists in rodents is unclear. Using a behavioral paradigm that does not entail prior training or reward, we found that mice scratched after observing a conspecific scratching. Molecular mapping showed increased neuronal activity in the suprachiasmatic nucleus (SCN) of the hypothalamus of mice that displayed contagious scratching. Ablation of gastrin-releasing peptide receptor (GRPR) or GRPR neurons in the SCN abolished contagious scratching behavior, which was recapitulated by chemogenetic inhibition of SCN GRP neurons. Activation of SCN GRP/GRPR neurons evoked scratching behavior. These data demonstrate that GRP-GRPR signaling is necessary and sufficient for transmitting contagious itch information in the SCN. The findings may have implications for our understanding of neural circuits that control socially contagious behaviors. © 2017, American Association for the Advancement of Science. All rights reserved.


Li M.,PLA Fourth Military Medical University
American Journal of Surgical Pathology | Year: 2017

Anaplastic diffuse large B-cell lymphoma (A-DLBCL) is a rare morphologic variant characterized by the presence of polygonal, bizarre-shaped tumor cells. However, the clinicopathologic and genetic features of this variant are largely unknown. In this study, we investigated 35 cases of A-DLBCL with regard to their clinical, pathologic, and genetic characteristics. The age of the patients ranged from 23 to 89 years (median age, 62 y) with a male to female ratio of 23:12. Twenty-two of 26 (85%) patients had Ann Arbor stage III or IV disease, and 17/26 (65%) patients had a high-intermediate or high International Prognostic Index score. For the 24 patients treated with aggressive chemotherapy regimens, the median overall survival (OS) was 16 months, and the 2-year OS rate was 36%. Immunophenotypically, 30/35 (86%) cases had a non–germinal center B-cell immunophenotype. CD30 expression was present in 18/35 (51%) cases, and the p53 protein stain was positive in 28/35 (80%) cases. Fifteen of 35 (43%) cases expressed both BCL2 and MYC (double expressor). Twenty-nine of 32 (91%) cases tested positive for RELA, RELB, or c-Rel in the nucleus, indicating activation of the NFκB signaling pathway. Cytogenetically, 11/27 (41%) cases had concurrent MYC and BCL2 and/or BCL6 abnormalities (translocation or extra copy), including 5 cases with triple abnormalities. TP53 mutation was found in 17/30 (57%) cases, whereas the MYD88 L265P, CD79B, and CARD11 mutations were found in 7/35, 4/30, and 5/30 cases, respectively. We compared the A-DLBCL group with 50 patients with DLBCL without anaplastic features (common DLBCL). The OS of patients with A-DLBCL was significantly worse than that of patients with DLBCL without anaplastic features (P=0.004). Cases of A-DLBCL more often had a high International Prognostic Index score and a non–germinal center B-cell immunophenotype, more frequently expressed CD30 and p53, and more often had mutations of TP53 and concurrent abnormalities of MYC and BCL2 and/or BCL6 (P<0.05). In conclusion, A-DLBCL displays clinicopathologic features that distinguish it from ordinary DLBCL. Most patients follow an aggressive clinical course and have a poor outcome. Cases of A-DLBCL have a high frequency of TP53 mutation and genetic abnormalities of MYC, BCL2, and BCL6. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.


Liu J.,PLA Fourth Military Medical University | Liu J.,Shaanxi Provincial Peoples Hospital | Li Y.,PLA Fourth Military Medical University | Luo M.,PLA Fourth Military Medical University | Yuan Z.,PLA Fourth Military Medical University
Experimental Cell Research | Year: 2017

Osteoblasts and osteoclasts coordinate to monitor the dynamic osteogenic balance between bone formation and bone resorption. Hence, an investigation of the regulatory mechanisms underlying osteogenic osteoblast differentiation will provide more methods for bone repair and bone regeneration. In the present study, human osteoblast hFOB 1.19 cells were cultured. MicroRNA-214 (miR-214) expression significantly down-regulated during the osteogenic differentiation of hFOB 1.19 cells. In addition, miR-214 overexpression by miR-214 precursor transfection markedly inhibited the expression of alkaline phosphatase (ALP), collagen type I α1 (col1α1) and runt-related transcription factor 2 (Runx2), which concomitantly decreased ALP activity and the number of mineralized nodules but promoted the expression of signal transducer and activator of transcription 1 (STAT1), an osteogenesis blocker. We next found that miR-214 inhibited the expression of baculoviral IAP repeat-containing 7 (BIRC7), a member of the inhibitor of apoptosis proteins family. However, BIRC7 overexpression, which was induced by plasmid transfection, notably reversed the inhibitory effects of miR-214, indicating a potential BIRC7-dependent osteogenic differentiation manner mediated by miR-214. Taken together, our results demonstrate for the first time that miR-214 suppresses osteogenesis by targeting BIRC7, providing a possible therapeutic target for bone degenerative diseases. © 2017 Elsevier Inc.


Yu Y.,Jilin University | Zhao N.,University of Science and Technology of China | An J.,PLA Fourth Military Medical University | Zhang X.,Jilin University
DNA and Cell Biology | Year: 2017

Autophagy is a main defense strategy by which infected host cells can virtually induce the killing of parasite, including Toxoplasma gondii. However, the regulatory mechanisms of autophagy in T. gondii-infected nonhematopoietic cells are still unknown. Emerging evidence indicates that CCAAT/enhancer-binding protein b (C/EBP β) is associated with the regulation of autophagy. Herein, we hypothesized that C/EBP β plays roles in inducing autophagy in nonhematopoietic cells. Expression of C/EBP b was aberrantly regulated in endothelial cells and retinal pigment epithelial cells challenged by T. gondii. Inhibition of C/EBP b reduced the killing of T. gondii in nonhematopoietic cells, whereas C/EBP β overexpression resulted in the enhancement of killing of T. gondii as well as the increase in autophagy in infected cells. Furthermore, the mammalian target of rapamycin (mTOR) activation was found to be reduced by C/EBP b overexpression, but increased by C/EBP b inhibition. The increase in T. gondii killing induced by C/EBP b overexpression was blocked by the mTOR activator phosphatidic acid and was increased by the inhibitor AZD8055. In conclusion, we demonstrate that C/EBP b expression is increased in nonhematopoietic cells infected by T. gondii, resulting in the activation of autophagy in host cells by inhibiting mTOR pathway. © Copyright 2017, Mary Ann Liebert, Inc. 2017.


Chen W.-H.,Huazhong University of Science and Technology | Lu G.,PLA Fourth Military Medical University | Chen X.,Tongji University | Zhao X.-M.,Tongji University | And 4 more authors.
Nucleic Acids Research | Year: 2017

OGEE is an Online GEne Essentiality database. To enhance our understanding of the essentiality of genes, in OGEE we collected experimentally tested essential and non-essential genes, as well as associated gene properties known to contribute to gene essentiality. We focus on large-scale experiments, and complement our data with text-mining results. We organized tested genes into data sets according to their sources, and tagged those with variable essentiality statuses across data sets as conditionally essential genes, intending to highlight the complex interplay between gene functions and environments/experimental perturbations. Developments since the last public release include increased numbers of species and gene essentiality data sets, inclusion of non-coding essential sequences and genes with intermediate essentiality statuses. In addition, we included 16 essentiality data sets from cancer cell lines, corresponding to 9 human cancers; with OGEE, users can easily explore the shared and differentially essential genes within and between cancer types. These genes, especially those derived from cell lines that are similar to tumor samples, could reveal the oncogenic drivers, paralogous gene expression pattern and chromosomal structure of the corresponding cancer types, and can be further screened to identify targets for cancer therapy and/or new drug development. © The Author(s) 2016.


Yu R.,South China Normal University | Zhao L.,Peking University | Tian J.,Xidian University | Qin W.,Xidian University | And 4 more authors.
Addiction Biology | Year: 2013

Recent studies have documented declined global cognitive function and abnormal task-related brain activation in chronic cigarette smokers. However, the effects of long-term heavy smoking on task-independent baseline brain activity are still unknown. Here, we used a regional homogeneity (ReHo) method combined with functional magnetic resonance imaging (fMRI) to investigate spontaneous neural activity in the resting state in heavy smokers. Compared with controls, heavy smokers exhibited decreased ReHo in prefrontal regions, as well as increased ReHo in insula and posterior cingulate cortex. Our study may better our understanding of the neurobiological consequences of smoking. © 2011 The Authors, Addiction Biology © 2011 Society for the Study of Addiction.


Xing H.,PLA Fourth Military Medical University | Taguchi Y.,Osaka Dental University | Sekino T.,Tohoku University
International Journal of Nanomedicine | Year: 2014

Background: Titanium surfaces play an important role in affecting osseointegration of dental implants. Previous studies have shown that the titania nanotube promotes osseointegration by enhancing osteogenic differentiation. Only relatively recently have the effects of titanium surfaces with other nanostructures on osteogenic differentiation been investigated. Methods: In this study, we used NaOH solutions with concentrations of 2.5, 5.0, 7.5, 10.0, and 12.5 M to develop a simple and useful titanium surface modification that introduces the nanonetwork structures with titania nanosheet (TNS) nanofeatures to the surface of titanium disks. The effects of such a modified nanonetwork structure, with different alkaline concentrations on the osteogenic differentiation of rat bone marrow mesenchymal stem cells (BMMSCs), were evaluated. Results: The nanonetwork structures with TNS nanofeatures induced by alkali etching markedly enhanced BMMSC functions of cell adhesion and osteogenesis-related gene expression, and other cell behaviors such as proliferation, alkaline phosphatase activity, extracellular matrix deposition, and mineralization were also significantly increased. These effects were most pronounced when the concentration of NaOH was 10.0 M. Conclusion: The results suggest that nanonetwork structures with TNS nanofeatures improved BMMSC proliferation and induced BMMSC osteogenic differentiation. In addition, the surfaces formed with 10.0 M NaOH suggest the potential to improve the clinical performance of dental implants. © 2014 Xing et al.


Wang L.,PLA Fourth Military Medical University | Zhou L.,Peking University | Hu H.,Livzon Pharmaceutical Institute | Lin S.,Peking University | Xia J.,PLA Fourth Military Medical University
Current Medical Research and Opinion | Year: 2012

Objective: The new proton pump inhibitor (PPI), ilaprazole performed better at the dose of 10mg/d relative to 5 or 20mg/d in a previous phase II trial. A larger phase III trial was carried out to confirm the efficacy and safety of ilaprazole (10mg/d) compared with omeprazole (20mg/d) and provide some characteristics of the relationship between ilaprazole metabolism and CYP2C19 for later studies. Research design and methods: Patients with at least one endoscopically diagnosed active duodenal ulcer (DU) were enrolled in a multicenter, randomized, double-blind, positive controlled trial and then assigned randomly to the ilaprazole group (10mg/d) or the omeprazole group (20mg/d) with a sample allocation ratio 2:1. The course of treatment was 4 weeks. Clinical trial registration: ClinicalTrials.gov registration number: NCT00952978. Main outcome measures: The primary endpoint was endoscopically diagnosed ulcer healing rate at week 4. Symptom relief was evaluated as a secondary endpoint by graded scores. Safety and tolerability were evaluated on basis of clinical assessments. In addition, blood samples were collected at baseline for CYP2C19 genotypes identification. Results: Efficacy analyses were based on 494 patients. At week 4, the ulcer healing rates were 93.0% in ilaprazole group and 90.8% in omeprazole group (rate difference: 2.2%; 95% confidence interval:-2.8% to 7.2%). No obvious variation of healing rate on different CYP2C19 genotypes was found in ilaprazole group. The majority of patients (>80%) became asymptomatic after treatment. Incidences of adverse drug reactions were similar between ilaprazole group and omeprazole group (8.5% vs. 11.5%). Conclusions: Ilaprazole (10mg/d) is as effective as omeprazole (20mg/d) in the treatment of DU with similar side effects. The efficacy of ilaprazole is not affected by CYP2C19 polymorphisms. © 2012 Informa UK Ltd.


Zhang W.,PLA Fourth Military Medical University | Zheng L.,PLA Fourth Military Medical University | Zhang Z.,PLA Fourth Military Medical University | Hai C.-X.,PLA Fourth Military Medical University
Carbohydrate Polymers | Year: 2012

Oxidative stress is associated with insulin resistance (IR) and is thought to contribute to the development and progression toward type 2 diabetes (T2DM). This study was undertaken to isolate the bioactive polysaccharide (SMPW1) from Salvia miltiorrhiza Bunge and investigated its protective effects on IR model in rats induced by tert-butyl hydroperoxide (t-BHP). In vivo animal experiments showed that SMPW1 (50 and 100 mg/kg) possessed high antioxidative and protective capacity against the injury induced by t-BHP, as reflected in the increased expression or activities of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), and the decreased formation of malondialdehyde (MDA) in serum and liver homogenates. In addition, SMPW1 (50 and 100 mg/kg) also attenuated IR and the morphological injury of liver and pancreas induced by t-BHP, and improved insulin sensitivity index. In conclusion, SMPW1 can protect against the development of T2DM and improve IR via reduction of oxidative stress. © 2012 Elsevier Ltd. All rights reserved.


Deng S.,PLA Fourth Military Medical University | Yang Y.,Shaanxi Province Peoples Hospital | Han Y.,PLA Fourth Military Medical University | Li X.,PLA Fourth Military Medical University | And 3 more authors.
PLoS ONE | Year: 2012

The Crosstalk between a tumor and its hypoxic microenvironment has become increasingly important. However, the exact role of UCP2 function in cancer cells under hypoxia remains unknown. In this study, UCP2 showed anti-apoptotic properties in A549 cells under hypoxic conditions. Over-expression of UCP2 in A549 cells inhibited reactive oxygen species (ROS) accumulation (P<0.001) and apoptosis (P<0.001) compared to the controls when the cells were exposed to hypoxia. Moreover, over-expression of UCP2 inhibited the release of cytochrome C and reduced the activation of caspase-9. Conversely, suppression of UCP2 resulted in the ROS generation (P = 0.006), the induction of apoptosis (P<0.001), and the release of cytochrome C from mitochondria to the cytosolic fraction, thus activating caspase-9. These data suggest that over-expression of UCP2 has anti-apoptotic properties by inhibiting ROS-mediated apoptosis in A549 cells under hypoxic conditions. © 2012 Deng et al.


Li Z.-l.,PLA Fourth Military Medical University | Li Z.-l.,PLA 452 Hospital | Liu J.-c.,PLA Fourth Military Medical University | Liu S.-b.,PLA Fourth Military Medical University | And 3 more authors.
PLoS ONE | Year: 2012

The G-protein coupled estrogen receptor 30 (GPR30) is a seven-transmembrane domain receptor that mediates rapid estrogen responses in a wide variety of cell types. This receptor is highly expressed in the cardiovascular system, and exerts vasodilatory effects. The objective of the present study was to investigate the effects of GPR30 on vascular responsiveness in diabetic ovariectomized (OVX) rats and elucidate the possible mechanism involved. The roles of GPR30 were evaluated in the thoracic aorta and cultured endothelial cells. The GPR30 agonist G1 induced a dose-dependent vasodilation in the thoracic aorta of the diabetic OVX rats, which was partially attenuated by the nitric oxide synthase (NOS) inhibitor, nitro-L-arginine methylester (L-NAME) and the GPR30-selective antagonist G15. Dose-dependent vasoconstrictive responses to phenylephrine were attenuated significantly in the rings of the thoracic aorta following the acute G1 administration in the diabetic OVX rats. This effect of G1 was abolished partially by L-NAME and G15. The acute administration of G1 increased significantly the eNOS activity and the concentration of NO in the endothelial cells exposed to high glucose. G1 treatment induced an enhanced endothelium-dependent relaxation to acetylcholine (Ach) in the diabetic OVX rats. Further examination revealed that G1 induced vasodilation in the diabetic OVX rats by increasing the phosphorylation of eNOS. These findings provide preliminary evidence that GPR30 activation leads to eNOS activation, as well as vasodilation, to a certain degree and has beneficial effects on vascular function in diabetic OVX rats. © 2012 Li et al.


He F.,Northwest University, China | Cao R.,Northwest University, China | Feng Z.,Beijing Normal University | Guan H.,Xijing Hospital | Peng J.,PLA Fourth Military Medical University
PLoS ONE | Year: 2013

Burn wounds are severely stressful events that can have a significant impact on the mental health of patients. However, the impact of burns on individuals with different personality traits can be different. The present study aimed to investigate the impact of dispositional optimism on the subjective well-being of burn patients, and mainly focused on the confirmation of the mediator role of psychological resilience. 410 burn patients from five general hospitals in Xi'an accomplished the revised Life Orientation Test, Connor-Davidson Resilience Scale, and Subjective Well-Being (SWB) scale. The results revealed that both dispositional optimism and psychological resilience were significantly correlated with SWB. Structural equation modelling indicated that psychological resilience partially mediated the relationship between dispositional optimism and SWB. The current findings extended prior reports and shed some light on how dispositional optimism influenced SWB. Limitations of the study were considered and suggestions for future studies were also discussed.


Yang W.,China Japan Friendship Hospital | Lu J.,Chinese People's Liberation Army | Weng J.,Sun Yat Sen University | Jia W.,Shanghai JiaoTong University | And 16 more authors.
New England Journal of Medicine | Year: 2010

BACKGROUND: Because of the rapid change in lifestyle in China, there is concern that diabetes may become epidemic. We conducted a national study from June 2007 through May 2008 to estimate the prevalence of diabetes among Chinese adults. METHODS: A nationally representative sample of 46,239 adults, 20 years of age or older, from 14 provinces and municipalities participated in the study. After an overnight fast, participants underwent an oral glucose-tolerance test, and fasting and 2-hour glucose levels were measured to identify undiagnosed diabetes and prediabetes (i.e., impaired fasting glucose or impaired glucose tolerance). Previously diagnosed diabetes was determined on the basis of self-report. RESULTS: The age-standardized prevalences of total diabetes (which included both previously diagnosed diabetes and previously undiagnosed diabetes) and prediabetes were 9.7% (10.6% among men and 8.8% among women) and 15.5% (16.1% among men and 14.9% among women), respectively, accounting for 92.4 million adults with diabetes (50.2 million men and 42.2 million women) and 148.2 million adults with prediabetes (76.1 million men and 72.1 million women). The prevalence of diabetes increased with increasing age (3.2%, 11.5%, and 20.4% among persons who were 20 to 39, 40 to 59, and ≥60 years of age, respectively) and with increasing weight (4.5%, 7.6%, 12.8%, and 18.5% among persons with a body-mass index [the weight in kilograms divided by the square of the height in meters] of <18.5, 18.5 to 24.9, 25.0 to 29.9, and ≥30.0, respectively). The prevalence of diabetes was higher among urban residents than among rural residents (11.4% vs. 8.2%). The prevalence of isolated impaired glucose tolerance was higher than that of isolated impaired fasting glucose (11.0% vs. 3.2% among men and 10.9% vs. 2.2% among women). CONCLUSIONS: These results indicate that diabetes has become a major public health problem in China and that strategies aimed at the prevention and treatment of diabetes are needed. Copyright © 2010 Massachusetts Medical Society. All rights reserved.


Wu Q.,PLA Fourth Military Medical University | Yang Z.-P.,PLA Fourth Military Medical University | Xu P.,Shanghai University | Gao L.-C.,PLA Fourth Military Medical University | Fan D.-M.,PLA Fourth Military Medical University
Colorectal Disease | Year: 2013

Aim: The existing evidence on the relationship between Helicobacter pylori infection and the risk of colorectal neoplasia is inconsistent. We conducted a systematic review with a meta-analysis to explore this relationship and to determine whether the relationship varies according to the study characteristics. Method: We searched the PubMed database and the reference lists of pertinent articles published up to July 2012. Summary odds ratios (ORs) with their 95% confidence intervals (CIs) were estimated using a random-effects model. Results: Twenty-seven studies including 3792 cases of colorectal adenoma (CRA) and 3488 cases of colorectal cancer (CRC) were identified. Overall, H. pylori infection was associated with an increased risk of CRA (OR = 1.66, 95% CI 1.39-1.97, I2 = 54.3%) and CRC (OR = 1.39, 95% CI 1.18-1.64, I2 = 35.8%), although there was significant heterogeneity among the studies. Subgroup analysis revealed that the positive correlation did not differ by sex, geographic variation or subsite of neoplasia, but might vary by the method of detection of H. pylori. The study was underpowered to determine the risk of colorectal neoplasia associated with cytotoxin-associated gene A-positive H. pylori. Conclusion: This meta-analysis demonstrates a positive association between H. pylori infection and the risk of colorectal neoplasia. Colorectal Disease © 2013 The Association of Coloproctology of Great Britain and Ireland.


Zhu J.,Soochow University of China | Wang Q.,PLA Fourth Military Medical University
American Journal of Physiology - Heart and Circulatory Physiology | Year: 2013

Cardioprotective effects of anesthetic preconditioning and cyclosporine A (CsA) are lost with aging. To extend our previous work and address a possible mechanism underlying age-related differences, we investigated the role of oxidative stress in the aging heart by treating senescent animals with the oxygen free radical scavenger Tempol. Old male Fischer 344 rats (22-24 mo) were randomly assigned to control or Tempol treatment groups for 2 or 4 wk (T×2wk and T×4wk, respectively). Rats received isoflurane 30 min before ischemia-reperfusion injury or CsA just before reperfusion. Myocardial infarction sizes were significantly reduced by isoflurane or CsA in the aged rats treated with Tempol (T×4wk) compared with old control rats. In other experiments, young (4-6 mo) and old rats underwent either chronic Tempol or vehicle treatment, and the levels of myocardial protein oxidative damage, antioxidant enzymes, mitochondrial Ca2+ uptake, cyclophilin D protein, and mitochondrial permeability transition pore opening times were measured. T×4wk significantly increased MnSOD enzyme activity, GSH-to-GSSH ratios, MnSOD protein level, mitochondrial Ca2+ uptake capacity, reduced protein nitrotyrosine levels, and normalized cyclophilin D protein expression in the aged rat heart. T×4wk also significantly prolonged mitochondrial permeability transition pore opening times induced by reactive oxygen species in old cardiomyocytes. Our studies demonstrate that 4 wk of Tempol pretreatment restores anesthetic preconditioning and cardioprotection by CsA in the old rat and that this is associated with decreased oxidative stress and improved mitochondrial function. Our results point to a new protective strategy for the ischemic myocardium in the high-risk older population. © 2013 the American Physiological Society.


Roayaie S.,New Hill | Jibara G.,Brookdales Medical Center | Tabrizian P.,Mount Sinai Medical Center | Park J.-W.,Center for Liver Cancer | And 11 more authors.
Hepatology | Year: 2015

Current guidelines recommend surgical resection as the primary treatment for a single hepatocellular cancer (HCC) with Child's A cirrhosis, normal serum bilirubin, and no clinically significant portal hypertension. We determined how frequently guidelines were followed and whether straying from them impacted survival. BRIDGE is a multiregional cohort study including HCC patients diagnosed between January 1, 2005 and June 30, 2011. A total of 8,656 patients from 20 sites were classified into four groups: (A) 718 ideal resection candidates who were resected; (B) 144 ideal resection candidates who were not resected; (C) 1,624 nonideal resection candidates who were resected; and (D) 6,170 nonideal resection candidates who were not resected. Median follow-up was 27 months. Log-rank and Cox's regression analyses were conducted to determine differences between groups and variables associated with survival. Multivariate analysis of all ideal candidates for resection (A+B) revealed a higher risk of mortality with treatments other than resection. For all resected patients (A+C), portal hypertension and bilirubin >1 mg/dL were not associated with mortality. For all patients who were not ideal candidates for resection (C+D), resection was associated with better survival, compared to embolization and "other" treatments, but was inferior to ablation and transplantation. Conclusions: The majority of patients undergoing resection would not be considered ideal candidates based on current guidelines. Not resecting ideal candidates was associated with higher mortality. The study suggests that selection criteria for resection may be modestly expanded without compromising outcomes, and that some nonideal candidates may still potentially benefit from resection over other treatment modalities. © 2015 by the American Association for the Study of Liver Diseases.


Huang Y.,U.S. Food and Drug Administration | Huang Y.,Northwest University, China | Lei Y.,U.S. Food and Drug Administration | Lei Y.,PLA Fourth Military Medical University | And 7 more authors.
Blood | Year: 2011

IL-12 exerts several regulatory effects on natural killer (NK) cells by activating IL-12 signaling. IL-12 signaling is tightly autoregulated to control its onset and termination, with prolonged IL-12 treatment resulting in IL-12 hyporesponsiveness. However, the mechanisms underlying IL-12 auto-regulation are still unclear. In this study we report that prolonged IL-12 treatment significantly up-regulates microRNAs (miRNAs), including miR-132, -212, and -200a in primary human NK cells. This up-regulation correlates temporally with gradually decreasing STAT4 levels and decreasing IFN-γ expression, after an initial increase within the first 16 hours of IL-12 treatment. The IL-12 hyporesponsiveness is dependent on IL-12 concentration, and associated up-regulation of miR-132, -212, and -200a. Furthermore, IL-12-hyporesponsive cells regain responsiveness of IFN-γ production 24 hours after IL-12 removal, which correlates with decreases in miR-132, -212, and -200a levels. Overexpression of miR-132, -212, and -200a by transfection into NK cells mimics IL-12 priming, inducing IL-12 hyporesponsiveness, whereas transfection of miR-132, -212, and -200a inhibitors largely abolishes IL-12 induction of IL-12 hyporesponsiveness. These data suggest that miR-132, -212, and -200a upregulation during prolonged IL-12 treatment, negatively regulates the IL-12 signaling pathway by reducing STAT4 expression in primary human NK cells.


Xu P.,CAS Institute of Zoology | Xu P.,University of Chinese Academy of Sciences | Zhao Y.,Peking University | Liu M.,CAS Institute of Zoology | And 9 more authors.
Hypertension | Year: 2014

Preeclampsia is a major cause of maternal and fetal mortality and morbidity worldwide. The differential expression of several microRNAs (miRNAs) has been found in preeclamptic placentas. However, great conflict exists regarding this aspect, and detailed examinations have largely been lacking of miRNA profiles in different parts of the placenta and in maternal plasma of women with this disorder. In this study, a total of 9 downregulated miRNAs (miR-195, miR-223, miR-218, miR-17, miR-18a, miR-19b1, miR-92a1, miR-379, and miR-411) and 7 upregulated miRNAs (miR-210, miR-30a-3p, miR-518b, miR-524, miR-17-3p, miR-151, and miR-193b) were identified in severe preeclampsia (sPE) placentas when compared with normal pregnant controls. In addition, sampling position in the chorionic or basal plate of placenta led to evident variations in differential miRNAs of sPE placentas. In a prospective pregnant cohort, we found that the circulating levels of 3 members of miR-17-92 cluster (ie, miR-18a, miR-19b1, and miR-92a1) were significantly lower, whereas that of miR-210 was higher in sPE patients than those in normal controls at gestational weeks 15 to 18 and at term. The results of in situ hybridization revealed the localization of miR-18a, miR-92a1, and miR-210 in various subtypes of placental trophoblasts and endothelial cells. In human trophoblast cell line, HTR8/SVneo cells, miR-18a could promote trophoblast cell invasion via targeting and suppressing Smad2 expression. This study provides fundamental evidences for exploring the roles of miRNAs in the pathogenesis of preeclampsia. © 2014 American Heart Association, Inc.


Luo B.,Shanghai University | Huang J.,PLA Fourth Military Medical University | Lu L.,PLA Fourth Military Medical University | Hu X.,PLA Fourth Military Medical University | And 2 more authors.
Journal of Neuroscience Research | Year: 2014

Regulating the production of brain-derived neurotrophic factor (BDNF) in Schwann cells (SCs) is critical for their application in traumatic nerve injury, neurodegenerative disorders, and demyelination disease in both central and peripheral nervous systems. The present study investigated the possibility of using electrical stimulation (ES) to activate SCs to release BDNF. We found that short-term ES was capable of promoting BDNF production from SCs, and the maximal BDNF release was achieved by ES at 6 V (3 Hz, 30 min). We further examined the involvement of intracellular calcium ions ([Ca2+]i) in the ES-induced BDNF production in SCs by pharmacological studies. We found that the ES-induced BDNF release required calcium influx through T-type voltage-gated calcium channel (VGCC) and calcium mobilization from internal calcium stores, including inositol triphosphate-sensitive stores and caffeine/ryanodine-sensitive stores. In addition, calcium-calmodulin dependent protein kinase IV (CaMK IV), mitogen-activated protein kinase (MAPK), and cAMP response element-binding protein (CREB) were found to play important roles in the ES-induced BDNF release from SCs. In conclusion, ES is capable of activating SCs to secrete BDNF, which requires the involvement of calcium influx through T-type VGCC and calcium mobilization from internal calcium stores. In addition, activation of CaMK IV, MAPK, and CREB were also involved in the ES-induced BDNF release. The findings indicate that ES can improve the neurotrophic ability in SCs and raise the possibility of developing electrically stimulated SCs as a source of cell therapy for nerve injury in both peripheral and central nervous systems. © 2014 Wiley Periodicals, Inc.


Wang W.,Tsinghua University | Lv N.,Tsinghua University | Zhang S.,Tsinghua University | Shui G.,National University of Singapore | And 8 more authors.
Nature Medicine | Year: 2012

Adequate lipid secretion by mammary glands during lactation is essential for the survival of mammalian offspring. However, the mechanism governing this process is poorly understood. Here we show that Cidea is expressed at high levels in lactating mammary glands and its deficiency leads to premature pup death as a result of severely reduced milk lipids. Furthermore, the expression of xanthine oxidoreductase (XOR), an essential factor for milk lipid secretion, is markedly lower in Cidea-deficient mammary glands. Conversely, ectopic Cidea expression induces the expression of XOR and enhances lipid secretion in vivo. Unexpectedly, as Cidea has heretofore been thought of as a cytoplasmic protein, we detected it in the nucleus and found it to physically interact with transcription factor CCAAT/enhancer-binding protein Î 2 (C/EBPβ) in mammary epithelial cells. We also observed that Cidea induces XOR expression by promoting the association of C/EBPβ onto, and the dissociation of HDAC1 from, the promoter of the Xdh gene encoding XOR. Finally, we found that Fsp27, another CIDE family protein, is detected in the nucleus and interacts with C/EBPβ to regulate expression of a subset of C/EBPβ downstream genes in adipocytes. Thus, Cidea acts as a previously unknown transcriptional coactivator of C/EBPβ in mammary glands to control lipid secretion and pup survival. © 2012 Nature America, Inc. All rights reserved.


Liu L.,PLA Fourth Military Medical University | Zhang J.,PLA Fourth Military Medical University | Duan Y.-Z.,PLA Fourth Military Medical University | Jin Y.,PLA Fourth Military Medical University
Journal of Tissue Engineering and Regenerative Medicine | Year: 2013

Induced pluripotent stem (iPS) cells possess the ability of self-renewal and can differentiate into cells of the three germ layers, both in vitro and in vivo. Here we report a new method to efficiently induce differentiation of mouse iPS cells into the odontogenic lineage. Using ameloblasts serum-free conditioned medium (ASF-CM), we successfully generated ameloblast-like cells from mouse iPS cells. Importantly, culturing mouse iPS cells in ASF-CM supplemented with BMP4 (ASF-BMP4) promoted odontogenic differentiation, which was evident by the upregulation of ameloblast-specific as well as odontoblast-specific genes. On the other hand, culturing mouse iPS cells in ASF-CM supplemented with noggin (ASF-noggin), an inhibitor of BMP4, abrogated this effect. These results suggest that mouse iPS cells can be induced by ASF-BMP4 to differentiate into ameloblast-like and odontoblast-like cells. The results of our study raise the possibility of using patient-specific iPS cells for tooth regeneration in the future. © 2013 John Wiley & Sons, Ltd..


Lau W.B.,Thomas Jefferson University | Wang Y.,Thomas Jefferson University | Li R.,PLA Fourth Military Medical University | Ma X.L.,Thomas Jefferson University
Antioxidants and Redox Signaling | Year: 2011

Adiponectin (Ad) is an abundant protein hormone regulatory of numerous metabolic processes. The 30kDa protein originates from adipose tissue, with full-length and globular domain circulatory forms. A collagenous domain within Ad leads to spontaneous self-assemblage into various oligomeric isoforms, including trimers, hexamers, and high-molecular-weight multimers. Two membrane-spanning receptors for Ad have been identified, with differing concentration distribution in various body tissues. The major intracellular pathway activated by Ad includes phosphorylation of AMP-activated protein kinase, which is responsible for many of Ad's metabolic regulatory, anti-inflammatory, vascular protective, and anti-ischemic properties. Additionally, several AMP-activated protein kinase-independent mechanisms responsible for Ad's anti-inflammatory and anti-ischemic (resulting in cardioprotective) effects have also been discovered. Since its 1995 discovery, Ad has garnered considerable attention for its role in diabetic and cardiovascular pathology. Clinical observations have demonstrated the association of hypoadiponectinemia in patients with obesity, cardiovascular disease, and insulin resistance. In this review, we elaborate currently known information about Ad malfunction and deficiency pertaining to cardiovascular disease risk (including atherosclerosis, endothelial dysfunction, and cardiac injury), as well as review evidence supporting Ad resistance as a novel risk factor for cardiovascular injury, providing insight about the future of Ad research and the protein's potential therapeutic benefits. © 2011 Mary Ann Liebert, Inc.


Yuan T.-F.,Nanjing Normal University | Li J.,PLA Fourth Military Medical University | Ding F.,Nanjing Normal University
Cell and Tissue Research | Year: 2014

Adult neurogenesis in rodents has been extensively studied. Here, we briefly summarize the studies of adult neurogenesis based on non-human primate brains and human postmortem brain samples in recent decades. The differences between rodent, primate and human neurogenesis are discussed. We conclude that these differences may contribute to distinct physiological roles and the self-repair mechanisms in the brain across species. © 2014, Springer-Verlag Berlin Heidelberg.


Liu Y.,University of Southern California | Liu Y.,Capital Medical University | Wang L.,University of Southern California | Wang L.,PLA Fourth Military Medical University | And 9 more authors.
Nature Medicine | Year: 2011

Stem cell-based regenerative medicine is a promising approach in tissue reconstruction. Here we show that proinflammatory T cells inhibit the ability of exogenously added bone marrow mesenchymal stem cells (BMMSCs) to mediate bone repair. This inhibition is due to interferon γ (IFN-γ)-induced downregulation of the runt-related transcription factor 2 (Runx-2) pathway and enhancement of tumor necrosis factor α (TNF-α) signaling in the stem cells. We also found that, through inhibition of nuclear factor κB (NF-κB), TNF-α converts the signaling of the IFN-γ-activated, nonapoptotic form of TNF receptor superfamily member 6 (Fas) in BMMSCs to a caspase 3- and caspase 8-associated proapoptotic cascade, resulting in the apoptosis of these cells. Conversely, reduction of IFN-γ and TNF-α concentrations by systemic infusion of Foxp3 + regulatory T cells, or by local administration of aspirin, markedly improved BMMSC-based bone regeneration and calvarial defect repair in C57BL/6 mice. These data collectively show a previously unrecognized role of recipient T cells in BMMSC-based tissue engineering.


Yang Z.,PLA Fourth Military Medical University | Ye X.,Shanghai University | Wu Q.,PLA Fourth Military Medical University | Wu K.,PLA Fourth Military Medical University | Fan D.,PLA Fourth Military Medical University
International Journal of Surgery | Year: 2014

Background and aims: A number of agents have been evaluated in clinical trials to reduce the risk of postoperative recurrence in Crohn's disease (CD). The aim of this study was to compare the efficacy of 5-aminosalicylates, immunomodulators and biologics for postoperative prophylaxis of CD recurrence by using a network meta-analytical approach. Methods: PubMed, Embase, and Cochrane Library were searched (update to November 2013) to identify randomized placebo-controlled, or head-to-head trials among the three drug classes for prevention of postoperative CD relapse. The primary endpoint for efficacy was endoscopic recurrence, and the secondary outcomes were clinical recurrence and adverse events. We conducted a Bayesian network meta-analysis with a mixed treatment comparisons to combine both direct and indirect evidences. Results: Fifteen trials involving 1507 patients were included in this analysis. Biological agents were associated with a large and significant reduction of both endoscopic and clinical recurrence compared with placebo, 5-aminosalicylates, or immunomodulators. Immunomodulators showed greater efficacy in terms of endoscopic and clinical recurrence prophylaxis compared with 5-aminosalicylates or placebo, but with higher incidence of adverse events. 5-aminosalicylates were superior to placebo for prevention of clinical recurrence, without increasing the rate of side effect. Conclusions: 5-aminosalicylates, immunomodulators, and biologics are more efficacious than placebo for postoperative CD prevention. Biologics are found to be the most effective medications to prevent CD recurrence. © 2014 Surgical Associates Ltd.


Liu L.,Xijing Hospital of Digestive Diseases | Wang W.,Xijing Hospital of Digestive Diseases | Chen H.,Xijing Hospital of Digestive Diseases | Zhao Y.,Xijing Hospital of Digestive Diseases | And 7 more authors.
Clinical Cancer Research | Year: 2014

Purpose: Published studies have not investigated the suitability of Response Evaluation Criteria in Solid Tumors (RECIST), European Association for the Study of the Liver (EASL) criteria, and modified RECIST (mRECIST) for assessing the response of patients with hepatocellular carcinoma to treatment with sorafenib combined with transarterial chemoembolization. Here, we aimed to define the earliest time at which the response to combination therapy could be accurately assessed and validate the prognostic value of these criteria at this early posttherapy time point. Experimental Design: A total of 114 consecutive patients with hepatocellular carcinoma receiving combination therapy were retrospectively enrolled. The therapy response at different time points was assessed using RECIST, EASL, and mRECIST. Cox regression analysis and Kaplan-Meier curves were used to assess overall survival (OS) in the responders and nonresponders. Results: At the third follow-up (median, 94 days; range, 89-102 days) after therapy, the response rates obtained using EASL (50.6%) and mRECIST (51.6%) were greater than that obtained using RECIST (16.5%). The agreement was strong between the mRECIST and EASL results (k 1/4 0.9) but weak between mRECIST and RECIST (k 1/4 0.3). The EASL and mRECIST responses significantly correlated with survival. Risk reductions of 52% and 50% were observed for EASL and mRECIST responders, respectively, compared with nonresponders. However, no significant association between the treatment response and survival was observed using RECIST. Conclusions: The earliest time to evaluate the response to combination therapy is 3 months (median, 94 days) after therapy. EASL and mRECIST responses are independent predictors for OS at this early time point. © 2014 American Association for Cancer Research.


Yin W.-H.,Peking University | Guo S.-P.,PLA Fourth Military Medical University | Yang H.-Y.,Peking University | Chan J.K.C.,Queen Elizabeth Hospital
Human Pathology | Year: 2010

Summary: Desmoplastic small round cell tumor is a highly aggressive neoplasm that generally involves the peritoneum and pelvis of young patients. Only rare cases occur outside the abdomen. We report a case presenting as a primary submandibular gland tumor in a 24-year-old man. Histologically, although there were irregular tumor islands lying in an abundant desmoplastic stroma, there were also areas comprising large cellular islands with scanty stroma in between, raising the differential diagnosis of various salivary gland carcinomas. The tumor cells were medium sized, with hyperchromatic nuclei and moderate amounts of cytoplasm. The diagnosis of desmoplastic small round cell tumor was confirmed by the presence of a polyphenotypic immunoprofile (positive for cytokeratin, desmin, and neuron-specific enolase) and the characteristic EWS-WT1 gene fusion. Although rare, desmoplastic small round cell tumor has to be considered in the differential diagnosis of poorly differentiated neoplasms of the salivary gland, especially in young patients. © 2010 Elsevier Inc. All rights reserved.


Wang W.,323th Hospital of PLA | Li F.,323th Hospital of PLA | Tu Y.,PLA Fourth Military Medical University | Yang Q.,PLA Fourth Military Medical University | Gao X.,PLA Fourth Military Medical University
Diagnostic Pathology | Year: 2013

Objective: Involvements of microRNA-22 (miR-22) in cancer development have attracted much attention, but its role in tumorigenesis of gastric cancer is still largely unknown. Therefore, the aim of this study was to investigate the expression patterns and clinical implications of miR-22 in gastric cancer. Methods: Quantitative RT-PCR was performed to evaluate the expression levels of miR-22 in 98 pairs of gastric cancer and normal adjacent mucosa. Results: Compared with normal adjacent mucosa, miR-22 expression was significantly downregulated in gastric cancer tissues (P < 0.001). Of 98 patients with gastric cancer, 58 (59.2%) were placed in the low miR-22 expression group and 40 (40.8%) were placed in the high miR-22 expression group. In addition, tumors with low miR-22 expression had greater extent of lymph node metastasis (P = 0.02) and distant metastasis (P = 0.01), and were at a worse stage (P = 0.01) than the tumors with high miR-22 expression. Moreover, the gastric cancer patients with low miR-22 expression had shorter overall survival than those with high miR-22 expression (P = 0.03). MiR-22, determined by multivariate analysis, was an independent prognostic factor for patients with gastric cancer. Conclusion: Our data offer the convincing evidence that the reduced expression of miR-22 was significantly associated with malignant development of gastric cancer and may be a novel prognostic marker of this disease. miR-22 might have potentials in the application of cancer therapy for patients with gastric cancer. © 2013 Wang et al.; licensee BioMed Central Ltd.


Chen C.-C.,University of Southern California | Chen C.-C.,Taipei Veterans General Hospital | Chen C.-C.,National Yang Ming University | Wang L.,PLA Fourth Military Medical University | And 13 more authors.
Cell | Year: 2015

Summary Coordinated organ behavior is crucial for an effective response to environmental stimuli. By studying regeneration of hair follicles in response to patterned hair plucking, we demonstrate that organ-level quorum sensing allows coordinated responses to skin injury. Plucking hair at different densities leads to a regeneration of up to five times more neighboring, unplucked resting hairs, indicating activation of a collective decision-making process. Through data modeling, the range of the quorum signal was estimated to be on the order of 1 mm, greater than expected for a diffusible molecular cue. Molecular and genetic analysis uncovered a two-step mechanism, where release of CCL2 from injured hairs leads to recruitment of TNF-α-secreting macrophages, which accumulate and signal to both plucked and unplucked follicles. By coupling immune response with regeneration, this mechanism allows skin to respond predictively to distress, disregarding mild injury, while meeting stronger injury with full-scale cooperative activation of stem cells. © 2015 Elsevier Inc.


The present invention discloses a cellulose derivative shown as formula (I), which is obtained as follows: the hydroxyl at position 6 of microcrystalline cellulose is protected with triphenylchloromethane, and then reacted with acyl chloride or isocyanate. After the protection of the hydroxyl at positions 2 and 3 of microcrystalline cellulose, triphenylmethyl is removed under acidic conditions to expose the hydroxyl at position 6. Finally, the hydroxyl at position 6 is chiral derivatized with amino acid acyl chloride or polypeptide acyl chloride, to obtain a micro chiral regulation cellulose derivative. The micro chiral regulation cellulose derivative thus obtained is coated onto the surface of a silica gel support, to form a chiral stationary phase, which is filled in a stainless steel column to form a chiral column for the separation of various different types of chiral compounds. The preparation method of the present invention is not only efficient and convenient, but also safe and reliable. The chiral column thus formed has stable performance, high separation efficiency, and is suitable for large scale production.


Wang Z.,PLA Fourth Military Medical University | Zhu S.,PLA Fourth Military Medical University | Shen M.,PLA Fourth Military Medical University | Liu J.,PLA Fourth Military Medical University | And 5 more authors.
Carcinogenesis | Year: 2013

The transcription factor signal transducer and activator of transcription 3 (STAT3) contributes to cell proliferation, apoptosis and motility in human cancer cells. We aim to elucidate the function of STAT3 in esophageal carcinogenesis process and molecular mechanisms. We showed that hyperactivated STAT3 in esophageal carcinogenesis tissues correlated with the overexpression of octamer transcription factor-1 (Oct-1). High STAT3 phosphorylation correlated with shorter survival compared with low STAT3 phosphorylation. STAT3 and Oct-1 expression levels affected the proliferation and colony formation of Eca-109 esophageal squamous cell carcinoma cells by altering Erk and Akt activation. Nevertheless, STAT3 regulated the migration and invasion of esophageal squamous cell carcinoma cells independent of Oct-1. In conjunction with Oct-1, STAT3 inhibited apoptosis in esophageal squamous cell carcinoma cells. Constitutively activated STAT3 in normal human esophageal epithelium cells (HET-1A) elevated Oct-1 expression, and promoted proliferation and decreased apoptosis. STAT3 activated HET-1A cells to form tumors in vivo, suggesting that overactivated STAT3 is sufficient for carcinogenesis. We further confirmed the colocalization of STAT3 and Oct-1 in the nucleus and found that STAT3 regulates the transcription and expression of Oct-1 by directly targeting its promoter. Activated STAT3 also upregulated many genes associated with Oct-1. Together, our results indicate that STAT3 plays a crucial role in esophageal carcinogenesis by regulating the cell proliferation and apoptosis in conjunction with Oct-1. © The Author 2012. Published by Oxford University Press. All rights reserved.


Yu-Hong W.,General Hospital of Beijing Military Area of PLA | Rui C.,PLA Fourth Military Medical University | Ding L.,No 261 Hospital Of Pla
Nanoscale Research Letters | Year: 2011

Background: The recent advance in nanomaterial research field prompts the development of diagnostics of infectious diseases greatly. Many nanomaterials have been developed and applied to molecular diagnostics in labs. At present, the diagnostic test of human papillomavirus (HPV) relies exclusively on molecular test. Hereon, we report a rapid and facile quantum dots (QDs) and superparamagnetic nanoparticle-based hybridization assay for the detection of (HPV) 16 infections which combines the merits of superparamagnetic nanoparticles and QDs and wholly differs from a conventional hybridization assay at that the reaction occurs at homogeneous solution, and total time for detection is no more than 1 h. Methods: The probes were labeled with superparamagnetic nanoparticles and QDs. Sixty cervical swab samples were used to perform a hybridization assay with these probes, and the results were compared with type-specific polymerase chain reaction (PCR) method. Results: The statistic analysis suggests that there is no significant difference between these two methods. Furthermore, this method is much quicker and easier than the type-specific PCR method. Conclusion: This study has successfully validated the clinical performance of our hybridization assay. The advantages in the time of detection and ease of process endow this method with great potential in clinical usage, especially mass epidemiological screening. © 2011 Yu-Hong et al.


Cao W.,PLA Fourth Military Medical University | Yu G.,Shaanxi Cancer Hospital | Lu Q.,PLA Fourth Military Medical University | Zhang J.,PLA Fourth Military Medical University
BMC Cancer | Year: 2013

Background: It is currently unclear whether a correlation exists between N-myc downstream-regulated gene 2 (NDRG2) expression and oesophageal squamous cell carcinoma (ESCC). The aim of this study was to examine the underlying clinical significance of NDRG2 expression in ESCC patients and to investigate the effects of NDRG2 up-regulation on ESCC cell growth in vitro and in vivo.Methods: Immunohistochemistry was used to determine the level of NDRG2 expressions in ESCC tissue, which was then compared to specific clinicopathological features in the patient and tissue specimens. Factors associated with patient survival were analysed. Moreover, the effects of up-regulating NDRG2 expression on the growth of an ESCC cell line were examined by MTT, colony formation, DNA replication activity and nude mouse model assays.Results: Notably low expression of NDRG2 in ESCC patients was inversely associated with clinical stage, NM classification, histological differentiation and patients' vital status (all P < 0.05). ESCC patients expressing high levels of NDRG2 exhibited a substantially higher 5-year overall survival rate than NDRG2-negative patients. Furthermore, NDRG2 over-expression reduced the proliferation, colony formation and DNA replication activity in ESCC cells, as well as inhibiting the growth of ESCC cells in vivo.Conclusion: The present experiments demonstrated that NDRG2 may be a diagnostic and prognostic marker in patients with ESCC, and up-regulation of NDRG2 might act as a promising therapeutic strategy for aggressive ESCC. © 2013 Cao et al.; licensee BioMed Central Ltd.


Shen L.,PLA Fourth Military Medical University | Shen L.,University of Utah | O'Shea J.M.,University of Utah | Kaadige M.R.,University of Utah | And 6 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2015

Triple-negative breast cancers (TNBCs) are aggressive and lack targeted therapies. Understanding how nutrients are used in TNBCs may provide new targets for therapeutic intervention. We demonstrate that the transcription factor c-Myc drives glucose metabolism in TNBC cells but does so by a previously unappreciated mechanism that involves direct repression of thioredoxin-interacting protein (TXNIP). TXNIP is a potent negative regulator of glucose uptake, aerobic glycolysis, and glycolytic gene expression; thus its repression by c-Myc provides an alternate route to c-Myc-driven glucose metabolism. c-Myc reduces TXNIP gene expression by binding to an E-box-containing region in the TXNIP promoter, possibly competing with the related transcription factor MondoA. TXNIP suppression increases glucose uptake and drives a dependence on glycolysis. Ectopic TXNIP expression decreases glucose uptake, reduces cell proliferation, and increases apoptosis. Supporting the biological significance of the reciprocal relationship between c-Myc and TXNIP, a Mychigh/TXNIPlow gene signature correlates with decreased overall survival and decreased metastasis-free survival in breast cancer. The correlation between the Mychigh/TXNIPlow gene signature and poor clinical outcome is evident only in TNBC, not in other breast cancer subclasses. Mutation of TP53, which is a defining molecular feature of TNBC, enhances the correlation between the Mychigh/TXNIPlow gene signature and death from breast cancer. Because Myc drives nutrient utilization and TXNIP restricts glucose availability, we propose that the Mychigh/TXNIPlow gene signature coordinates nutrient utilization with nutrient availability. Further, our data suggest that loss of the p53 tumor suppressor cooperates with Mychigh/TXNIPlow-driven metabolic dysregulation to drive the aggressive clinical behavior of TNBC. © 2015, National Academy of Sciences. All rights reserved.


Li X.,Shanghai JiaoTong University | Ma X.-Y.,PLA Fourth Military Medical University | Feng Y.-F.,PLA Fourth Military Medical University | Ma Z.-S.,PLA Fourth Military Medical University | And 5 more authors.
Biomaterials | Year: 2015

Chitosan coated porous titanium alloy implant (CTI) is demonstrated a promising approach to improve osseointegration capacity of pure porous titanium alloy implant (TI). Since chitosan has been demonstrated to exhibit antioxidant activity, we propose CTI may ameliorate the ROS overproduction, thus reverse the poor osseointegration under diabetic conditions, and investigate the underlying mechanisms. Primary rat osteoblasts incubated on the TI and the CTI were subjected to normal serum (NS), diabetic serum (DS), DS+NAC (a potent ROS inhibitor) and DS+LY294002 (a PI3K/AKT-specific inhibitor). Invivo study was performed on diabetic sheep implanted with TI or CTI into the bone defects on crista iliaca. Results showed that diabetes-induced ROS overproduction led to osteoblast dysfunction and apoptosis, concomitant with the inhibition of AKT in osteoblasts on the TI substrate. While CTI stimulated AKT phosphorylation through ROS attenuation, thus reversed osteoblast dysfunction evidenced by improved osteoblast adhesion, increased proliferation and ALP activity, and decreased cytotoxicity and apoptotic rate, which exerted same effect to NAC treatment on the TI. These effects were further confirmed by the improved osseointegration within the CTI invivo evidenced by Micro-CT and histological examinations. In addition, the aforementioned promotive effects afforded by CTI were abolished by blocking PI3K/AKT pathway with addition of LY294002. These results demonstrate that the chitosan coating markedly ameliorates diabetes-induced impaired bio-performance of TI via ROS-mediated reactivation of PI3K/AKT pathway, which elicits a new surface functionalization strategy for better clinical performance of titanium implant in diabetic patients. © 2014 Elsevier Ltd.


Niu L.-N.,PLA Fourth Military Medical University | Zhang W.,Huazhong University of Science and Technology | Pashley D.H.,Georgia Regents University | Breschi L.,CNR Institute of Molecular Genetics | And 3 more authors.
Dental Materials | Year: 2014

Objectives Remineralization of demineralized dentin is important for improving dentin bonding stability and controlling primary and secondary caries. Nevertheless, conventional dentin remineralization strategy is not suitable for remineralizing completely demineralized dentin within hybrid layers created by etch-and-rinse and moderately aggressive self-etch adhesive systems, or the superficial part of a caries-affected dentin lesion left behind after minimally invasive caries removal. Biomimetic remineralization represents a different approach to this problem by attempting to backfill the demineralized dentin collagen with liquid-like amorphous calcium phosphate nanoprecursor particles that are stabilized by biomimetic analogs of noncollagenous proteins. Methods This paper reviewed the changing concepts in calcium phosphate mineralization of fibrillar collagen, including the recently discovered, non-classical particle-based crystallization concept, formation of polymer-induced liquid-precursors (PILP), experimental collagen models for mineralization, and the need for using phosphate-containing biomimetic analogs for biomimetic mineralization of collagen. Published work on the remineralization of resin-dentin bonds and artificial caries-like lesions by various research groups was then reviewed. Finally, the problems and progress associated with the translation of a scientifically sound concept into a clinically applicable approach are discussed. Results and significance The particle-based biomimetic remineralization strategy based on the PILP process demonstrates great potential in remineralizing faulty hybrid layers or caries-like dentin. Based on this concept, research in the development of more clinically feasible dentin remineralization strategy, such as incorporating poly(anionic) acid-stabilized amorphous calcium phosphate nanoprecursor-containing mesoporous silica nanofillers in dentin adhesives, may provide a promising strategy for increasing of the durability of resin-dentin bonding and remineralizing caries-affected dentin. © 2013 Academy of Dental Materials.


Ye R.,Xijing Hospital | Ye R.,Jinling Hospital | Yang Q.,Xijing Hospital | Kong X.,PLA Fourth Military Medical University | And 6 more authors.
Critical Care Medicine | Year: 2012

Objective: Anesthetic preconditioning appears to be a viable strategy to treat ischemic cerebral injury. Here we investigated 1) whether the protection conferred by sevoflurane preconditioning sustains in time; 2) whether sevoflurane preconditioning diminishes mitochondrial dysfunction following cerebral ischemia; and 3) whether mitochondrial permeability transition pore plays a crucial role in the sevoflurane preconditioning. Design: Laboratory investigation. Setting: University research laboratory. Subjects: Sprague-Dawley rats. Interventions: Rats underwent 2 hrs of focal cerebral ischemia induced by middle cerebral artery occlusion. Preconditioning was elicited with sevoflurane (2.3%) for 60 mins at 24 hrs before ischemia. The involvement of mitochondrial permeability transition pore was determined with a mitochondrial permeability transition pore opener atractyloside and a specific mitochondrial permeability transition pore inhibitor cyclosporin A. In vitro study was performed on acutely isolated mitochondria subjected to calcium overload. Measurements and Main Results: Sevoflurane preconditioning significantly decreased the infarct size by 35.9% (95% confidence interval 6.5-28.4, p < .001). This reduction of injury volume was associated with a long-term improvement of neurological function according to modified neurological severity score (F = 13.6, p = .001) and sticky-tape test (F = 29.1, p < .001) for 42 days after ischemia. Furthermore, sevoflurane preconditioning markedly protected mitochondria, as indicated by preserved respiratory chain complex activities and membrane potential, lowered mitochondrial hydrogen-peroxide production, and attenuated mitochondrial permeability transition pore opening. Isolated mitochondria also demonstrated a reduced sensitivity to Ca-induced mitochondrial permeability transition pore opening after pre-exposure to sevoflurane in vitro (95% confidence interval 24.2-196.5,p = .006). Inhibiting mitochondrial permeability transition pore using cyclosporin A resulted in protective effects similar to those seen with sevoflurane preconditioning, whereas pharmacologically opening the mitochondrial permeability transition pore with atractyloside abrogated all the positive effects of sevoflurane preconditioning and cyclosporin A, including suppression of mitochondrial permeability transition pore opening, counteraction of mitochondria-dependent apoptotic pathway, and subsequent histological and behavioral improvements. Conclusions: Sevoflurane preconditioning protects mitochondria from cerebral ischemia/reperfusion injury and ameliorates long-term neurological deficits. Inhibition of mitochondrial permeability transition pore opening is a crucial step in mediating the neuroprotection of sevoflurane preconditioning. © 2012 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins.


Koga K.,University of Toronto | Koga K.,University of Science and Technology of China | Liu M.-G.,University of Toronto | Liu M.-G.,Shanghai JiaoTong University | And 10 more authors.
Journal of Neuroscience | Year: 2015

Fragile X syndrome is a common inherited form of mental impairment. Fragile X mental retardation protein (FMRP) plays important roles in the regulation of synaptic protein synthesis, and loss of FMRP leads to deficits in learning-related synaptic plasticity and behavioral disability. Previous studies mostly focus on postsynaptic long-term potentiation (LTP) in Fmr1 knock-out (KO) mice. Here,we investigate the role ofFMRPin presynapticLTP(pre-LTP) in the adultmouseanterior cingulate cortex (ACC). Low-frequency stimulation induced LTP in layer II/III pyramidal neurons under the voltage-clamp mode. Paired-pulse ratio, which is a parameter for presynaptic changes, was decreased after the low-frequency stimulation in Fmr1 wild-type (WT) mice. Cingulate pre-LTP was abolished in Fmr1 KO mice. We also used a 64-electrode array system for field EPSP recording and found that the combination of low-frequency stimulation paired with a GluK1-containing kainate receptor agonist induced NMDA receptor-independent and metabotropic glutamate receptordependent pre-LTP in theWTmice. This potentiation was blocked in Fmr1KOmice. Biochemical experiments showed that Fmr1KOmice displayed altered translocation of protein kinase A subunits in the ACC. Our results demonstrate that FMRP plays an important role in pre-LTP in the adult mouse ACC, and loss of this pre-LTP may explain some of the behavioral deficits in Fmr1 KO mice. © 2015 the authors.


Niu L.-N.,PLA Fourth Military Medical University | Jiao K.,PLA Fourth Military Medical University | Ryou H.,University of Maryland Baltimore County | Yiu C.K.Y.,University of Hong Kong | And 5 more authors.
Angewandte Chemie - International Edition | Year: 2013

Why waste space? In the first stage of the multiphase biomineralization of collagen, silicic acid precursors (purple) infiltrated the collagen fibril (yellow) and condensed into amorphous silica to give a hierarchical composite. Amorphous calcium phosphate precursors (red) then filled the intrafibrillar spaces of the silicified collagen, where the precipitation and maturation of apatite crystallites (blue) occurred to complete the process. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Pan L.,Shanghai JiaoTong University | He M.,Shanghai JiaoTong University | Ma J.,Shanghai JiaoTong University | Tang W.,East China University of Science and Technology | And 4 more authors.
Theranostics | Year: 2013

Upconversion nanocrystals with small size and strong fluorescent signals own great potential in applications such as biomolecule-labeling, in vivo tracking and molecular imaging. Herein we reported that NaYbF4: 25%Gd, 2%Tm upconversion nanocrystals with small size and strong fluorescent signals were controllably synthesized by oleic acid (OA)/ ionic liquid (IL) two-phase system for targeted fluorescent imaging of gastric cancer in vivo. The optimal synthesis condition of NaYbF4: 25%Gd, 2%Tm upconversion nanocrystals by OA/IL two-phase system was established, adding more metal ion such as Na+ ion could facilitate the size control and crystal-phase transition, more importantly, markedly enhancing fluorescent intensity of beta-phase nanocrystals compared with traditional methods. Alpha-phase NaYbF4, 2%Tm upconversion nanocrystals with less than 10nm in diameter and beta-phase NaYbF4: 25%Gd, 2%Tm upconversion nanocrystals with 30 nm or so in diameter and strong fluorescent signals were obtained, these synthesized nanocrystals exhibited very low cytotoxicity. Folic acid-conjugated silica-modified beta-phase NaYbF4: 25%Gd, 2%Tm upconversion nanocrystals were prepared, could actively target gastric cancer tissues implanted into nude mice in vivo, and realized targeted fluorescent imaging. Folic acid-conjugated silica-modified NaYbF4: 25%Gd, 2%Tm upconversion nanocrystals show great potential in applications such as targeted near infared radiation fluorescent imaging, magnetic resonance imaging and targeted therapy of gastric cancer in the near future. © Ivyspring International Publisher.


Li F.,Beijing Institute of Biotechnology | Li F.,Chongqing Medical University | Lan Y.,Beijing Institute of Biotechnology | Wang Y.,Beijing Institute of Biotechnology | And 9 more authors.
Developmental Cell | Year: 2011

Cerebrovascular dysfunction is strongly associated with neonatal intracranial hemorrhage (ICH) and stroke in adults. Cerebrovascular endothelial cells (ECs) play important roles in maintaining a stable cerebral circulation in the central nervous system by interacting with pericytes. However, the genetic mechanisms controlling the functions of cerebral ECs are still largely unknown. Here, we report that disruption of Smad4, the central intracellular mediator of transforming growth factor-β (TGF-β) signaling, specifically in the cerebral ECs, results in perinatal ICH and blood-brain barrier breakdown. Furthermore, the mutant vessels exhibit defective mural cell coverage. Smad4 stabilizes cerebrovascular EC-pericyte interactions by regulating the transcription of N-cadherin through associating with the Notch intracellular complex at the RBP-J binding site of the N-cadherin promoter. These findings uncover a distinct role of endothelial Smad4 in maintaining cerebrovascular integrity and suggest important implications for genetic or functional deficiencies in TGF-β/Smad signaling in the pathogenesis of cerebrovascular dysfunction. © 2011 Elsevier Inc.


Jia D.,PLA Fourth Military Medical University | Deng Y.,Xian Childrens Hospital | Gao J.,The Ninth Hospital of Xian | Liu X.,Xian Childrens Hospital | And 2 more authors.
International Journal of Biological Macromolecules | Year: 2014

Our present study was conducted to investigate whether Panax notoginseng plysaccharides (PNPS) exerted a neuroprotective effect against focal cerebral ischemia/reperfusion (I/R) injury in rats. Before mice were subjected to middle cerebral artery occlusion (MCAO) for 2. h and reperfusion for 22. h, PNPS at the doses of 50, 100, and 200. mg/kg was administered once a day intragastrically for continuous 7 days. Oral administration of PNPS could significantly reduce the severity of neurological deficits, infarct volumes, cerebral edema, and neuronal death caused by MCAO in rats. Moreover, in the presence of PNPS, the Bcl-2/Bax ratio increased, but the level of cleaved caspase-3 reduced. Thus, these finding suggested that suppressing apoptosis through increasing Bcl-2/Bax ratio and evoking caspase-3 cascade should be potential mechanism by which PNPS exerts its neuroprotective function against focal cerebral I/R injury. © 2013 Elsevier B.V.


Zhang S.,PLA Fourth Military Medical University | Zhang S.,Jinling Hospital | Mao T.,PLA Fourth Military Medical University | Chen F.,Northwest University, China
International Journal of Oral and Maxillofacial Surgery | Year: 2011

This study evaluated the effect of platelet-rich plasma (PRP) on the bone formation of marrow stromal cells (MSCs) in porous coral. MSCs in 50 μl of PRP were seeded into natural coral disks (diameter 8.0 mm; thickness 2.0 mm). The composites were clotted and cultured in vitro or implanted subcutaneously into nude mice. Coral scaffolds loading MSCs or PRP alone acted as control. Alkaline phosphatase (ALP) activity of the specimens cultured in vitro for 7 and 14 days was measured, and the level of ectopic bone formation was investigated 4 and 8 weeks after operation. The samples from the coral/PRP/MSC group exhibited significantly higher ALP activity, compared with that from the coral/MSC group or the coral/PRP group (p < 0.05). New bone and/or cartilage formation could be observed in specimens from both coral/PRP/MSC and coral/MSC groups in ectopic sites, and osteogenesis followed the pattern of endochondral bone formation. Histomorphometric analyses showed enhanced cartilage and/or bone formation in the coral/PRP/MSC group, 4 and 8 weeks after implantation. No bone or cartilage formation could be observed in the coral/PRP group. The authors concluded that PRP could improve the ALP activity of MSCs on coral and increase ectopic bone formation. © 2011 International Association of Oral and Maxillofacial Surgeons.


Liu H.,National Engineering Center for Biochip at Shanghai | Liu H.,Chinese National Human Genome Center at Shanghai | Zhu L.,PLA Fourth Military Medical University | Liu B.,Shanghai JiaoTong University | And 6 more authors.
Cancer Letters | Year: 2012

Recent studies demonstrated that in several human malignancies aberrant expression profiles of circulating microRNAs (miRNAs) anticipate great cancer diagnostic potential. Here we showed that serum miR-378 could serve as a novel noninvasive biomarker in gastric cancer (GC) detection. Genome-wide miRNA expression profiles followed with Real-Time quantitative RT-PCR (qRT-PCR) assays revealed that miR-187 *, miR-371-5p and miR-378 were significantly elevated in GC patients. Further validation indicated that miR-378 alone could yields a ROC curve area of 0.861 with 87.5% sensitivity and 70.73% specificity in discriminating GC patients from healthy controls. Collectively, these data support our contention that serum miR-378 has strong potential as a novel noninvasive biomarker in gastric cancer detection. © 2011 Elsevier Ireland Ltd.


Wang S.,Chengdu Medical College | Chen Y.,PLA Fourth Military Medical University | Qu F.,PLA Fourth Military Medical University | He S.,PLA Fourth Military Medical University | And 5 more authors.
Neuro-Oncology | Year: 2014

Background. Compelling epidemiological evidence indicates that alterations of telomere length are associated with risks of many malignancies in a tumor-specific manner, such as lung cancer, breast cancer, and non-Hodgkin's lymphoma. However, the association between leukocyte telomere length and glioma risk has not been investigated. Methods. Relative telomere length (RTL) of peripheral blood leukocytes from 467 glioma patients and 467 healthy controls, matched by age and sex, was measured using the real-time PCR-based method in a case-control study. An unconditional multivariate logistic regression model was applied to estimate the association between RTL and glioma risk. Results. Glioma patients showed notably longer RTL than controls (median, 0.555 vs 0.444; P >. 04). RTL was negatively correlated with age in both cases (ρ = -0.430; P <. 001) and controls (ρ = -0.388; P <. 001). After adjusting for age, sex, smoking status and family history of cancer, multivariate logistic regression analysis showed that there was a U-shaped association between RTL and glioma risk (P for nonlinearity <.001). Compared with individuals in the second tertile of RTL, the odds ratios (95% CI) for participants in the first and third tertiles were 2.16 (range, 1.52-3.09) and 3.51 (range, 2.45-5.00), respectively. Stratified analysis showed that the association between RTL and glioma risk was not modulated by major host characteristics. Conclusions. Our study demonstrates for the first time that either shorter or longer RTL in peripheral blood leukocytes is associated with increased glioma risk, which warrants further investigation in the future. © 2013 © The Author(s) 2013.


Mi Y.-J.,Shanghai JiaoTong University | Hou B.,Beijing Institute of Radiation Medicine | Liao Q.-M.,Shanghai JiaoTong University | Ma Y.,Shanghai JiaoTong University | And 5 more authors.
Cell Death and Differentiation | Year: 2012

Nogo-A is originally identified as an inhibitor of axon regeneration from the CNS myelin. Nogo-A is mainly expressed by oligodendrocytes, and also by some neuronal subpopulations, particularly in the developing nervous system. Although extensive studies have uncovered regulatory roles of Nogo-A in neurite outgrowth inhibition, precursor migration, neuronal homeostasis, plasticity and neurodegeneration, its cell-autonomous functions in neurons are largely uncharacterized. Here, we show that HIV-1 trans-activating-mediated amino-Nogo-A protein transduction into cultured primary cortical neurons achieves an almost complete neuroprotection against oxidative stress induced by exogenous hydrogen peroxide (H 2O 2). Endogenously expressed neuronal Nogo-A is significantly downregulated upon H 2O 2 treatment. Furthermore, knockdown of Nogo-A results in more susceptibility to acute oxidative insults and markedly increases neuronal death. Interacting with peroxiredoxin 2 (Prdx2), amino-Nogo-A reduces reactive oxygen species (ROS) generation and extracellular signal-regulated kinase phosphorylation to exert neuroprotective effects. Structure-function mapping experiments reveal that, out of NiG-Δ20, a novel region comprising residues 290-562 of amino-Nogo-A is indispensable for preventing oxidative neuronal death. Moreover, mutagenesis analysis confirms that cysteine residues 424, 464 and 559 are involved in the inhibition of ROS generation and neuroprotective role of amino-Nogo-A. Our data suggest that neuronal Nogo-A might play a cell-autonomous role in improving neuronal survival against oxidative insult through interacting with Prdx2 and scavenging of ROS. © 2012 Macmillan Publishers Limited All rights reserved.


Lu S.,PLA Fourth Military Medical University | Guo X.,ChenCang Hospital | Zhao P.,PLA Fourth Military Medical University
Molecules | Year: 2011

The aim of the study was to investigate the effect of Ginkgo biloba extract 50 (GBE50), a well-known natural antioxidant, against immunity and antioxidant enzyme activities in ischemia reperfusion (IR) rats. Rats were then divided into six groups fed for 15 days with the same diet: three groups (IV, V, VI) were treated by different doses of GBE50 suspension [20, 40, or 60 mg/kg body weight by oral gavage every day at a fixed time (10.00 a.m.)] (equal to 5, 10 and 20 times, respectively, the maximum recommended human dose), and three groups (I, II, III) were untreated. At the end of the experiment, rats' hearts were subjected to 30 min of ischemia followed by 90 min of reperfusion. Results showed that IR significantly enhanced heart rate, S-T height, myocardium (myeloperoxidase) MPO activity and blood interleukin-8 (IL-8), tumor necrosis factor Alpha (TNF-α), interleukin-1β (IL-1β) levels, blood aspartate transaminase (AST), lactate dehydrogenase (LDH), and creatinine kinase (CK) activities, reduced myocardium sodium-potassium adenosine triphosphatase (Na +-K +-ATPase), calciummagnesium adenosine triphosphatase (Ca 2+-Mg 2+-ATPase) activities and antioxidant enzyme activities in IR group (III) compared to sham control group (II). Pretreatment of GBE50 markedly significantly reduced heart rate, S-T height, myocardium MPO activity and blood IL-8, TNF-α, IL-1β levels, blood AST, LDH, and CK activities, enhanced myocardium Na +-K +-ATPase, Ca 2+-Mg 2+-ATPase activities and antioxidant enzyme activities in IR group (II) compared to IR group (III). The results suggested that the GBE50 may reduce the oxidative stress in the reperfused myocardium, and increased immunity and antioxidant activities in IR rats. © 2011 by the authors; licensee MDPI, Basel, Switzerland.


Han J.,Shaanxi Normal University | Kesner P.,Ottawa Health Research Institute | Metna-Laurent M.,French Institute of Health and Medical Research | Metna-Laurent M.,University of Bordeaux 1 | And 19 more authors.
Cell | Year: 2012

Impairment of working memory is one of the most important deleterious effects of marijuana intoxication in humans, but its underlying mechanisms are presently unknown. Here, we demonstrate that the impairment of spatial working memory (SWM) and in vivo long-term depression (LTD) of synaptic strength at hippocampal CA3-CA1 synapses, induced by an acute exposure of exogenous cannabinoids, is fully abolished in conditional mutant mice lacking type-1 cannabinoid receptors (CB 1R) in brain astroglial cells but is conserved in mice lacking CB 1R in glutamatergic or GABAergic neurons. Blockade of neuronal glutamate N-methyl-D-aspartate receptors (NMDAR) and of synaptic trafficking of glutamate α-amino-3-hydroxy-5-methyl-isoxazole propionic acid receptors (AMPAR) also abolishes cannabinoid effects on SWM and LTD induction and expression. We conclude that the impairment of working memory by marijuana and cannabinoids is due to the activation of astroglial CB 1R and is associated with astroglia-dependent hippocampal LTD in vivo. PaperFlick: © 2012 Elsevier Inc.


Zhao X.,PLA Fourth Military Medical University | Dai J.,Shanghai JiaoTong University | Dai J.,Aurora University | Ma Y.,Shanghai JiaoTong University | And 5 more authors.
GLIA | Year: 2014

The ten-eleven translocation (TET) family of methylcytosine dioxygenases catalyze oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and promote DNA demethylation. Despite the abundance of 5hmC and TET proteins in the brain, little is known about their role in oligodendrocytes (OLs). Here, we analyzed TET expression during OL development in vivo and in vitro, and found that three TET family members possess unique subcellular and temporal expression patterns. Furthermore, the level of 5hmC exhibits dynamic changes during OL maturation, which implies that 5hmC modification may play a role in the expression of critical genes necessary for OL maturation. siRNA-mediated silencing of the TET family proteins in OLs demonstrated that each of the TET proteins is required for OL differentiation. However, based on their unique domain structures, we speculate that the three TET members may function by different mechanisms. In summary, we have established the temporal expression of TET proteins and the dynamic level of 5hmC during OL development and demonstrate that all three TET members are necessary for OL differentiation. GLIA 2014;62:914-926 Main points: Three TET family members show distinctive expression patterns during oligodendrocyte differentiation. © 2014 Wiley Periodicals, Inc.


Zhang H.,Texas A&M University | Jiang Y.,Texas A&M University | Jiang Y.,PLA Fourth Military Medical University | Qin C.,Texas A&M University | And 3 more authors.
Journal of Bone and Mineral Research | Year: 2015

Tooth is made of crown and root. It is widely believed that dentin formation in crown and root uses the same regulatory mechanism. However, identification of nuclear factor 1 C (NFIC)'s unique function in determining root but not crown dentin formation challenges the old thinking. In searching for the target molecules downstream of NFIC, we unexpectedly found a sharp reduction of osterix (OSX), the key transcription factor in skeleton formation, in the Nfic knockout (Nfic-KO) tooth root. We then demonstrated a dose-dependent increase of Osx in the odontoblast cell line due to a transient transfection of Nfic expression plasmid. Studies of global and conditional Osx-KO mice revealed no apparent changes in the crown dentin tubules and dentin matrix. However, the OSX conditional KO (cKO) mice (crossed to the 2.3-kb collagen type 1 [Col1]-Cre) displayed an increase in cell proliferation but great decreases in expressions of root dentin matrix proteins (dentin matrix protein 1 [DMP1] and dentin sialophosphoprotein [DSPP]), leading to an inhibition in odontoblast differentiation, and short, thin root dentin with few dentin tubules. Compared to the Nfic-KO tooth, which contains essentially no dentin tubules and remains in a "root-less" status at adult stages, the Osx-cKO root phenotype had partially improved at the late stage, indicating that other factors can compensate for OSX function. Thus, we conclude that OSX, one of the key downstream molecules of NFIC, plays a critical role in root, but not crown, formation. © 2014 American Society for Bone and Mineral Research. © 2014 American Society for Bone and Mineral Research.


Cao F.-L.,88th Hospital of PLA | Xu M.,88th Hospital of PLA | Wang Y.,PLA Fourth Military Medical University | Gong K.-R.,University of California at San Francisco | Zhang J.-T.,88th Hospital of PLA
Pharmacology Biochemistry and Behavior | Year: 2015

Neuropathic pain, characterized by spontaneous pain, hyperalgesia and allodynia, is a devastating neurological disease that seriously affects patients' quality of life. We have previously shown that tanshinone IIA (TIIA), an important lipophilic component of Danshen, had significant anti-nociceptive effect in somatic and visceral pain, it is surprisingly noted that few pharmacological studies have been carried out to explore the possible analgesic action of TIIA on neuropathic pain and the underlying mechanisms. Therefore, in the present study, by using spinal nerve ligation (SNL) pain model, the antinociceptive and antihyperalgesic effects of TIIA on neuropathic pain were evaluated by intraperitoneal administration in rats. The results indicated that TIIA dose-dependently inhibited SNL-induced mechanical hyperalgesia. As revealed by OX42 levels, TIIA effectively repressed the activation of spinal microglial activation in SNL-induced neuropathic pain. Meanwhile, TIIA also decreased the expressions of inflammatory cytokines TNF-α and IL-1β in the spinal cord. Furthermore, TIIA inhibited oxidative stress by significantly rescuing the superoxide dismutase (SOD) activity and decreasing the malondialdehyde (MDA). Moreover, TIIA depressed SNL-induced MAPKs activation in spinal cord. Conclusion Taken together, our study provides evidence that TIIA inhibited SNL-induced neuropathic pain through depressing microglial activation and immune response by the inhibition of mitogen-activated protein kinases (MAPKs) pathways. Our findings suggest that TIIA might be a promising agent in the treatment of neuropathic pain. © 2014 Published by Elsevier Inc.


Lin Y.,306 Hospital of PLA | Xu J.,XiAn No1 Hospital | Liao H.,Affiliated Hospital of xiAn Medical College | Li L.,306 Hospital of PLA | Pan L.,PLA Fourth Military Medical University
Tumor Biology | Year: 2014

The aim of this study was to evaluate the cytotoxic and apoptotic effects of piperine on human lung cancer A549 cells and to explore its mechanisms. Piperine was found to exert the greatest cytotoxic effect against A549 cells in a dose-dependent manner, whereas it showed no effect on WI38 human lung fibroblasts. This cell growth-inhibitory effect might be attributed to cell DNA damage and cytotoxic effects. Besides, piperine had the ability to cause cell cycle arrest in G2/M phase and to activate caspase-3 and caspase-9 cascades in A549 cells. Furthermore, piperine-induced apoptosis could be blocked by the broad caspase inhibitor z-VAD-fmk in majority. In addition, piperine treatment decreased Bcl-2 protein expression, but increased Bax protein expression in A549 cells, which were positively correlated with an elevated expression of p53 compared to control. Taken together, these results suggested that piperine could induce p53-mediated cell cycle arrest and apoptosis via activation of caspase-3 and caspase-9 cascades, as well as increasing the Bax/Bcl-2 ratio. Thus, piperine could be developed as an effective antitumor agent in the prevention and treatment of lung cancer without toxicity to the host. © 2013 International Society of Oncology and BioMarkers (ISOBM).


Ma X.-Y.,PLA Fourth Military Medical University | Feng Y.-F.,PLA Fourth Military Medical University | Ma Z.-S.,PLA Fourth Military Medical University | Li X.,Shanghai JiaoTong University | And 3 more authors.
Biomaterials | Year: 2014

Composited Chitosan/Hydroxyapatite (CS/HA) material coated on titanium surface (cTi) is a promising approach to produce biomaterials with better osseointegration capacity, but its bio-performance under diabetic conditions and the mechanisms involved remain elusive. We propose that the alterations in the Wnt/β-catenin pathway may play a role in mediating the improvement effect of cTi on diabetes-induced impaired implant osteointegration. To confirm the hypothesis, primary rat osteoblasts incubated on Ti and cTi were subjected to normal serum (NS), diabetic serum (DS), DS+Wnt3a (a specific Wnt agonist) and DS+Dkk1 (a specific Wnt antagonist) treatment. Invivo study was performed on diabetic sheep implanted with Ti or cTi into the bone defect on crista iliaca. Results showed that diabetes depressed osteoblast function evidenced by impaired cell adhesion and morphology, decreased cell proliferation and ALP activity, and higher apoptotic rate on Ti. Importantly, both cTi and Wnt3a treatment ameliorated osteoblastic dysfunction and apoptosis under diabetic condition. Implantation with cTi significantly improved osteointegration evidenced by Micro-CT and histological examinations compared with Ti. Moreover, the aforementioned promotive effects afforded by cTi were abolished by blocking Wnt pathway with Dkk1. Our study explicitly demonstrates that CS/HA composite material improves diabetes-induced impaired osteointegration of Ti via the reactivation of Wnt/β-catenin pathway and provides a target point for biomaterial modification to attain better clinical performance in diabetic patients. © 2014 Elsevier Ltd.


Wang P.-A.,PLA Fourth Military Medical University | Zhang S.-Y.,PLA Fourth Military Medical University | Kagan H.B.,University Paris - Sud
Beilstein Journal of Organic Chemistry | Year: 2013

A series of chiral 10-heteroazatriquinanes were synthesized from enantiopure asymmetric cis-2,5-disubstituted pyrrolidines through a one-pot tandem cyclization procedure. The structures and configurations of these new chiral 10-heteroazatriquinanes are confirmed by X-ray single-crystal diffraction analysis. © 2013 Wang et al.


He B.-R.,Xi'an Jiaotong University | Xie S.-T.,PLA Fourth Military Medical University | Wu M.-M.,PLA Fourth Military Medical University | Hao D.-J.,Xi'an Jiaotong University | Yang H.,Shanghai JiaoTong University
Molecular Neurobiology | Year: 2014

Compelling evidence from animal models and clinical studies suggest that transplantation of olfactory ensheathing cells (OECs), specialized glia in the olfactory system, combined with specific training may be therapeutically useful in the central nervous system (CNS) injuries and neurodegenerative diseases. The unique function of OECs could mainly attribute to both production of cell adhesion molecules and secretion of growth factors in OECs, which support neuron survival and neurite outgrowth. However, little is known about whether engulfment of neuronal degenerative debris by OECs also equally contributes to neuronal survival and neurite outgrowth. Furthermore, the molecular mechanisms responsible for neuronal degenerative corpses' removal remain elusive. Here, we used an in vitro model of primary culture of spinal cord neurons to investigate the effect of engulfment of degenerative neuron debris by OECs on neuronal survival and neurite outgrowth and the possible molecular mechanisms. Our results showed that OECs can engulf an amount of degenerated neuron debris, and this phagocytosis can make a substantial contribution to neuron growth, as demonstrated by increased number of neurons with longer neurite length and richer neurite branches when compared with the combination of neuron debris and OEC conditioned medium (OECCM). Moreover, p38 mitogen-activated protein kinase (p38MAPK) signaling pathway may mediate the OEC engulfment of debris because the p38MAPK-specific inhibitor, SB203580, can abrogate all the positive effects of OECs, including clearance of degenerated neuron debris and generation of bioactive molecules, indicating that p38MAPK is required for the process of phagocytosis of the neuron debris. In addition, the OEC phagocytic activity had no influence on its generation of bioactive molecules. Therefore, these findings provide new insight into further investigations on the OEC role in the repair of traumatic CNS injury and neurodegenerative diseases. © 2013 Springer Science+Business Media.


Zhang D.-W.,PLA Fourth Military Medical University | Wang Z.-L.,No113 Hospital Of Pla | Qi W.,PLA Fourth Military Medical University | Qi W.,520th Hospital of PLA | And 2 more authors.
Inflammation | Year: 2014

The effect of cordycepin (3′-deoxyadenosine) on inflammation-induced osteoporosis (IMO) was studied in this paper. After the rats were treated orally with cordycepin (20 mg/kg), serum osteocalcin (OC), homocysteine (HCY), C-terminal cross-linked telopeptides of collagen type I (CTX), maleic dialdehyde (MDA), polymorphonuclear cells (PMN), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α), they were examined by ELISA or immunohistochemistry. The specimens from the liver were also processed for light microscopic examination. The IMO rats showed a significant increase in plasma CTX, MDA, PMN, IL-1β, TNF-α, and nitrate levels as well as a significant decrease in plasma OC. These changes were attenuated by cordycepin (20 mg/kg) supplementation in the IMO rats. Examination of the liver specimens revealed mononuclear cell infiltration in the portal areas in the IMO rats which was not detected in the cordycepin (20 mg/kg) rats. These results suggest that cordycepin may act as an anti-inflammatory agent in magnesium silicate-induced inflammation in osteoporosis. © 2014 Springer Science+Business Media.


Han Y.,PLA Fourth Military Medical University | Shi J.-P.,Zhejiang Chinese Medical University | Ma A.-L.,China Japan Friendship Hospital | Xu Y.,Zhengzhou University | And 2 more authors.
Clinical Drug Investigation | Year: 2014

Background: Non-alcoholic fatty liver disease (NAFLD) is associated with a high morbidity in patients with impaired fasting glucose (IFG). Bicyclol is a synthetic compound known to protect the liver against oxidation and lipid injuries. Objective: The objective of this study was to evaluate the efficacy and safety of metformin and bicyclol in the treatment of NAFLD patients with IFG. Methods: After lifestyle changes and metformin treatment (500 mg orally three times daily), the 248 patients enrolled with NAFLD and IFG were equally randomized to two 24-week treatment groups: bicyclol 25 mg three times daily or vitamin E (α-tocopherol) 100 mg three times daily (control). Anthropometric measurements, serum biochemistry, liver/spleen computed tomography ratio, and changes in liver histological parameters were compared before and after treatments. Results: A total of 223 patients completed the treatment, and there were significant improvements in body mass index, waist-to-hip ratio, and biochemical parameters in both groups (P < 0.01). Compared with the control group, the improvement in serum alanine aminotransferase levels in the bicyclol group was statistically significant (P < 0.01). Liver histological assessments revealed that steatosis, inflammation, hepatocellular ballooning, and NAFLD activity scores (NAS) were all decreased in both groups after treatment (P < 0.01). However, decreases in inflammation and NAS in the bicyclol group were statistically significant compared with the vitamin E group (P < 0.01). Adverse events in the bicyclol and control groups occurred in 1.79 and 1.80 %, respectively. Conclusion: Metformin combined with bicyclol is effective and safe in the treatment of patients with NAFLD and IFG. However, further studies with a larger sample size are needed to confirm the efficacy and safety of the combination. © 2013 Springer International Publishing Switzerland.


Ren D.,Shaanxi Normal University | Zhao Y.,PLA Fourth Military Medical University | Nie Y.,Shaanxi Normal University | Yang N.,Shaanxi Normal University | Yang X.,Shaanxi Normal University
International Journal of Biological Macromolecules | Year: 2014

Intake of dietary high fructose (HF) exerts a number of adverse metabolic effects. The present study was to investigate whether Artemisia sphaerocephala Krasch seed polysaccharides (ASKP) alleviated hyperglycemia, hepatic steatosis and oxidative injury in mice fed HF water. After 8 weeks of the experiment, administration of ASKP at 400 and 800. mg/kg. bw significantly reduced the fasting serum glucose, insulin concentrations and the homeostasis model assessment of basal insulin resistance (HOMA-IR) of the mice fed 20% HF water. In the oral glucose tolerance test, the administration of ASKP at 400 and 800. mg/kg. bw had a reduced plasma glucose concentrations after 15. min of glucose loading in HF-fed mice, indicating that ASKP improved glucose intolerance. ASKP also remarkably ameliorated the HF-induced elevation of liver lipid contents and oxidative injury in mice, and caused the reduction of liver lipid peroxidation and the elevation of hepatic antioxidant system. Histopathology of the liver by conventional H&E and Oil Red O staining confirmed the liver steatosis and oxidative injury induced by HF diet and the hepatoprotective effect of ASKP. This is the first report showing that ASKP can ameliorate the high fructose-induced hyperglycemia, hepatic steatosis and oxidative injury. © 2014 Elsevier B.V.


Lian P.,Peking Union Medical College | Sun Y.,National Defense University | Ji Z.,Peking Union Medical College | Li H.,Peking Union Medical College | Peng J.,PLA Fourth Military Medical University
PLoS ONE | Year: 2014

Background: Academic burnout refers to students who have low interest, lack of motivation, and tiredness in studying. Studies concerning how to prevent academic burnout are rare. Objective: The present study aimed to investigate the impact of core self-evaluations on the academic burnout of university students, and mainly focused on the confirmation of the mediator role of life satisfaction. Methods: A total of 470 university students accomplished the core self-evaluation scale, Satisfaction with Life, and academic burnout scale. Results: Both core self-evaluations and life satisfaction were significantly correlated with academic burnout. Structural equation modeling indicated that life satisfaction partially mediated the relationship between core self-evaluations and academic burnout. Conclusions: Core self-evaluations significantly influence academic burnout and are partially mediated by life satisfaction. © 2014 Lian et al.


Jia H.,PLA Fourth Military Medical University | Yu L.,Jinan General Hospital | Jiang Z.,PLA Fourth Military Medical University | Ji Q.,PLA Fourth Military Medical University
Archives of Medical Research | Year: 2011

Background and Aims: Genome-wide association studies recently found IGF2BP2 rs4402960 polymorphism associated with enhanced risk of type 2 diabetes mellitus (T2DM). Numerous studies have been published to replicate the association. However, results were inconsistent and inconclusive. To clarify the relationship of IGF2BP2 rs4402960 polymorphism and T2DM, we conducted this meta-analysis. Methods: We searched PubMed for all eligible studies up to February 2011. Forty eight independent study groups from 28 case-control studies and two prospective studies were identified. Pooled odds ratio (OR) and 95% confidential interval (95% CI) were adopted to evaluate the association. Results: The pooled results indicated that the rs4402960 polymorphism of the IGF2BP2 gene was related to increased risk of T2DM for T allele vs. G allele (OR = 1.13, 95% CI 1.11-1.15) under additive genetic model. Significant associations were also found under dominant (OR = 1.17, 95% CI 1.14-1.20) and recessive (OR = 1.20, 95% CI 1.15-1.25) genetic models. There was no significant heterogeneity among all studies. Subgroup analyses stratified by ethnicity showed that significant increased risks were observed in European, East Asian and South Asian populations, and the effect sizes were similar. For Africans, no significant association was detected under all genetic models. Conclusions: Our meta-analysis suggested that IGF2BP2 rs4402960 polymorphism conferred elevated risk of T2DM, especially in European, East Asian and South Asian populations. © 2011 IMSS.


Tian L.,Shaanxi Normal University | Zhao Y.,PLA Fourth Military Medical University | Guo C.,Shaanxi Normal University | Yang X.,Shaanxi Normal University
Carbohydrate Polymers | Year: 2011

This study is designed to compare the antioxidant potential of a water-soluble polysaccharide (HCP) with solvent extracts (water, ethanol, ethyl acetate and chloroform) from Houttuynia cordata Thunb. The results showed that polar water extract exhibited the highest reducing power and scavenging activities against 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical, superoxide radical and hydroxyl radical, which were correlated with its high level of biopolymer HCP. Furthermore, the active HCP was identified as an acid hetero-polysaccharide by a rapid HPLC technology within 20 min, and galacturonic acid (29.4%) and galactose (24.0%) were approved as the prominent components of HCP, followed by rhamnose (17.2%), arabinose (13.5%), glucuronic acid (6.8%), glucose (5.3%), xylose (2.1%) and mannose (1.8%) in the molar percentages. This finding suggests that HCP is one of the main active ingredients responsible for antioxidant effect of H. cordata, which might be valuable as a natural antioxidant source applied in both healthy medicine and food industry. © 2010 Elsevier Ltd. All rights reserved.


Tang Y.,Xi'an University of Science and Technology | Mi C.,Shaanxi Normal University | Mi C.,Xi'an University of Science and Technology | Liu J.,Xi'an University of Science and Technology | And 2 more authors.
Cardiovascular Pathology | Year: 2014

Background Hypertension leads to cardiac hypertrophy as an adaptive response to increased workload. While initial development of hypertrophy is compensatory when contractile function is maintained, persistent stress on heart leads to deteriorated cardiac function and onset of heart failure. Mitochondrial dysfunction develops in the failing heart; however, whether it presents in compensatory cardiac hypertrophy is controversial. Methods Spontaneously hypertensive rats (SHRs) and age-matched normotensive Wistar Kyoto rats were used in the study. Mitochondrial function and remodeling-related mechanisms in the left ventricles were measured by enzyme activity tests, Western blots, and reverse transcriptase polymerase chain reaction. Results Compensatory cardiac hypertrophy in SHR was indicated by higher heart/weigh ratio, left ventricular systolic pressure and ±dp/dtmax (P<.001, P<.05, and P<.01, respectively). Enzyme activities of mitochondrial complex I and II were significantly reduced (P<.05 and P<.01) in SHR in concert with decreased expression of complex subunits (P<.01 for NDUFS3, P=.068 for SDHB, and P<.05 for ATP5A1). Mitochondrial fission protein Drp1 was decreased (P<.05), while fusion protein OPA1 was increased (P<.01). Parkin and SirT1/AMPK-PGC-1α signaling, responsible for mitochondrial elimination and biogenesis respectively, were decreased in SHR (P<.01 for Parkin, P<.001 for SirT1 and p-AMPK). Conclusion Our results implicated that mitochondrial function and remodeling, indicated by mitochondrial enzyme activities and remodeling-related molecules, were compromised in compensatory hypertrophied myocardium of the SHR hypertensive model. Summary Mitochondrial function in compensatory hypertrophied myocardium is controversial. Our present study found mitochondrial dysfunction in the left ventricle of spontaneously hypertensive rats, which was possibly a result of compromised mitochondrial remodeling including mitochondrial dynamics, elimination, and biogenesis. © 2014 Elsevier Inc.


Yuan L.-J.,University of Pennsylvania | Yuan L.-J.,PLA Fourth Military Medical University | Wang T.,University of Pennsylvania | Wang T.,Glaxosmithkline | And 2 more authors.
Journal of the American Society of Echocardiography | Year: 2011

Background: The aim of this study was to develop a simple and reasonably precise echocardiographic method for the assessment of infarct size (IS) and cardiac dysfunction in mice after myocardial infarction. Methods: In vivo experiments were performed in C57BL/6J wild-type mice (n = 18) before and 48 hours after left anterior descending coronary artery ligation. Endocardial length-based echocardiographic IS was validated with that by three different histologic measurements. Left ventricular function was evaluated. Results: Excellent agreement was found between endocardial length-based echocardiographic measurement and angle-based histologic measurement of IS (r = 0.82, P < .001), and both methods strongly correlated with Tei index (r = 0.82, P < .001, and r = 0.74, P < .01) and fractional area change (r = -0.61, P < .05, and r = -0.81, P < .001). Conclusions: Endocardial length-based echocardiographic measurement proved to be a useful method for assessing myocardial IS and is applicable for biomedical and imaging research, and appears particularly promising in studies of left ventricular remodeling after myocardial infarction.© ; 2011 by the American Society of Echocardiography.


Zhang R.,Shaanxi Normal University | Zhao Y.,PLA Fourth Military Medical University | Sun Y.,Shaanxi Normal University | Lu X.,Shaanxi Normal University | Yang X.,Shaanxi Normal University
Journal of Agricultural and Food Chemistry | Year: 2013

This study was aimed to isolate and characterize the raffinose family oligosaccharides (RGOs) from a novel plant source of Rehmannia glutinosa Libosch, and further evaluate whether RGOs can attenuate CCl4-induced oxidative stress and hepatopathy in mice. HPLC analysis showed that RGOs were mainly composed of stachyose (61.7%, w/w), followed by 23.7% raffinose and 7.1% sucrose. Administration of RGOs orally daily in mice for 21 days significantly reduced the impact of CCl4 toxicity on the serum markers of liver damage, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total-cholesterol (TC), and triglycerides (TG). RGOs also increased antioxidant levels of hepatic glutathione (GSH), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), and total antioxidant capacity (T-AOC), and ameliorated the elevated hepatic formation of malonaldehyde (MDA) induced by CCl4 in mice, which coincided with the histological alteration. These findings exhibited the potential prospect of RGOs as functional ingredients to prevent ROS-related liver damage. © 2013 American Chemical Society.


Yang X.,Shaanxi Normal University | Yang S.,Shaanxi Normal University | Guo Y.,Shaanxi Normal University | Jiao Y.,Shaanxi Normal University | Zhao Y.,PLA Fourth Military Medical University
Food Chemistry | Year: 2013

Water-soluble apple peel polysaccharides (APP) and apple flesh polysaccharides (AFP) were isolated from Pink Lady fruits, and their in vitro antioxidant capacities were characterised by DPPH, HO, and O2 - systems, and ferric-reducing antioxidant power assay. Oral administration of APP at 250 and 500 mg/kg bw in mice was shown to be as effective as AFP in lowering the CCl4-caused increases of serum alanine aminotransferase, aspartate aminotransferase and lactic dehydrogenase activities, and hepatic malondialdehyde level, and antagonising the decreases in antioxidant superoxide dismutase and glutathione peroxidase activities caused by CCl4 (p < 0.05). Histopathological examinations further confirmed that both APP and AFP could protect the liver from CCl 4-induced histological alteration. HPLC analysis also showed similar profiles of monosaccharide composition for APP and AFP with arabinose, galactose and galacturonic acid being main component monosaccharides. All of these findings demonstrate that the extracts of both APP and AFP possess antioxidant and hepatoprotective potential. © 2012 Elsevier Ltd. All rights reserved.


Mani S.,Lakehead University | Cao W.,Lakehead University | Cao W.,Thunder Bay Regional Research Institute | Cao W.,PLA Fourth Military Medical University | And 3 more authors.
Nitric Oxide - Biology and Chemistry | Year: 2014

Hydrogen sulfide (H2S) is a gasotransmitter that regulates numerous physiological and pathophysiological processes in our body. Enzymatic production of H2S is catalyzed by cystathionine c-lyase (CSE), cystathionine b-synthase (CBS), and 3-mercaptopyruvate sulfurtransferase (MST). All these three enzymes present in the liver and via H2S production regulate liver functions. The liver is the hub for metabolism of glucose and lipids, and maintains the level of circulatory lipids through lipoprotein metabolism. Hepatic H2S metabolism affects glucose metabolism, insulin sensitivity, lipoprotein synthesis, mitochondrial biogenetics and biogenesis. Malfunction of hepatic H2S metabolism may be involved in many liver diseases, such as hepatic fibrosis and hepatic cirrhosis. © 2014 Elsevier Inc. All rights reserved.


He N.,Shaanxi Normal University | He N.,Shangluo University | Shi X.,Shaanxi Normal University | Zhao Y.,PLA Fourth Military Medical University | And 3 more authors.
Journal of Agricultural and Food Chemistry | Year: 2013

Dietary supplementation of selenium-enriched tea is known to have an anticancer health benefit. This study was to investigate the inhibitory effect of selenium-containing tea polysaccharides (Se-GTPs) from a new variety of selenium-enriched Ziyang green tea against human MCF-7 breast cancer cells. Se-GTPs dose-dependently exhibited an effective cell growth inhibition with an IC50 of 140.1 μg/mL by inducing MCF-7 cancer cells to undergo G2/M phase arrest and apoptosis. The blockade of cell cycle was associated with an up-regulation of p53 expression, but not CDK2. Se-GTPs clearly triggered the mitochondrial apoptotic pathway, as indicated by an increase in Bax/Bcl-2 ratio and subsequent caspase-3 and caspase-9 activation. It was also found that the generation of intracellular ROS is a critical mediator in Se-GTPs-induced cell growth inhibition. These findings suggest that Se-GTPs may serve as a potential novel dietary agent for human breast cancer chemoprevention. © 2012 American Chemical Society.


Lu X.,Shaanxi Normal University | Zhao Y.,PLA Fourth Military Medical University | Sun Y.,Shaanxi Normal University | Yang S.,Shaanxi Normal University | Yang X.,Shaanxi Normal University
Food Chemistry | Year: 2013

This study was to examine the hepatoprotective effects of polysaccharides from green tea of Huangshan Maofeng (HMTP) against CCl4-induced oxidative damage in mice. HMTP is an acidic heteropolysaccharide with galactose (35.0%, mol.%), arabinose (28.9%) and galacturonic acid (11.3%) being the main monosaccharide components. HMTP (400 and 800 mg/kg·bw) administered orally daily for 14 days before CCl4 administration significantly reduced the impact of CCl4 toxicity on the serum markers of liver damage, alanine aminotransferase, aspartate aminotransferase, total-cholesterol and triglycerides. This method of HMTP administration also markedly restrained hepatic lipid peroxidation formation of malondialdehyde and 15-F2t isoprostanes, and elevated the antioxidant levels of hepatic glutathione and superoxide dismutase. These results together with liver histopathology indicated that HMTP exhibited hepatoprotection against CCl4-induced injury, which was found to be comparable to that of biphenyldicarboxylate. The hepatoprotective effects of HMTP may be due to both the inhibition of lipid peroxidation and the increase of antioxidant activity. © 2013 Elsevier Ltd. All rights reserved.


Bai Y.,Albany Medical College | Bai Y.,PLA Fourth Military Medical University | Yang J.,Albany Medical College | Eisele L.E.,New York State Department of Health | And 5 more authors.
Journal of Bacteriology | Year: 2013

Cyclic di-AMP (c-di-AMP) and cyclic di-GMP (c-di-GMP) are signaling molecules that play important roles in bacterial biology and pathogenesis. However, these nucleotides have not been explored in Streptococcus pneumoniae, an important bacterial pathogen. In this study, we characterized the c-di-AMP-associated genes of S. pneumoniae. The results showed that SPD_1392 (DacA) is a diadenylate cyclase that converts ATP to c-di-AMP. Both SPD_2032 (Pde1) and SPD_1153 (Pde2), which belong to the DHH subfamily 1 proteins, displayed c-di-AMP phosphodiesterase activity. Pde1 cleaved c-di-AMP into phosphoadenylyl adenosine (pApA), whereas Pde2 directly hydrolyzed c-di-AMP into AMP. Additionally, Pde2, but not Pde1, degraded pApA into AMP. Our results also demonstrated that both Pde1 and Pde2 played roles in bacterial growth, resistance to UV treatment, and virulence in a mouse pneumonia model. These results indicate that c-di-AMP homeostasis is essential for pneumococcal biology and disease. © 2013, American Society for Microbiology.


Imtiyaz H.Z.,University of Pennsylvania | Imtiyaz H.Z.,Howard Hughes Medical Institute | Williams E.P.,Howard Hughes Medical Institute | Williams E.P.,University of Pennsylvania | And 11 more authors.
Journal of Clinical Investigation | Year: 2010

Hypoxia-inducible factor 1α (HIF-1α) and HIF-2α display unique and sometimes opposing activities in regulating cellular energy homeostasis, cell fate decisions, and oncogenesis. Macrophages exposed to hypoxia accumulate both HIF-1α and HIF-2α, and overexpression of HIF-2α in tumor-associated macrophages (TAMs) is specifically correlated with high-grade human tumors and poor prognosis. However, the precise role of HIF-2α during macrophage-mediated inflammatory responses remains unclear. To fully characterize cellular hypoxic adaptations, distinct functions of HIF-1α versus HIF-2α must be elucidated. We demonstrate here that mice lacking HIF-2α in myeloid cells (Hif2aΔ/Δ mice) are resistant to lipopolysaccharide-induced endotoxemia and display a marked inability to mount inflammatory responses to cutaneous and peritoneal irritants. Furthermore, HIF-2α directly regulated proinflammatory cytokine/chemokine expression in macrophages activated in vitro. Hif2a Δ/Δ mice displayed reduced TAM infiltration in independent murine hepatocellular and colitisassociated colon carcinoma models, and this was associated with reduced tumor cell proliferation and progression. Notably, HIF-2α modulated macrophage migration by regulating the expression of the cytokine receptor M-CSFR and the chemokine receptor CXCR4, without altering intracellular ATP levels. Collectively, our data identify HIF-2α as an important regulator of innate immunity, suggesting it may be a useful therapeutic target for treating inflammatory disorders and cancer.


Sun Y.,Shaanxi Normal University | Yang X.,Shaanxi Normal University | Lu X.,Shaanxi Normal University | Wang D.,Shaanxi Normal University | Zhao Y.,PLA Fourth Military Medical University
Food and Chemical Toxicology | Year: 2013

This study was designed to investigate chemical characterization of the water-soluble polysaccharides extracted from Keemun black tea (KBTP), and their antioxidant and hepatoprotective effects against CCl4-induced oxidative damage in mice. HPLC analysis revealed that KBTP is the typical acidic heteropolysaccharides and consisted of nine monosaccharides. Furthermore, KBTP showed highly ferric-reducing antioxidant power and scavenging effects against DPPH, OH and O2- in vitro. Administration of KBTP (200, 400 and 800mg/kgbw) in mice ahead of CCl4 injection could observably antagonize the CCl4-induced increases in serum ALT, AST, TG and TC, and the hepatic MDA and 8-iso-PGF2a levels, respectively. Mice with KBTP pretreatment displayed a better profile of hepatosomatic index and the improved GSH and SOD activities in comparison with CCl4-intoxicated mice. These biochemical results were further supported with liver histopathological assessment, revealing that KBTP has an observable prevention of liver damage induced by CCl4 in mice. © 2013 Elsevier Ltd.


Wang D.,Shaanxi Normal University | Zhao Y.,PLA Fourth Military Medical University | Sun Y.,Shaanxi Normal University | Yang X.,Shaanxi Normal University
Food Chemistry | Year: 2014

This study was designed to investigate the hepatoprotective effects of the tea polysaccharides (ZTPs) extracted from a selenium-enriched Ziyang green tea (Camellia sinensis). ZTPs were identified as the heteropolysaccharides with glucose (31.4%), arabinose (23.5%) and galactose (21.8%) being the main constitutive monosaccharides. ZTPs displayed noteworthy scavenging effects against DPPH., OH. and O2 -, and high antioxidant effects in vitro, and the effects were further verified by suppressing CCl 4-induced oxidative liver damage in mice at 100, 200 and 400 mg/kg BW. Administration of ZTPs in mice prior to CCl4 significantly prevented the CCl4-induced increases in serum alanine aminotransferase, aspartate amino-transferase and lactic dehydrogenase, as well as hepatic malondialdehyde level. Mice treated with ZTPs showed normal glutathione peroxidase and superoxide dismutase activities, relative to CCl 4-treated group. ZTPs also prevented the CCl4-caused liver histological alteration, as indicated by histopathological evaluation. These findings demonstrate that ZTPs have protective effects against acute CCl 4-induced oxidative liver damage. © 2013 Elsevier Ltd. All rights reserved.


Wang D.,Shaanxi Normal University | Zhao Y.,PLA Fourth Military Medical University | Jiao Y.,Shaanxi Normal University | Yu L.,Shaanxi Normal University | And 2 more authors.
Carbohydrate Polymers | Year: 2012

This study was designed to characterize the chemical composition, antioxidant activity and hepatoprotective effect of the polysaccharides from Zizyphus jujube cv. Shaanbeitanzao (ZSP). HPLC analysis showed that ZSP was the heteropolysaccharides with l-arabinose being the main component monosaccharide (50.2%, molar percentage). ZSP displayed strong antioxidant activity in vitro, and the effect was further verified by suppressing CCl 4-induced oxidative stress in liver at three tested doses of ZSP (100, 200, and 400 mg/kg BW) in mice. Administration of ZSP (400 mg/kg) significantly (p < 0.01) reduced the activities of CCl 4-elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactic dehydrogenase (LDH) in serum, and hepatic malondialdehyde (MDA) level. Mice treated with ZSP showed a better profile of hepatosomatic index (HI) and antioxidant system with normal glutathione peroxidase (GSH-Px), and superoxide dismutase (SOD) activities in liver. These results suggest that ZSP exerts an effective protection against CCl 4-induced hepatic injury by mediating antioxidative and free radical scavenging activities. © 2012 Elsevier Ltd. All rights reserved.


Wang T.,PLA Fourth Military Medical University | Yang X.,Shaanxi Normal University | Wang D.,Shaanxi Normal University | Jiao Y.,Shaanxi Normal University | And 2 more authors.
Carbohydrate Polymers | Year: 2012

A simple, sensitive and specific analytical method has been established for high efficient separation and simultaneously high sensitive determination of thirteen reducing carbohydrates, including aldohexose and aldopentoses as well as maltose and lactose. Reducing carbohydrates were derivatized with 1-phenyl-3-methyl-5-pyrazolone (PMP), separated by capillary zone electrophoresis (CZE) with use of methanol modifier in 175 mM borate buffer (pH 11.0), and detected by UV at 245 nm. The optimized CZE method was found to be well suited to examine the compositional reducing monosaccharides of the isolated polysaccharides from Lycopus lucidus and Jujube, and free mono- and disaccharides in beer and milk. Quantitative recoveries of the compositional carbohydrates in the samples were in the range of 93.2-104.0%, and RSD values ranged from 2.9% to 4.9%. The developed CZE method proves to be precise and practical for quality control of reducing carbohydrates, and will provide more highly efficient separation in food analysis in the future. © 2012 Elsevier Ltd. All rights reserved.


Zhang J.,University of Houston | Zhang J.,PLA Fourth Military Medical University | Guo X.,University of Houston | Guo X.,Shihezi University | And 5 more authors.
Modern Pathology | Year: 2012

As a putative marker for cancer stem cells in human malignant tumors, including ovarian cancer, CD133 expression may define a tumor-initiating subpopulation of cells and is associated with the clinical outcome of patients. However, at this time its clinical significance in ovarian cancer remains uncertain. The aim of this study was to clarify the clinical role of CD133 expression in human ovarian cancer. Immunohistochemical staining of CD133 expression was performed in 400 ovarian carcinoma samples using tissue microarray. The associations among CD133 expression and clinical factors (diagnosis, tumor grade, cancer stage, and clinical response to chemotherapy), overall survival and disease-free survival time were analyzed. CD133 expression was found in 31% of ovarian carcinoma samples. Fisher's exact test and one-way analysis of variance suggested that CD133 expression was associated with high-grade serous carcinoma (P=0.035), late-stage disease (P<0.001), ascites level (P=0.010), and non-response to chemotherapy (P=0.023). CD133 expression was also associated with shorter overall survival time (P=0.007) and shorter disease-free survival time (P<0.001) by log-rank test. Moreover, CD133 expression was an independent predictor of shorter disease-free survival time in an unconditional logistic regression analysis with multiple covariates (P=0.024). Our results thus show that CD133 expression is a predictor of poor clinical outcome for patients with ovarian cancer, supporting the proposed link between CD133 and cancer stem cells. © 2012 USCAP, Inc. All rights reserved.


Zhou L.,Tsinghua University | Xu L.,Chinese Academy of Agricultural Sciences | Ye J.,PLA Fourth Military Medical University | Li D.,Tsinghua University | And 6 more authors.
Hepatology | Year: 2012

High levels of dietary saturated fat have been closely associated with the development of hepatic steatosis, but the factors that mediate this process remain elusive. Here, we observed that the level of cell death-inducing DNA fragmentation factor-alpha-like effector a (Cidea) expression was highly correlated with the severity of hepatic steatosis in humans. Overexpression of Cidea in mouse liver resulted in increased hepatic lipid accumulation and the formation of large lipid droplets (LDs). In contrast, mice with a Cidea deficiency had decreased lipid accumulation and alleviated hepatic steatosis when they received a high-fat-diet feeding or in ob/ob mice. Furthermore, the knockdown of Cidea in livers of ob/ob mice resulted in significantly reduced hepatic lipid accumulation and smaller LDs. Importantly, we observed that Cidea expression in hepatocytes was specifically induced by saturated fatty acids (FAs), and such induction was reduced when sterol response element-binding protein (SREBP)1c was knocked down. In contrast, the overexpression of SREBP1c restored the saturated FA-induced expression of Cidea. In addition, we observed that the stability of Cidea protein in hepatocytes increased significantly in response to treatment with FAs. Conclusion: Cidea plays critical roles in promoting hepatic lipid accumulation and in the development of hepatic steatosis by acting as a sensor that responds to diets that contain FAs. © 2012 American Association for the Study of Liver Diseases.


Shi X.,Shaanxi Normal University | Zhao Y.,PLA Fourth Military Medical University | Jiao Y.,Shaanxi Normal University | Shi T.,Shaanxi Normal University | Yang X.,Shaanxi Normal University
PLoS ONE | Year: 2013

Background:A greater reduction in cancer risk associated with mushroom diet rich in fungus polysaccharides is generally accepted. Meanwhile, edible Pleurotus abalonus as a member of Abalone mushroom family is a popular nutritional supplement that purportedly prevents cancer occurrence. However, these anecdotal claims are supported by limited studies describing tumor-inhibitory responses to the promising polysaccharides, and the molecular mechanisms underlying these properties have not yet been elucidated.Methodology/Principal Findings:We here fractionated the crude polysaccharide preparation from the fruiting bodies of P. abalonus into three fractions, namely PAP-1, PAP-2 and PAP-3, and tested these fractions for antiproliferative activity in human breast cancer MCF-7 cells. The largest PAP-3, an acidic polysaccharide fraction with a molecular mass of 3.68×105Da, was the most active in inhibiting MCF-7 cancer cells with an IC50 of 193 μg/mL. The changes in cell normal morphology were observed by DAPI staining and the PAP-3-induced apoptosis was confirmed by annexin V/propidium iodide staining. The apoptosis was involved in mitochondria-mediated pathway including the loss of mitochondrial membrane potential (Δψm), the increase of Bax/Bcl-2 ratio, caspase-9/3 activation, and poly(ADP-ribose) polymerase (PARP) degradation, as well as intracellular ROS production. PAP-3 also induced up-regulation of p53, and cell cycle arrest at the S phase. The incubation of MCF-7 cells with antioxidant superoxide dismutase (SOD) and N-acetylcysteine (NAC) significantly attenuated the ROS generation and apoptosis caused by PAP-3, indicating that intracellular ROS plays a pivotal role in cell death.Conclusions/Significance:These findings suggest that the polysaccharides, especially acidic PAP-3, are very important nutritional ingredients responsible for, at least in part, the anticancer health benefits of P. abalonus via ROS-mediated mitochondrial apoptotic pathway. It is a major breakthrough bringing new insight of the potential use of the polysaccharides as health-care food or medicine to provide significant natural defense against human cancer. © 2013 Shi et al.


Liu H.,Beihang University | Li X.,Beihang University | Zhou G.,Beihang University | Fan H.,PLA Fourth Military Medical University | Fan Y.,Beihang University
Biomaterials | Year: 2011

One of the major downfalls of tissue-engineered small-diameter vascular grafts is the inability to obtain a confluent endothelium on the lumenal surface. Loosely attached endothelial cells (ECs) are easily separated from the vessel wall when exposed to the in vivo vascular system. Thus any denuded areas on the lumenal surface of vascular grafts may lead to thrombus formation via platelet deposition and activation. If the denuded areas could express anticoagulant activity until the endothelial cell lining is fully achieved, it may greatly improve the chances of successful vascular reconstruction. In this study, we fabricate sulfated silk fibroin nanofibrous scaffolds (S-silk scaffolds) and assess the anticoagulant activity and cytocompatibility of S-silk scaffolds in vitro in order to improve the antithrombogenicity and get some insights into its potential use for vascular tissue engineering. Sulfated silk fibroin was prepared by reaction with chlorosulphonic acid in pyridine, and then was developed to form an S-silk scaffold by electrospinning technique. FTIR analyses identified the successful incorporation of sulfate groups in silk fibroin molecules. It was found that the anticoagulant activity of S-silk scaffolds was significantly enhanced compared with silk fibroin nanofibrous scaffolds (Silk scaffolds). Vascular cells, including ECs and smooth muscle cells (SMCs), demonstrated strong attachment to S-silk scaffolds and proliferated well with higher expression of some phenotype-related marker genes and proteins. Overall, the data in this study suggest the suitability of S-silk scaffolds used along with vascular cells for the development of tissue-engineered vascular grafts. © 2011 Elsevier Ltd.


Yang X.,Shaanxi Normal University | Lv Y.,Shaanxi Normal University | Lv Y.,Lund University | Tian L.,Shaanxi Normal University | Zhao Y.,PLA Fourth Military Medical University
Journal of Agricultural and Food Chemistry | Year: 2010

This study was undertaken to characterize the water-soluble polysaccharides isolated from an herbal tea, the leaves of L. lucidus Turcz. HPLC analysis showed that L. lucidus polysaccharides (LLPs) were mainly composed of galactose (50.1 mol %), followed by galacturonic acid (14.2 mol %), accounting for 64.3 mol % of all quantitative nine monosaccharides. Furthermore, we evaluated the systemic immunological efficacy of LLPs in mice. Mice were intragastrically administered once daily with low-dose (50 mg/kg), intermediate-dose (100 mg/kg), and high-dose (300 mg/kg) of LLPs, respectively, for 30 consecutive days. In comparison with vehicle, LLPs significantly enhanced the plaque-forming cells (PFCs), and serum hemolysin level, and delayed-type hypersensitivity (DTH) in response to sheep red blood cells (SRBC) in a dose-dependent manner (p < 0.01). In LLPs-treated mice, phagocytosis capacity and concanavalin A-induced spleenocyte proliferation were remarkably increased (p < 0.05). The intermediate- and high-dose of LLPs also caused a significant increase in the indices of thymus and spleen organs of mice (p < 0.05). This suggests that the polysaccharides derived from the tea leaves of L. lucidus improves the immune system and might be regarded as a biological response modifier. © 2010 American Chemical Society.


Tian Y.,University of Pennsylvania | Yuan L.,University of Pennsylvania | Yuan L.,PLA Fourth Military Medical University | Goss A.M.,University of Pennsylvania | And 8 more authors.
Developmental Cell | Year: 2010

Little is understood about the molecular mechanisms underlying the morphogenesis of the posterior pole of the heart. Here we show that Wnt2 is expressed specifically in the developing inflow tract mesoderm, which generates portions of the atria and atrio-ventricular canal. Loss of Wnt2 results in defective development of the posterior pole of the heart, resulting in a phenotype resembling the human congenital heart syndrome complete common atrio-ventricular canal. The number and proliferation of posterior second heart field progenitors is reduced in Wnt2-/- mutants. Moreover, these defects can be rescued in a temporally restricted manner through pharmacological inhibition of Gsk-3β. We also show that Wnt2 works in a feedforward transcriptional loop with Gata6 to regulate posterior cardiac development. These data reveal a molecular pathway regulating the posterior cardiac mesoderm and demonstrate that cardiovascular defects caused by loss of Wnt signaling can be rescued pharmacologically in vivo. © 2010 Elsevier Inc. All rights reserved.


Chen Y.-T.,New York Medical College | Chen Y.-T.,Sloan Kettering Cancer Center | Chiu R.,Sloan Kettering Cancer Center | Lee P.,Sloan Kettering Cancer Center | And 3 more authors.
Human Reproduction | Year: 2011

Background: Cancer/testis (CT) antigens are cancer antigens normally expressed in adult testicular germ cells. The expression of chromosome X-encoded CT antigens (CT-X antigens) in human fetal gonads and in testicular seminomas was examined.Methods: The expression of 10 CT-X antigens (MAGEA, NY-ESO-1, GAGE, CT7/MAGEC1, CT10/MAGEC2, CT45, SAGE1, SSX2, NXF2 and SPANX) was studied immunohistochemically.Results: In adult human testis, SPANX is expressed in late spermatids and spermatozoa, whereas all other CT-X antigens are predominantly expressed in spermatogonia or primary spermatocytes. All CT-X antigens except SPANX are expressed in human fetal germ cells. CT-X-positive germ cells appear as early as 13 weeks after gestation, increase with age and reach a plateau at around 22 weeks. In the fetal ovary, CT-X-positive oogonia are most abundant at around 24 weeks and sharply decrease subsequently. CT-X antigens are almost exclusively expressed in OCT3/4-negative gonocytes and their expression appears to coincide with the loss of pluripotency. Spermatocytic seminoma, a neoplasm derived from adult pre-meiotic germ cells, showed uniform expression of all CT-X antigens except SPANX. In contrast, most seminomas (>80) express CT7, CT45, GAGE and CT10 but express MAGEA, NXF2 and NY-ESO-1 at lower frequency, and very rarely express SSX2 and SAGE1. Conclusions: Most CT-X antigens are expressed in human fetal germ cells after they have lost stem cell characteristics, with predominant expression in pre-meiotic germ cells. Spermatocytic seminomas showed expression of all CT-X antigens except SPANX, whereas classical seminomas only express some CT-X antigens, reflecting their different origins from adult versus fetal germ cells. © 2011 The Author. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.


Chen C.,University of Southern California | Akiyama K.,Okayama University of Science | Yamaza T.,Kyushu University | You Y.-O.,University of Southern California | And 4 more authors.
EMBO Molecular Medicine | Year: 2014

Bone marrow mesenchymal stem cells (BMMSCs) are capable of differentiating into multiple cell types and regulating immune cell response. However, the mechanisms that govern the immunomodulatory properties of BMMSCs are still not fully elucidated. Here we show that telomerase-deficient BMMSCs lose their capacity to inhibit T cells and ameliorate the disease phenotype in systemic sclerosis mice. Restoration of telomerase activity by telomerase reverse transcriptase (TERT) transfection in TERT-/- BMMSCs rescues their immunomodulatory functions. Mechanistically, we reveal that TERT, combined with β-catenin and BRG1, serves as a transcriptional complex, which binds the FAS ligand (FASL) promoter to upregulate FASL expression, leading to an elevated immunomodulatory function. To test the translational value of these findings in the context of potential clinical therapy, we used aspirin treatment to upregulate telomerase activity in BMMSCs, and found a significant improvement in the immunomodulatory capacity of BMMSCs. Taken together, these findings identify a previously unrecognized role of TERT in improving the immunomodulatory capacity of BMMSCs, suggesting that aspirin treatment is a practical approach to significantly reduce cell dosage in BMMSC-based immunotherapies. © 2014 The Authors.


Zhang Y.,University of Michigan | Yan W.,University of Michigan | Collins M.A.,University of Michigan | Bednar F.,University of Michigan | And 9 more authors.
Cancer Research | Year: 2013

Pancreatic cancer, one of the deadliest human malignancies, is almost invariably associated with the presence of an oncogenic form of Kras. Mice expressing oncogenic Kras in the pancreas recapitulate the stepwise progression of the human disease. The inflammatory cytokine interleukin (IL)-6 is often expressed by multiple cell types within the tumor microenvironment. Here, we show that IL-6 is required for the maintenance and progression of pancreatic cancer precursor lesions. In fact, the lack of IL-6 completely ablates cancer progression even in presence of oncogenic Kras. Mechanistically, we show that IL-6 synergizes with oncogenic Kras to activate the reactive oxygen species detoxification program downstream of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling cascade. In addition, IL-6 regulates the inflammatory microenvironment of pancreatic cancer throughout its progression, providing several signals that are essential for carcinogenesis. Thus, IL-6 emerges as a key player at all stages of pancreatic carcinogenesis and a potential therapeutic target. © 2013 AACR.


Tian Y.,University of Pennsylvania | Tian Y.,Temple University | Liu Y.,University of Pennsylvania | Wang T.,University of Pennsylvania | And 15 more authors.
Science Translational Medicine | Year: 2015

In contrast to lower vertebrates, the mammalian heart has limited capacity to regenerate after injury in part due to ineffective reactivation of cardiomyocyte proliferation. We show that the microRNA cluster miR302-367 is important for cardiomyocyte proliferation during development and is sufficient to induce cardiomyocyte proliferation in the adult and promote cardiac regeneration. In mice, loss of miR302-367 led to decreased cardiomyocyte proliferation during development. In contrast, increased miR302-367 expression led to a profound increase in cardiomyocyte proliferation, in part through repression of the Hippo signal transduction pathway. Postnatal reexpression of miR302-367 reactivated the cell cycle in cardiomyocytes, resulting in reduced scar formation after experimental myocardial infarction. However, long-term expression of miR302-367 induced cardiomyocyte dedifferentiation and dysfunction, suggesting that persistent reactivation of the cell cycle in postnatal cardiomyocytes is not desirable. This limitation can be overcome by transient systemic application of miR302-367 mimics, leading to increased cardiomyocyte proliferation and mass, decreased fibrosis, and improved function after injury. Our data demonstrate the ability of microRNA-based therapeutic approaches to promote mammalian cardiac repair and regeneration through the transient activation of cardiomyocyte proliferation. © 2015, American Association for the Advancement of Science. All rights reserved.


Zhang Y.,University of Pennsylvania | Li S.,University of Pennsylvania | Yuan L.,University of Pennsylvania | Yuan L.,PLA Fourth Military Medical University | And 6 more authors.
Genes and Development | Year: 2010

Cardiomyocyte proliferation is high in early development and decreases progressively with gestation, resulting in the lack of a robust cardiomyocyte proliferative response in the adult heart after injury. Little is understood about how both cell-autonomous and nonautonomous signals are integrated to regulate the balance of cardiomyocyte proliferation during development. In this study, we show that a single transcription factor, Foxp1, can control the balance of cardiomyocyte proliferation during development by targeting different pathways in the endocardium and myocardium. Endocardial loss of Foxp1 results in decreased Fgf3/Fgf16/Fgf17/Fgf20 expression in the heart, leading to reduced cardiomyocyte proliferation. This loss of myocardial proliferation can be rescued by exogenous Fgf20, and is mediated, in part, by Foxp1 repression of Sox17. In contrast, myocardial-specific loss of Foxp1 results in increased cardiomyocyte proliferation and decreased differentiation, leading to increased myocardial mass and neonatal demise. We show that Nkx2.5 is a direct target of Foxp1 repression, and Nkx2.5 expression is increased in Foxp1-deficient myocardium. Moreover, transgenic overexpression of Nkx2.5 leads to increased cardiomyocyte proliferation and increased ventricular mass, similar to the myocardial-specific loss of Foxp1. These data show that Foxp1 coordinates the balance of cardiomyocyte proliferation and differentiation through cell lineage-specific regulation of Fgf ligand and Nkx2.5 expression. © 2010 by Cold Spring Harbor Laboratory Press.


Liang L.,University of Pennsylvania | Liang L.,PLA Fourth Military Medical University | Wei H.,University of Pennsylvania
Alzheimer Disease and Associated Disorders | Year: 2015

Alzheimer disease (AD) is a fatal progressive disease and the most common form of dementia without effective treatments. Previous studies support that the disruption of endoplasmic reticulum Ca2+ through overactivation of ryanodine receptors plays an important role in the pathogenesis of AD. Normalization of intracellular Ca2+ homeostasis could be an effective strategy for AD therapies. Dantrolene, an antagonist of ryanodine receptors and an FDA-approved drug for clinical treatment of malignant hyperthermia and muscle spasms, exhibits neuroprotective effects in multiple models of neurodegenerative disorders. Recent preclinical studies consistently support the therapeutic effects of dantrolene in various types of AD animal models and were summarized in the current review. © 2014 Wolters Kluwer Health, Inc. All rights reserved.


Yin A.-A.,PLA Fourth Military Medical University | Cai S.,No 101 Hospital Of The Peoples Liberation Army | Dong Y.,PLA Fourth Military Medical University | Zhang L.-H.,PLA Fourth Military Medical University | And 3 more authors.
Journal of Neuro-Oncology | Year: 2014

Temozolomide (TMZ) alone has been proposed as a promising alternative to radiotherapy (RT) in elderly glioblastoma (GBM) patients. We report a meta-analysis to systematically evaluate TMZ monotherapy in older GBM patients. A systematic literature search was performed using PubMed, EMBASE and the Cochrane database. Studies comparing TMZ versus RT in elderly patients (≥65 years) with newly diagnosed GBM were eligible for inclusion. Two randomized clinical trials (RCTs) and three comparative studies were included in the analyses, which revealed an overall survival (OS) advantage for TMZ compared with RT (HR [hazard ratio] 0.86, 95 % CI [confidence interval] 0.74-1.00). However, a sensitivity analysis of 2 RCTs only supported its non-inferiority (HR 0.91, 95 % CI 0.66-1.27). Most elderly patients tolerated TMZ despite an increased risk of grade 3-4 (G3-4) toxicities, especially hematological toxicities. The quality of life was similar between the groups. In the MGMT analysis, methylated tumors were associated with a longer OS than unmethylated tumors among elderly patients receiving TMZ monotherapy (HR 0.50, 95 % CI 0.35-0.70). Moreover, in patients with methylated tumors, TMZ was more beneficial than RT alone in improving OS (TMZ vs. RT: HR 0.66, 95 % CI 0.47-0.93) whereas the opposite was true for those with unmethylated tumors (HR 1.32, 95 % CI 1.00-1.76). Although the meta-analysis demonstrated the non-inferiority to RT in improving OS, TMZ alone was not a straightforward solution for elderly GBM patients because of an increased risk of G3-4 toxicities, especially hematological toxicities. MGMT testing might be helpful for determining individualized treatment. © 2013 Springer Science+Business Media New York.


Li L.,University of Michigan | Li L.,PLA Fourth Military Medical University | Hao X.,University of Michigan | Hao X.,Hainan Medical College Hospital | And 12 more authors.
Gastroenterology | Year: 2014

Background & Aims CD44s is a surface marker of tumor-initiating cells (TICs); high tumor levels correlate with metastasis and recurrence, as well as poor outcomes for patients. Monoclonal antibodies against CD44s might eliminate TICs with minimal toxicity. This strategy is unclear for treatment of pancreatic cancer, and little is known about how anti-CD44s affect pancreatic cancer initiation or recurrence after radiotherapy. Methods One hundred ninety-two pairs of human pancreatic adenocarcinoma and adjacent nontumor pancreatic tissues were collected from patients undergoing surgery. We measured CD44s levels in tissue samples and pancreatic cancer cell lines by immunohistochemistry, real-time polymerase chain reaction, and immunoblot; levels were correlated with patient survival times. We studied the effects of anti-CD44s in mice with human pancreatic tumor xenografts and used flow cytometry to determine the effects on TICs. Changes in CD44s signaling were examined by real-time polymerase chain reaction, immunoblot, reporter assay, and in vitro tumorsphere formation assays. Results Levels of CD44s were significantly higher in pancreatic cancer than adjacent nontumor tissues. Patients whose tumors expressed high levels of CD44s had a median survival of 10 months compared with >43 months for those with low levels. Anti-CD44s reduced growth, metastasis, and postradiation recurrence of pancreatic xenograft tumors in mice. The antibody reduced the number of TICs in cultured pancreatic cancer cells and xenograft tumors, as well as their tumorigenicity. In cultured pancreatic cancer cell lines, anti-CD44s down-regulated the stem cell self-renewal genes Nanog, Sox-2, and Rex-1 and inhibited signal transducer and activator of transcription 3-mediated cell proliferation and survival signaling. Conclusions The TIC marker CD44s is up-regulated in human pancreatic tumors and associated with patient survival time. CD44s is required for initiation, growth, metastasis, and postradiation recurrence of xenograft tumors in mice. Anti-CD44s eliminated bulk tumor cells as well as TICs from the tumors. Strategies to target CD44s cab be developed to block pancreatic tumor formation and post-radiotherapy recurrence in patients. © 2014 by the AGA Institute.


Liao Y.-H.,CAS Chengdu Institute of Organic Chemistry | Liao Y.-H.,University of Chinese Academy of Sciences | Liu X.-L.,CAS Chengdu Institute of Organic Chemistry | Liu X.-L.,University of Chinese Academy of Sciences | And 4 more authors.
Chemistry - A European Journal | Year: 2012

An asymmetric conjugate addition of 3-monosubstituted oxindoles to a range of (E)-1,4-diaryl-2-buten-1,4-diones, catalyzed by commercially available cinchonine, is described. This organocatalytic asymmetric reaction affords a broad range of 3,3'-disubstituted oxindoles that contain a 1,4-dicarbonyl moiety and vicinal quaternary and tertiary stereogenic centers in high-to-excellent yields (up to 98 %), with excellent diastereomeric and moderate-to-high enantiomeric ratios (up to 99:1 and 95:5, respectively). Subsequently, cyclization of the 1,4-dicarbonyl moiety in the resultant Michael adducts under different Paal-Knorr conditions results in two new kinds of 3,3'-disubstituted oxindoles-3-furanyl- and 3-pyrrolyl-3-alkyl-oxindoles-in high yields and good enantioselectivities. Notably, the studies presented here sufficiently confirm that this two-step strategy of sequential conjugate addition/Paal-Knorr cyclization is not only an attractive method for the indirect enantioselective heteroarylation of 3-alkyloxindoles, but also opens up new avenues toward asymmetric synthesis of structurally diverse 3,3'-disubstituted oxindole derivatives. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Liao Y.-H.,CAS Chengdu Institute of Organic Chemistry | Liao Y.-H.,University of Chinese Academy of Sciences | Liu X.-L.,CAS Chengdu Institute of Organic Chemistry | Liu X.-L.,University of Chinese Academy of Sciences | And 4 more authors.
Advanced Synthesis and Catalysis | Year: 2011

A highly diastereo- and enantioselective conjugate addition of α-substituted cyanoacetates to maleimides in the presence of a chiral bifunctional thiourea-tertiary amine catalyst has been investigated for the first time. The procedure was capable of tolerating a relatively wide range of substrates with respect to α-substituted cyanoacetates and maleimides, providing a series of substituted succinimidates bearing two vicinal quaternary-tertiary stereocenters in excellent yields (up to 97%) with excellent diastereo- (up to 98:2) and enantioselectivities (up to 98%) under mild reaction conditions. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Jia H.,PLA Fourth Military Medical University | Yu L.,Jinan General Hospital | Gao B.,PLA Fourth Military Medical University | Ji Q.,PLA Fourth Military Medical University
Endocrine | Year: 2011

Accumulating evidence has suggested that transforming growth factor-beta 1 (TGF-β1) is a functional candidate for diabetic nephropathy (DN). However, association studies investigating the relationship of TGF-β1 gene T869C polymorphism and DN generate inconsistent results. To comprehensively clarify this issue, we performed a meta-analysis to evaluate the impact of the polymorphism on DN. We searched studies from PubMed and China National Knowledge Infrastructure (CNKI) through March 2011. Pooled ORs were calculated under allelic/additive/dominant/recessive/over-dominant genetic models. Nine studies with 1776 cases and 1740 controls were included. Our results indicated that C allele of T869C conferred a significantly increased risk of DN compared with T allele (OR = 1.25, 95% CI: 1.05-1.48) for allelic contrast. Similar results were also found under additive (OR = 1.57, 95% CI: 1.10-2.23) and dominant (OR = 1.40, 95% CI: 1.06-1.85) genetic models. However, subgroup analyses stratified by types of diabetes showed that significantly increased risks were only observed in type 2 diabetic patients, and the association persistently existed in further analysis for Asian populations. As for type 1 diabetic subjects, no significant association was detected under all the genetic models (P>0.05). Our meta-analysis suggested that the TGF-β1 T869C polymorphism conferred an elevated risk of DN. However, significant associations were only observed in type 2 diabetic patients. © Springer Science+Business Media, LLC 2011.


Hao W.,Shandong University | Pang L.,Ningxia Medical University | Jiang M.,General Hospital of Jinan Military Area | Lv R.,PLA Fourth Military Medical University | And 2 more authors.
Journal of Orthopaedic Research | Year: 2010

In bone tissue engineering, the cell distribution mode in the scaffold may affect in vivo osteogenesis. Therefore, we fabricated a novel biomimetic construct based on a combination of rabbit adipose-derived stem cells (rASCs) encapsulated in collagen I gel with a PLGA-β-TCP scaffold (rASCs-COL/PLGA-β-TCP, group A), the combination of rASCs and PLGA-β-TCP (rASCs/PLGA-β-TCP, group B), the combination of collagen I gel and PLGA-β-TCP (COL/PLGA-β-TCP, group C), and PLGA-β-TCP scaffold (group D). The composites were implanted into a 15-mm length critical-sized segmental radial defect. The results were assessed by histology, radiographs, bone mineral density (BMD), and mechanical testing. After 24 weeks, the medullary cavity recanalized, bone was rebuilt, and molding finished, the bone contour remodeled smoothly and the scaffold degraded completely in group A. The BMDs and mechanical properties were similar to normal. However, the bone defect remained unrepaired in groups B, C, and D. Moreover, the scaffold degradation rate in group A was significantly higher than the other groups. Thus, enhanced in vivo osteogenesis of rASCs wrapped in collagen I gel combined with PLGA-β-TCP was achieved, and the bone defect was repaired. We hope this study provides new insights into ASCs-based bone tissue engineering. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.


Cui Y.,PLA Fourth Military Medical University | Yang X.,Shaanxi Normal University | Lu X.,Shaanxi Normal University | Chen J.,PLA Fourth Military Medical University | Zhao Y.,PLA Fourth Military Medical University
Chemico-Biological Interactions | Year: 2014

The study was to characterize the polyphenolic composition, antioxidant properties, and hepatoprotective effects of a polyphenols-enriched extract (HMTP) from Huangshan Maofeng green tea. HPLC analysis showed that three predominantly polyphenolic compounds present in HMTP were epigallocatechin (271.2 μg/mg extract), rutin (239.3 μg/mg) and epicatechin (89.3 μg/mg). HMTP was shown to exhibit strong scavenging activities against DPPH, O2 -, and OH, and ferric-reducing antioxidant power in vitro. Administration of HMTP at 200, 400 and 800 mg/kg bw in mice prior to CCl4 injury significantly decreased the CCl4-induced elevation of serum ALT, AST and ALP activities, and prevented an increase in hepatic MDA levels (p < 0.05). Mice with HMTP pretreatment displayed a better profile of hepatosomatic index and the improved GSH-Px and SOD activities in the liver, relative to CCl4-intoxicated mice. Liver pathological observation also confirmed the protection on CCl4-caused histological alteration, suggesting that HMTP has potential to be explored as valuable hepatoprotective function food. © 2014 Elsevier Ireland Ltd. All rights reserved.


Chu D.,PLA Fourth Military Medical University | Zhao Z.,PLA Fourth Military Medical University | Li Y.,General Hospital of Chengdu Military Region | Li J.,PLA Fourth Military Medical University | And 4 more authors.
PLoS ONE | Year: 2014

MicroRNAs are noncoding RNAs that regulate multiple cellular processes during cancer progression. Among various microRNAs, MiR-630 has recently been identified to be implicated in many critical processes in human malignancies. We aimed to investigate the significance and prognostic value of miR-630 in human gastric cancer. Gastric cancer and adjacent normal specimens from 236 patients from who had not received neoadjuvant chemotherapy were collected. The expression of miR-630 was investigated by quantitative real-time PCR assay and its association with overall survival of patients was analyzed by statistical analysis. MiR-630 expression level was significantly elevated in gastric cancer in comparison to adjacent normal specimens. It is also proved that miR-630 expression was to be associated with gastric cancer invasion, lymph node metastasis, distant metastasis and TNM stage. In addition, survival analysis proved that elevated miR-630 expression was associated with poor overall survival of patients. Multivariate survival analysis also proved that miR-630 was an independent prognostic marker after adjusted for known prognostic factors. The present study proved the overexpression of miR-630 and its association with tumor progression in human gastric cancer. It also provided the first evidence that miR-630 expression was an independent prognostic factor for patients with gastric cancer, which might be a potential valuable biomarker for gastric cancer. © 2014 Chu et al.


He N.-W.,Shaanxi Normal University | Zhao Y.,PLA Fourth Military Medical University | Guo L.,Shaanxi Normal University | Shang J.,Shaanxi Normal University | Yang X.-B.,Shaanxi Normal University
Journal of Medicinal Food | Year: 2012

Dietary and medicinal uses of Panax notoginseng have been associated with reduced risk of cancer. This study was designed to investigate the profiles of P. notoginseng saponin extract (PNSE), the major bioactive ingredients in P. notoginseng (Burk.) F.H. Chen, by high-performance liquid chromatography, and, for the first time, the anticancer effect of PNSE in the human colon cancer cell line LoVo was further evaluated. The major saponins present in PNSE were ginsenosides Rg1 (31.1%) and Rb1 (34.4%), and the total content of the eight saponins identified (notoginsenoside R1, ginsenosides Rg1, Re, Rb1, Rc, and Rd, and isomeric ginsenosides Rb2 and Rb3) was 81.7%, indicating that it was a highly purified standardized saponin extract. Furthermore, PNSE was found to have a markedly cytotoxic effect and antiproliferative activity against the LoVo cell line in a dose- and time-dependent manner. Flow cytometry analysis demonstrated that PNSE caused cell cycle arrest at S phase. Moreover, PNSE was found to possess antioxidative capacities in the 1,1-diphenyl-2-picrylhydrazyl free radical scavenging assay and hydroxyl radical scavenging assay in vitro. Taken together, the present results suggest that naturally occurring PNSE may provide significant natural defense against human colon cancer. © Copyright 2012, Mary Ann Liebert, Inc. and Korean Society of Food Science and Nutrition.


Tao L.,Shaanxi Normal University | Zhang K.,PLA Fourth Military Medical University | Sun Y.,PLA Fourth Military Medical University | Jin B.,PLA Fourth Military Medical University | And 2 more authors.
Biosensors and Bioelectronics | Year: 2012

In this paper, a sensitive and selective sensor for detecting colon cancer cells based on nanoparticle covalent modified anti-human epithelial cell adhesion molecule (EpCAM) antibody is developed. The transmission electron microscope (TEM) images showed that the nanoparticle and functionalized nanoparticle had good decentrality for application. The NaIO 4 oxidation method, which was used as oxidizing antibody for immobilization of conjugating antibody on the silica-coated fluorescent nanoparticles, maintained the activities of antibodies very well. The fluorescence microscopy imaging and flow cytometer (FCM) experiments demonstrated that the nanosensor could increase the signal intensity obviously and distinguish three kinds of target cells (colo205, sw480 and NCM460) well. The membrane and nuclear staining showed the distribution and abundance of EpCAM in cells' membrane. It also provides a possibility to quantify special membrane proteins on different regions of cells' surface. At the end, the result of detecting a simple sample proved that colo205 cells were selected by anti-EpCAM antibody nanosensors in this environment, and made a good foundation for subsequent research. © 2012 Elsevier B.V.


Sausen M.,Ludwig Center for Cancer Genetics and Therapeutics | Leary R.J.,Ludwig Center for Cancer Genetics and Therapeutics | Jones S.,Ludwig Center for Cancer Genetics and Therapeutics | Jones S.,Hopkins Inc. | And 15 more authors.
Nature Genetics | Year: 2013

Neuroblastomas are tumors of peripheral sympathetic neurons and are the most common solid tumor in children. To determine the genetic basis for neuroblastoma, we performed whole-genome sequencing (6 cases), exome sequencing (16 cases), genome-wide rearrangement analyses (32 cases) and targeted analyses of specific genomic loci (40 cases) using massively parallel sequencing. On average, each tumor had 19 somatic alterations in coding genes (range of 3-70). Among genes not previously known to be involved in neuroblastoma, chromosomal deletions and sequence alterations of the chromatin-remodeling genes ARID1A and ARID1B were identified in 8 of 71 tumors (11%) and were associated with early treatment failure and decreased survival. Using tumor-specific structural alterations, we developed an approach to identify rearranged DNA fragments in sera, providing personalized biomarkers for minimal residual disease detection and monitoring. These results highlight the dysregulation of chromatin remodeling in pediatric tumorigenesis and provide new approaches for the management of patients with neuroblastoma. © 2013 Nature America, Inc. All rights reserved.


Chen R.,Shaanxi Normal University | Wang J.-B.,Shaanxi Normal University | Zhang X.-Q.,PLA Fourth Military Medical University | Ren J.,Shaanxi Normal University | Zeng C.-M.,Shaanxi Normal University
Archives of Biochemistry and Biophysics | Year: 2011

Increasing evidence has demonstrated that EGCG possesses prooxidant potential in biological systems, including modifying proteins, breaking DNA strands and inducing the generation of reactive oxygen species. In the present study, the prooxidant effect of EGCG on erythrocyte membranes was investigated. SDS-PAGE and NBT-staining assay were utilized to detect the catechol-protein adducts that generated upon treating the membranes with EGCG. The results indicated that EGCG was able to bind covalently to sulfhydryl groups of membrane proteins, leading to the formation of protein aggregates with intermolecular cross-linking. We suggested that the catechol-quinone originated from the oxidation of EGCG acted as a cross-linker on which peptide chains were combined through thiol-S-alkylation at the C2- and C6-sites of the gallyl ring. EGC showed similar effects as EGCG on the ghost membranes, whereas ECG and EC did not, suggesting that a structure with a gallyl moiety is a prerequisite for a catechin to induce the aggregation of membrane proteins and to deplete membrane sulfhydryls. EDTA and ascorbic acid inhibited the EGCG-induced aggregation of membrane proteins by blocking the formation of catechol-quinone. The information of the present study may provide a fresh insight into the prooxidant effect and cytotoxicity of tea catechins. © 2011 Elsevier Inc. All rights reserved.


Han Y.-Y.,CAS Chengdu Institute of Organic Chemistry | Han Y.-Y.,University of Chinese Academy of Sciences | Wu Z.-J.,CAS Chengdu Institute of Biology | Chen W.-B.,CAS Chengdu Institute of Organic Chemistry | And 4 more authors.
Organic Letters | Year: 2011

A simple catalyst system assembled from an enantiomerically pure diamine ligand and Ni(OAc) 2 efficiently generates chiral metal enolates derived from 3-substituted oxindoles bearing an N-1 carbonyl group. The enolates smoothly undergo diastereo- and enantioselective conjugate addition to a wide range of nitroolefins under mild reaction conditions, furnishing 3,3-disubstituted oxindole products bearing two vicinal quaternary/tertiary stereocenters in 74-95% yields and 60:40 to 99:1 dr, 71-97% ee. © 2011 American Chemical Society.


Wei X.-Y.,PLA Fourth Military Medical University | Zhao Y.,PLA Fourth Military Medical University | Wong-Riley M.T.T.,Medical College of Wisconsin | Ju G.,PLA Fourth Military Medical University | Liu Y.-Y.,PLA Fourth Military Medical University
Journal of Neurochemistry | Year: 2012

The pre-Bötzinger complex (pre-BötC) in the ventrolateral medulla oblongata is critical for the generation of respiratory rhythm in mammals. Somatostatin (SST) and neurokinin 1 receptor (NK1R) immunoreactivity have been used as markers of the pre-BötC. SST immunoreactivity almost completely overlaps with small fusiform NK1R-immunoreactive (ir) neurons, the presumed rhythmogenic neurons, but not with large multipolar NK1R-ir neurons. Understanding the neurochemical characteristics, especially the synaptic relationship of SST/NK1R-ir neurons within the pre-BötC network is essential in providing cellular and structural bases for understanding their physiological significance. This work has not been documented so far. We found that SST immunoreactivity was highly expressed in terminals, somas, and primary dendrites in the pre-BötC. Besides the small fusiform neurons, a small population of medium-sized NK1R-ir neurons also colocalized with SST. Large NK1R-ir neurons were not SST-ir, but received somatostatinergic inputs. SST-ir terminals were glutamatergic or GABAergic, and synapsed with NK1R-ir neurons. Most of synapses between them were of the symmetric type, indicating their inhibitory nature. Asymmetric synapses were evident between SST-ir terminals and NK1R-ir dendrites, strongly suggesting an excitatory innervation from the presumed rhythmogenic neurons as these neurons are glutamatergic. We speculate that SST-mediated excitatory and inhibitory synaptic transmission onto NK1R-ir rhythmogenic and follower neurons synchronizes their activity to contribute to respiratory rhythmogenesis and control. © 2012 The Authors.


Song W.,PLA Fourth Military Medical University | Song W.,Shaanxi Province Peoples Hospital | Sun J.,PLA Fourth Military Medical University | Su B.,PLA Fourth Military Medical University | And 3 more authors.
Journal of Thoracic and Cardiovascular Surgery | Year: 2013

Background: It is well known that ischemic postconditioning reduces ischemic-reperfusion injury, but the underlying mechanism is not fully understood. The current study investigated the role of reactive oxygen species-mediated upregulation of endogenous antioxidant enzymes in the generation of a protective effect induced by ischemic postconditioning against spinal cord reperfusion injury in the rabbit. Methods: New Zealand White rabbits were randomly allocated to sham, ischemia-reperfusion, and postconditioning groups (3 cycles of 30 seconds of reperfusion and 30 seconds of occlusion during the onset of reperfusion). Spinal cord ischemia was induced by clamping the infrarenal abdominal aorta for 20 minutes in the ischemia-reperfusion and postconditioning groups. Forty-eight hours after reperfusion, the neurologic status of the lower limbs was assessed. Blood samples were collected for analysis of serum neuron-specific enolase levels, and the lumbar spinal cord segments (L5-7) were harvested for histopathologic and antioxidant enzyme activities and mRNA analysis with or without administration of N-2-mercaptopropionylglycine (an effective oxygen free radical scavenger) given at different reperfusion times. Results: Continuous administration of N-2-mercaptopropionylglycine for 13 minutes, starting at 10 minutes before (but not 10 minutes after) the beginning of reperfusion, attenuated the neuroprotective effect of postconditioning against spinal cord ischemia and reversed the increase in activity of the antioxidant enzymes superoxide dismutase and catalase in spinal cord tissue subjected to ischemic postconditioning. Conclusions: The results indicate that reactive oxygen species-triggered upregulation of endogenous antioxidant enzyme activities may be involved in the mechanism of neuroprotection of ischemic postconditioning. © 2013 by The American Association for Thoracic Surgery.


Zhang H.,Shaanxi Normal University | Zhang M.,Shaanxi Normal University | Yu L.,Shaanxi Normal University | Zhao Y.,PLA Fourth Military Medical University | And 2 more authors.
Food and Chemical Toxicology | Year: 2012

This study is designed to compare the anticancer effects of quercetin and its water-soluble sulfated derivative, quercetin-5',8-disulfonate (QS), in human colon cancer LoVo cells and breast cancer MCF-7 cells. It was found that both quercetin and QS can inhibit the growth of cancer cells in a dose-dependent manner, with the IC 50 values of 40.2 and 28.0μM for LoVo cells and 30.8 and 19.9μM for MCF-7 cells, respectively, suggesting QS was more effective against the cancer cells than quercetin. Moreover, flow cytometric assay revealed that quercetin and QS could mediate the cell-cycle arrest principally in the S phase after 24h of treatment with the two tumor cells. It was also found that 69.6% of LoVo cells and 90.6% of MCF-7 cells entered the early phase of apoptosis when treated with 100μM QS for 48h. Furthermore, we firstly found the generation of ROS is a critical mediator in QS-induced cell growth inhibition. Taken together, the novel sulfated derivative of quercetin possesses strong antitumor activity via a ROS-dependent apoptosis pathway, and has the excellent potential to be developed into an antitumor precursor compound. © 2012 Elsevier Ltd.


He N.,Shaanxi Normal University | Yang X.,Shaanxi Normal University | Jiao Y.,Shaanxi Normal University | Tian L.,Wageningen University | Zhao Y.,PLA Fourth Military Medical University
Food Chemistry | Year: 2012

Wolfberry fruit polysaccharides (WFPs) were isolated by hot-water extraction and ethanol precipitation. With HPLC analysis, WFPs were for the first time identified as acidic polysaccharides with galacturonic acid being the main component monosaccharide (24.9%), followed by galactose (21.3%), arabinose (18.5%), and glucose (15.9%), accounting for up to 80.6% of the molar percentage. WFPs exhibited a high antioxidant activity and a dose-dependent antiproliferative effect, with IC 50 values of 134.9, 70.1 and 138.4 μg/mL against A549, MCF-7 and LoVo cancer cells after 48 h of incubation as estimated by MTT assay, respectively. Flow cytometry analysis showed that WFPs exerted a stimulatory effect on apoptosis of MCF-7 cells, and induced the cell-cycle arrest at the G0/G1 phase, with the observation of intracellular ROS production and DNA damage. The present study demonstrated that these polysaccharides might have the potential to provide significant natural defence against human cancer. © 2012 Elsevier Ltd. All rights reserved.


Chen W.-B.,CAS Chengdu Institute of Organic Chemistry | Chen W.-B.,University of Chinese Academy of Sciences | Du X.-L.,PLA Fourth Military Medical University | Cun L.-F.,CAS Chengdu Institute of Organic Chemistry | And 2 more authors.
Tetrahedron | Year: 2010

A highly enantioselective aldol reaction of acetaldehyde and a wide scope of isatins has been presented only using readily available 4-hydroxydiarylprolinol as catalyst, affording various desired 3-substituted 3-hydroxyindolin-2-one adducts with moderate to high yield (up to 95%) and good enantioselectivities (up to 98% ee). This method not only represents an example of concise stereoselective synthesis of enantiopure (R)-convolutamydines B and E, but also firstly exhibits expedient asymmetric synthesis optically active (-)-donaxaridine and (R)-chimonamidine. © 2009 Elsevier Ltd. All rights reserved.


Zhu F.,U.S. Center for Disease Control and Prevention | Xu W.,National Institutes for Viral Disease Control and Prevention | Xia J.,PLA Fourth Military Medical University | Liang Z.,National Institute for Food and Drug Control | And 27 more authors.
New England Journal of Medicine | Year: 2014

BACKGROUND: Enterovirus 71 (EV71) is one of the major causative agents of outbreaks of hand, foot, and mouth disease or herpangina worldwide. This phase 3 trial was designed to evaluate the efficacy, safety, and immunogenicity of an EV71 vaccine. METHODS: We conducted a randomized, double-blind, placebo-controlled, multicenter trial in which 10,007 healthy infants and young children (6 to 35 months of age) were randomly assigned in a 1:1 ratio to receive two intramuscular doses of either EV71 vaccine or placebo, 28 days apart. The surveillance period was 12 months. The primary end point was the occurrence of EV71-associated hand, foot, and mouth disease or herpangina. RESULTS: During the 12-month surveillance period, EV71-associated disease was identified in 0.3% of vaccine recipients (13 of 5041 children) and 2.1% of placebo recipients (106 of 5028 children) in the intention-to-treat cohort. The vaccine efficacy against EV71-associated hand, foot, and mouth disease or herpangina was 94.8% (95% confidence interval [CI], 87.2 to 97.9; P<0.001) in this cohort. Vaccine efficacies against EV71-associated hospitalization (0 cases vs. 24 cases) and hand, foot, and mouth disease with neurologic complications (0 cases vs. 8 cases) were both 100% (95% CI, 83.7 to 100 and 42.6 to 100, respectively). Serious adverse events occurred in 111 of 5044 children in the vaccine group (2.2%) and 131 of 5033 children in the placebo group (2.6%). In the immunogenicity subgroup (1291 children), an anti-EV71 immune response was elicited by the two-dose vaccine series in 98.8% of participants at day 56. An anti-EV71 neutralizing antibody titer of 1:16 was associated with protection against EV71-associated hand, foot, and mouth disease or herpangina. CONCLUSIONS: The EV71 vaccine provided protection against EV71-associated hand, foot, and mouth disease or herpangina in infants and young children. Copyright © 2014 Massachusetts Medical Society.


Tong Z.,Sun Yat Sen University | Ni L.,PLA Fourth Military Medical University | Ling J.,Sun Yat Sen University
Peptides | Year: 2014

Although the antimicrobial peptide nisin has been extensively studied in the food industry for decades, its application in the oral cavity remains to develop and evaluate its feasibility in treating oral common diseases. Nisin is an odorless, colorless, tasteless substance with low toxicity and with antibacterial activities against Gram-positive bacteria. These biologic properties may establish its use in promising products for oral diseases. This article summarizes the antibacterial efficiency of nisin against pathogenic bacteria related to dental caries and root canal infection and discusses the combination of nisin and common oral drugs. © 2014 Elsevier Inc.


Liu S.,Weatherall Institute of Molecular Medicine | Liu S.,John Radcliffe Hospital | Liu S.,PLA Fourth Military Medical University | Knapp S.,Old Road Campus Research Building | And 2 more authors.
Cancer Research | Year: 2014

While genetic alteration in the p85a-p110a (PI3K) complex represents one of the most frequent driver mutations in cancer, the wild-type complex is also required for driving cancer progression through mutations in related pathways. Understanding the mechanistic basis of the function of the phosphoinositide 3-kinase (PI3K) is essential for designing optimal therapeutic targeting strategies. Recent structural data of the p85a/p110a complex unraveled key insights into the molecular mechanisms of the activation of the complex and provided plausible explanations for the well-established biochemical data on p85/p110 dimer regulation. A wealth of biochemical and biologic information supported by recent genetic findings provides a strong basis for additional p110-independent function of p85a in the regulation of cell survival. In this article, we review the structural, biochemical, and biologic mechanisms through which p85a regulates the cancer cell life cycle with an emphasis on the recently discovered genetic alterations in cancer. As cancer progression is dependent on multiple biologic processes, targeting key drivers such as the PI3K may be required for efficacious therapy of heterogeneous tumors typically present in patients with late-stage disease. © 2014 AACR.


Li W.,University of California at Los Angeles | Li W.,PLA Fourth Military Medical University | Zhang Z.,PLA Fourth Military Medical University | Saxon A.,University of California at Los Angeles | Zhang K.,University of California at Los Angeles
Allergy: European Journal of Allergy and Clinical Immunology | Year: 2012

Background: Treatment options for food allergy remain limited. Development of novel approaches for the prevention and/or treatment of severe peanut allergy and other food allergies is urgently needed. The objective of this study was to test whether skin application of food allergen can be used as a prophylactic and/or therapeutic intervention for food allergy. Methods: Balb/C mice were given 5 weekly cutaneous application of complete peanut extract (CPE) or ovalbumin (OVA) ranging from 10 to 1000 lg on the shaved back skin, followed by 5 weekly treatments with oral CPE or OVA plus cholera toxin to induce allergic reactivity to the food. At various time points, the immunologic responses and allergic clinical manifestations to allergens were examined. Results: Skin application of a 10-1000 lg dose of CPE or OVA to structurally intact skin did not lead to allergic sensitization to peanut or OVA. Rather, cutaneous allergen application blocked, in a dose-dependent fashion, the subsequent induction of the oral sensitization including inhibiting oral sensitization-induced CPE-specific IgE, IgG1, and IgG2a production, suppressing the peanut anaphylaxis, and modulating the oral sensitization-promoted cytokine production. The cutaneous OVA application also resulted in similar results as seen with CPE application. Conclusion: Cutaneous application of intact skin with peanut or OVA can block the development of orally induced corresponding food allergies, suggesting that allergic tolerance to peanuts and OVA might be achieved via allergen cutaneous application. © 2012 John Wiley & Sons A/S.


Yu Q.,PLA Fourth Military Medical University | Gao F.,PLA Fourth Military Medical University | Ma X.L.,Thomas Jefferson University
Cardiovascular Research | Year: 2011

It is well recognized that insulin resistance found in patients with type 2 diabetes and obesity is a major risk factor for cardiovascular disease. Since its discovery in the 1920s, insulin has been used as an essential therapeutic agent in diabetes for blood glucose management. Recent studies demonstrate that insulin signalling is essential for normal cardiovascular function, and lack of it (i.e. insulin resistance) will result in cardiovascular dysfunction and disease. Moreover, insulin is the key component of glucoseinsulinpotassium cocktail and exerts significant cardiovascular protective effect via a phosphatidylinositol 3′-kinaseprotein kinase Bendothelial nitric oxide synthase (PI3K-Akt-eNOS)-dependent signalling mechanism in addition to its metabolic modulation, which renders it a potent organ protector in multiple clinical applications. This review focuses on insulin-initiated PI3K-Akt-eNOS survival signalling, with nitric oxide as an 'end effector' delivering cardioprotection in health and disease (especially in ischaemic heart disease), and highlights the impairment of this survival signalling as a key link between insulin resistance and cardiovascular disease. © 2010 The Author.


Yuan Y.,PLA Fourth Military Medical University | Li P.,Tsinghua University | Ye J.,PLA Fourth Military Medical University
Protein and Cell | Year: 2012

Atherosclerosis is a chronic, inflammatory disorder characterized by the deposition of excess lipids in the arterial intima. The formation of macrophage-derived foam cells in a plaque is a hallmark of the development of atherosclerosis. Lipid homeostasis, especially cholesterol homeostasis, plays a crucial role during the formation of foam cells. Recently, lipid droplet-associated proteins, including PAT and CIDE family proteins, have been shown to control the development of atherosclerosis by regulating the formation, growth, stabilization and functions of lipid droplets in macrophage-derived foam cells. This review focuses on the potential mechanisms of formation of macrophage-derived foam cells in atherosclerosis with particular emphasis on the role of lipid homeostasis and lipid droplet-associated proteins. Understanding the process of foam cell formation will aid in the future discovery of novel therapeutic interventions for atherosclerosis. © 2012 Higher Education Press and Springer-Verlag Berlin Heidelberg.


Zeng Z.,PLA Fourth Military Medical University | Qu X.,PLA Fourth Military Medical University | Tan Y.,Tsinghua University | Tan R.,Tsinghua University | Zhang S.,Tsinghua University
Optics Express | Year: 2015

A simple and high-accuracy self-mixing interferometer based on single high-order orthogonally polarized feedback effects is presented. The single high-order feedback effect is realized when dual-frequency laser reflects numerous times in a Fabry-Perot cavity and then goes back to the laser resonator along the same route. In this case, two orthogonally polarized feedback fringes with nanoscale resolution are obtained. This self-mixing interferometer has the advantages of higher sensitivity to weak signal than that of conventional interferometer. In addition, two orthogonally polarized fringes are useful for discriminating the moving direction of measured object. The experiment of measuring 2.5nm step is conducted, which shows a great potential in nanometrology. © 2015 Optical Society of America.


Yi W.,PLA Fourth Military Medical University | Yi W.,Thomas Jefferson University | Sun Y.,PLA Fourth Military Medical University | Sun Y.,Thomas Jefferson University | And 10 more authors.
Circulation | Year: 2012

Background-Obesity and diabetes mellitus adversely affect postischemic heart remodeling via incompletely understood mechanisms. C1q/tumor necrosis factor-related protein-3 (CTRP3) is a newly identified adipokine exerting beneficial metabolic regulation, similar to adiponectin. The aim of the present study was to determine whether CTRP3 may regulate postischemic cardiac remodeling and cardiac dysfunction, and, if so, to elucidate the underlying mechanisms. Methods and Results-Male adult mice were subjected to myocardial infarction (MI) via left anterior descending coronary artery occlusion. Both the effect of MI on endogenous CTRP3 expression/production and the effect of exogenous CTRP3 (adenovirus or recombinant CTRP3) replenishment on MI injury were investigated. MI significantly inhibited adipocyte CTRP3 expression and reduced the plasma CTRP3 level, reaching a nadir 3 days after MI. CTRP3 replenishment improved survival rate (P<0.05), restored cardiac function, attenuated cardiomyocyte apoptosis, increased revascularization, and dramatically reduced interstitial fibrosis (all P<0.01). CTRP3 replenishment had no significant effect on cardiac AMP-activated protein kinase phosphorylation but significantly increased Akt phosphorylation and expression of hypoxia inducing factor-1α and vascular endothelial growth factor. Surprisingly, treatment of human umbilical vascular endothelial cells with CTRP3 did not directly affect nitric oxide production or tube formation. However, preconditioned medium from CTRP3-treated cardiomyocytes significantly enhanced human umbilical vascular endothelial cell tube formation, an effect blocked by either pretreatment of cardiomyocytes with a PI3K inhibitor or pretreatment of human umbilical vascular endothelial cells with a vascular endothelial growth factor inhibitor. Finally, the protective effect of adipocyte-conditioned medium against hypoxia-induced cardiomyocyte injury is significantly blunted when CTRP3 is knocked down. Conclusion-CTRP3 is a novel antiapoptotic, proangiogenic, and cardioprotective adipokine, the expression of which is significantly inhibited after MI. © 2012 American Heart Association, Inc.


Gibson S.A.,University of Aberdeen | Gao G.-D.,PLA Fourth Military Medical University | McDonagh K.,National University of Ireland | Shen S.,National University of Ireland
Stem Cell Research and Therapy | Year: 2012

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive accumulation of Lewy body inclusions along with selective destruction of dopaminergic (DA) neurons in the nigrostriatal tract of the brain. Genetic studies have revealed much about the pathophysiology of PD, enabling the identification of both biomarkers for diagnosis and genetic targets for therapeutic treatment, which are evolved in tandem with the development of stem cell technologies. The discovery of induced pluripotent stem (iPS) cells facilitates the derivation of stem cells from adult somatic cells for personalized treatment and thus overcomes not only the limited availability of human embryonic stem cells but also ethical concerns surrounding their use. Non-viral, non-integration, or non-DNA-mediated reprogramming technologies are being developed. Protocols for generating midbrain DA neurons are undergoing constant refinement. The iPS cell-derived DA neurons provide cellular models for investigating disease progression in vitro and for screening molecules of novel therapeutic potential and have beneficial effects on improving the behavior of parkinsonian animals. Further progress in the development of safer non-viral/non-biased reprogramming strategies and the subsequent generation of homogenous midbrain DA neurons shall pave the way for clinical trials. A combined approach of drugs, cell replacement, and gene therapy to stop disease progression and to improve treatment may soon be within our reach. © 2012 BioMed Central Ltd.


Yang H.,Chinese Academy of Sciences | Shi L.,Chinese Academy of Sciences | Wang B.-A.,Chinese Academy of Sciences | Liang D.,Chinese Academy of Sciences | And 9 more authors.
Cell | Year: 2012

Haploid cells are amenable for genetic analysis. Recent success in the derivation of mouse haploid embryonic stem cells (haESCs) via parthenogenesis has enabled genetic screening in mammalian cells. However, successful generation of live animals from these haESCs, which is needed to extend the genetic analysis to the organism level, has not been achieved. Here, we report the derivation of haESCs from androgenetic blastocysts. These cells, designated as AG-haESCs, partially maintain paternal imprints, express classical ESC pluripotency markers, and contribute to various tissues, including the germline, upon injection into diploid blastocysts. Strikingly, live mice can be obtained upon injection of AG-haESCs into MII oocytes, and these mice bear haESC-carried genetic traits and develop into fertile adults. Furthermore, gene targeting via homologous recombination is feasible in the AG-haESCs. Our results demonstrate that AG-haESCs can be used as a genetically tractable fertilization agent for the production of live animals via injection into oocytes. PaperClip: © 2012 Elsevier Inc.


Yang J.,Albany Medical College | Yang J.,PLA Fourth Military Medical University | Bai Y.,Albany Medical College | Zhang Y.,Albany Medical College | And 3 more authors.
Molecular Microbiology | Year: 2014

Summary: Tuberculosis (TB) remains a major cause of morbidity and mortality worldwide. The pathogenesis by the causative agent, Mycobacterium tuberculosis, is still not fully understood. We have previously reported that M. tuberculosisRv3586 (disA) encodes a diadenylate cyclase, which converts ATP to cyclic di-AMP (c-di-AMP). In this study, we demonstrated that a protein encoded by Rv2837c (cnpB) possesses c-di-AMP phosphodiesterase activity and cleaves c-di-AMP exclusively to AMP. Our results showed that in M. tuberculosis, deletion of disA abolished bacterial c-di-AMP production, whereas deletion of cnpB significantly enhanced the bacterial c-di-AMP accumulation and secretion. The c-di-AMP levels in both mutants could be corrected by expressing the respective gene. We also found that macrophages infected with ΔcnpB secreted much higher levels of IFN-β than those infected with the wild type (WT) or the complemented mutant. Interestingly, mice infected with M. tuberculosis ΔcnpB displayed significantly reduced inflammation, less bacterial burden in the lungs and spleens, and extended survival compared with those infected with the WT or the complemented mutant. These results indicate that deletion of cnpB results in attenuated virulence, which is correlated with elevated c-di-AMP levels. © 2014 John Wiley & Sons Ltd.


Liu X.,PLA Fourth Military Medical University | Liao Q.,PLA Fourth Military Medical University | Wang H.,University of California at Los Angeles
Optics Letters | Year: 2013

X-ray luminescence computed tomography (XLCT) is a new molecular imaging modality. In this Letter, we first in vivo tomographically image the near-IR-emitting nanophosphor (Gd2O3:Eu3+) in nude mice (N = 2). In practically, incorporating the compressive sensing technique, the XLCT reconstruction is performed only using single-view data. The experimental results indicate that the single-view reconstruction is feasible to image XLCT in vivo. The location error is less than 1.5 mm. Further, the imaging time can be greatly reduced compared with previous XLCT systems. Therefore, it is suited for imaging fast distribution of x-ray-excitable nanophosphors within a biological object. © 2013 Optical Society of America.


Li J.,University of Virginia | Li J.,Sun Yat Sen University | Deng J.,University of Virginia | Deng J.,PLA Fourth Military Medical University | And 2 more authors.
Pharmacology Biochemistry and Behavior | Year: 2012

Diabetes increases the risk of Alzheimer's disease (AD). The pathological hallmarks for AD brains are extracellular amyloid plaques formed by β-amyloid peptide (Aβ) and intracellular neurofibrillary tangles consisting of hyperphosphorylated tau protein. This study was designed to determine AD-like brain changes in mice modeling for type 2 diabetes. The effects of metformin on these changes also were studied. Seven-week old male db/db mice received intraperitoneal injection of 200 mg kg - 1 d - 1 metformin for 18 weeks. They were subjected to Barnes maze at an age of 21 weeks and fear conditioning at an age of 24 weeks to assess their cognitive functions. Hippocampus was harvested after these tests for biochemical evaluation. The db/db mice had more tau phosphorylated at S396 and total tau in their hippocampi than their non-diabetic control db + mice. Activated/phosphorylated c-jun N-terminal kinase (JNK), a tau kinase, was increased in the db/db mouse hippocampus. Metformin attenuated the increase of total tau, phospho-tau and activated JNK. The db/db mice had increased Aβ levels. Metformin attenuated the reduction of synaptophysin, a synaptic protein, in the db/db mouse hippocampus. Metformin did not attenuate the impairments of spatial learning and memory as well as long-term hyperglycemia in the db/db mice. Our results suggest that the db/db mice have multiple AD-like brain changes including impaired cognitive functions, increased phospho-tau and Aβ as well as decreased synaptic proteins. Activation of JNK may contribute to the increased phospho-tau in the db/db mice. Metformin attenuates AD-like biochemical changes in the brain of these mice. © 2012 Elsevier Inc.


Qu F.,PLA Fourth Military Medical University | Liu X.,PLA Fourth Military Medical University | Zhou F.,PLA Fourth Military Medical University | Yang H.,Thomas Jefferson University | And 3 more authors.
Cancer | Year: 2011

Backkground: Compelling epidemiological evidence indicated that alterations of mitochondrial DNA (mtDNA), including mutations and abnormal content of mtDNA, were implicated in the tumorigenesis of several malignancies in a tumor-specific manner, such as lung cancer, breast cancer, and non-Hodgkin lymphoma. This study was undertaken to investigate whether mtDNA content in peripheral blood lymphocytes (PBLs) could be used as a risk predictor for colorectal cancer (CRC). Methods: The mtDNA content was measured by using quantitative real-time polymerase chain reaction in PBLs from 320 CRC patients and 320 matched controls. Results: The authors found that CRC patients exhibited statistically significantly higher mtDNA content than matched controls (median, 1.03 vs.86; P <.001). They further assessed the association between mtDNA content and CRC risk using multivariate logistic regression. By using the median value in controls as the cutoff point, they found that, compared with low mtDNA content, high mtDNA content was associated with a significantly increased CRC risk (adjusted odds ratio, 2.03; 95% confidence interval, 1.41-2.81). In a trend analysis, they found a statistically significant dose-response relationship between higher mtDNA content and increased CRC risk (P for trend <.001). Stratified analysis showed that the association between mtDNA content and CRC risk was not modulated by major host characteristics. Conclusions: These findings provide the first epidemiological evidence linking the high mtDNA content in PBLs to elevated CRC risk. © 2011 American Cancer Society.


Dong M.,PLA Fourth Military Medical University | Dong M.,University of Wyoming | Zheng Q.,PLA Fourth Military Medical University | Ford S.P.,University of Wyoming | And 3 more authors.
Journal of Molecular and Cellular Cardiology | Year: 2013

Maternal obesity has risen dramatically over the past 20. years, by nearly 42% in African-Americans and 29% in Caucasians. Maternal obesity is afflicted with many maternal obstetric complications in the offspring including high blood pressure, obesity, gestational diabetes and increased perinatal morbidity. Maternal nutritional environment plays a rather important role in the programming of the health set-points in the offspring such as glucose and insulin metabolism, energy balance and predisposition to metabolic disorders. In particular, maternal obesity is associated with elevated prevalence of cardiovascular diseases in the offspring. Evidence from human and experimental studies including rodents and nonhuman primates has indicated that maternal obesity or overnutrition programs offspring for an increased risk of adult obesity. Maternal obesity or fat diet exposure predisposes the onset and development of obesity, insulin resistance, cardiac hypertrophy and myocardial contractile anomalies in the offspring. A number of mechanisms including elevated hormones (leptin, insulin), nutrients (fatty acids, triglycerides and glucose) and inflammatory cytokines have been postulated to play a key role in maternal obesity-induced postnatal cardiovascular sequelae. In addition, lipotoxicity (accumulation of lipid metabolites) resulting from maternal obesity is capable of activating a number of stress signaling cascades including pro-inflammatory cytokines and oxidative stress to exacerbate maternal obesity-induced cardiovascular complications later on in adult life. This mini-review summarizes the recent knowledge with regard to the role of lipotoxicity in maternal obesity-induced change in cardiovascular function in the offspring. This article is part of a Special Issue entitled "Focus on Cardiac Metabolism". © 2012 Elsevier Ltd.


Deng J.,University of Virginia | Deng J.,PLA Fourth Military Medical University | Zhang J.,University of Virginia | Feng C.,University of Virginia | And 2 more authors.
Cardiovascular Research | Year: 2014

Aims About one-third of American adults and 20% of teenagers are obese. Obesity and its associated metabolic disturbances including hyperlipidaemia are risk factors for cardiovascular diseases including stroke. They can worsen neurological outcome after stroke.We determined whether obesity and hyperlipidaemia could induce cerebral vascular remodelling via matrix metalloproteases (MMP) and whether this remodelling affected neurological outcome after brain ischaemia. Methods and results Six-week-old male CD1, C57BL/6J, and MMP-9-/- micewere fed regular diet (RD) or high-fat diet (HFD) for 10weeks. They were subjected to vascular casting or a 90 min middle cerebral arterial occlusion (MCAO). Mice on HFD were heavier and had higher blood glucose and lipid levels than those on RD. HFD-fed CD1 and C57BL/6J mice had an increased cerebral vascular tortuosity index and decreased inner diameters of the middle cerebral arterial root. HFD increased microvessel density in CD1 mouse cerebral cortex. After MCAO, CD1 and C57BL/6J mice on HFD had a bigger infarct volume, more severe brain oedema and blood-brain barrier damage, higher haemorrhagic transformation rate, greater haemorrhagic volume, and worse neurological function. HFDincreased MMP-9 activity in the ischaemic and non-ischaemic brain tissues. Although HFD increased the body weights, blood glucose, and lipid levels in the MMP-9-/- mice on a C57BL/6J genetic background, the HFD-induced cerebral vascular remodelling and worsening of neurological outcome did not occur in these mice. Conclusion HFD induces cerebral vascular remodelling and worsens neurological outcome after transient focal brain ischaemia. MMP-9 activation plays a critical role in these HFD effects. © The Author 2014.


Guo H.,Thomas Jefferson University | Guo H.,PLA Fourth Military Medical University | Li Q.,Thomas Jefferson University | Chou D.W.,Thomas Jefferson University | Uitto J.,Thomas Jefferson University
Journal of Molecular Medicine | Year: 2013

Pseudoxanthoma elasticum (PXE), a multisystem heritable disorder with aberrant mineralization of arterial blood vessels, is caused by mutations in the ABCC6 gene. Previous studies have suggested that carriers of the ABCC6 mutations, particularly of p.R1141X, are at increased risk for coronary artery disease. In this study, we used Abcc6 tm1Jfk knock-out mice to determine the serum lipid profiles and examine the effects of atorvastatin on the aberrant mineralization in this model of PXE. First, serum lipid profiles at 12 weeks of age, after overnight fasting, revealed a statistically significant increase in total cholesterol and triglyceride levels in Abcc6 tm1Jfk mice compared to their wild-type littermates. Placing these mice at 4 weeks of age for 20 weeks on atorvastatin, either 0.01 % or 0.04 % of the diet (low statin and high statin groups, respectively), reduced the total triglyceride and cholesterol levels, which was accompanied with significantly reduced mineralization of the dermal sheath of vibrissae, a biomarker of the aberrant mineralization process in these mice. However, if the mice were placed on atorvastatin for 12 weeks at 12 weeks of age, at which time point significant mineralization had already taken place, no difference in the amount of mineralization was noted. These observations suggest that statins, particularly atorvastatin, can prevent, but not reverse, aberrant mineralization in this mouse model of PXE. For a clinical perspective, a survey of 1,747 patients with PXE was conducted regarding their present or past use of statins. The results indicated that about one third of all PXE patients are currently or have previously been on cholesterol-lowering drugs. Thus, a sizable number of patients with PXE could be subject to modulation of their mineralization processes by concomitant statin treatment. Key message: The Abcc6 -/- mice serve as a model system for PXE, an ectopic mineralization disorder Abcc6 -/- mice were shown to have elevated serum cholesterol and triglyceride levels Feeding of the Abcc6 -/- mice with atorvastatin prevented connective tissue mineralization A third of patients with PXE was found to be on cholesterol-lowering therapy Atorvastatin may potentially be beneficial for patients with PXE © 2013 Springer-Verlag Berlin Heidelberg.


Hann H.-W.,Thomas Jefferson University | Wan S.,Thomas Jefferson University | Myers R.E.,Thomas Jefferson University | Hann R.S.,Thomas Jefferson University | And 3 more authors.
PLoS ONE | Year: 2012

Background: Serum liver enzymes are frequently tested in clinics to aid disease diagnosis. Large observational studies indicated that these enzymes might predict cancer risk and mortality. However, no prospective study has reported on their relationships with the risk of HBV-related hepatocellular carcinoma (HCC). Methodology/Principal Findings: We evaluated the predictive values of four routinely tested liver enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP], and gamma-glutamyltransferase [GGT]) in HCC risk in a prospectively enrolled clinical cohort of 588 Korean American HBV patients. For all four enzymes, the baseline level as well as the average and maximum levels during the first 1 or 2 years of follow-up were analyzed using multivariate Cox proportional hazards model. Patients were categorized into a normal or an elevated group based on the clinical cut-off of each enzyme. During a median follow-up of 7.5 years, 52 patients (incidence rate, 8.8%) developed HCC. The incidence rates were higher in the elevated groups for all four enzymes. The most significant finding was for GGT, with the highest incidence rate of 16.4% in the elevated group compared to 4.6% in the normal group (P<0.001). Compared to patients with normal baseline GGT, those with elevated GGT exhibited a significantly increased HCC risk with a hazards ratio (HR) of 2.60 (95% confidence interval [CI], 1.41-4.77, P = 0.002). Further analyses revealed a cumulative effect between baseline GGT and ALP (HR = 3.41, 95% CI 1.54-7.56, P = 0.003). Conclusions Significance: Serum GGT might predict HCC risk in HBV patients individually or jointly with other enzymes. © 2012 Hann et al.


Baskys A.,Alzheimers Disease Prevention and Treatment Center | Cheng J.-X.,PLA Fourth Military Medical University | Cheng J.-X.,University of California at Los Angeles
Experimental Gerontology | Year: 2012

Vascular dementia (VaD) is a common dementing illness. There are no pharmacological agents with a regulatory approval for its treatment or prevention. Review of published clinical trial reports indicates that early treatment of hypertension, a risk factor for stroke, reduces VaD risk and slows progression. However, unlike stroke, treatment of hyperlipidemia with statin class drugs or treatment of blood clotting abnormalities with acetylsalicylic acid do not appear to have an effect on VaD incidence or progression. Pharmacological agents for treatment of Alzheimer's dementia (AD) such as memantine or acetylcholinesterase inhibitors have small positive effects on cognition in VaD, which are likely due to their action on co-existing AD-related neuropathology. Drug development efforts using novel approaches such as patient stratification by their genotype are needed in order to address the increasing need for effective VaD therapeutics. © 2012 Elsevier Inc.


Liu R.,PLA Fourth Military Medical University | Lin G.,University of California at Los Angeles | Xu H.,PLA Fourth Military Medical University
PLoS ONE | Year: 2013

Background: The dorsal root ganglia (DRG) neuron is an invaluable tool in axon growth, growth factor regulation, myelin formation and myelin-relevant researches. The purification of DRG neurons is a key step in these studies. Traditionally, purified DRG neurons were obtained in two weeks after exposure to several rounds of anti-mitotic reagent. Methods and Results: In this report, a novel, simple and efficient method for DRG purification is presented. DRG cultures were treated once with a high-dose anti-mitotic reagent cocktail for 72 hours. Using this new method, DRG neurons were obtained with 99% purification within 1 week. We confirmed that the neurite growth and the viability of the purified DRG neurons have no difference from the DRG neurons purified by traditional method. Furthermore, P0 and MBP expression was observed in myelin by immunocytochemistry in the DRG/SC co-culture system. The formation of mature node of Ranvier in DRG-Schwann cell co-culture system was observed using anti-Nav 1.6 and anti-caspr antibody. Conclusion and Significance: The results indicate that this high dose single treatment did not compromise the capacity of DRG neurons for myelin formation in the DRG/SC co-culture system. In conclusion, a convenient approach for purifying DRG neurons was developed which is time-saving and high-efficiency. © 2013 Liu et al.


Luo C.,PLA Fourth Military Medical University | Kuner T.,University of Heidelberg | Kuner R.,University of Heidelberg
Trends in Neurosciences | Year: 2014

Chronic pain represents a major challenge to clinical practice and basic science. Excitatory neurotransmission in somatosensory nociceptive pathways is predominantly mediated by glutamatergic synapses. A key feature of these synapses is their ability to adapt synaptic strength in an activity-dependent manner. Such disease-induced synaptic plasticity is paramount to alterations in synaptic function and structure. Recent work has recognized that synaptic plasticity at both excitatory and inhibitory synapses can function as a prime mechanism underlying pathological pain. In this review, cellular and molecular mechanisms underlying synaptic plasticity in nociceptive pathways will be reviewed and discussed. New insights derived from these advances are expected to expedite development of novel interventional approaches for treatment of pathological pain. © 2014 Elsevier Ltd.


Tao L.,PLA Fourth Military Medical University | Wang Y.,Thompson Building | Gao E.,Thomas Jefferson University | Zhang H.,PLA Fourth Military Medical University | And 5 more authors.
Circulation Research | Year: 2010

Rationale: Patients treated with peroxisome proliferator-activated receptor (PPAR)-γ agonist manifest favorable metabolic profiles associated with increased plasma adiponectin (APN). However, whether increased APN production as a result of PPAR-γ agonist treatment is an epiphenomenon or is causatively related to the cardioprotective actions of PPAR-γ remains unknown. Objective: To determine the role of APN in rosiglitazone (RSG) cardioprotection against ischemic heart injury. Methods and Results: Adult male wild-type (WT) and APN knockdown/knockout (APN+/- and APN -/-) mice were treated with vehicle or RSG (20 mg/kg per day), and subjected to coronary artery ligation 3 days after beginning treatment. In WT mice, RSG (7 days) significantly increased adipocyte APN expression, elevated plasma APN levels (2.6-fold), reduced infarct size (17% reduction), decreased apoptosis (0.23±0.02% versus 0.47±0.04% TUNEL-positive in remote nonischemic area), attenuated oxidative stress (48.5% reduction), and improved cardiac function (P<0.01). RSG-induced APN production and cardioprotection were significantly blunted (P<0.05 versus WT) in APN+/-, and completely lost in APN-/- (P>0.05 versus vehicle-treated APN -/- mice). Moreover, treatment with RSG for up to 14 days significantly improved the postischemic survival rate of WT mice (P<0.05 versus vehicle group) but not APN knockdown/knockout mice. Conclusions: The cardioprotective effects of PPAR-γ agonists are critically dependent on its APN stimulatory action, suggesting that under pathological conditions where APN expression is impaired (such as advanced type 2 diabetes), the harmful cardiovascular effects of PPAR-γ agonists may outweigh its cardioprotective benefits. © 2010 American Heart Association, Inc.


Jiao Y.,PLA Fourth Military Medical University | Zhu B.,University of Jinan | Chen J.,PLA Fourth Military Medical University | Duan X.,PLA Fourth Military Medical University
Theranostics | Year: 2015

Fluoride ions have the important roles in a lot of physiological activities related with biological and medical system, such as water fluoridation, caries treatment, and bone disease treatment. Great efforts have been made to develop new methods and strategies for F- detection in the past decades. Traditional methods for the detection of F- including ion chromatography, ion-selective electrodes, and spectroscopic techniques have the limitations in the biomedicine research. The fluorescent probes for F- are very promising that overcome some drawbacks of traditional fluoride detection methods. These probes exhibit high selectivity, high sensitivity as well as quick response to the detection of fluoride anions. The review commences with a brief description of photophysical mechanisms for fluorescent probes for fluoride, including photo induced electron transfer (PET), intramolecular charge transfer (ICT), fluorescence resonance energy transfer (FRET), and excited-state intramolecular proton transfer (ESIPT). Followed by a discussion about common dyes for fluorescent fluoride probes, such as anthracene, naphalimide, pyrene, BODIPY, fluorescein, rhodamine, resorufin, coumarin, cyanine, and near-infrared (NIR) dyes. We divide the fluorescent probes for fluoride in cellular application systems into nine groups, for example, type of hydrogen bonds, type of cleavage of Si-O bonds, type of Si-O bond cleavage and cylization reactions, etc. We also review the recent reported carriers in the delivery of fluorescent fluoride probes. Seventy-four typical fluorescent fluoride probes are listed and compared in detail, including quantum yield, reaction medium, excitation and emission wavelengths, linear detection range, selectivity for F-, mechanism, and analytical applications. Finally, we discuss the future challenges of the application of fluorescent fluoride probes in cellular system and in vivo. We wish that more and more excellent fluorescent fluoride probes will be developed and applied in the biomedicine field in the future. © Ivyspring International Publisher.


Gadani S.P.,University of Virginia | Walsh J.T.,University of Virginia | Smirnov I.,University of Virginia | Zheng J.,University of Virginia | And 2 more authors.
Neuron | Year: 2015

Inflammation is a prominent feature of CNS injury that heavily influences neuronal survival, yet the signals that initiate and control it remain poorly understood. Here we identify the nuclear alarmin, interleukin (IL)-33, as an important regulator of theinnate immune response after CNS injury. IL-33 is expressed widely throughout the healthy brain and is concentrated in white mater due to predominant expression in post-mitotic oligodendrocytes. IL-33 is released immediately after CNS injury fromdamaged oligodendrocytes, acting on local astrocytes and microglia to induce chemokines critical for monocyte recruitment. Mice lacking IL-33 haveimpaired recovery after CNS injury, which isassociated with reduced myeloid cell infiltrates anddecreased induction of M2 genes at the injury site. These results demonstrate a novel molecular mediator contributing to immune cell recruitment tothe injured CNS and may lead to new therapeuticinsights in CNS injury and neurodegenerative diseases. © 2015 Elsevier Inc.


Deng C.,PLA Fourth Military Medical University | Sun Z.,PLA Fourth Military Medical University | Tong G.,PLA Fourth Military Medical University | Yi W.,PLA Fourth Military Medical University | And 6 more authors.
PLoS ONE | Year: 2013

Background: The present study investigates the effects and mechanisms of α-Lipoic acid (LA) on myocardial infarct size, cardiac function and cardiomyocyte apoptosis in rat hearts subjected to in vivo myocardial ischemia/reperfusion (MI/R) injury. Methodology/Principal Findings: Male adult rats underwent 30 minutes of ischemia followed by 3, 24, or 72 h of reperfusion. Animals were pretreated with LA or vehicle before coronary artery ligation. The level of MI/R- induced LDH and CK release, infarct size, cardiomyocyte apoptosis and cardiac functional impairment were examined and compared. Western blot analysis was performed to elucidate the mechanism of LA pretreatment. The level of inflammatory cytokine TNF-α released to serum and accumulated in injured myocardium as well as neutrophil accumulation in injured myocardium were also examined after MI/R injury. Our results reveal that LA administration significantly reduced LDH and CK release, attenuated myocardial infarct size, decreased cardiomyocytes apoptosis, and partially preserved heart function. Western blot analysis showed that LA pretreatment up-regulated Akt phosphorylation and Nrf2 nuclear translocation while producing no impact on p38MAPK activation or nitric oxide (NO) production. LA pretreatment also increased expression of HO-1, a major target of Nrf2. LA treatment inhibited neutrophil accumulation and release of TNF-α. Moreover, PI3K inhibition abolished the beneficial effects of LA. Conclusions/Significance: This study indicates that LA attenuates cardiac dysfunction by reducing cardiomyoctyes necrosis, apoptosis and inflammation after MI/R. LA exerts its action by activating the PI3K/Akt pathway as well as subsequent Nrf2 nuclear translocation and induction of cytoprotective genes such as HO-1. © 2013 Deng et al.


Zhang H.-M.,PLA Fourth Military Medical University | Zhang Y.,University of Texas Health Science Center at San Antonio
Journal of Pineal Research | Year: 2014

Melatonin (N-acetyl-5-methoxytryptamine), an indoleamine produced in many organs including the pineal gland, was initially characterized as a hormone primarily involved in circadian regulation of physiological and neuroendocrine function. Subsequent studies found that melatonin and its metabolic derivatives possess strong free radical scavenging properties. These metabolites are potent antioxidants against both ROS (reactive oxygen species) and RNS (reactive nitrogen species). The mechanisms by which melatonin and its metabolites protect against free radicals and oxidative stress include direct scavenging of radicals and radical products, induction of the expression of antioxidant enzymes, reduction of the activation of pro-oxidant enzymes, and maintenance of mitochondrial homeostasis. In both in vitro and in vivo studies, melatonin has been shown to reduce oxidative damage to lipids, proteins and DNA under a very wide set of conditions where toxic derivatives of oxygen are known to be produced. Although the vast majority of studies proved the antioxidant capacity of melatonin and its derivatives, a few studies using cultured cells found that melatonin promoted the generation of ROS at pharmacological concentrations (μm to mm range) in several tumor and nontumor cells; thus, melatonin functioned as a conditional pro-oxidant. Mechanistically, melatonin may stimulate ROS production through its interaction with calmodulin. Also, melatonin may interact with mitochondrial complex III or mitochondrial transition pore to promote ROS production. Whether melatonin functions as a pro-oxidant under in vivo conditions is not well documented; thus, whether the reported in vitro pro-oxidant actions come into play in live organisms remains to be established. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.


Qi Y.-P.,Sun Yat Sen University | Li N.,Fujian University of Traditional Chinese Medicine | Niu L.-N.,PLA Fourth Military Medical University | Primus C.M.,Primus Consulting | And 3 more authors.
Acta Biomaterialia | Year: 2012

Fluoride-releasing restorative materials are available for remineralization of enamel and root caries. However, remineralization of dentin is more difficult than remineralization of enamel due to the paucity of apatite seed crystallites along the lesion surface for heterogeneous crystal growth. Extracellular matrix proteins play critical roles in controlling apatite nucleation/growth in collagenous tissues. This study examined the remineralization efficacy of mineral trioxide aggregate (MTA) in phosphate-containing simulated body fluid (SBF) by incorporating polyacrylic acid and sodium tripolyphosphate as biomimetic analogs of matrix proteins for remineralizing caries-like dentin. Artificial caries-like dentin lesions incubated in SBF were remineralized over a 6 week period using MTA alone or MTA containing biomimetic analogs in the absence or presence of dentin adhesive application. Lesion depths and integrated mineral loss were monitored with microcomputed tomography. The ultrastructure of baseline and remineralized lesions was examined by transmission electron microscopy. Dentin remineralization was best achieved using MTA containing biomimetic analogs regardless of whether an adhesive was applied; dentinal tubules within the remineralized dentin were occluded by apatite. It is concluded that the version of MTA employed in this study may be doped with biomimetic analogs for remineralization of unbonded and bonded artificial caries-like lesions in the presence of SBF. © 2011 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.


Li X.-Y.,PLA Fourth Military Medical University | Wu Z.-B.,PLA Fourth Military Medical University | Ding J.,PLA Fourth Military Medical University | Zheng Z.-H.,PLA Fourth Military Medical University | And 3 more authors.
Biochemical and Biophysical Research Communications | Year: 2012

The blood CD4 + CXCR5 + T cells, known as " circulating" Tfh, have been shown to efficiently induce naïve B cells to produce immunoglobulin. They play an important role in certain autoimmune diseases. In the present study, we show for the first time that the frequency of CD4 + CXCR5 + T cells is increased in pSS patients and positively correlated with autoantibodies in the blood. The concentration of Th17-like subsets (CD4 + CXCR5 + CCR6 +) in pSS patients was found to be significantly higher than in healthy controls. Functional assays showed that activated Th17-like subtypes in the blood display the key features of Tfh cells, including invariably coexpressed PD-1, ICOS, CD40L and IL-21. Th17 subsets were found to highly express Bcl-6 protein and Th1 and Th2 were not. Bcl-6 is believed to be a master transforming factor for Tfh cell differentiation and facilitate B cell proliferation and somatic hypermutation within the germinal center. These data indicate that Th17 subsets of CD4 + CXCR5 + T cells in the blood may participate in the antibody-related immune responses and that high frequency of CD4 + CXCR5 + CCR6 + Tfh cells in blood may be suitable biomarkers for the evaluation of the active immune stage of pSS patients. It might provide insights into the pathogenesis and perhaps help researchers identify novel therapeutic targets for pSS. © 2012 Elsevier Inc.


Sun Y.,PLA Fourth Military Medical University | Sun Y.,Thomas Jefferson University | Yi W.,PLA Fourth Military Medical University | Yi W.,Thomas Jefferson University | And 11 more authors.
Circulation | Year: 2013

BACKGROUND - C1q/tumor necrosis factor-related protein-9 (CTRP9) is a newly identified adiponectin paralog with established metabolic regulatory properties. However, the role of CTRP9 in postmyocardial infarction remodeling remains completely unknown. This study determined whether CTRP9 may regulate cardiac remodeling after acute myocardial infarction (AMI) and elucidated the underlying mechanisms. METHODS AND RESULTS - Male adult mice were subject to AMI by left anterior descending coronary artery ligation or sham surgery and treated with saline (vehicle) or globular CTRP9 via peritoneal implant osmotic pumps for 6 weeks. H9C2 cardiac cell lines were used in vitro for determining underlying mechanisms. Adipocyte CTRP9 expression and plasma CTRP9 levels were both significantly reduced after AMI. Compared with vehicle, CTRP9 treatment improved animal survival rate (P<0.05), restored cardiac function (P<0.05), attenuated adverse remodeling (P<0.01), and ameliorated cardiomyocyte apoptosis and fibrosis after AMI (P<0.01). Among the multiple antiremodeling molecules determined, AMP-activated protein kinase, protein kinase A (PKA), and Akt were significantly activated in CTRP9-treated heart. Surprisingly, CTRP9 remains cardioprotective in mice with cardiomyocyte-specific overexpression of a mutant AMP-activated protein kinase α2 subunit (AMPK-DN). Additional in vitro experiments demonstrated that administration of either PKA inhibitor or PKA-specific small interfering RNA virtually abolished the antiapoptotic effect of CTRP9 (P<0.05), whereas inhibition of Akt is less effective in blocking CTRP9 cardioprotection. Finally, CTRP9 phosphorylates BCL-2-associated agonist of cell death at its multiple antiapoptotic sites, an effect blocked by PKA inhibitor. CONCLUSIONS - We demonstrate that adipokine CTRP9 attenuates adverse cardiac remodeling after AMI, largely via a PKA-dependent pathway. © 2013 American Heart Association, Inc.


Bai Y.,Albany Medical College | Bai Y.,PLA Fourth Military Medical University | Yang J.,Albany Medical College | Zarrella T.M.,Albany Medical College | And 3 more authors.
Journal of Bacteriology | Year: 2014

Cyclic di-AMP (c-di-AMP) has been shown to play important roles as a second messenger in bacterial physiology and infections. However, understanding of how the signal is transduced is still limited. Previously, we have characterized a diadenylate cyclase and two c-di-AMP phosphodiesterases in Streptococcus pneumoniae, a Gram-positive pathogen. In this study, we identified a c-di-AMP binding protein (CabP) in S. pneumoniae using c-di-AMP affinity chromatography. We demonstrated that CabP specifically bound c-di-AMP and that this interaction could not be interrupted by competition with other nucleotides, including ATP, cAMP, AMP, phosphoadenylyl adenosine (pApA), and cyclic di-GMP (c-di-GMP). By using a bacterial two-hybrid system and genetic mutagenesis, we showed that CabP directly interacted with a potassium transporter (SPD_0076) and that both proteins were required for pneumococcal growth in media with low concentrations of potassium. Interestingly, the interaction between CabP and SPD_0076 and the efficiency of potassium uptake were impaired by elevated c-di-AMP in pneumococci. These results establish a direct c-di-AMP-mediated signaling pathway that regulates pneumococcal potassium uptake. © 2014, American Society for Microbiology.


Zhang H.,PLA Fourth Military Medical University | Zhang H.,DuPont Company | Wu J.,Xi'an Jiaotong University | Wu J.,DuPont Company | And 5 more authors.
Clinical Science | Year: 2014

AngII (angiotensin II) is a potent neurohormone responsible for cardiac hypertrophy, in which TGF (transforming growth factor)-β serves as a principal downstream mediator. We recently found that ablation of fibulin-2 in mice attenuated TGF-β signalling, protected mice against progressive ventricular dysfunction, and significantly reduced the mortality after experimental MI (myocardial infarction). In the present study, we investigated the role of fibulin-2 in AngII-induced TGF-β signalling and subsequent cardiac hypertrophy. We performed chronic subcutaneous infusion of AngII in fibulin-2 null (Fbln2-/-), heterozygous (Fbln2+/-) and WT (wild-type) mice by a mini-osmotic pump. After 4 weeks of subpressor dosage of AngII infusion (0.2 μg/kg of body weight per min), WT mice developed significant hypertrophy, whereas the Fbln2-/- showed no response. In WT, AngII treatment significantly up-regulated mRNAs for fibulin-2, ANP (atrial natriuretic peptide), TGF-β1, Col I (collagen type I), Col III (collagen type III), MMP (matrix metalloproteinase)-2 and MMP-9, and increased the phosphorylation of TGF-β-downstream signalling markers, Smad2, TAK1 (TGF-β-activated kinase 1) and p38 MAPK (mitogen-activated protein kinase), which were all unchanged in AngII-treated Fbln2-/- mice. The Fbln2+/- mice consistently displayed AngII-induced effects intermediate between WT and Fbln2-/-. Pressor dosage of AngII (2 mg/kg of body weight per min) induced significant fibrosis in WT but not in Fbln2-/- mice with comparable hypertension and hypertrophy in both groups. Isolated CFs (cardiac fibroblasts) were treated with AngII, in which direct AngII effects and TGF-β-mediated autocrine effects was observed in WT. The latter effects were totally abolished in Fbln2-/- cells, suggesting that fibulin-2 is essential for AngII-induced TGF-β activation. In conclusion our data indicate that fibulin-2 is essential for AngII-induced TGF-β-mediated cardiac hypertrophy via enhanced TGF-β activation and suggest that fibulin-2 is a potential therapeutic target to inhibit AngII-induced cardiac remodelling. © 2014 Biochemical Society.


Liu X.,PLA Fourth Military Medical University | Liao Q.,PLA Fourth Military Medical University | Wang H.,University of California at Los Angeles
IEEE Transactions on Biomedical Engineering | Year: 2014

X-ray luminescence computed tomography (XLCT) opens new possibilities to perform molecular imaging with X-ray. However, challenges remain in dynamic XLCT imaging, where short scan time, good spatial resolution, and whole-body field of view should be considered simultaneously. In this paper, by the use of a single-view XLCT reconstruction method based on a compressive sensing (CS) technique, incorporating a cone beam XLCT imaging system, we implement fast 3-D XLCT imaging. To evaluate the performance of the method, two types of phantom experiments were performed based on a cone beam XLCT imaging system. In Case 1, one tube filled with the X-ray-excitable nanophosphor (Gd2O 3 :Eu3+) was immerged in different positions in the phantom to evaluate the effect of the source position on single-view XLCT reconstruction accuracy. In Case 2, two tubes filled with Gd2O 3 :Eu3+ were immerged in different heights in the phantom to evaluate the whole-body imaging performance of single-view XLCT reconstruction. The experimental results indicated that the tubes used in previous phantom experiments can be resolved from single-view XCLT reconstruction images. The location error is less than 1.2 mm. In addition, since only one view data are needed to implement 3-D XLCT imaging, the acquisition time can be greatly reduced (~1 frame/s) compared with previous XLCT systems. Hence, the technique is suited for imaging the fast distribution of the X-ray-excitable nanophosphors within a biological object. © 1964-2012 IEEE.


Niu L.-N.,PLA Fourth Military Medical University | Jiao K.,PLA Fourth Military Medical University | Qi Y.-P.,Sun Yat Sen University | Yiu C.K.Y.,University of Hong Kong | And 6 more authors.
Angewandte Chemie - International Edition | Year: 2011

A biosilicification approach based on infiltration of fluidic choline-stabilized silicic acid precursors into polyallylamine-enriched collagen fibrils is presented. The latter serve as template and catalyst for intrafibrillar polymerization of the silica precursors to reproduce the cross-banding and microfibrillar architecture of collagen fibrils. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Guo Y.,PLA Fourth Military Medical University | Chang H.,PLA Fourth Military Medical University | Li J.,Navy General Hospital | Xu X.-Y.,PLA Fourth Military Medical University | And 3 more authors.
Apoptosis | Year: 2015

Thymosin alpha 1 (Tα1), an immunoactive peptide, has been shown to inhibit cell proliferation and induce apoptosis in human leukemia, non-small cell lung cancer, melanoma, and other human cancers. However, the response and molecular mechanism of breast cancer cells exposed to Tα1 remain unclear. PTEN, a tumor suppressor gene, is frequently mutated in a variety of human cancers. In the present study, we aimed to investigate the biological roles of PTEN in the growth inhibition of human breast cancer cells exposed to Tα1. Using wild-type and mutant PTEN-expressing cells, we found a strong correlation between PTEN status and Tα1-mediated growth inhibition of breast cancer cells. The growth inhibition effect was more pronounced in breast cancer cells in which Tα1 enhanced PTEN expression, whereas endogenous PTEN knockdown reversed the growth inhibition effect of Tα1 in breast cancer cells. Further investigation revealed that PTEN up-regulation, which was induced by Tα1, can inhibit the activation of the PI3K/Akt/mTOR signaling pathway, leading to the growth inhibition of breast cancer cells. The addition of the synergy between Tα1 and the inhibition of PI3K/Akt/mTOR activation could strongly block cell viability in PTEN down-regulated breast cancer cells. PTEN-overexpressing cells not only up-regulated Bax and cleaved caspase-3/9 and PARP expression but also down-regulated Bcl-2 compared to the treatment with Tα1 alone. Together these findings suggest that PTEN mediates Tα1-induced apoptosis through the mitochondrial death cascade and inhibition of the PI3K/Akt/mTOR signaling pathway in breast cancer cells. © 2015 Springer Science+Business Media.


Guo S.-J.,Sun Yat Sen University | Sun Z.-J.,202 Hospital of PLA | Li W.,PLA Fourth Military Medical University
Medical Hypotheses | Year: 2012

Of all men consulted for infertility, around 30% appear to have a varicocele, therefore, this male dysfunction has been considered as a potential cause of infertility in many patients. Emerging studies point out spermatozoa progressive motility as the most important predictor of fertility provided that the analysis was carried out with infertility duration, thus leaving unsolved problem to evaluate the spontaneous testicular damage during the very early phase in varicoceles. Given the deterioration of testicular function caused by varicoceles is progressive, the early and efficient evaluation of testicular damage would be of great importance for the future medical intervention in this population. The resultant mechanism by which varicoceles affect testicular function remains unclear, but the increase in testicular temperature is most commonly accepted aetiology. In this context, we hypothesize that metastasis-associated protein 1 (MTA1), an intrinsic DNA damage response component, possessing transient protective effect in primary spermatocytes against heat stress, bears the potential to be a diagnostic biomarker for the assessment of early testicular damage in varicoceles. The facet that the decrease of MTA1 expression appears much earlier than the beginning of apoptotic wave after heat stress warrants its theoretical rationality and technical accessibility for biochemical application. Basically, MTA1 participates in the maintenance of early apoptotic balance induced by hyperthermal stimulation by elevating the deacetylation level of p53, a master regulator responsible for the initial phase of germ cell apoptosis induced by hyperthermia. These knowledges collectively promote our belief that information from future experiments designed to further study MTA1 during spermatogenesis will provide a scientific basis for the development of a novel biomarker for early diagnosis of testicular detriment in varicoceles, which should lead to improved outcomes in this progressive pathology. © 2012 Elsevier Ltd.


Xing J.,PLA Fourth Military Medical University | Wan S.,Thomas Jefferson University | Zhou F.,PLA Fourth Military Medical University | Qu F.,PLA Fourth Military Medical University | And 7 more authors.
Cancer Epidemiology Biomarkers and Prevention | Year: 2012

Background: Cumulative data have shown that microRNAs (miRNA) are involved in the etiology and prognosis of colorectal cancer (CRC). Genetic polymorphisms in pre-miRNA genes may influence the biogenesis and functions of their host miRNAs. However, whether these polymorphisms are associated with CRC prognosis remains unknown. Methods: Weanalyzed the effects of seven single-nucleotide polymorphisms (SNP) in pre-miRNA genes on the prognosis of a Chinese population with 408 CRC patients with surgically-resected adenocarcinoma. Results: Two SNPs were identified to be significantly associated with recurrence-free survival and overall survival of the patients. The most significant SNP was rs6505162 in pre-miR-423. Compared with the homozygous wild-type genotype, the variant-containing genotypes of this SNP were significantly associated with both the overall survival (HR = 2.12, 95% CI = 1.34-3.34, P = 0.001) and the recurrence-free survival (HR = 1.59, 95% CI = 1.08-2.36, P = 0.019). Another SNP, rs4919510 in pre-miR-608, was also associated with altered recurrence-free survival (HR = 0.61, 95% CI = 0.41-0.92, P = 0.017). These effects were evident only in patients receiving chemotherapy but not in those without chemotherapy. In addition, the combined analysis of the two SNPs conferred a 2.84-fold (95% CI = 1.50-5.37, P = 0.001) increased risk of recurrence and/or death. Similarly, this effect was only prominent in those receiving chemotherapy (P < 0.001) but not in those without chemotherapy (P = 0.999). Conclusions: Our data suggest that genetic polymorphisms in pre-miRNA genes may impact CRC prognosis especially in patients receiving chemotherapy, a finding that warrants further independent validation. Impact: This is one of the first studies showing a prognostic role of pre-miRNA gene SNPs in CRC. ©2011 AACR.


Walsh J.T.,University of Virginia | Zheng J.,University of Virginia | Zheng J.,PLA Fourth Military Medical University | Smirnov I.,University of Virginia | And 3 more authors.
Journal of Immunology | Year: 2014

Previous research investigating the roles of T effector (Teff) and T regulatory (Treg) cells after injury to the CNS has yielded contradictory conclusions, with both protective and destructive functions being ascribed to each of these T cell subpopulations. In this work, we study this dichotomy by examining how regulation of the immune system affects the response to CNS trauma. We show that, in response to CNS injury, Teff and Treg subsets in the CNS-draining deep cervical lymph nodes are activated, and surgical resection of these lymph nodes results in impaired neuronal survival. Depletion of Treg, not surprisingly, induces a robust Teff response in the draining lymph nodes and is associated with impaired neuronal survival. Interestingly, however, injection of exogenous Treg cells, which limits the spontaneous beneficial immune response after CNS injury, also impairs neuronal survival. We found that no Treg accumulate at the site of CNS injury, and that changes in Treg numbers do not alter the amount of infiltration by other immune cells into the site of injury. The phenotype of macrophages at the site, however, is affected: both addition and removal of Treg negatively impact the numbers of macrophages with alternatively activated (tissue-building) phenotype. Our data demonstrate that neuronal survival after CNS injury is impaired when Treg cells are either removed or added. With this exacerbation of neurodegeneration seen with both addition and depletion of Treg, we recommend exercising extreme caution when considering the therapeutic targeting of Treg cells after CNS injury, and possibly in chronic neurodegenerative conditions. © 2014 by The American Association of Immunologists, Inc.


Wei F.,Jilin University | Liu Y.,Academy of Military Medical science | Liu Y.,PLA Fourth Military Medical University | Guo Y.,PLA Fourth Military Medical University | And 4 more authors.
Molecular Cancer | Year: 2013

Background: Radiation exerts direct antitumor effects and is widely used in clinics, but the efficacy is severely compromised by tumor resistance. Therefore uncovering the mechanism of radioresistance might promote the development of new strategies to overcome radioresistance by manipulating activity of the key molecules.Methods: Immunohistochemistry were used to find whether mTOR were over-activated in radioresistant patients' biopsies. Then Western blot, real-time PCR and transfection were used to find whether radiotherapy regulates the expression and activity of mTOR by modulating its targeting microRNA in human pancreatic cancer cell lines PANC-1, Capan-2 and BxPC-3. Finally efficacy of radiation combined with mTOR dual inhibitor AZD8055 was assessed in vitro and in vivo.Results: Ionizing radiation promoted mTOR expression and activation in pancreatic cancer cells through reducing miR-99b expression, which negatively regulated mTOR. Novel mTOR inhibitor, AZD8055 (10 nM, 100 nM, 500 nM) synergistically promoted radiation (0-10 Gy) induced cell growth inhibition and apoptosis. In human pancreatic cancer xenografts, fractionated radiation combined with AZD8055 treatment further increased the anti-tumor effect, the tumor volume was shrinked to 278 mm3 after combination treatment for 3 weeks compared with single radiation (678 mm3) or AZD8055 (708 mm3) treatment (P < 0.01).Conclusions: Our data provide a rationale for overcoming radio-resistance by combined with mTOR inhibitor AZD8055 in pancreatic cancer therapy. © 2013 Wei et al.; licensee BioMed Central Ltd.


Li X.,Tsinghua University | Ye J.,PLA Fourth Military Medical University | Zhou L.,Tsinghua University | Gu W.,Tsinghua University | And 2 more authors.
Journal of Lipid Research | Year: 2012

Regulation of hepatic very low density lipoprotein (VLDL) assembly and maturation is crucial in controlling lipid homeostasis and in the development of metabolic disorders, including obesity, hepatic steatosis, and insulin resistance. Cideb, a member of cell death-inducing DFF45-like effector (CIDE) protein family, has been previously shown to promote VLDL lipidation and maturation. However, the precise subcellular location of Cideb-mediated VLDL lipidation and the factors modulating its activity remain elusive. In addition to its localization to endoplasmic reticulum (ER) and lipid droplets (LD), we observed that Cideb was also localized to the Golgi apparatus. Mature and lipid-rich VLDL particles did not accumulate in the Golgi apparatus in Cideb-/- livers. Interestingly, we observed that hepatic perilipin 2/adipose differentiation-related protein (ADRP) levels were markedly increased in Cideb-/- mice. Liver-specific knockdown of perilipin 2 in Cideb-/- mice resulted in the reduced accumulation of hepatic triglycerides (TAG), increased VLDL-TAG secretion, and the accumulation of mature TAG-rich VLDL in the Golgi apparatus. These data reveal that Cideb and perilipin 2 play opposing roles in controlling VLDL lipidation and hepatic lipid homeostasis. Copyright © 2012 by the American Society for Biochemistry and Molecular Biology, Inc.


Yin T.,PLA Fourth Military Medical University | Hou R.,PLA Fourth Military Medical University | Liu S.,PLA Fourth Military Medical University | Lau W.B.,Thomas Jefferson University | And 2 more authors.
Journal of Molecular and Cellular Cardiology | Year: 2010

Hyperglycemia (HG) significantly increases mortality after myocardial infarction (MI) in patients with and without established diabetes. The specific underlying mechanism remains unknown. The present study attempted to determine whether nitrative inactivation of thioredoxin-1 (Trx-1) may contribute to the exaggerated myocardial ischemia/reperfusion (I/R) injury observed in the hyperglycemic condition. Diabetes was induced by multiple intraperitoneal injections of low-dose streptozotocin (STZ) in mice. After 30. min ischemia by slip-knot ligature of the left anterior descending coronary artery, the myocardium was reperfused for 3. h after knot release (for apoptosis, Trx-1-activity, and -nitration determination) or 24. h (for cardiac function and infarct size determination). At 10 min before reperfusion, diabetic mice were randomized to receive vehicle, EUK134 (a peroxynitrite scavenger), recombinant human Trx-1 (rhTrx-1), or SIN-1 (a peroxynitrite donor) nitrated Trx-1 (N-Trx-1) administration. Diabetes intensified I/R-induced myocardial injury, evidenced by further enlarged infarct size, increased apoptosis, and decreased cardiac function in diabetic mice. Trx-1 nitrative inactivation was elevated in the diabetic heart before I/R and was further amplified after I/R. Treatment with EUK134 or rhTrx-1, but not N-Trx-1, before reperfusion significantly reduced Trx-1 nitration, preserved Trx-1 activity, attenuated apoptosis, reduced infarct size, and improved cardiac function in diabetic mice. Taken together, our results demonstrated that HG increased cardiac vulnerability to I/R injury by enhancing nitrative inactivation of Trx-1, suggesting that blockade of Trx-1 nitration, or supplementation of exogenous rhTrx-1, might represent novel therapies to attenuate cardiac injury after MI in diabetic patients. © 2010 Elsevier Ltd.


Chen M.,PLA Fourth Military Medical University | Sato P.Y.,Temple University | Chuprun J.K.,Temple University | Peroutka R.J.,Temple University | And 6 more authors.
Circulation Research | Year: 2013

RATIONALE: G protein-coupled receptor kinase 2 (GRK2) is abundantly expressed in the heart, and its expression and activity are increased in injured or stressed myocardium. This upregulation has been shown to be pathological. GRK2 can promote cell death in ischemic myocytes, and its inhibition by a peptide comprising the last 194 amino acids of GRK2 (known as carboxyl-terminus of β-adrenergic receptor kinase [bARKct]) is cardioprotective. OBJECTIVE: The aim of this study was to elucidate the signaling mechanism that accounts for the prodeath signaling seen in the presence of elevated GRK2 and the cardioprotection afforded by the carboxyl-terminus of β-adrenergic receptor kinase. METHODS AND RESULTS: Using in vivo mouse models of ischemic injury and also cultured myocytes, we found that GRK2 localizes to mitochondria, providing novel insight into GRK2-dependent pathophysiological signaling mechanisms. Mitochondrial localization of GRK2 in cardiomyocytes was enhanced after ischemic and oxidative stress, events that induced prodeath signaling. Localization of GRK2 to mitochondria was dependent on phosphorylation at residue Ser670 within its extreme carboxyl-terminus by extracellular signal-regulated kinases, resulting in enhanced GRK2 binding to heat shock protein 90, which chaperoned GRK2 to mitochondria. Mechanistic studies in vivo and in vitro showed that extracellular signal-regulated kinase regulation of the C-tail of GRK2 was an absolute requirement for stress-induced, mitochondrial-dependent prodeath signaling, and blocking this led to cardioprotection. Elevated mitochondrial GRK2 also caused increased Ca-induced opening of the mitochondrial permeability transition pore, a key step in cellular injury. CONCLUSIONS: We identify GRK2 as a prodeath kinase in the heart, acting in a novel manner through mitochondrial localization via extracellular signal-regulated kinase regulation. Copyright © 2013 American Heart Association, Inc.


Xiang A.,PLA Fourth Military Medical University | Wei F.,Jilin University | Lei X.,PLA Fourth Military Medical University | Liu Y.,PLA Fourth Military Medical University | Guo Y.,PLA Fourth Military Medical University
European Journal of Clinical Microbiology and Infectious Diseases | Year: 2013

The quantitative measurement of serum hepatitis B surface antigen (HBsAg) is important for monitoring anti-hepatitis B virus (HBV) therapy and evaluating the safety of blood products or blood transfusion. This study is aimed at generating and evaluating a capillary-based chemiluminescence immunoassay for the simple and rapid detection of human serum HBsAg. A simple and rapid capillary chemiluminescence immunoassay (CCIA) was developed using a portable analyzer for quantitatively detecting the levels of HBsAg in human serum. The experimental conditions were optimized, and the sensitivity and specificity of the CCIA were validated in positive HBsAg (HBsAg+) and negative HBsAg (HBsAg-) human sera. The CCIA quantitatively detected the levels of human serum HBsAg at 0.4-15.0 ng/mL, which resulted in dose-dependent increases in the chemiluminescence (CL) signals, with a sensitivity of 0.3 ng/mL. The assay took only 25 min for the analysis of a single sample. The CCIA only detected HBsAg, but not hepatitis C virus (HCV), human immunodeficiency virus-1 (HIV-1) p24, Treponema (TP) antigens, or other serum proteins and lipids tested with a specificity of 100 %. The CCIA for detecting HBsAg was reproducible, with a low intra-assay coefficient of variation (CV) (6.7 %) and inter-assay CV (7.4 %). The validation of 280 known HBsAg+ or HBsAg- clinical serum samples revealed that the CCIA detected 97.5 % of HBsAg+ sera without false-positives, with a sensitivity and specificity similar to that of the Architect i2000SR HBsAg assay (Kappa value = 0.983). The CCIA is a simple and rapid method for quantitatively measuring the levels of serum HBsAg to monitor anti-HBV therapy and evaluate the safety of blood samples for transfusion. © 2013 Springer-Verlag Berlin Heidelberg.


Wu X.,Xiamen University | Zhong D.,PLA Fourth Military Medical University | Gao Q.,Xiamen University | Zhai W.,Xiamen University | And 2 more authors.
International Journal of Medical Sciences | Year: 2013

Aberrant expression of MicroRNAs (miRNAs) has been implicated in several types of cancer. As a direct target gene of p53, miR-34a has been suggested to mediate the tumor suppressor function of p53. Ether à go-go 1 (Eag1) channel is overexpressed in a variety of cancers and plays important roles in cancer progression. However, the link between miR-34a and Eag1 in cancer is unclear. In this study, we used human osteosarcoma as the model to demonstrate that miR-34a was significantly downregulated in osteosarcoma tissues and cell lines compared with normal brain tissues and osteoblastic cell line. Next we evaluated the role of miR-34a in the regulation of osteosarcoma cell proliferation by CCK-8 and colony formation assays. The results showed that overexpression of miR-34a inhibited the proliferation of MG-63 and Saos-2 cells. Furthermore, xenograft nude mice model showed that miR-34a inhibited osteosarcoma growth in vivo. Mechanistically, we found that overexpression of miR-34a led to decreased Eag1 expression in osteosarcoma cells while inhibition of miR-34a increased Eag1 expression. Taken together, our results suggest that miR-34a could inhibit osteosarcoma growth via the down regulation of Eag1 expression. © Ivyspring International Publisher.


Wang H.-B.,Chinese Academy of Sciences | Zhaoa B.,Chinese Academy of Sciences | Zhonga Y.-Q.,Chinese Academy of Sciences | Li K.-C.,Chinese Academy of Sciences | And 10 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2010

Morphine-induced analgesia and antinociceptive tolerance are known to be modulated by interaction between δ-opioid receptors (DORs) and μ-opioid receptors (MORs) in the pain pathway. However, evidence for expression of DORs in nociceptive small-diameter neurons in dorsal root ganglia (DRG) and for coexistence of DORs with MORs and neuropeptides has recently been challenged. We now report, using in situ hybridization, single-cell PCR, and immunostaining, that DORs are widely expressed not only in large DRG neurons but in small ones and coexist with MORs in peptidergic small DRG neurons, with protachykinin-dependent localization in large dense-core vesicles. Importantly, both DOR and MOR agonists reduce depolarization-induced Ca2+ currents in single small DRG neurons and inhibit afferent C-fiber synaptic transmission in the dorsal spinal cord. Thus, coexistence of DORs and MORs in small DRG neurons is a basis for direct interaction of opioid receptors in modulation of nociceptive afferent transmission and opioid analgesia.


Liu X.,PLA Fourth Military Medical University | Luo H.,PLA Fourth Military Medical University | Zhang L.,PLA Fourth Military Medical University | Leung F.W.,Sepulveda Ambulatory Care Center | And 9 more authors.
Gut | Year: 2014

Background Despite advances in bowel preparation methods, the quality of bowel preparation in some patients undergoing colonoscopy remains unsatisfactory. The effect of telephone re-education (TRE) on the day before colonoscopy on the quality of bowel preparation and other outcome measures had not been studied. Methods A prospective colonoscopist-blinded study was conducted. All patients received regular instructions during a visit to discuss colonoscopy. Those scheduled for colonoscopy were randomly assigned to receive TRE on the day before colonoscopy (TRE group) for bowel preparation or no TRE (control group). The primary outcome was the rate of adequate bowel preparation. The secondary outcomes included polyp detection rate (PDR), non-compliance with instructions, and willingness to repeat bowel preparation. Results A total of 605 patients were randomised, 305 to the TRE group and 300 to the control group. In an intention-to-treat analysis of the primary outcome, adequate preparation was found in 81.6% vs 70.3% of TRE and control patients, respectively ( p=0.001). PDR was 38.0% vs 24.7% in the TRE and control group, respectively (p<0.001). Among patients with successful colonoscopy, the Ottawa scores were 3.0±2.3 in the TRE group and 4.9±3.2 in the control group (p<0.001). Fewer patients who showed non-compliance with instructions were found in the TRE group (9.4% vs 32.6%, p<0.001). No significant differences were observed between the two groups with regard to willingness to have a repeat bowel preparation (p=0.409). Conclusions TRE about the details of bowel preparation on the day before colonoscopy significantly improved the quality of bowel preparation and PDR.


Song B.,State University of New York at Stony Brook | Zhang G.,PLA Fourth Military Medical University | Zhu W.,State University of New York at Stony Brook | Liang Z.,State University of New York at Stony Brook
International Journal of Computer Assisted Radiology and Surgery | Year: 2014

Purpose: Computer-aided detection and diagnosis (CAD) of colonic polyps always faces the challenge of classifying imbalanced data. In this paper, three new operating point selection strategies based on receiver operating characteristic curve are proposed to address the problem. Methods: Classification on imbalanced data performs inferiorly because of a major reason that the best differentiation threshold shifts due to the degree of data imbalance. To address this decision threshold shifting issue, three operating point selection strategies, i.e., shortest distance, harmonic mean and anti-harmonic mean, are proposed and their performances are investigated. Results: Experiments were conducted on a class-imbalanced database, which contains 64 polyps in 786 polyp candidates. Support vector machine (SVM) and random forests (RFs) were employed as basic classifiers. Two imbalanced data correcting techniques, i.e., cost-sensitive learning and training data down sampling, were applied to SVM and RFs, and their performances were compared with the proposed strategies. Comparing to the original thresholding method, i.e., 0.488 sensitivity and 0.986 specificity for RFs and 0.526 sensitivity and 0.977 specificity for SVM, our strategies achieved more balanced results, which are around 0.89 sensitivity and 0.92 specificity for RFs and 0.88 sensitivity and 0.90 specificity for SVM. Meanwhile, their performance remained at the same level regardless of whether other correcting methods are used. Conclusions: Based on the above experiments, the gain of our proposed strategies is noticeable: the sensitivity improved from 0.5 to around 0.88 for RFs and 0.89 for SVM while remaining a relatively high level of specificity, i.e., 0.92 for RFs and 0.90 for SVM. The performance of our proposed strategies was adaptive and robust with different levels of imbalanced data. This indicates a feasible solution to the shifting problem for favorable sensitivity and specificity in CAD of polyps from imbalanced data. © 2013 CARS.


Zhu H.,State University of New York at Stony Brook | Fan Y.,State University of New York at Stony Brook | Lu H.,PLA Fourth Military Medical University | Liang Z.,State University of New York at Stony Brook
Physics in Medicine and Biology | Year: 2010

Reducing the number of false positives (FPs) as much as possible is a challenging task for computer-aided detection (CAD) of colonic polyps. As part of a typical CAD pipeline, an accurate and robust process for segmenting initial polyp candidates (IPCs) will significantly benefit the successive FP reduction procedures, such as feature-based classification of false and true positives (TPs). In this study, we introduce an improved scheme for segmenting IPCs. It consists of two main components. One is geodesic distance-based merging, which merges suspicious patches (SPs) for IPCs. Based on the merged SPs, another component, called convex dilation, grows each SP beyond the inner surface of the colon wall to form a volume of interest (VOI) for that IPC, so that the inner border of the VOI beyond the colon inner surface could be segmented as convex, as expected. The IPC segmentation strategy was evaluated using a database of 50 patient studies, which include 100 scans at supine and prone positions with 84 polyps and masses sized from 6 to 35 mm. The presented IPC segmentation strategy (or VOI extraction method) demonstrated improvements, in terms of having no undesirably merged true polyp and providing more helpful mean and variance of the image intensities rooted from the extracted VOI for classification of the TPs and FPs, over two other VOI extraction methods (i.e. the conventional method of Nappi and Yoshida (2003 Med. Phys. 30 1592-601) and our previous method (Zhu et al 2009 Cancer Manag. Res. 1 1-13). At a by-polyp sensitivity of 0.90, these three methods generated the FP rate (number of FPs per scan) of 4.78 (new method), 6.37 (Nappi) and 7.01 (Zhu) respectively. © 2010 Institute of Physics and Engineering in Medicine.


Liang Y.,PLA Fourth Military Medical University | Dong Y.,463 Hospital of PLA | Zhao J.,PLA Fourth Military Medical University | Li W.,PLA Fourth Military Medical University
Biology of Reproduction | Year: 2013

Deregulated expression of protein tyrosine phosphorylation has been implicated in testicular response to different stimuli. Herein, YES1, a nonreceptor protein tyrosine kinase, was found to be significantly up-regulated in pachytene spermatocytes (PS) during early recovery from a transient testicular heat stress. Coculture of PS with Sertoli cells (SCs) could enhance the hyperthermia-induced YES1 activation, indicative of a positive regulation of the paracrine signaling. Moreover, SU6656, a selective YES1 inhibitor, was shown to effectively block YES1 activity, thereafter resulting in a dramatic increase of heat stressinduced apoptosis in primary cultured PS. Mechanistically, the antiapoptotic effect of YES1 activation in response to testicular heat insult may mediate via the regulation of extracellular signal-regulated kinase (ERK)/metastasis-associated 1 (MTA1) cascade. From a clinical standpoint, a notably higher level of YES1 expression was observed in the pathological testis from varicocele patients as compared to a negligible staining in the control group. Taken together, our present results provide the first evidence that the YES1/ERK/MTA1/p53 cascade may serve as a naturally occurring, indispensable self-defensive mechanism maintaining apoptotic balance during meiotic heat stress. Our study may have also partially answered the question of how activation of signal pathways at the cell membrane surface interacts with the key regulatory events occurring in the nucleus during testicular heat shock. © 2013 by the Society for the Study of Reproduction, Inc.


Zhu H.,State University of New York at Stony Brook | Fan Y.,State University of New York at Stony Brook | Lu H.,PLA Fourth Military Medical University | Liang Z.,State University of New York at Stony Brook
Academic Radiology | Year: 2011

Rationale and Objectives: Current schemes for computer-aided detection (CAD) of colon polyps usually use kernel methods to perform curvature-based shape analysis. However, kernel methods may deliver spurious curvature estimations if the kernel contains two surfaces, because of the vanished gradient magnitudes. The aim of this study was to use the Knutsson mapping method to deal with the difficulty of providing better curvature estimations and to assess the impact of improved curvature estimation on the performance of CAD schemes. Materials and Methods: The new method was compared to two widely used kernel methods in terms of the performance of two stages of CAD: initial detection and true-positive and false-positive classification. The evaluation was conducted on a database of 130 computed tomographic scans from 67 patients. In these patient scans, there were 104 clinically significant polyps and masses >5 mm. Results: In the initial detection stage, the detection sensitivity of the three methods was comparable. In the classification stage, at a 90% sensitivity level on the basis of the input of this step, the new technique yielded 3.15 false-positive results per scan, demonstrating reductions in false-positive findings of 30.2% (P < .01) and 27.9% (P < .01) compared to the two kernel methods. Conclusions: The new method can benefit CAD schemes with reduced false-positive rates, without sacrificing detection sensitivity. © 2011 AUR.


Koga K.,Xi'an University of Science and Technology | Koga K.,University of Toronto | Descalzi G.,University of Toronto | Chen T.,Xi'an University of Science and Technology | And 13 more authors.
Neuron | Year: 2015

Chronic pain can lead to anxiety and anxiety canenhance the sensation of pain.[U+3000]Unfortunately, little is known about the synaptic mechanisms that mediate these re-enforcing interactions. Here we characterized two forms of long-term potentiation (LTP) in the anterior cingulate cortex (ACC); a presynaptic form (pre-LTP) that requires kainate receptors and a postsynaptic form (post-LTP) that requires N-methyl-D-aspartate receptors. Pre-LTP also involves adenylyl cyclase and protein kinase A and is expressed via a mechanism involving hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Interestingly, chronic pain and anxiety both result in selective occlusion of pre-LTP. Significantly, microinjection of the HCN blocker ZD7288 into the ACC invivo produces both anxiolytic and analgesic effects. Our results provide a mechanism by which two forms of LTP in the ACC may converge to mediate the interaction between anxiety and chronic pain. © 2015 Elsevier Inc.


Sun B.,Beihua University | Pu B.,222nd Hospital of PLA | Chu D.,PLA Fourth Military Medical University | Chu X.,Beihua University | And 2 more authors.
Journal of Neuro-Oncology | Year: 2013

MicroRNAs are known as non-coding RNAs that regulate the expression of target mRNA. Accumulating evidence has indicated that microRNA expression in human malignancies can be utilized as a prognostic marker for patients. However, the prognostic value of miR-650 in human glioma has not been investigated yet. In the present investigation, we have recruited 168 cases glioma specimens and 21 normal control brain specimens. Quantitative real-time PCR was carried out to investigate the expression of miR-650. Kaplan-Meier analysis and Cox's proportional hazards model was used to evaluate the association of miR-650 with prognosis of glioma patients. Results showed that miR-650 expression was increased in glioma compared with normal control specimens (P < 0.001). It was also found that miR-650 expression was related to World Health Organization grade and Karnofsky performance score (KPS) for high expression was more frequently detected in glioma of high grade or low KPS score (P < 0.001). The prognosis of glioma with high miR-650 expression was significantly worse compared with that of glioma with low miR-650 expression. These results proved that miR-650 expression was a significant prognostic indicator in glioma, which may suggest new management of human glioma. © 2013 Springer Science+Business Media New York.


Wang C.,Fudan University | Liu F.,Fudan University | Liu Y.-Y.,PLA Fourth Military Medical University | Zhao C.-H.,PLA Fourth Military Medical University | And 10 more authors.
Cell Research | Year: 2011

It is of great interest to identify new neurons in the adult human brain, but the persistence of neurogenesis in the subventricular zone (SVZ) and the existence of the rostral migratory stream (RMS)-like pathway in the adult human forebrain remain highly controversial. In the present study, we have described the general configuration of the RMS in adult monkey, fetal human and adult human brains. We provide evidence that neuroblasts exist continuously in the anterior ventral SVZ and RMS of the adult human brain. The neuroblasts appear singly or in pairs without forming chains; they exhibit migratory morphologies and co-express the immature neuronal markers doublecortin, polysialylated neural cell adhesion molecule and ΒIII-tubulin. Few of these neuroblasts appear to be actively proliferating in the anterior ventral SVZ but none in the RMS, indicating that neuroblasts distributed along the RMS are most likely derived from the ventral SVZ. Interestingly, no neuroblasts are found in the adult human olfactory bulb. Taken together, our data suggest that the SVZ maintains the ability to produce neuroblasts in the adult human brain. © 2011 IBCB, SIBS, CAS All rights reserved.


Pan Y.,PLA Fourth Military Medical University | Gao Y.,PLA Fourth Military Medical University | Chen L.,PLA Fourth Military Medical University | Chen L.,Xi'an University of Science and Technology | And 5 more authors.
Clinical Cancer Research | Year: 2011

Purpose: Although autophagy occurs in most tumor cells following DNA damage, it is still a mystery how this DNA-damaging event turns on the autophagy machinery in multiple myeloma (MM) and how the functional status of autophagy impacts on its susceptibility to death in response to DNA-damaging chemotherapy. Experimental Design: We investigate the effects of DNA damage on autophagy in MM cells and elucidate its underlying molecular mechanism. Then, we examined the impacts of pharmacologic or genetic inhibition of autophagy on DNA damage-induced apoptosis. Furthermore, the antimyeloma activity of autophagy inhibitor in combination with DNA-damaging agents was evaluated inMMxenograft models. Results: We showed that DNA-damaging drugs, doxorubicin and melphalan, induce caspase-dependent apoptosis and concurrently trigger Beclin 1-regulated autophagy in human MM cell lines H929 and RPMI 8226. Mechanistically, association of autophagy execution proteins Beclin 1 with class III phosphoinositide 3-kinase, which is inhibited by Bcl-2 recruitment, contributes directly to the autophagic process. Importantly, targeting suppression of autophagy by minimally toxic concentrations of pharmacologic inhibitors (hydroxychloroquine and 3-methyladenine) or short hairpin RNAs against autophagy genes, Beclin 1 and Atg5, dramatically augments proapoptotic activity of DNA-damaging chemotherapy both in vitro using MM cell lines or purified patient MM cells and in vivo in a human plasmacytoma xenograft mouse model. Conclusion: These data can help unravel the underlying molecular mechanism of autophagy in DNA-damaged MM cells and also provide a rationale for clinical evaluation of autophagy inhibitors in combination with DNA-damaging chemotherapy in MM. ©2011 AACR.


Zhang L.,PLA Fourth Military Medical University | Zhang L.,406 Hospital | Zhang H.-Q.,Xi'an University of Science and Technology | Liang X.-Y.,PLA Fourth Military Medical University | And 3 more authors.
Behavioural Brain Research | Year: 2013

Sleep deprivation (SD) has been shown to induce oxidative stress which causes cognitive impairment. Melatonin, an endogenous potent antioxidant, protects neurons from oxidative stress in many disease models. The present study investigated the effect of melatonin against SD-induced cognitive impairment and attempted to define the possible mechanisms involved. SD was induced in rats using modified multiple platform model. Melatonin (15. mg/kg) was administered to the rats via intraperitoneal injection. The open field test and Morris water maze were used to evaluate cognitive ability. The cerebral cortex (CC) and hippocampus were dissected and homogenized. Nitric oxide (NO) and malondialdehyde (MDA) levels and the superoxide dismutase (SOD) enzyme activity of hippocampal and cortical tissues (10% wet weight per volume) were performed to determine the level of oxidative stress. The expression of brain-derived neurotrophic factor (BDNF) and calcium-calmodulin dependent kinase II (CaMKII) proteins in CC and hippocampus was assayed by means of immunohistochemistry. The results revealed that SD impairs cognitive ability, while melatonin treatment prevented these changes. In addition, melatonin reversed SD-induced changes in NO, MDA and SOD in both of the CC and hippocampus. The results of immunoreactivity showed that SD decreased gray values of BDNF and CaMKII in CC and hippocamal CA1, CA3 and dentate gyrus regions, whereas melatonin improved the gray values. In conclusion, our results suggest that melatonin prevents cognitive impairment induced by SD. The possible mechanism may be attributed to its ability to reduce oxidative stress and increase the levels of CaMKII and BDNF in CC and hippocampus. © 2013 Elsevier B.V.


Tang Y.,Xi'an University of Science and Technology | Zhao K.,Xi'an University of Science and Technology | Hu L.,Xi'an University of Science and Technology | Wu Z.,PLA Fourth Military Medical University
Ceramics International | Year: 2013

Hydroxyapatite (HA) porous scaffolds with bionic bone graded structure were fabricated by a two-step freeze casting. The phase, porosity, pore morphology, and compressive strength of the fabricated HA scaffolds were characterised. The HA scaffolds did not decompose after sintering at 1250 C. The porosity of the inside and outside of the graded-porosity HA scaffolds was controlled by adjusting the initial HA content of the casting slurries. Cylindrical HA scaffolds with a radially aligned porosity gradient from the inside (highly porous) to the outside (less porous) were prepared, and a natural transition was found at the interface because partial melting-recrystallization occurred between the two sides. The compressive strength of the graded HA scaffolds depended on the porosity of the inner part. A compressive strength of 22.2±4.1 MPa was achieved at an average porosity of 42.3% and outer thickness of about 2 mm. © 2013 Elsevier Ltd and Techna Group S.r.l.


Qu X.,Xi'an University of Science and Technology | Shen L.,PLA Fourth Military Medical University | Zheng Y.,Xi'an Jiaotong University | Cui Y.,Xi'an University of Science and Technology | And 3 more authors.
Journal of Investigative Dermatology | Year: 2014

Both SKP2 (S-phase kinase-associated protein 2) and transforming growth factor-β1 (TGF-β1) play important roles in cancer metastasis through different mechanisms: TGF-β1 via induction of epithelial-mesenchymal transition (EMT) and SKP2 via downregulating p27kip1. Recent studies indicated that c-Myc and Akt1 were active players in metastasis. In this study we demonstrated a crosstalk between these pathways. Specifically, we found that TGF-β1 treatment increased SKP2 expression accompanied with increased phosphorylation of Akt1 and c-Myc protein accumulation during EMT. We demonstrated that Akt1 was required for TGF-β1-mediated SKP2 upregulation and that c-Myc transcription factor specifically bound to the promoter of SKP2 for its enhanced transcription. Analysis of 25 samples of normal human skin, nevi, and melanomas revealed a positive correlation between c-Myc and SKP2 accumulation. Furthermore, accumulation of SKP2 and c-Myc proteins was significantly higher in metastatic melanoma samples as compared with that in primary melanomas, which again was higher than that in normal skin or nevi. In summary, our results integrated TGF-β1 signals to SKP2 via Akt1 and c-Myc during EMT, and provided, to our knowledge, a previously unreported mechanistic molecular event for TGF-β1-induced metastasis in human melanoma. © 2014 The Society for Investigative Dermatology.


Liu Z.,Chinese Institute of Basic Medical Sciences | Wang H.,Chinese Institute of Basic Medical Sciences | Wang Y.,Chinese Institute of Basic Medical Sciences | Lin Q.,Chinese Institute of Basic Medical Sciences | And 7 more authors.
Biomaterials | Year: 2012

One challenge of cellular cardiomyoplasty for myocardial infarction (MI) is how to improve MI microenvironment to facilitate stem cell engraftment, survival and homing for myocardial repair. The application of injectable hydrogels is an effective strategy. However, it has not been thoroughly investigated on the role of the injectable scaffolds, in improving MI microenvironment, providing space and guidance for cell survival, engraftment and homing. We explored an injectable chitosan hydrogel for stem cell delivery into ischemic heart and investigated the beneficial effects and mechanisms of the hydrogel. Invitro, H 2O 2-treatment was used to mimic reactive oxygen species (ROS) microenvironment. The influence of ROS and protection of chitosan components on adipose-derived mesenchymal stem cells (ADSCs) was analyzed too. Invivo, MI was induced by the left anterior descending artery ligation in SD rats. PBS, chitosan hydrogel, ADSC/PBS and ADSC/chitosan hydrogel were injected into the border of infracted hearts respectively. Multi-techniques were used to assess the beneficial effects of chitosan hydrogel after transplantation. We observed that ROS generated by ischemia would impair ADSC adhesion molecules, including integrin-related adhesion molecules integrin αV and β1, focal adhesion-related molecules p-FAK and p-Src, and corresponding ligands of host myocardium ICAM1 and VCAM1. Chitosan hydrogel could rescue these molecules through ROS scavenging and recruit key chemokine for stem cell homing, such as SDF-1. The results suggest that chitosan hydrogel could improve MI microenvironment, enhance stem cell engraftment, survival and homing in ischemic heart through ROS scavenging and chemokine recruitment, contributing to myocardial repair. © 2011 Elsevier Ltd.


Liu Y.,State University of New York at Stony Brook | Liang Z.,State University of New York at Stony Brook | Ma J.,Southern Medical University | Lu H.,PLA Fourth Military Medical University | And 3 more authors.
IEEE Transactions on Medical Imaging | Year: 2014

Previous studies have shown that by minimizing the total variation (TV) of the to-be-estimated image with some data and/or other constraints, a piecewise-smooth X-ray computed tomography image can be reconstructed from sparse-view projection data. However, due to the piecewise constant assumption for the TV model, the reconstructed images are frequently reported to suffer from the blocky or patchy artifacts. To eliminate this drawback, we present a total variation-stokes-projection onto convex sets (TVS-POCS) reconstruction method in this paper. The TVS model is derived by introducing isophote directions for the purpose of recovering possible missing information in the sparse-view data situation. Thus the desired consistencies along both the normal and the tangent directions are preserved in the resulting images. Compared to the previous TV-based image reconstruction algorithms, the preserved consistencies by the TVS-POCS method are expected to generate noticeable gains in terms of eliminating the patchy artifacts and preserving subtle structures. To evaluate the presented TVS-POCS method, both qualitative and quantitative studies were performed using digital phantom, physical phantom and clinical data experiments. The results reveal that the presented method can yield images with several noticeable gains, measured by the universal quality index and the full-width-at-half-maximum merit, as compared to its corresponding TV-based algorithms. In addition, the results further indicate that the TVS-POCS method approaches to the gold standard result of the filtered back-projection reconstruction in the full-view data case as theoretically expected, while most previous iterative methods may fail in the full-view case because of their artificial textures in the results. © 1982-2012 IEEE.


Chen T.,Xi'an University of Science and Technology | Chen T.,PLA Fourth Military Medical University | Lu J.-S.,Xi'an University of Science and Technology | Song Q.,Xi'an University of Science and Technology | And 8 more authors.
Neuropsychopharmacology | Year: 2014

Fragile X syndrome, caused by the mutation of the Fmr1 gene, is characterized by deficits of attention and learning ability. In the hippocampus of Fmr1 knockout mice (KO), long-term depression is enhanced whereas long-term potentiation (LTP) including late-phase LTP (L-LTP) is reduced or unaffected. Here we examined L-LTP in the anterior cingulate cortex (ACC) in Fmr1 KO mice by using a 64-electrode array recording system. In wild-type mice, theta-burst stimulation induced L-LTP that does not occur in all active electrodes/channels within the cingulate circuit and is typically detected in ∼75% of active channels. Furthermore, L-LTP recruited new responses from previous inactive channels. Both L-LTP and the recruitment of inactive responses were blocked in the ACC slices of Fmr1 KO mice. Bath application of metabotropic glutamate receptor 5 (mGluR5) antagonist or glycogen synthase kinase-3 (GSK3) inhibitors rescued the L-LTP and network recruitment. Our results demonstrate that loss of FMRP will greatly impair L-LTP and recruitment of cortical network in the ACC that can be rescued by pharmacological inhibition of mGluR5 or GSK3. This study is the first report of the network properties of L-LTP in the ACC, and provides basic mechanisms for future treatment of cortex-related cognitive defects in fragile X patients. © 2014 American College of Neuropsychopharmacology. All rights reserved.


Wu H.,Northeastern University | Wu H.,PLA Fourth Military Medical University | Zhu L.,Northeastern University | Torchilin V.P.,Northeastern University
Biomaterials | Year: 2013

To introduce pH sensitivity into the DSPE-PEG-based micellar system and achieve the quick intracellular drug release in response to the acidity in endosomes, a mixed polymeric micelle was developed based on three grafted copolymers, including 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-polyethylene glycol-2000(DSPE-PEG2000), antinucleosome antibody (mAb 2C5)-modified DSPE-PEG3400 (DSPE-PEG3400-2C5), and poly(ethylene glycol)-coupled poly(l-histidine) (PHIS-PEG2000). The structure of PHIS-PEG2000 was confirmed by 1H NMR spectroscopy. The mixed micelles with the diameter ranging from 110 to 135 nm were prepared using a dialysis method against pH 7.6 PBS. Paclitaxel (PCT) was used as a model drug, the encapsulation efficiency and loading content of PCT were 88% and 5%, respectively. The mixed micelles composed with 50wt% of PHIS-PEG2000 showed the desired pH-dependent drug release property with much faster drug release than micelles without PHIS-PEG2000. At pH around 5.5, about 75-95% of the loaded drug was released within 2 h. The MTT assay showed PCT-loaded mixed micelles had higher cytotoxicity at pH 5.8 than that at pH 7.4. Further modification of the mixed micelles with anti-cancer nucleosome-specific monoclonal antibody 2C5 significantly increased their cellular uptake efficiency and cytotoxicity. Thus, the low pH in endosomes could trigger the PCT release from the pH-sensitive mixed micelles after 2C5-mediated endocytosis. The results of this study suggest that the mixed micelles (DSPE-PEG2000/DSPE-PEG3400-2C5/PHIS-PEG2000) could enhance the tumor cell-specific internalization and trigger the quick drug release, resulting in the improved anti-cancer efficacy. © 2012 Elsevier Ltd.


Wang Z.,General Hospital of PLA | Fu S.,Guangzhou Military Area General Hospital | Wu Z.-X.,PLA Fourth Military Medical University | Zhang Y.,PLA Fourth Military Medical University | Lei W.,PLA Fourth Military Medical University
Spine | Year: 2013

STUDY DESIGN.: A finite element analysis was used. OBJECTIVE.: To evaluate the feasibility of using the Ti-24Nb-4Zr-7.9Sn (Ti2448) pedicle screw system to augment single-level posterior lumbar interbody fusion (PLIF). SUMMARY OF BACKGROUND DATA.: The Ti-6Al-4V pedicle screw system increases the risk of adjacent disc degeneration and stress-shielding effect due to enormous rigidity. A titanium alloy with much lower elastic modulus, Ti2448, may help to resolve the complications. METHODS.: A finite element model of intact L3-S1 was established and then validated. Single-level PLIF at L4-L5 with or without a supplementary titanium-alloy pedicle screw system was simulated. A pure moment of 7.6 Nm and a 400 N preload was applied to the finite element model of PLIF, PLIF with the Ti-6Al-4V screw system, and PLIF with the Ti2448 screw system in flexion, extension, axial rotation, and lateral bending. RESULTS.: The axial displacement at the fusion level decreased to 64%, 72%, 84%, and 92% of screw-free status in flexion, extension, axial rotation, and lateral bending, respectively, after augmentation of the Ti2448 screw system, which was 1% to 3% lower than the performance of the Ti-6Al-4V system. The angular displacement at the fusion level with the Ti2448 system was similar to that of the Ti-6Al-4V system, only 2% lower in flexion. Compared with the Ti-6Al-4V system, the Ti2448 system suppressed the increase of intradiscal pressures at the upper adjacent disc in all bending directions, but only in extension and axial rotation at the lower adjacent disc; the maximum stress experienced by cages and screws was higher in all bending directions when augmented with the Ti2448 system. CONCLUSION.: Using the Ti2448 screw system is suggested for augmenting single-level PLIF because it induces less disc intradiscal pressure at adjacent levels and the stress-shielding effect at implant-bone surface with stabilization performance compared with the Ti-6Al-4V screw system. © 2013, Lippincott Williams & Wilkins.


Xu R.,Xi'an University of Science and Technology | Xu R.,PLA Fourth Military Medical University | Feng X.,PLA Fourth Military Medical University | Xie X.,Northwest University, China | And 3 more authors.
Brain Research | Year: 2012

Brain homeostasis is maintained by the blood-brain barrier (BBB), which prevents the entrance of circulating molecules and immune cells into the central nervous system. The BBB is formed by specialized brain endothelial cells that are connected by tight junctions (TJ). Previous studies have proven that the Tat protein of human immunodeficiency virus type 1 (HIV-1) alters TJ protein expression. However, the mechanisms by which the alterations occur have not been characterized in detail. In this study, primary human brain microvascular endothelial cells (HBMEC) were exposed to recombinant HIV-1 Tat protein, and the effects on occludin were observed. Tat treatment decreased occludin mRNA and protein levels. This effect was partially abrogated by addition of the RhoA inhibitor C3 exoenzyme and the p160-Rho-associated coiled kinase (ROCK) inhibitor Y-27632. Meanwhile, Tat also induced MMP-9 expression. RNA interference targeting MMP-9 reduced both the paracellular permeability of Tat-treated HBMEC and the concentration of soluble occludin in supernatants from the cells. Taken together, these results show that the HIV-1 Tat protein disrupts BBB integrity, at least in part by decreasing the production of occludin. © 2011 Elsevier B.V. All rights reserved.


Dong J.,PLA Fourth Military Medical University | Cui G.,General Hospital of PLA | Bi L.,PLA Fourth Military Medical University | Li J.,General Hospital of PLA | Lei W.,PLA Fourth Military Medical University
International Journal of Nanomedicine | Year: 2013

In order to improve the mechanical and biological properties of calcium phosphate cement (CPC, nanometer-biomaterial) for bone reconstruction in the rabbit femoral defect model, fibrin glue (FG, the natural product, purified from the blood) was introduced at three different ratios. The CPC powder and the FG solution were mixed, respectively, at the powder/liquid (P/L) ratios (g/mL) of 1:1, 3:1, and 5:1 (g/mL), and pure CPC was used as a control. After being implanted into the femoral defect in rabbit, the healing process was evaluated by micro-computed tomography scan, biomechanical testing, and histological examination. By micro-computed tomography analysis, the P/L ratio of 1:1 (g/mL) group indicated the largest quantity of new bone formation at 4 weeks, 8 weeks, and 12 weeks after implantation, respectively. Bone volume per trabecular volume of the 1:1 group was highest in the four groups, which was 1.45% ± 0.42%, 7.35% ± 1.45%, and 29.10% ± 1.67% at 4 weeks, 8 weeks, and 12 weeks after the operation, respectively. In the biomechanical tests, the compressive strength and the elastic modulus of the three CPC-FG groups were much higher than those of the pure CPC group at the determined time point (P < 0.05). The histological evaluation also showed the best osseointegration in the 1:1 group at 4 weeks, 8 weeks, and 12 weeks after the operation, respectively. In the 1:1 group, the bone grew into the pore of the cement in the laminar arrangement and connected with the cement tightly at the 12th week after the operation. This present study indicated that the CPC-FG composite at the P/L ratio of 1:1 (g/mL) stimulated bone regeneration better than any other designed group, which suggested that CPC-FG at the P/L ratio of 1:1 has significant potential as the bioactive material for the treatment of bone defects. © 2013 Dong et al, publisher and licensee Dove Medical Press Ltd.


Si Y.,Hospital 309 of PLA | Wang J.,General Hospital of PLA | Guan J.,Hospital 309 of PLA | Han Q.,Hospital 309 of PLA | Hui Y.,PLA Fourth Military Medical University
Journal of Ocular Pharmacology and Therapeutics | Year: 2013

Purposes: (1) To evaluate the association between expression of α-smooth muscle actin (α-SMA) in proliferative vitreoretinopathy (PVR) and the pathological grading of PVR, and the effect of platelet-derived growth factor (PDGF) on the expression of α-SMA by human retinal pigment epithelial (RPE) cells. (2) To investigate the potential induction of PDGF on the proliferation and migration of human RPE cells as well as the signaling pathways responsible. Methods: We immunohistochemically investigated the expression of α-SMA in PVR. To further investigate the effect of PDGF and the downstream signaling, exogenous PDGF-BB and signaling inhibitors were added to cultured human RPE cells. The MTT method was performed to detected cell proliferation, while cell migration was also measured. Results: α-SMA expression was positively correlated with the pathological grading of PVR. PDGF-BB could stimulate the proliferation and migration of cultured RPE cells through the participation of mitogen-activated protein kinase. In addition, PDGF induced α-SMA expression. The promotion of proliferate/migration and α-SMA expression by PDGF-BB was enhanced by the presence of serum. Conclusions: PDGF and α-SMA are 2 potential therapeutic targets for the treatment of PVR. © Copyright 2013, Mary Ann Liebert, Inc. 2013.


Ma J.,State University of New York at Stony Brook | Ma J.,Southern Medical University | Liang Z.,State University of New York at Stony Brook | Fan Y.,State University of New York at Stony Brook | And 4 more authors.
Medical Physics | Year: 2012

Purpose: Low-dose x-ray computed tomography (CT) is clinically desired. Accurate noise modeling is a fundamental issue for low-dose CT image reconstruction via statistics-based sinogram restoration or statistical iterative image reconstruction. In this paper, the authors analyzed the statistical moments of low-dose CT data in the presence of electronic noise background. Methods: The authors first studied the statistical moment properties of detected signals in CT transmission domain, where the noise of detected signals is considered as quanta fluctuation upon electronic noise background. Then the authors derived, via the Taylor expansion, a new formula for the mean-variance relationship of the detected signals in CT sinogram domain, wherein the image formation becomes a linear operation between the sinogram data and the unknown image, rather than a nonlinear operation in the CT transmission domain. To get insight into the derived new formula by experiments, an anthropomorphic torso phantom was scanned repeatedly by a commercial CT scanner at five different mAs levels from 100 down to 17. Results: The results demonstrated that the electronic noise background is significant when low-mAs (or low-dose) scan is performed. Conclusions: The influence of the electronic noise background should be considered in low-dose CT imaging. © 2012 American Association of Physicists in Medicine.


Ma J.,Southern Medical University | Ma J.,State University of New York at Stony Brook | Huang J.,Southern Medical University | Feng Q.,Southern Medical University | And 4 more authors.
Medical Physics | Year: 2011

Purpose: In current computed tomography (CT) examinations, the associated x-ray radiation dose is of a significant concern to patients and operators. A simple and cost-effective means to perform the examinations is to lower the milliampere-seconds (mAs) or kVp parameter (or delivering less x-ray energy to the body) as low as reasonably achievable in data acquisition. However, lowering the mAs parameter will unavoidably increase data noise and the noise would propagate into the CT image if no adequate noise control is applied during image reconstruction. Since a normal-dose high diagnostic CT image scanned previously may be available in some clinical applications, such as CT perfusion imaging and CT angiography (CTA), this paper presents an innovative way to utilize the normal-dose scan as a priori information to induce signal restoration of the current low-dose CT image series.Methods: Unlike conventional local operations on neighboring image voxels, nonlocal means (NLM) algorithm utilizes the redundancy of information across the whole image. This paper adapts the NLM to utilize the redundancy of information in the previous normal-dose scan and further exploits ways to optimize the nonlocal weights for low-dose image restoration in the NLM framework. The resulting algorithm is called the previous normal-dose scan induced nonlocal means (ndiNLM). Because of the optimized nature of nonlocal weights calculation, the ndiNLM algorithm does not depend heavily on image registration between the current low-dose and the previous normal-dose CT scans. Furthermore, the smoothing parameter involved in the ndiNLM algorithm can be adaptively estimated based on the image noise relationship between the current low-dose and the previous normal-dose scanning protocols.Results: Qualitative and quantitative evaluations were carried out on a physical phantom as well as clinical abdominal and brain perfusion CT scans in terms of accuracy and resolution properties. The gain by the use of the previous normal-dose scan via the presented ndiNLM algorithm is noticeable as compared to a similar approach without using the previous normal-dose scan.Conclusions: For low-dose CT image restoration, the presented ndiNLM method is robust in preserving the spatial resolution and identifying the low-contrast structure. The authors can draw the conclusion that the presented ndiNLM algorithm may be useful for some clinical applications such as in perfusion imaging, radiotherapy, tumor surveillance, etc. © 2011 American Association of Physicists in Medicine.


Qi X.,General Hospital of Shenyang Military Command | Wang D.,PLA Fourth Military Medical University | Su C.,PLA Fourth Military Medical University | Li H.,General Hospital of Shenyang Military Command | Guo X.,General Hospital of Shenyang Military Command
Oncotarget | Year: 2015

Background&Aims: According to the Barcelona Clinic Liver Cancer (BCLC) staging system, hepatic resection and transarterial chemoembolization (TACE) should be recommended in patients with hepatocellular carcinoma (HCC) within and beyond the BCLC stage A, respectively. We conducted a systematic review and meta-analysis to compare the overall survival between HCC patients undergoing hepatic resection and TACE. Methods: PubMed, EMBASE, and Cochrane library databases were searched. All relevant studies were considered, if they reported the survival data in HCC patients undergoing hepatic resection and TACE. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated for the comparison of cumulative overall survival. Odds ratios (ORs) with 95%CIs were calculated for the comparison of 1-, 3-, and 5-year survival rates. Subgroup analyses were performed according to the BCLC stages and portal vein tumor thrombus (PVTT). Sensitivity analyses were performed in moderate- and high-quality studies and in studies published after 2005. Results: Fifty of 2029 retrieved papers were included. One, 15, and 34 studies were of high-, moderate-, and low-quality, respectively. The overall meta-analysis demonstrated a statistically significantly higher overall survival in hepatic resection group than in TACE group (HR=0.60, 95%CI=0.55-0.66). Additionally, 1-, 3-, and 5-year survival rates were statistically significantly higher in hepatic resection group than in TACE group (OR=1.82, 95%CI=1.56-2.14; OR=3.09, 95%CI=2.60-3.67; OR=3.48, 95%CI=2.83-4.27). The subgroup meta-analyses confirmed the statistical significance in HCC within the BCLC stage A (HR=0.72, 95%CI=0.64-0.80), in HCC beyond the BCLC stage A (HR=0.60, 95%CI=0.51-0.69), in HCC within the BCLC stage B alone (HR=0.48, 95%CI=0.25-0.90), and in HCC with PVTT (HR=0.78, 95%CI=0.68-0.91). The statistical significance was also confirmed by sensitivity analyses in moderate- and high-quality studies (HR=0.62, 95%CI=0.53-0.71) and in studies published after 2005 (HR=0.59, 95%CI=0.53-0.66). Conclusions: Based on a systematic review and meta-analysis, hepatic resection may be considered in HCC beyond the BCLC stage A. However, given the limitations of study quality, more well-designed randomized controlled trials should be warranted to confirm these findings.


Wang X.-M.,PLA Fourth Military Medical University | Jia R.-H.,Peoples Liberation Army 457th Hospital | Wei D.,PLA Fourth Military Medical University | Cui W.-Y.,Tianjin Neurological Institute | Jiang W.,PLA Fourth Military Medical University
Neuroscience Letters | Year: 2014

Status epilepticus (SE) is a life-threatening neurological disorder associated with significant morbidity and mortality. MicroRNAs (miRNAs) are small, non-coding RNAs that act post-transcriptionally modulating messenger RNA (mRNA) translation or stability which may have important roles in the pathogenesis of epilepsy. It has been reported that silencing microRNA-134 in vivo has significant neuroprotective and prolonged seizure-suppressive effects. However, the mechanism by which miR-134 inhibition suppressed seizures and whether miR-134 inhibition works in an in vitro model of SE, is unknown. Compared to a complex in vivo system, in vitro models of SE-like electrographic activity can be powerful tools to study this miRNA. Using a cell culture model of low Mg2+ treatment of rat hippocampal neurons, we found SE-like electrographic activity increased expression of miR-134. Inhibiting expression of miR-134 using an inhibitor lentivirus with two miR-134 binding sites reduced SE-like electrographic activity in the hippocampal neurons and reduced neuronal death. This study provides direct evidence that inhibition of miR-134 can block status epilepticus-like discharges and is neuroprotective in hippocampal neuronal cultures and implies that inhibiting miR-134 may be a potential candidate for the clinical treatment of SE. © 2014 Elsevier Ireland Ltd.


Yuan P.,No 451 Hospital Of The Pla | Yuan P.,PLA Fourth Military Medical University | Chen B.,PLA Fourth Military Medical University | Huang Y.,PLA Fourth Military Medical University | Xin X.,PLA Fourth Military Medical University
Human Reproduction | Year: 2012

Background A previous study demonstrated that local application of levonorgestrel-loaded polylactic acid microspheres (LNG microspheres) resulted in significant regression of endometriotic cysts in a rabbit model for 6 months without disturbing the metabolic parameters or ovarian function. In order to investigate the feasibility of local application of LNG microspheres as a long-term maintenance treatment for endometriosis, the suppressive effect of a single intra-cystic injection of LNG microspheres was studied for 1 year in a rat model. Methods AND RESULTSTwenty four rats with experimental endometriotic cysts were randomized to be treated with a single intra-cystic injection of LNG microspheres (n 8); 6-month GnRH agonist (GnRHa, n 8) or control (n 8). Intra-cystic injection of LNG microspheres and GnRHa treatment caused comparable regression and atrophy in endometriotic cysts in the first 6 months. Compared with the control, the wet weight of the endometriotic cysts was significantly lower in both groups at Month 6 but by Month 12 only remained low in the LNG microspheres group (P < 0.01). The immunostaining of estrogen receptors (ERs) in both the epithelium and stroma and progesterone receptors (PRs) in the stroma was significantly weakened in the LNG microspheres group at Month 6 and was not fully restored at Month 12 (P < 0.01). Metabolic parameters and estrous cycle were not disturbed by local application of LNG microspheres. Conclusions In a rat endometriosis model, the suppressive effect of a single intra-cystic injection of LNG microspheres was comparable to that of GnRHa, and was maintained for 1 year. The down-regulation of ERs and PRs might serve as possible mechanism of long-term effectiveness. © The Author 2012. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.


Shang Y.,PLA Fourth Military Medical University | Zhang Z.,PLA Fourth Military Medical University | Liu Z.,PLA Fourth Military Medical University | Feng B.,PLA Fourth Military Medical University | And 10 more authors.
Oncogene | Year: 2014

Multidrug resistance (MDR) is usually correlated with the poor prognosis of gastric cancer. In this study, we revealed a total of 11 microRNAs (miRNA) that regulated MDR of gastric cancer via high-throughput functional screening, and miR-508-5p reversed MDR most efficiently among these candidate miRNAs. The overexpression of miR-508-5p was sufficient to reverse cancer cell resistance to multiple chemotherapeutics in vitro and sensitize tumours to chemotherapy in vivo. Further studies showed that miR-508-5p could directly target the 3′-untranslated regions of ABCB1 and Zinc ribbon domain-containing 1 (ZNRD1), and suppress their expression at the mRNA and protein levels. Meanwhile, the suppression of ZNRD1 led to a decrease in ABCB1. These findings suggest that a miR-508-5p/ZNRD1/ABCB1 regulatory loop has a critical role in MDR in gastric cancer. In addition, miR-508-5p could be used as a prognostic factor for overall survival in gastric cancer. These data reveal an important role for miR-508-5p in the regulation of MDR in gastric cancer, and suggest the potential application of miR-508-5p in drug resistance prediction and treatment. © 2014 Macmillan Publishers Limited.


Zhou H.,University of Sichuan | Zhou H.,University of Maryland, Baltimore | Li F.,University of Maryland, Baltimore | Li F.,PLA Fourth Military Medical University | And 3 more authors.
Journal of Dentistry | Year: 2013

Objectives Antibacterial bonding agents are promising to combat bacteria and caries at tooth-restoration margins. The objectives of this study were to incorporate new quaternary ammonium methacrylates (QAMs) to bonding agent and determine the effects of alkyl chain length (CL) and quaternary amine charge density on dental plaque microcosm bacteria response for the first time. Methods Six QAMs were synthesized with CL = 3, 6, 9, 12, 16, 18. Each QAM was incorporated into Scotchbond multi-purpose (SBMP). To determine the charge density effect, dimethylaminododecyl methacrylate (DMAHDM, CL = 16) was mixed into SBMP at mass fraction = 0%, 2.5%, 5%, 7.5%, 10%. Charge density was measured using a fluorescein dye method. Dental plaque microcosm using saliva from ten donors was tested. Bacteria were inoculated on resins. Early-attachment was tested at 4 h. Biofilm colony-forming units (CFU) were measured at 2 days. Results Incorporating QAMs into SBMP reduced bacteria early-attachment. Microcosm biofilm CFU for CL = 16 was 4 log lower than SBMP control. Charge density of bonding agent increased with DMAHDM content. Bacteria early-attachment decreased with increasing charge density. Biofilm CFU at 10% DMAHDM was reduced by 4 log. The killing effect was similarly-strong against total microorganisms, total streptococci, and mutans streptococci. Conclusions Increasing alkyl chain length and charge density of bonding agent was shown for the first time to decrease microcosm bacteria attachment and reduce biofilm CFU by 4 orders of magnitude. Novel antibacterial resins with tailored chain length and charge density are promising for wide applications in bonding, cements, sealants and composites to inhibit biofilms and caries. © 2013 Elsevier Ltd.


Li F.,PLA Fourth Military Medical University | Li F.,University of Maryland, Baltimore | Weir M.D.,University of Maryland, Baltimore | Fouad A.F.,University of Maryland, Baltimore | And 2 more authors.
Journal of Dentistry | Year: 2013

Objectives The objectives of this study were to investigate: (1) the antibacterial activity of two antibacterial monomers, dimethylaminododecyl methacrylate (DMADDM) and dimethylammoniumethyl dimethacrylate (DMAEDM), against eight different species of oral pathogens for the first time; (2) the cytotoxicity of DMAEDM and DMADDM. Methods DMAEDM and DMADDM were synthesized by reacting a tertiary amine group with an organo-halide. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against eight species of bacteria were tested. Time-kill determinations were performed to examine the bactericidal kinetics. Cytotoxicity of monomers on human gingival fibroblasts (HGF) was assessed using a methyl thiazolyltetrazolium assay and live/dead viability assay. Results DMADDM showed strong bactericidal activity against all bacteria, with MIC of 1.2-9.8 μg/mL. DMAEDM had MIC of 20-80 mg/mL. Time-kill determinations indicated that DMADDM and DMAEDM had rapid killing effects against eight species of bacteria, and eliminated all bacteria in 30 min at the concentration of 4-fold MBC. Median lethal concentration for DMADDM and DMAEDM was between 20 and 40 μg/mL, which was 20-fold higher than 1-2 μg/mL for BisGMA control. Conclusions DMAEDM and DMADDM were tested in time-kill assay against eight species of oral bacteria for the first time. Both were effective in bacteria-inhibition, but DMADDM had a higher potency than DMAEDM. Different killing efficacy was found against different bacteria species. DMAEDM and DMADDM had much lower cytotoxicity than BisGMA. Therefore, DMADDM and DMAEDM are promising for use in bonding agents and other restorative/preventive materials to combat a variety of oral pathogens.


Zhou H.,University of Maryland, Baltimore | Zhou H.,PLA Fourth Military Medical University | Chen W.,University of Maryland, Baltimore | Weir M.D.,University of Maryland, Baltimore | And 2 more authors.
Tissue Engineering - Part A | Year: 2012

Stem cell-encapsulating microbeads could be mixed into a paste such as calcium phosphate cement (CPC), where the microbeads could protect the cells from the mixing and injection forces. After being placed, the microbeads could quickly degrade to release the cells throughout the scaffold, while creating macropores. The objectives of this study were to (1) construct alginate-fibrin microbeads encapsulating human umbilical cord mesenchymal stem cells (hUCMSCs) embedded in the surface of novel biofunctionalized CPC and (2) investigate microbead degradation, cell release, and osteodifferentiation on CPC. Hydrogel microbeads were fabricated that encapsulated hUCMSCs at 1×106 cells/mL. CPC was biofunctionalized with fibronectin (Fn) and Arg-Gly-Asp (RGD). Four scaffolds were tested: CPC control, CPC mixed with Fn, CPC mixed with RGD, and CPC grafted with RGD. The degradable microbeads released hUCMSCs at 7 days, which attached to CPC. Adding Fn or RGD to CPC greatly improved cell attachment. CPC grafted with RGD showed the fastest cell proliferation, with cell density being ninefold that on CPC control. The released hUCMSCs underwent osteodifferentiation. Alkaline phosphatase, osteocalcin, collagen 1, and runt-related transcription factor 2 (Runx2) gene expression increased by 10 to 30 fold at 7-21 days, compared with day 1. The released cells on CPC synthesized bone minerals, with the mineralization amount at 21 days being two orders of magnitude higher than that at 7 days. In conclusion, alginate-fibrin microbeads embedded in CPC surface were able to quickly release the hUCMSCs that attached to biofunctionalized CPC. Incorporating Fn and RGD into CPC greatly improved cell function, and CPC grafted with RGD had the fastest cell proliferation. The released cells on CPC differentiated into the osteogenic lineage and synthesized bone minerals. The new biofunctionalized CPC with hUCMSC-encapsulating microbeads is promising for bone regeneration applications. © 2012 Copyright, Mary Ann Liebert, Inc.


Qi X.-S.,PLA Fourth Military Medical University | Qi X.-S.,General Hospital of Shenyang Military Command | Qi X.-S.,463 Hospital of Chinese PLA | Bai M.,PLA Fourth Military Medical University | Fan D.-M.,PLA Fourth Military Medical University
World Journal of Gastroenterology | Year: 2014

Currently, nonselective β-blockers (NSBBs) are commonly used for the prevention of variceal bleeding in liver cirrhosis. The beneficial effects of NSBBs are primarily attributed to the reduction in cardiac output by blockade of β1 receptors and vasoconstriction of the splanchnic circulation by the blockade of β2 receptors. The prognostic value of occlusive portal vein thrombosis (PVT) in cirrhotic patients has been increasingly recognized. The most important risk factor for the development of PVT in liver cirrhosis is the decreased portal vein inflow velocity. Collectively, we propose that the use of NSBBs potentially increases the development of portal vein thrombosis by reducing portal vein inflow velocity. The hypothesis should be confirmed by prospective cohort studies, in which cirrhotic patients without prior PVT treated with and without NSBBs are enrolled, and the development of PVT during follow-up is compared between the two groups. Additionally, subgroup analyses should be performed according to the dosage of NSBBs and the reduction of portal inflow velocity after use of NSBBs. © 2014 Baishideng Publishing Group Inc. All rights reserved.


Li F.,University of Maryland, Baltimore | Li F.,PLA Fourth Military Medical University | Weir M.D.,University of Maryland, Baltimore | Chen J.,PLA Fourth Military Medical University | And 2 more authors.
Dental Materials | Year: 2013

Objective: Antibacterial primer and adhesive are promising to help combat biofilms and recurrent caries. The objectives of this study were to compare novel bonding agent containing quaternary ammonium dimethacrylate (QADM) with bonding agent containing nanoparticles of silver (NAg) in antibacterial activity, contact-inhibition vs. long-distance inhibition, glucosyltransferases (gtf) gene expressions, and cytotoxicity for the first time. Methods: QADM and NAg were incorporated into Scotchbond Multi-Purpose adhesive and primer. Microtensile dentin bond strength was measured. Streptococcus mutans (S. mutans) biofilm on resin surface (contact-inhibition) as well as S. mutans in culture medium away from the resin surface (long-distance inhibition) were tested for metabolic activity, colony-forming units (CFUs), lactic acid production, and gtf gene expressions. Eluents from cured primer/adhesive samples were used to examine cytotoxicity against human gingival fibroblasts. Results: Bonding agent with QADM greatly reduced CFU and lactic acid of biofilms on the resin surface (p < 0.05), while having no effect on S. mutans in culture medium away from the resin surface. In contrast, bonding agent with NAg inhibited not only S. mutans on the resin surface, but also S. mutans in culture medium away from the resin surface. Bonding agent with QADM suppressed gtfB, gtfC and gtfD gene expressions of S. mutans on its surface, but not away from its surface. Bonding agent with NAg suppressed S. mutans gene expressions both on its surface and away from its surface. Bonding agents with QADM and NAg did not adversely affect microtensile bond strength or fibroblast cytotoxicity, compared to control (p > 0.1). Significance: QADM-containing adhesive had contact-inhibition and inhibited bacteria on its surface, but not away from its surface. NAg-containing adhesive had long-distance killing capability and inhibited bacteria on its surface and away from its surface. The novel antibacterial adhesives are promising for caries-inhibition restorations, and QADM and NAg could be complimentary agents in inhibiting bacteria on resin surface as well as away from resin surface. © 2013 Published by Elsevier Ltd on behalf of Academy of Dental Materials.


Li F.,PLA Fourth Military Medical University | Li F.,University of Maryland, Baltimore | Weir M.D.,University of Maryland, Baltimore | Fouad A.F.,University of Maryland, Baltimore | And 2 more authors.
Dental Materials | Year: 2014

Objectives Antibacterial primer and adhesive are promising to inhibit biofilms and caries. Since restorations in vivo are exposed to saliva, one concern is the attenuation of antibacterial activity due to salivary pellicles. The objective of this study was to investigate the effects of salivary pellicles on bonding agents containing a new monomer dimethylaminododecyl methacrylate (DMADDM) or nanoparticles of silver (NAg) against biofilms for the first time. Methods DMADDM and NAg were synthesized and incorporated into Scotchbond Multi-Purpose adhesive and primer. Specimens were either coated or not coated with salivary pellicles. A microcosm biofilm model was used with mixed saliva from ten donors. Two types of culture medium were used: an artificial saliva medium (McBain), and Brain Heart Infusion (BHI) medium without salivary proteins. Metabolic activity, colony-forming units (CFU), and lactic acid production of plaque microcosm biofilms were measured (n = 6). Results Bonding agents containing DMADDM and NAg greatly inhibited biofilm activities, even with salivary pellicles. When using BHI, the pre-coating of salivary pellicles on resin surfaces significantly decreased the antibacterial effect (p < 0.05). When using artificial saliva medium, pre-coating of salivary pellicles on resin did not decrease the antibacterial effect. These results suggest that artificial saliva yielded medium-derived pellicles on resin surfaces, which provided attenuating effects on biofilms similar to salivary pellicles. Compared with the commercial control, the DMADDM-containing bonding agent reduced biofilm CFU by about two orders of magnitude. Significance Novel DMADDM- and NAg-containing bonding agents substantially reduced biofilm growth even with salivary pellicle coating on surfaces, indicating a promising usage in saliva-rich environment. DMADDM and NAg may be useful in a wide range of primers, adhesives and other restoratives to achieve antibacterial and anti-caries capabilities. © 2013 Academy of Dental Materials.


Li F.,PLA Fourth Military Medical University | Li F.,University of Maryland, Baltimore | Weir M.D.,University of Maryland, Baltimore | Chen J.,PLA Fourth Military Medical University | And 2 more authors.
Dental Materials | Year: 2014

Objective Quaternary amine charge density is important because when the negatively charged bacteria contact the positive quaternary amine charge, the electric balance is disturbed and the bacterium could be disrupted. There has been no report on the effects of charge density on the antibacterial efficacy of dental bonding agents. The objective of this study was to synthesize a new quaternary ammonium methacrylate, and investigate the effects of charge density of bonding agent on bacteria early-attachment, biofilm colony-forming units (CFU) and dentin bond strength. Methods Dimethylaminododecyl methacrylate (DMAHDM) with an alkyl chain length of 16 was synthesized and mixed into Scotchbond Multi-Purpose adhesive and primer (SBMP) at mass fractions of 0%, 2.5%, 5%, 7.5%, and 10%. A microtensile dentin bond test was performed. The density of quaternary ammonium groups was measured using a fluorescein dye method. Streptococcus mutans (S. mutans) early-attachment was examined at 4 h, and biofilm colony-forming units (CFU) were measured at 2 days. Results All groups had similar microtensile bonding strengths (mean ± sd; n = 40) of about 60 MPa (p > 0.1). Quaternary amine charge density of bonding agents monotonically increased with increasing DMAHDM mass fraction. Bacteria early-attachment coverage greatly decreased with increasing DMAHDM content in the resin. Biofilm CFU at 10% DMAHDM was reduced by more than 4 log, compared to SBMP control. Charge density of bonding agent was inversely proportional to bacteria early-attachment coverage and biofilm CFU. Significance Increasing the quaternary amine charge density of dentin bonding agent resin was shown to greatly reduce S. mutans attachment and decrease biofilm CFU by four orders of magnitude, without compromising the dentin bond strength. The new DMAHDM is promising for use in bonding agents and other antibacterial restorative materials to inhibit caries.


Imazato S.,Osaka University | Ma S.,PLA Fourth Military Medical University | Chen J.-H.,PLA Fourth Military Medical University | Xu H.H.K.,University of Maryland, Baltimore
Dental Materials | Year: 2014

Objectives Many recent adhesives on the market exhibit reasonable clinical performance. Future innovations in adhesive materials should therefore seek out novel properties rather than simply modifying existing technologies. It is proposed that adhesive materials that are "bio-active" could contribute to better prognosis of restorative treatments. Methods This review examines the recent approaches used to achieve therapeutic polymers for dental adhesives by incorporating bio-active components. A strategy to maintain adhesive restorations is the focus of this paper. Results Major trials on therapeutic dental adhesives have looked at adding antibacterial activities or remineralization effects. Applications of antibacterial resin monomers based on quaternary ammonium compounds have received much research attention, and the loading of nano-sized bioactive particles or multiple ion-releasing glass fillers have been perceived as advantageous since they are not expected to influence the mechanical properties of the carrier polymer. Significance The therapeutic polymer approaches described here have the potential to provide clinical benefits. However, not many technological applications in this category have been successfully commercialized. Clinical evidence as well as further advancement of these technologies can be a driving force to make these new types of materials clinically available. © 2013 Academy of Dental Materials.


Bai M.,Xijing University | Qi X.-S.,Xijing University | Yang Z.-P.,Xijing University | Yang M.,Xijing University | And 2 more authors.
World Journal of Gastroenterology | Year: 2014

AIM: To compare the liver transplantation-free (LTF) survival rates between patients who underwent transjugular intrahepatic portosystemic shunts (TIPS) and those who underwent paracentesis by an updated meta-analysis that pools the effects of both number of deaths and time to death. METHODS: MEDLINE, EMBASE, and the Cochrane Library were searched from the inception to October 2012. LTF survival, liver transplantation, liver diseaserelated death, non-liver disease-related death, recurrent ascites, hepatic encephalopathy (HE) and severe HE, and hepatorenal syndrome were assessed as outcomes. LTF survival was estimated using a HR with a 95%CI. Other outcomes were estimated using OR with 95%CIs. Sensitivity analyses were performed to assess the effects of potential outliers in the studies according to the risk of bias and the study characteristics. RESULTS: Six randomized controlled trials with 390 patients were included. In comparison to paracentesis, TIPS significantly improved LTF survival (HR = 0.61, 95%CI: 0.46-0.82, P < 0.001). TIPS also significantly decreased liver disease-related death (OR = 0.62, 95%CI: 0.39-0.98, P = 0.04), recurrent ascites (OR = 0.15, 95%CI: 0.09-0.24, P < 0.001) and hepatorenal syndrome (OR = 0.32, 95%CI: 0.12-0.86, P = 0.02). However, TIPS increased the risk of HE (OR = 2.95, 95%CI: 1.87-4.66, P = 0.02) and severe HE (OR = 2.18, 95%CI: 1.27-3.76, P = 0.005). CONCLUSION: TIPS significantly improved the LTF survival of cirrhotic patients with refractory ascites and decreased the risk of recurrent ascites and hepatorenal syndrome with the cost of increased risk of HE compared with paracentesis. Further studies are warranted to validate the survival benefit of TIPS in clinical practice settings. © 2014 Baishideng Publishing Group Co., Limited. All rights reserved.


Liu H.,PLA Fourth Military Medical University | Zhang L.,Peoples Hospital of Long Xian | Lu S.,PLA Fourth Military Medical University
Molecules | Year: 2012

The present study was designed to evaluate the effect of quercetin on myocardial oxidative stress and immunity function impairment induced by isoproterenol in rats. To induce myocardial ischemia, Wistar rats were subcutaneously injected with isoproterenol (70 mg/kg). Blood immunity index, cardiac marker enzymes and antioxidative parameters in hearts were measured. It was found that the levels of blood AST, creatine kinase, NO, NOS, IL-10, IL-1, IL-8 and lactate dehydrogenase in isoproterenol-treated rats were significantly increased. The rats administrated with isoproterenol showed the declines in myocardial antioxidant enzymes activities. Administration of quercetin significantly ameliorated myocardial oxidative injury and immunity function impairment induced by isoproterenol. The results indicated that quercetin possesses activity against isoproterenol-induced myocardial oxidative injury and immunity function impairment, and that the mechanism of pharmacological action was related at least in part to the antioxidant activity of quercetin. © 2012 by the authors.


Qi X.-S.,General Hospital of Shenyang Military Command | Qi X.-S.,PLA Fourth Military Medical University | Guo X.-Z.,General Hospital of Shenyang Military Command | Han G.-H.,PLA Fourth Military Medical University | And 2 more authors.
World Journal of Gastroenterology | Year: 2015

The current standard treatment option for advanced hepatocellular carcinoma (HCC) is sorafenib, but its clinical benefit is modest. In spite of many attempts, few drugs can provide any significant improvement of survival as the first-or second-line therapy of choice in phase III randomized controlled trials. Recently, the subgroup analysis of a phase II randomized controlled trial has shown that tivantinib, a selective MET inhibitor, can significantly improve the overall survival in patients with MET-positive advanced HCC after the failure or intolerance of a prior systemic therapy. These findings enlighten the role of MET inhibitors in the treatment of advanced HCC. In this paper, we review all ongoing and completed clinical trials regarding this topic. As for the first-line therapy of advanced HCC, INC280 and foretinib are being evaluated in 2 phase II single-arm trials; and MSC2156119J and golvatinib plus sorafenib are being compared with sorafenib alone in 2 phase II randomized controlled trials. As for the second-line therapy of advanced HCC, tivantinib and cabozantinib are being compared with placebo in 2 phase III randomized controlled trials. © The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.


Qi X.,General Hospital of Shenyang Military Command | Guo X.,General Hospital of Shenyang Military Command | Su C.,PLA Fourth Military Medical University
Current Stem Cell Research and Therapy | Year: 2015

Aims: A systematic review and meta-analysis were performed to explore the clinical outcome of the transplantation of stem cells from various human tissue sources in cirrhotic patients. Methods: The relevant papers were searched via PubMed, EMBASE, and Cochrane Library databases. Changes in liver function before and after stem cell therapy were evaluated (self-control data). Difference in liver function and incidence of procedure-related complications, hepatocellular carcinoma (HCC), and death between patients undergoing stem cell therapy and conventional treatment were evaluated (case-control data). Results: Of 786 papers initially identified, 31 were included. The sources of stem cell included bone marrow (n=26), umbilical cord (n=3), peripheral blood (n=1), and human fetal liver (n=1). No severe procedure-related complications were reported. According to the meta- analyses of self-control data, model for end-stage liver diseases (MELD) score was significantly reduced at the 3rd-4th and 6th months after stem cell therapy, but this reduction was not statistically significant at the 1st-2nd or 12th postoperative months. Child-Pugh score was also reduced after stem cell therapy, but the reduction was not statistically significant at all follow-up time points. According to the meta-analyses of case-control data, MELD and Child-Pugh scores were not significantly different between treatment and control groups at all follow-up time points. The incidence of HCC was not significantly different between treatment and control groups (odds ratio [OR] to=0.41, P=0.53). The mortality was not significantly different between the two groups (OR=0.48, P=0.20). Conclusion: Stem cell therapy could improve the liver function without any severe procedure-related complications. However, compared with conventional treatment, the benefit of stem cell therapy appeared to be not significant in improving the liver function and survival. © 2015 Bentham Science Publishers.


Chen W.,University of Maryland, Baltimore | Chen W.,University of Sichuan | Zhou H.,University of Maryland, Baltimore | Zhou H.,PLA Fourth Military Medical University | And 3 more authors.
Acta Biomaterialia | Year: 2012

The need for bone repair has increased as the population ages. The objectives of this study were to (1) develop a novel biofunctionalized and macroporous calcium phosphate cement (CPC) containing alginate-fibrin microbeads encapsulating human umbilical cord mesenchymal stem cells (hUCMSC) and, for the first time, (2) investigate hUCMSC proliferation and osteogenic differentiation inside the CPC. A macroporous CPC was developed using calcium phosphate powder, chitosan, and a gas-foaming porogen. Five types of CPC were fabricated: a CPC control, CPC + 0.05% fibronectin (Fn), CPC + 0.1% Fn, CPC + 0.1% arginine-glycine-aspartate (RGD), and CPC + 0.1% Fn + 0.1% RGD. Alginate-fibrin microbeads containing 10 6 hUCMSC per ml were encapsulated in the CPC paste. After the CPC had set, the degradable microbeads released hUCMSC within it. The hUCMSC proliferated inside the CPC, with the cell density after 21 days being 4-fold that on day1. CPC + 0.1% RGD had the highest cell density, which was 4-fold that of the CPC control. The released cells differentiated along the osteogenic lineage and synthesized bone mineral. The hUCMSC inside the CPC + 0.1% RGD construct expressed the genes alkaline phosphatase, osteocalcin and collagen I, at twice the level of the CPC control. Mineral synthesis by hUCMSC inside the CPC + 0.1% RGD construct was 2-fold that in the CPC control. RGD and Fn incorporation in the CPC did not compromise its strength, which matched the reported strength of cancellous bone. In conclusion, degradable microbeads released hUCMSC which proliferated, differentiated and synthesized minerals inside the macroporous CPC. The CPC with RGD greatly enhanced cell function. The novel biofunctionalized and macroporous CPC-microbead-hUCMSC construct is promising for bone tissue engineering applications. © 2012 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.


Xie C.,PLA Fourth Military Medical University | Lu H.,PLA Fourth Military Medical University | Li W.,General Hospital of Shenyang Military Command | Chen F.-M.,PLA Fourth Military Medical University | Zhao Y.-M.,PLA Fourth Military Medical University
Journal of Materials Science: Materials in Medicine | Year: 2012

Since calcium phosphates (CaPs) were first proposed, a wide variety of formulations have been developed and continuously optimized, some of which (e.g. calcium phosphate cements, CPCs) have been successfully commercialized for clinical applications. These CaP-based biomaterials have been shown to be very attractive bone substitutes and efficient drug delivery vehicles across diverse biomedical applications. In this article, CaP biomaterials, principally CPCs, are addressed as alternatives/ complements to autogenous bone for grafting in implant dentistry and as coating materials for enhancing the osteoinductivity of titanium implants, highlighting their performance benefits simultaneously as carriers for growth factors and as scaffolds for cell proliferation, differentiation and penetration. Different strategies for employing CaP biomaterials in dental implantology aim to ultimately reach the same goal, namely to enhance the osseointegration process for dental implants in the context of immediate loading and to augment the formation of surrounding bone to guarantee long-term success. © 2012 Springer Science+Business Media, LLC.


Yuan L.-B.,PLA Fourth Military Medical University | Dong H.-L.,PLA Fourth Military Medical University | Zhang H.-P.,PLA Fourth Military Medical University | Zhao R.-N.,PLA Fourth Military Medical University | And 4 more authors.
Anesthesiology | Year: 2011

Background: Recent studies suggest that the novel neuropeptide orexin-A may play an essential role during neuronal damage. However, the function of orexin-A during brain ischemia remains unclear. Recently, hypoxia-inducible factor-1α (HIF-1α) was shown to be activated by orexin-A. The aim of the current study is to test the hypothesis that administration of exogenous orexin-A can attenuate ischemia-reperfusion injury through the facilitation of HIF-1α expression. Methods: Sprague-Dawley rats were subjected to transient middle cerebral artery occlusion for 120 min. Rats were treated with different doses of orexin-A or vehicle before the ischemia and at the onset of reperfusion. To investigate the action of HIF-1α in the neuroprotective effects of orexin-A, the HIF-1α inhibitor YC-1 was used alone or combined with orexin-A. Neurologic deficit scores and infarct volume were assessed. Brains were harvested for immunohistochemical staining and western blot analysis. Results: Orexin-A significantly ameliorated neurologic deficit scores and reduced infarct volume after cerebral ischemia reperfusion. Administration of 30 μg/kg orexin-A showed optimal neuroprotective effects. This effect was still present 7 days after reperfusion. Furthermore, orexin-A decreased the number of apoptotic cells and significantly enhanced HIF-1α expression after cerebral ischemia reperfusion. Moreover, the facilitation of HIF-1α expression was accompanied with inhibition of von Hippel-Lindau expression. Administration of HIF-1α inhibitor suppressed the increase of HIF-1α and reversed the neuroprotective effects of orexin-A. Conclusions: Orexin-A has a neuroprotective effect against cerebral ischemia-reperfusion injury. These effects may be mediated through the HIF-1α pathway. © 2011, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins. Anesthesiology.


Pei Y.-L.,PLA Fourth Military Medical University | Zhang H.-L.,PLA Fourth Military Medical University | Han H.-G.,General Hospital
Tumor Biology | Year: 2013

Several genome-wide association studies on breast cancer have reported similar findings of a new cancer susceptibility locus, 8q24 rsl3281615. Subsequent case-control studies have rapidly investigated the association between the single nucleotide polymorphism of rsl3281615 at chromosome 8q24 and breast cancer risk, but the effect of 8q24 rsl3281615 polymorphism on breast cancer is still unclear due to the inconsistence among those studies. Given the contradictory findings, a meta-analysis was performed to determine the association between 8q24 rsl3281615 polymorphism and breast cancer risk. 12 eligible case-control studies with a total of 42,508 cases and 53,928 controls were finally included into this meta-analysis by searching the PubMed, Embase, and China Biology Medicine (CBM) databases. We estimated the summary odds ratio (OR) with its corresponding 95 % confidence interval (95 % CI) to assess this association. Meta-analyses of total 12 studies showed 8q24 rsl3281615 polymorphism was significantly associated with an increased risk of breast cancer in all contrast models (ORG vs. A = 1.10, 95 % CI 1.05-1.14, P OR < 0.001; ORGG vs. AA = 1.20, 95 % CI 1.11-1.29, P OR < 0.001; ORAG vs. AA = 1.08, 95 % CI 1.05-1.12, P OR < 0.001; ORGG vs. AA +AG = 1.13, 95 % CI 1.07-1.19, P OR < 0.001; ORGG+AG vs. AA = 1.13, 95 % CI 1.07-1.19, P OR < 0.001). Meta-analyses of studies with high quality showed that 8q24 rsl3281615 polymorphism was still significantly associated with an increased risk of breast cancer under the five genetic contrast models. Sensitivity analyses by sequential omission of any individual studies and subgroup analyses by ethnicity further identified the significant association between 8q24 rsl3281615 polymorphism and breast cancer risk. Conclusively, this meta-analysis shows a significant association between 8q24 rsl3281615 polymorphism and breast cancer risk. © 2012 International Society of Oncology and BioMarkers (ISOBM).


Leung T.C.H.,Hong Kong Baptist University | Lui C.N.P.,Hong Kong Baptist University | Chen L.W.,PLA Fourth Military Medical University | Yung W.H.,Chinese University of Hong Kong | And 2 more authors.
ACS Chemical Neuroscience | Year: 2012

Parkinson's disease is caused by the degeneration of dopaminergic neurons in substantia nigra. There is no current promising treatment for neuroprotection of dopaminergic neurons. Ceftriaxone is a beta-lactam antibiotic and has been reported to offer neuroprotective effects (Rothstein, J.-D., Patel, S., Regan, M.-R., Haenggeli, C., Huang, Y.-H., Bergles, D.-E., Jin, L., Dykes, H.-M., Vidensky, S., Chung, D.-S., Toan, S.-V., Bruijn, L.-I., Su, Z.-Z., Gupta, P., and Fisher, P.-B. (2005) Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression Nature433, 73-77). In the present study, efficacy of ceftriaxone in neuroprotection of dopaminergic neurons and amelioration of motor deficits in a rat model of Parkinson's disease were investigated. Ceftriaxone was administrated in 6-hydroxydopamine-lesioned rats. Using behavioral tests, grip strength and numbers of apomorphine-induced contralateral rotation were declined in the ceftriaxone-treated group. More importantly, cell death of dopaminergic neurons was found to decrease. In addition, both the protein expression and immunoreactivity for GLT-1 were up-regulated. The present results strongly indicate that ceftriaxone is a potential agent in the treatment of Parkinson's disease. © 2011 American Chemical Society.


Chu J.M.T.,Hong Kong Baptist University | Chan Y.S.,University of Hong Kong | Chen L.W.,PLA Fourth Military Medical University | Yung K.K.L.,Hong Kong Baptist University
Journal of Neurochemistry | Year: 2012

Neurokinin 3 (NK3) receptor is predominantly expressed in striatum and substantia nigra (SN). Evidences have indicated the roles of NK3 receptor in the pathogenesis of Parkinson's disease. By administrating NK3 receptor agonist senktide into 6-hydroxydopamine (6-OHDA)-lesioned rats, exacerbation of dopaminergic degeneration was found in striatum and substantia nigra pars compacta. From apomorphine rotation test, significant increase of contralateral rotation number was detected in 6-OHDA-lesioned rats with senktide injection. Furthermore, tyrosine hydroxylase expression in striatum and substantia nigra pars compacta were examined by immunohistochemistry and Western blotting. Further reduction of tyrosine hydroxylase immunoreactivities was found in 6-OHDA-lesioned rats that received senktide treatment. Also, phosphorylation of N-methyl-D-aspartate receptor 1 subunit was investigated in SN region and significant up-regulation was revealed in senktide-treated 6-OHDA-lesioned rats. Finally, phosphorylation of mitogen-activated protein kinase c-Jun N-terminal kinase (JNK) and c-Jun were examined in nigral region. Up-regulation of phosphorylated JNK molecules was shown in SN region after senktide injection. In line with this evidence, phosphorylation of c-Jun at Ser 63 and Ser 73 was also up-regulated by senktide treatment, thus presenting new aspects that NK3 peptide could exacerbate 6-OHDA toxicity in in vivo models and the possible mechanism may be contributed by the modulation of N-methyl-D-aspartate receptor 1 subunit and JNK pathway activities. Neurokinin receptor 3 (NK3R) is colocalized with dopaminergic neurons, but the roles of this receptor in Parkinson's disease are still unclear. Administration of NK3 peptide senktide into 6-OHDA-lesioned rats resulted in exacerbation of dopaminergic degeneration, activation of NR1 and JNK pathway. Our data indicated that NK3R may involve in the onset of PD progress and subsequent neuronal degeneration. © 2012 International Society for Neurochemistry.


Ning Q.,Huazhong University of Science and Technology | Han M.,Huazhong University of Science and Technology | Sun Y.,PLA Fourth Military Medical University | Jiang J.,Fujian Medical University | And 5 more authors.
Journal of Hepatology | Year: 2014

Background & Aims: Durable post-treatment response is uncommon in chronic hepatitis B (CHB) patients on nucleos(t)ide analogue therapy. Response, response predictors and safety were assessed in patients who switched from long-term entecavir (ETV) to peginterferon alfa-2a. Methods: Hepatitis B e antigen (HBeAg)-positive CHB patients who had received ETV for 9-36 months, with HBeAg <100 PEIU/ ml and HBV DNA 61000 copies/ml, were randomised 1: 1 to receive peginterferon alfa-2a 180 lg/week or ETV 0.5 mg/day for 48 weeks. The primary endpoint was HBeAg seroconversion at week 48 (ClinicalTrials.gov: NCT00940485). Results: 200 patients were randomised; 197 received P1 study drug dose. Five patients who were anti-HBe-positive at baseline were excluded from the modified intention-to-treat population (peginterferon alfa-2a, n = 94; ETV, n = 98). Patients who switched to peginterferon alfa-2a achieved higher week 48 HBeAg seroconversion rates vs. those who continued ETV (14.9% vs. 6.1%; p = 0.0467). Only patients receiving peginterferon alfa-2a achieved HBsAg loss (8.5%). Among peginterferon alfa-2atreated patients with HBeAg loss and HBsAg <1500 IU/ml at randomisation, 33.3% and 22.2% achieved HBeAg seroconversion and HBsAg loss, respectively. Early on-treatment HBsAg decline predicted response at week 48; highest rates were observed in patients with week 12 HBsAg <200 IU/ml (HBeAg seroconversion, 66.7%; HBsAg loss, 77.8%). Alanine aminotransferase elevations were not associated with viral rebound (n = 38). Peginterferon alfa-2a was well-tolerated. Conclusions: For patients who achieve virological suppression with ETV, switching to a finite course of peginterferon alfa-2a significantly increases rates of HBeAg seroconversion and HBsAg loss. A response-guided approach may identify patients with the greatest chance of success. © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.


Qi X.,General Hospital of Shenyang Military Command | Qi X.,PLA Fourth Military Medical University | De Stefano V.,Catholic University | Li H.,General Hospital of Shenyang Military Command | And 3 more authors.
European Journal of Internal Medicine | Year: 2015

Background & aims Systematic review and meta-analysis were performed to evaluate the safety and efficacy of anticoagulation for the treatment of portal vein thrombosis (PVT) in cirrhotic patients. Methods The PubMed, EMBASE, Cochrane Library, and ScienceDirect databases were searched. The rates of bleeding complications and portal vein recanalization in patients who received anticoagulant therapy were pooled. The odds ratio (OR) with 95% confidence interval (CI) was calculated to express the difference in the rate of portal vein recanalization between anticoagulation and non-anticoagulation groups. All meta-analyses were conducted by using a random-effects model. Results Sixteen of 960 initially identified papers were included. Two studies reported a low incidence of major anticoagulation-related complications (4% [2/55] and 3% [1/33]), but no lethal complications occurred. The rate of anticoagulation-related bleeding ranged from 0% to 18% with a pooled rate of 3.3% (95% CI = 1.1%-6.7%). The heterogeneity was not significant in the meta-analysis. The total rate of portal vein recanalization ranged from 37% to 93% with a pooled rate of 66.6% (95% CI = 54.7%-77.6%). The rate of complete portal vein recanalization ranged from 0% to 75% with a pooled rate of 41.5% (95% CI = 29.2%-54.5%). However, the heterogeneity was significant in the 2 meta-analyses. The rate of complete portal vein recanalization was significantly higher in anticoagulation group than in non-anticoagulation group (OR = 4.16, 95% CI = 1.88-9.20, P = 0.0004). The heterogeneity was not significant in the meta-analysis. Conclusion Anticoagulation could achieve a relatively high rate of portal vein recanalization in cirrhotic patients with PVT. Given that only a small number of non-randomized comparative studies are reported, randomized controlled trials are warranted to confirm the risk-to-benefit of anticoagulation in such patients, especially anticoagulation-related bleeding. © 2014 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.


Yang M.,PLA Fourth Military Medical University | Xu D.D.,PLA Fourth Military Medical University | Zhang Y.,PLA Fourth Military Medical University | Liu X.,PLA Fourth Military Medical University | And 2 more authors.
American Journal of Chinese Medicine | Year: 2014

We performed a systematic review to evaluate the efficacy of natural medicines for the treatment of Alzheimer's disease (AD) in randomized controlled trials (RCTs). Disease-specific and intervention terms were searched in MEDLINE, EMBASE, the Cochrane Library and PsycINFO to identify RCTs for the AD intervention of natural medicines, and searched for literatures in English language. The RCTs compared natural medicines and either placebo or orthodox medication in AD patients. The quality of literature was evaluated by Jadad's score and the Cochrane assessing tool to reduce the risk of bias. Meta-analysis and the heterogeneity of results across the trials were performed. Out of the literatures, 21 clinical reports were included in this review that satisfied the particular selection criteria. Apart from Ginkgo, other treatments we came across had minimal benefits and/or the methodological quality of the available trials was poor. The meta-analyses showed that Ginkgo had better outcomes than the placebo, with the standardized mean difference (SMD) between Ginkgo and the placebo on cognition being -1.62 (95% CI: -2.69 to -0.56) and on activities of daily living being -1.55 (95% CI: -2.55 to -0.55), with the existence of significant heterogeneity across studies. The meta-analysis for assessing the prevention effect of Ginkgo against AD suggested that risk ratio (RR) is 1.06 (95% CI: 0.92 to 1.22) between Gingko and the placebo, with no significant heterogeneity across studies (test for heterogeneity, p = 0.49). Our results suggest that Ginkgo may help established AD patients with cognitive symptoms but cannot prevent the neurodegenerative progression of the disease. © 2014 World Scientific Publishing Company.


Xiao X.,Xijing University | Wang W.,PLA Fourth Military Medical University | Wang Z.,Xijing University
Pediatric Drugs | Year: 2014

Results: The weighted average overall response rate (CR + PR) for the combination of ifosfamide, etoposide and high-dose methotrexate therapy was 62 %, and the tumor control rate (CR + PR + SD) was 92.3 %; the highest of all six regimens. The weighted average overall response rate and tumor control rate of ifosfamide–etoposide therapy (41.7 and 77.9 %, respectively) were the highest of the two-drug regimens. Weighted average overall response rate and tumor control rate for the remaining regimens were 20.5 and 56.8 %, respectively, for cyclophosphamide-etoposide; 30.0 and 73.5 % for ifosfamide, carboplatin, and etoposide; 12.0 and 40.0 % for cyclophosphamide–topotecan; and 14.5 and 36.4 % for gemcitabine–docetaxel.Methods: We performed a search of PubMed and EMBASE to identify published articles reporting on validated clinical outcomes measures (the rate of complete response [CR] and partial response [PR], the rate of stable disease [SD] and progressive disease [PD] and the 5-year overall survival) after chemotherapy in patients with metastatic, relapsed and refractory osteosarcoma. A total of 20 articles were identified and stratified by different regimens. Finally, six regimens that have at least two drugs were reviewed. Weighted averages of each outcome were computed.Summary of Background Data: Despite a large number of publications on outcomes of second-line chemotherapy for osteosarcoma, there is little consensus on efficacy of the therapy.Objective: Our objective was to systematically categorize published evidence for chemotherapy for metastatic, relapsed and refractory osteosarcoma in order to provide an updated and comprehensive analysis of the clinical outcomes.Conclusion: A chemotherapy regimen comprising both a cell cycle-specific drug and a cell cycle-nonspecific drug could increase response rates. The combination of ifosfamide and etoposide therapy is our first choice in two-drug regimens. Regarding three-drug regimens, adding a cell cycle-specific drug to ifosfamide–etoposide therapy may result in a better response rate than adding a cell cycle-nonspecific drug, or any other two-drug regimens in current studies. Hence, we recommend the use of second-line chemotherapy based on the combination ifosfamide–etoposide regimen in patients with metastatic, relapsed and refractory osteosarcoma. © 2014, Springer International Publishing Switzerland.


Xu G.,University of Pittsburgh | Xu G.,PLA Fourth Military Medical University | Liu K.,University of Pittsburgh | Anderson J.,University of Pittsburgh | And 5 more authors.
Blood | Year: 2012

BM stromal cells (BMSCs) are key players in the microenvironmental support of multiple myeloma (MM) cell growth and bone destruction. A spliced form of the X-box-binding protein-1 (XBP1s), a major proximal effector of unfolded protein response signaling, is highly expressed in MM cells and plays an indispensable role in MM pathogenesis. In the present study, we found that XBP1s is induced in the BMSCs of the MM microenvironment. XBP1s overexpression in healthy human BMSCs enhanced gene and/or protein expression of VCAM-1, IL-6, and receptor activator of NF-ΚB ligand (RANKL), enhancing BMSC support of MM cell growth and osteoclast formation in vitro and in vivo. Conversely, deficiency of XBP1 in healthy donor BMSCs displayed a range of effects on BMSCs that were opposite to those cells with overexpression of XBP1s. Knock-down of XBP1 in MM patient BMSCs greatly compromised their increased VCAM-1 protein expression and IL-6 and RANKL secretion in response to TNFαand reversed their enhanced support of MM-cell growth and osteoclast formation. Our results demonstrate that XBP1s is a pathogenic factor underlying BMSC support of MM cell growth and osteoclast formation and therefore represents a therapeutic target for MM bone disease.


Li J.,PLA Fourth Military Medical University | Zhang F.,PLA Fourth Military Medical University | Zhang F.,Kunlun Hospital | Wang S.,Zhengzhou Orthopaedics Hospital
Tumor Biology | Year: 2014

Pomegranate (Punica granatum L.) peels, as one of the most valuable by-products of the food industry, has attracted much attention due to its wide range of bioactivities. In this study, the potential anticancer effect of a polysaccharide from pomegranate peels (PPP) on human osteosarcoma cancer cells was investigated. PPP was found to induce the arrest of G2/M phase, induce apoptosis, and inhibit the growth of U-2 osteosarcoma (OS) cells in a dose-dependent manner. Moreover, Western blotting analysis showed that PPP triggered the mitochondrial apoptotic pathway, as indicated by an increase in Bax/Bcl-2 ratios, a loss of mitochondrial membrane potential, release of cytochrome c, activation of caspase-9 and caspase-3, and cleavage of poly(ADP-ribose) polymerase (PARP) in U-2 OS cells. Our results indicate that PPP inhibits the proliferation of human osteosarcoma cancer cells by inducing apoptosis through the intrinsic mitochondrial pathway. © 2014, International Society of Oncology and BioMarkers (ISOBM).


Wang K.,Xi'an Jiaotong University | Fu Q.,Xi'an Jiaotong University | Chen X.,PLA Fourth Military Medical University | Gao Y.,Xi'an Jiaotong University | Dong K.,Xi'an Jiaotong University
RSC Advances | Year: 2012

In this paper, a new kind of pH-sensitive hydrogel based on poly(lactic acid) (PLA), methoxyl poly(ethylene glycol) (MPEG) and itaconic acid (IA) was prepared by heat-initiated free radical polymerization method without any organic solvent. The obtained macromonomers and hydrogels were characterized by 1H NMR and FTIR. Detailed swelling behavior of hydrogels under variational pH-conditions revealed that the dynamic sensitivity of P(MPEG-PLA-co-IA-MEGMA) hydrogels [P(LE-IA-MEG) hydrogels] as well as the diffusional mechanisms might be causing the network expansion and collapse. In vitro drug release behavior was investigated using VB 12 and paclitaxel (PTX) as model drugs, revealing that the P(LE-IA-MEG) hydrogel could control the diffusion of the drug. The prepared new kind of pH-sensitive hydrogel with great pH-responsiveness and good properties for drug delivery might have great potential application in smart drug delivery systems. This journal is © 2012 The Royal Society of Chemistry.


Yu Y.,PLA Fourth Military Medical University | Wang W.,Xi'an Jiaotong University | Zhai S.,Xi'an Jiaotong University | Dang S.,Xi'an Jiaotong University | Sun M.,Xi'an Jiaotong University
Molecular Biology Reports | Year: 2012

A number of case-control studies were conducted to investigate the association of IL6 gene polymorphisms with colorectal cancer (CRC). However, the results were not always consistent. We performed a systematic review and meta-analysis to examine the association between the IL6 gene polymorphisms and CRC. Data were collected from the following electronic databases: PubMed, EMBASE, Web of Science, BIOSIS Previews, HuGENet, and Chinese Biomedical Literature Database, with the last report up to July 2011. A total of 17 studies involving 4 SNPs were included (16 for rs1800795, 2 for rs1800796, 2 for rs1800797, and 1 for rs13306435). Overall, no significant association of these polymorphisms with CRC was found in heterozygote comparisons as well as homozygote comparison, dominant genetic model and recessive model. In subgroup analysis, among studies using population-based controls, fulfilling Hardy-Weinberg equilibrium, or using Taqman genotyping method, we did not find any significant association. However, the rs1800795 C allele was significantly associated with reduced risk for CRC among persons who regularly or currently took NSAIDs (four studies, OR = 0.750; 95 % CI, 0.64-0.88; P = 0.474 for heterogeneity test), and with increased risk for CRC among persons who drank (one study, OR = 1.97; 95 % CI, 1.32-2.94). Individuals with the rs1800795 C allele in the IL6 gene have a significantly lower risk of CRC, but in the setting of NSAIDs use. Further studies are merited to assess the association between the IL6 gene polymorphisms and CRC risk among persons who take NSAIDs, drink or smoke, etc. © 2012 Springer Science+Business Media B.V.


Zhou S.,PLA Fourth Military Medical University | Zhou S.,Xi'an Jiaotong University | Ye W.,PLA Fourth Military Medical University | Zhang M.,PLA Fourth Military Medical University | Liang J.,PLA Fourth Military Medical University
Critical Reviews in Eukaryotic Gene Expression | Year: 2012

To date, preclinical and clinical data have shown that various cancer patients benefit from antiangiogenic therapy because of the important role of angiogenesis in the tumor development process. NF-E2- related factor 2 (Nrf2) is recognized as a key transcription factor of genes coding for various antioxidant and cytoprotective enzymes, and Nrf2 plays important roles during tumor progression. Recent studies have begun to explore the role of Nrf2 in tumor angiogenesis, which may be to promote the advancement of tumor antiangiogenic therapy. This article reviews the Nrf2-related pathways involved in tumor angiogenesis and summarizes the possible mechanisms of Nrf2 action as a pro-angiogenic factor in tumor progression. © 2012 Begell House, Inc.


Ma X.,Xi'an Jiaotong University | Wang Y.,PLA Fourth Military Medical University | Guo H.,Changzhou Institute of Technology | Wang J.,Xi'an Jiaotong University
Journal of Bioactive and Compatible Polymers | Year: 2011

A three-dimensional porous nano-hydroxyapatite (nHA)/chitosan (CS) biocomposite was synthesized. The rod-like nHA grains of 15-30 × 5-10 nm in size were observed by TEM and confirmed by characteristic XRD patterns. The diameters of the interconnecting pores of the nHA/CS biocomposite, determined by SEM, were 120-300 μm. Standard critical-sized calvarial bone defect ( Ø = 6.5 mm) was created in Sprague-Dawley (SD) rats. In group 1, nHA/CS was implanted and in group 2, no implant was made in the defect. After 1 week, the histological assessment of group 1 clearly showed that a large number of living cells were anchored in the pores of the nHA/CS implants. New bone formation, both at the edge and in the center of implants, was found as early as 2 weeks. Histological assays confirmed that the newly formed bone tissue was bioactive and neovascularized. After 5 weeks, the mineral content and volume of the newly formed bone tissue in the defects were significantly greater in group 1 than in group 2 (p < 0.01). These results indicate that implantation of the nHA/CS enhanced the repair of bone defect and confirm the potential of this biocomposite as a bioactive bone grafting substitute. © 2011 The Author(s).


Wang Q.,PLA Fourth Military Medical University | Li X.,PLA Fourth Military Medical University | Chen Y.,Xi'an Jiaotong University | Wang F.,PLA Fourth Military Medical University | And 4 more authors.
Stroke | Year: 2011

Background and Purpose- Our previous study has demonstrated that the rapid tolerance to cerebral ischemia by electroacupuncture (EA) pretreatment was possibly mediated through an endocannabinoid system-related mechanism. The purpose of this study was to investigate whether activation of epsilon protein kinase C (ϵPKC) was involved in EA pretreatment-induced neuroprotection via cannabinoid receptor type 1 in a rat model of transient focal cerebral ischemia. Methods- The activation of ϵPKC in the ipsilateral brain tissues after EA pretreatment was investigated in the presence or absence of cannabinoid receptor antagonists. At 2 hours after the end of EA pretreatment, focal cerebral ischemia was induced by middle cerebral artery occlusion for 120 minutes in rats. The neurobehavioral scores, infarction volumes, neuronal apoptosis, and the expression of Bcl-2 and Bax were evaluated after reperfusion in the presence or absence of ϵPKC-selective peptide inhibitor (TAT-ϵV1-2) or activator (TAT-ψϵRACK). Results- EA pretreatment enhanced ϵPKC activation. Systemic delivery of TAT-ψϵRACK conferred neuroprotection against a subsequent cerebral ischemic event when delivered 2 hours before ischemia. Pretreatment with EA reduced infarct volumes, improved neurological outcome, inhibited neuronal apoptosis, and increased the Bcl-2-to-Bax ratio after reperfusion, and the beneficial effects were attenuated by TAT-ϵV1-2. In addition, the blockade of cannabinoid receptor type 1, but not cannabinoid receptor type 2 receptor, reversed the increase in ϵPKC activation and neuroprotection induced by EA pretreatment. CONCLUSION-: EA pretreatment may activate endogenous ϵPKC-mediated anti-apoptosis to protect against ischemic damage after focal cerebral ischemia via cannabinoid receptor type 1, which represents a new mechanism of EA pretreatment-induced rapid tolerance to focal cerebral ischemia in rats. © 2011 American Heart Association, Inc.


Zhang Y.,East Tennessee State University | Zhang Y.,PLA Fourth Military Medical University | Ma C.J.,East Tennessee State University | Wang J.M.,East Tennessee State University | And 5 more authors.
Journal of Leukocyte Biology | Year: 2012

Tim-3 and PD-1 are powerful immunoinhibitory molecules involved in immune tolerance, autoimmune responses, and antitumor or antiviral immune evasion. A current model for Tim-3 regulation during immune responses suggests a divergent function, such that Tim-3 acts synergistically with TLR signaling pathways in innate immune cells to promote inflammation, yet the same molecule terminates Th1 immunity in adaptive immune cells. To better understand how Tim-3 might be functioning in innate immune responses, we examined the kinetics of Tim-3 expression in human CD14 + M/M 4 in relation to expression of IL-12, a key cytokine in the transition of innate to adaptive immunity. Here, we show that Tim-3 is constitutively expressed on unstimulated peripheral blood CD14 + monocytes but decreases rapidly upon TLR stimulation. Conversely, IL-12 expression is low in these cells but increases rapidly in CD14 + M/M.J, in correlation with the decrease in Tim-3. Blocking Tim-3 signaling or silencing Tim-3 expression led to a significant increase in TLR-mediated IL-12 production, as well as a decrease in activation-induced up-regula-tion of the immunoinhibitor, PD-1; TNF-a production was not altered significantly, but IL-10 production was increased. These results suggest that Tim-3 has a role as a regulator of pro- and anti-inflammatory innate immune responses. © Society for Leukocyte Biology.


Liu J.,China University of Petroleum - East China | Xia R.,Wuhan University | Zhou X.,PLA Fourth Military Medical University
Science China: Physics, Mechanics and Astronomy | Year: 2012

In this study, we considered the wetting phenomenon on a general substrate from a new viewpoint of continuum mechanics. The analyses first show how the Wenzel and the Cassie models deviate the practical results in some special substrates, and then elucidate the mechanism of the triple contact line (TCL) moving. Based upon variational theory of the total free functional dealing with the movable boundary condition, we show that the macroscopic contact angle (MCA) expression is the corresponding transversality condition. It manifests that the MCA depends only on the chemical and geometric property at the TCL, and is not affected by the gravity of the droplet and the contact area beneath the liquid. Our continuum model also shows the exploration of the pinning effect on a sharp wedge or the interface between two different phases. This investigation will help designing super-hydrophobic materials for novel micro-fluidic devices. © Science China Press and Springer-Verlag Berlin Heidelberg 2012.


Li J.,PLA Air Force Aviation University | Men K.,PLA Fourth Military Medical University | Yang Y.,PLA Air Force Aviation University | Li D.,PLA Fourth Military Medical University
Journal of Theoretical Biology | Year: 2015

A mathematical model for HCV infection is established, in which the effect of dendritic cells (DC) and cytotoxic T lymphocytes (CTL) on HCV infection is considered. The basic reproduction numbers of chronic HCV infection and immune control are found. The obtained results show that the infection dies out finally as the basic reproduction number of HCV infection is less than unity, and the infection becomes chronic as it is greater than unity. In the presence of chronic infection, the existence of immune control equilibrium is discussed completely, which illustrates that the backward bifurcation may occur under certain conditions, and that the two quantities, the sizes of the activated DC and the removed CTL during their average life-terms, play a critical role in controlling chronic HCV infection and immune response. The occurrence of backward bifurcation implies that there may be bistability for the model, i.e., the outcome of infection depends on the initial situation. By choosing the activated rate of non-activated DC or the cross-representation rate of activated DC as bifurcation number, Hopf bifurcation for certain condition shows the existence of periodic solution of the model. Again, numerical simulations suggest the dynamical complexity of the model including the instability of immune control equilibrium and the existence of stable periodic solution. © 2014 Elsevier Ltd.


Niu X.,PLA Fourth Military Medical University | Niu X.,Johns Hopkins University | Watts V.L.,Johns Hopkins University | Cingolani O.H.,Johns Hopkins University | And 10 more authors.
Journal of the American College of Cardiology | Year: 2012

Objectives: The aim of this study was to determine whether activation of β3-adrenergic receptor (AR) and downstream signaling of nitric oxide synthase (NOS) isoforms protects the heart from failure and hypertrophy induced by pressure overload. Background: β3-AR and its downstream signaling pathways are recognized as novel modulators of heart function. Unlike β1- and β2-ARs, β3-ARs are stimulated at high catecholamine concentrations and induce negative inotropic effects, serving as a "brake" to protect the heart from catecholamine overstimulation. Methods: C57BL/6J and neuronal NOS (nNOS) knockout mice were assigned to receive transverse aortic constriction (TAC), BRL37344 (β3 agonist, BRL 0.1 mg/kg/h), or both. Results: Three weeks of BRL treatment in wild-type mice attenuated left ventricular dilation and systolic dysfunction, and partially reduced cardiac hypertrophy induced by TAC. This effect was associated with increased nitric oxide production and superoxide suppression. TAC decreased endothelial NOS (eNOS) dimerization, indicating eNOS uncoupling, which was not reversed by BRL treatment. However, nNOS protein expression was up-regulated 2-fold by BRL, and the suppressive effect of BRL on superoxide generation was abrogated by acute nNOS inhibition. Furthermore, BRL cardioprotective effects were actually detrimental in nNOS -/- mice. Conclusions: These results are the first to show in vivo cardioprotective effects of β3-AR-specific agonism in pressure overload hypertrophy and heart failure, and support nNOS as the primary downstream NOS isoform in maintaining NO and reactive oxygen species balance in the failing heart. © 2012 American College of Cardiology Foundation.


Li X.,PLA Fourth Military Medical University | Chen J.,Xi'an Jiaotong University
Journal of Convergence Information Technology | Year: 2012

To improve the accuracy and efficiency of pathological diagnosis, this paper analyzes and presents knowledge acquisition, notation and reasoning mechanism of pathologic diagnosis expert system. Methods and steps of knowledge acquisition are particularly analyzed. The existing knowledge notations and reasoning mechanism are studied on the base. The pathologic system has the characters of huge information and coupling, so this paper uses production rules to note knowledge and introduced reliability to deduce imprecisely and finally generates the diagnosis report and treatment scheme. The method is of highly feasibility and effectiveness.


Ye M.,PLA Fourth Military Medical University | Zhang J.,401 Hospital | Zhang J.,PLA Fourth Military Medical University | Miao Q.,PLA Fourth Military Medical University | And 2 more authors.
Cancer Letters | Year: 2015

Curcumin has attracted increasing interest as an anti-cancer drug for decades. The mechanisms of action involve multiple cancer-related signaling pathways. Recent studies highlighted curcumin has epigenetic regulatory effects on miRNA in cancers. In the present study, we demonstrated the proapoptotic effects of curcumin in vitro and in vivo. miRNA microarray and qPCR indicated that miR-192-5p and miR-215 were the most responsive miRNAs upon curcumin treatment in H460 and A427 cells. Functional studies showed miR-192-5p/215 were putative tumor suppressors in non-small cell lung cancer. Curcumin also promoted miR-192-5p/215 expressions in A549 cells (p53 wild type) but not in H1299 cells (p53-null). Conditional knockdown of p53 by tetracycline inducible expression system significantly abrogated curcumin-induced miR-192-5p/215 upregulation in the p53 wild-type H460, A427 and A549 cells. Conversely, ectopic expression of exogenous wild-type but not R273H mutant p53 in the p53-null H1299 cells enabled miR-192-5p/215 response to curcumin treatment. The proapoptotic effects of curcumin also depended on miR-192-5p/215 induction, and antagonizing miR-192-5p/215 expression attenuated curcumin-induced apoptosis in H460, A427 and A549 cells, but not in H1299 cells. Finally, X-linked inhibitor of apoptosis (XIAP) is proved to be a novel transcriptional target of miR-192-5p/215. Taken together, this study highlights that the proapoptotic effects of curcumin depend on miR-192-5p/215 induction and the p53-miR-192-5p/215-XIAP pathway is an important therapeutic target for non-small cell lung cancer. © 2014 Elsevier Ireland Ltd.


Li Y.-N.,Xi'an Jiaotong University | Pan R.,University of New Mexico | Qin X.-J.,PLA Fourth Military Medical University | Yang W.-L.,Xi'an Jiaotong University | And 5 more authors.
Journal of Neurochemistry | Year: 2014

Blood-brain barrier (BBB) disruption occurring within the first few hours of ischemic stroke onset is closely associated with hemorrhagic transformation following thrombolytic therapy. However, the mechanism of this acute BBB disruption remains unclear. In the neurovascular unit, neurons do not have direct contact with the endothelial barrier; however, they are highly sensitive and vulnerable to ischemic injury, and may act as the initiator for disrupting BBB when cerebral ischemia occurs. Herein, we employed oxygen-glucose deprivation (OGD) and an in vitro BBB system consisting of brain microvascular cells and astrocytes to test this hypothesis. Neurons (CATH.a cells) were exposed to OGD for 3-h before co-culturing with endothelial monolayer (bEnd 3 cells), or endothelial cells plus astrocytes (C8-D1A cells). Incubation of OGD-treated neurons with endothelial monolayer alone did not increase endothelial permeability. However, when astrocytes were present, the endothelial permeability was significantly increased, which was accompanied by loss of occludin and claudin-5 proteins as well as increased vascular endothelial growth factor (VEGF) secretion into the conditioned medium. Importantly, all these changes were abolished when VEGF was knocked down in astrocytes by siRNA. Our findings suggest that ischemic neurons activate astrocytes to increase VEGF production, which in turn induces endothelial barrier disruption. © 2013 International Society for Neurochemistry.


Li X.,Wuhan University | Li X.,PLA Fourth Military Medical University | Ke B.,Wuhan University | Shi X.,Wuhan University | Du Y.,Wuhan University
Carbohydrate Polymers | Year: 2011

We prepared chitosan/chitin whisker/rectorite ternary films and studied the cooperative effects of nanofibril whisker and layered organic rectorite on the properties of chitosan matrix. The ternary film exhibited higher thermal stability and smoother surface than the whisker or rectorite reinforced binary films due to the intercalation of chitosan chains into the layered rectorite and the impregnation between the clay and rod-like whisker. With increasing the ratio of mixed fillers from 0 to 229 mg/g, the break elongation first increased to a maximum value (144%) with the mixed fillers of 114.5 mg/g and then decreased. Antimicrobial assay against Escherichia coli and Staphylococcus aureus showed that the ternary films had higher antimicrobial effect than the pure or binary films because of the significant adsorption capacities of the enlarged interlayer of rectorite. Overall, the chitosan-based ternary film with chitin whisker and rectorite proves to be a suitable material for food-packaging applications. © 2011 Elsevier Ltd © 2011 Published by Elsevier Ltd.


Shi Z.,Xi'an Jiaotong University | Wei Q.,University of Toronto | Zhang M.,PLA Fourth Military Medical University | She J.,Xi'an Jiaotong University
Critical Reviews in Eukaryotic Gene Expression | Year: 2014

Bladder cancer (UBC) is a common cancer worldwide and has a high rate of recurrence and progression despite systemic therapy. The molecular mechanisms of UBC are not completely understood. MicroRNAs are noncoding RNA molecules of approximately 23 nucleotides that play important roles in multiple steps during the progression of UBC. Here, we review the expression profiles of miRNAs and their biological functions, regulation, and clinical implications in UBC. Either down-regulation or up-regulation of miRNAs occurs in UBC through epigenetic changes or defects of the biogenesis apparatus. Deregulation of miRNAs is involved in cell-cycle arrest, apoptosis, proliferation, metastasis, drug resistance, and other functions in UBC. A number of miRNAs, including urine miRNAs, have been associated with tumor type, stage, or patient survival, and miRNAs might be developed as diagnostic or prognostic markers. Better understanding of the roles of miRNAs in UBC will shed light on the molecular mechanisms of UBC. © 2014 Begell House, Inc.


Hong L.,Xijing Hospital of Digestive Diseases | Hong L.,PLA Fourth Military Medical University | Han Y.,PLA Fourth Military Medical University | Brain L.,Johns Hopkins University
Expert Review of Gastroenterology and Hepatology | Year: 2014

Despite tremendous efforts to reduce deaths due to gastric cancer, it represents the second leading cause of cancer-related deaths worldwide. EGF receptor (EGFR) plays important roles in gastric carcinogenesis by regulation of cell cycle, angiogenesis and apoptosis. This review evaluates the functions, mechanisms and clinical uses of EGFR in gastric cancer. Although EGFR targeted single therapy shows limited effect, the combination of EGFR targeted agents with traditional chemotherapy regimens may bring about important progress in cancer therapy. More clinical trials should be performed to clarify both the prognostic and therapeutic value of EGFR in gastric cancer. © 2014 Informa UK Ltd.


Zhang L.,Xi'an Jiaotong University | Wang N.,Xi'an Jiaotong University | Zhou S.,Xi'an Jiaotong University | Ye W.,PLA Fourth Military Medical University | And 2 more authors.
Journal of Experimental and Clinical Cancer Research | Year: 2012

Background: Propofol is one of the most commonly used intravenous anaesthetic agents during cancer resection surgery, but the effect of propofol on gallbladder cancer is not clear. NF-E2-related factor 2 (Nrf2) is abundantly expressed in cancer cells and relates to proliferation, invasion, and chemoresistance. The aims of the current study were to evaluate effects of propofol on the behavior of human GC cells and role of Nrf2 in these effects. Method. The effects of propofol on cell proliferation, apoptosis, and invasion were detected by MTT assays, flow cytometry, and transwell assay. Also, activation of Nrf2 was determined by western blot, RT-PCR, and immunofluorescence assays. Nrf2 was knocked-down in GBC-SD cells by shRNA before evaluating the role of Nrf2 in the influence of propofol on biological behaviors. Results: Propofol promoted the proliferation of GBC-SD cells in a dose- and time- dependent manner. After exposure to propofol for 48 h, GBC-SD cells showed decreased apoptosis and increased invasion. Also, propofol over-expressed Nrf2 at both the protein and mRNA levels and induced translocation of Nrf2 into the nucleus. Finally, loss of Nrf2 by shRNA reversed the effect of propofol on cell proliferation, apoptosis, and invasion. Conclusion: Propofol induces proliferation and promotes invasion of GC cells through activation of Nrf2. © 2012 Zhang et al.; licensee BioMed Central Ltd.


Chen T.,PLA Fourth Military Medical University | Chen T.,123th Hospital of PLA | Fei F.,PLA Fourth Military Medical University | Jiang X.-F.,PLA Fourth Military Medical University | And 4 more authors.
Free Radical Biology and Medicine | Year: 2012

Glutamate-mediated excitotoxicity is involved in many acute and chronic brain diseases. Homer proteins, a new member of the postsynaptic scaffolding proteins, regulate glutamatergic signaling and intracellular calcium mobilization in the central nervous system. Here we investigated the effects of down-regulating Homer1b/c, a constitutively expressed long form of Homer proteins, on glutamate excitotoxicity-induced neuronal injury. In our in vitro excitotoxic models, we demonstrated that glutamate insults led to a dose-dependent neuronal injury, which was mediated by the intracellular calcium-dependent reactive oxygen species (ROS) production. We found that down-regulation of Homer1b/c with specific small interfering RNA (siRNA) improved neuronal survival, inhibited intracellular ROS production, and reduced apoptotic cell death after neurotoxicity. Homer1b/c knockdown decreased the intracellular calcium overload through inhibition of the group I metabotropic glutamate receptor (mGluR)/inositol 1,4,5-trisphosphate receptor (IP3R)-mediated Ca2 + release from the endoplasmic reticulum (ER) in injured neurons. In addition, Homer1b/c siRNA transfection attenuated the activation of eukaryotic initiation factor 2α (eIF2α), RNA-dependent protein kinase-like ER kinase (PERK) and caspase-12, and inhibited the up-regulation of glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP) after glutamate treatment. Homer1b/c knockdown also preserved the mitochondrial membrane potential (MMP), reduced cytochrome c (Cyt. c) release, and partly blocked the increase of capase-9 activity and Bax/Bcl-2 ratio. Taken together, these results suggest that down-regulation of Homer1b/c protects cortical neurons against glutamate-induced excitatory damage, and this neuroprotection may be dependent at least in part on the inhibition of calcium-dependent ROS production and the preservation of the ER and mitochondrial function. © 2011 Elsevier Inc.


Haien Z.,PLA Fourth Military Medical University | Yong J.,Xi'an Jiaotong University | Baoan M.,PLA Fourth Military Medical University | Mingjun G.,PLA Fourth Military Medical University | Qingyu F.,PLA Fourth Military Medical University
PLoS ONE | Year: 2013

Background: Total hip or knee arthroplasty is an elective procedure that is usually accompanied by substantial blood loss, which may lead to acute anemia. As a result, almost half of total joint arthroplasty patients receive allogeneic blood transfusions (ABT). Many studies have shown that post-operative auto-transfusion (PAT) significantly reduces the need for ABT, but other studies have questioned the efficacy of this method. Methods: The protocol for this trial and supporting CONSORT checklist are available as supporting information; see Checklist S1. To evaluate the efficacy of PAT, we conducted a Cochrane systematic review that combined all available data from randomized controlled trials. Data from the six included trials were pooled for analysis. We then calculated relative risks with 95% confidence intervals (CIs) for dichotomous outcomes and mean differences with 95% CIs for continuous outcomes. Findings and Conclusion: To our knowledge, this is the first meta-analysis to compare the clinical results between PAT and a control in joint replacement patients. This meta-analysis has proven that the use of a PAT reinfusion system reduced significantly the demand for ABT, the number of patients who require ABT and the cost of hospitalization after total knee and hip arthroplasty. This study, together with other previously published data, suggests that PAT drains are beneficial. Larger, sufficiently powered studies are necessary to evaluate the presumed reduction in the incidence of infection as well as DVT after joint arthroplasty with the use of PAT. © 2013 Haien et al.


Hong L.,PLA Fourth Military Medical University | Yang J.,PLA Fourth Military Medical University | Han Y.,PLA Fourth Military Medical University | Lu Q.,PLA Fourth Military Medical University | And 2 more authors.
Gene | Year: 2012

Background: Many microRNAs (miRNAs) exhibit altered expression levels in cancers, and they may be considered as valuable prognostic biomarkers for cancers. Here we aimed to summarize the recent advances in miR-210 involvement in human breast cancer and analyze the predicting role of miR-210 for survival. Methods: A meta-analysis was performed by searching PubMed, Cochrane Library, and Science Direct databases. Data were extracted from studies comparing survival in patients with breast cancer having higher expression of miR-210 with those having lower expression. Pooled hazard ratios (HRs) and 95% confidence intervals (CI) were calculated. Results: A total of 511 cases of breast cancer were involved for this global meta-analysis. For post-operational survival, the HR of higher miR-210 expression in breast cancer tissue was 3.39 (95% CI: 2.04-5.63, P < 0.05), which could significantly predict poorer survival. Conclusions: High expression of miR-210 might predict poor survival in patients with breast cancer. © 2012 Elsevier B.V.


Yan J.,PLA Fourth Military Medical University | Sun J.-F.,Xi'an Jiaotong University | Chu P.K.,City University of Hong Kong | Han Y.,Xi'an Jiaotong University | Zhang Y.-M.,PLA Fourth Military Medical University
Journal of Biomedical Materials Research - Part A | Year: 2013

Strontium-containing hydroxyapatites (Sr-HA) combine the desirable bone regenerative properties of hydroxyapatites (HA) with anabolic and anti-catabolic effects of strontium cations. In the present work, a series of SryHA [SryCa(10-y)(PO4)6(OH)2; y = 0, 0.5, 1, 2] coatings on titanium are produced by micro-arc oxidation (MAO), and the effects of the in vivo osseointegration ability of the coatings are investigated by using a rabbit model. All samples are subjected to biomechanical, surface elemental, micro-CT and histological analysis after 4 and 12 weeks of healing. The obtained results show that the MAO-formed coatings exhibit a microporous network structure composed of SryHA/Sr yHA-SrxCa(1-x)TiO3/Sr xCa(1-x)TiO3-TiO2 multilayers, in which the outer SryHA and intermediate SryHA-Sr xCa(1-x)TiO3 layers have a nanocrystalline structure. All Sr-HA coated implants induce marked improvements in the behavior of bone formation, quantity and quality of bone tissue around the implants than the control HA implant and in particular, the 20%Sr-HA coating promotes early bone formation as identified by polyfluorochrome sequential labeling. The bone-to-implant contact is increased by 46% (p < 0.05) and the pull-out strength is increased by 103% over the HA group (p < 0.01). Extensive areas of mineralized tissue densely deposit on the 20%Sr-HA coating after biomechanical testing, and the greatest improvement of bone microarchitecture are observed around the 20%Sr-HA implant. The identified biological parameters successfully demonstrate the osteoconductivity of 20%Sr-HA surfaces, which results not only in an acceleration but also an improvement of bone-implant integration. The study demonstrates the immense potential of 20%Sr-HA coatings in dental and orthopedic applications. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 101A: 2465-2480, 2013. Copyright © 2012 Wiley Periodicals, Inc.


Shan T.,Xi'an Jiaotong University | Cui X.,Xi'an Jiaotong University | Li W.,PLA Fourth Military Medical University | Lin W.,Shandong Provincial Hospital | And 3 more authors.
Cancer Science | Year: 2014

Norepinephrine and epinephrine, catecholamine hormones that are major mediators for chronic stress-induced cancers, are implicated in the progression of a number of cancer cells, including gastric adenocarcinoma. However, the underlying mechanisms of these hormones have not been well elucidated. Epithelial-mesenchymal transition (EMT) is a crucial event responsible for cancer cell invasion and metastasis. The hypothesis regarding whether the promotive effects of norepinephrine (NE) on cancer are in part due to its ability to induce an EMT program has not been proven. In this study, we show that NE does not only obviously induce EMT alterations in the morphological characteristics of gastric adenocarcinoma cells, but also increases the markers of EMT, including vimentin expression, and decreases E-cadherin expression, further resulting in cell motility and invasiveness. We also reveal that these actions are mainly mediated through the activation of β2-AR-HIF-1α-Snail signaling pathways. In summary, this study implies that NE induces EMT in gastric adenocarcinoma through the regulation of β2-AR-HIF-1α-Snail activity. The data provide a new perspective on chronic stress in a negative social and psychological state, which may be a risk factor for cancer development and progression. EMT: a novel regulatory program for stress hormone norepinephrine. EMT and gastric adenocarcinoma. © 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.


Tan H.,University of South Carolina | Biechler S.,University of South Carolina | Junor L.,University of South Carolina | Yost M.J.,University of South Carolina | And 4 more authors.
Developmental Biology | Year: 2013

Fibrous development of the extracellular matrix (ECM) of cardiac valves is necessary for proper heart function. Pathological remodeling of valve ECM is observed in both pediatric and adult cardiac disorders. It is well established that intracardiac hemodynamics play a significant role in the morphogenesis of cardiovascular tissues. However, the mechanisms that transduce mechanical forces into morphogenetic processes are not well understood. Here, we report the development of a three-dimensional, in vitro culture system that allows for culture of embryonic valve tissue under specific pulsatile flow conditions. This system was used to investigate the role that fluid flow plays in fibrous ECM expression during valve formation and to test the underlying cellular mechanisms that regulate this mechanotransduction. When cultured under pulsatile flow, developing valve tissues upregulated fibrous ECM expression at both the transcript and protein levels in comparison to no-flow controls. Flow-cultured valve tissues also underwent morphological development, as cushions elongated into leaflet-like structures that were absent in no-flow controls. Furthermore, rhoA, a member of the cytoskeletal actin-regulating GTPase family of proteins, was upregulated and activated by flow culture. Inhibition of the downstream rhoA effector kinase, ROCK, blocked flow-driven fibrous ECM accumulation and tissue stiffening, while the addition of lysophosphatidic acid (LPA), a rhoA activator, stimulated fibrous ECM deposition and tissue stiffening. These results support a prominent role for the rhoA pathway in the mechanotransduction of hemodynamic forces during fibrous remodeling of developing valve tissue. Our results also point to a potential link between regulation of the actinomyosin cytoskeleton and fibrous ECM synthesis in cardiovascular tissues. © 2012 Elsevier Inc.


Jin F.,Xi'an Jiaotong University | Mu D.,PLA Fourth Military Medical University | Xie Y.,PLA Fourth Military Medical University | Fu E.,PLA Fourth Military Medical University | Guo Y.,Xi'an Jiaotong University
Journal of Thoracic and Cardiovascular Surgery | Year: 2013

Objective: The purpose of this study was to evaluate the efficacy and safety of bronchoscopic argon plasma coagulation for tumorous endobronchial tuberculosis. Methods: We analyzed the records of 115 patients with tumorous endobronchial tuberculosis who did not show luminal narrowing of the bronchus at diagnosis. Of these 115 patients, 41 patients received bronchoscopic argon plasma coagulation plus routine antituberculosis chemotherapy (argon plasma coagulation group) and the other 74 patients received only routine antituberculosis chemotherapy (chemotherapy group). The treatment effects between these 2 groups were compared based on changes in lesions, rate of lesion disappearance, and complications associated with bronchoscopic argon plasma coagulation. Results: The complete removal rate was 100% in patients in argon plasma coagulation group. About 84.6% lesions disappeared completely in patients in the chemotherapy group. The rate of disappearance of lesions in the argon plasma coagulation group was faster than that of the chemotherapy group. There were no severe complications in the argon plasma coagulation group. Conclusions: Bronchoscopic argon plasma coagulation can accelerate the healing of tumorous endobronchial tuberculosis and can help prevent progressive bronchial stenosis resulting from tumorous endobronchial tuberculosis, and it is a very safe method. © 2013 by The American Association for Thoracic Surgery.


Zhou Y.,PLA Fourth Military Medical University | Zhang Y.,PLA Fourth Military Medical University | Yao Z.,East Tennessee State University | Moorman J.P.,East Tennessee State University | Jia Z.,PLA Fourth Military Medical University
Immunology | Year: 2012

Hepatitis C virus (HCV) has chronically infected an estimated 170million people worldwide. There are many impediments to the development of an effective vaccine for HCV infection. Dendritic cells (DC) remain the most important antigen-presenting cells for host immune responses, and are capable of either inducing productive immunity or maintaining the state of tolerance to self and non-self antigens. Researchers have recently explored the mechanisms by which DC function is regulated during HCV infection, leading to impaired antiviral T-cell responses and so to persistent viral infection. Recently, DC-based vaccines against HCV have been developed. This review summarizes the current understanding of DC function during HCV infection and explores the prospects of DC-based HCV vaccine. In particular, it describes the biology of DC, the phenotype of DC in HCV-infected patients, the effect of HCV on DC development and function, the studies on new DC-based vaccines against HCV infection, and strategies to improve the efficacy of DC-based vaccines. © The Authors. Immunology © Blackwell Publishing Ltd.


Wang L.,Xi'an Jiaotong University | Shi S.,PLA Fourth Military Medical University | Guo Z.,PLA Fourth Military Medical University | Zhang X.,PLA Fourth Military Medical University | And 4 more authors.
PLoS ONE | Year: 2013

Background and Objective:Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif