Chongqing, China
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Yu H.,Daping Hospital | Yu H.,Second Affiliated Hospital | Jin H.,Peking University | Gong W.,First Affiliated Hospital | And 2 more authors.
Molecules | Year: 2013

Evodiamine, a naturally occurring indole alkaloid, is one of the main bioactive ingredients of Evodiae fructus. With respect to the pharmacological actions of evodiamine, more attention has been paid to beneficial effects in insults involving cancer, obesity, nociception, inflammation, cardiovascular diseases, Alzheimer's disease, infectious diseases and themoregulative effects. Evodiamine has evolved a superior ability to bind various proteins, so we also argue that it is good starting point for multi-target drugs. This review is primarily addressed to the description of the recent advances in the biological activity studies of evodiamine, with a focus on pharmacological mechanism. The present review also includes the pharmacokinetics and the detailed exploration of target-binding properties of evodiamine in an attempt to provide a direction for further multi-target drug design. © 2013 by the authors.


Wang W.E.,Daping Hospital | Yang D.,Daping Hospital | Li L.,Daping Hospital | Peng Y.,Daping Hospital | And 15 more authors.
Circulation Research | Year: 2013

Rationale: Transplantation of stem cells into damaged hearts has had modest success as a treatment for ischemic heart disease. One of the limitations is the poor stem cell survival in the diseased microenvironment. Prolyl hydroxylase domain protein 2 (PHD2) is a cellular oxygen sensor that regulates 2 key transcription factors involved in cell survival and inflammation: hypoxia-inducible factor and nuclear factor-κB. Objective: We studied whether and how PHD2 silencing in human adipose-derived stem cells (ADSCs) enhances their cardioprotective effects after transplantation into infarcted hearts. Methods and Results: ADSCs were transduced with lentiviral short hairpin RNA against prolyl hydroxylase domain protein 2 (shPHD2) to silence PHD2. ADSCs, with or without shPHD2, were transplanted after myocardial infarction in mice. ADSCs reduced cardiomyocyte apoptosis, fibrosis, and infarct size and improved cardiac function. shPHD2-ADSCs exerted significantly more protection. PHD2 silencing induced greater ADSC survival, which was abolished by short hairpin RNA against hypoxia-inducible factor-1α. Conditioned medium from shPHD2-ADSCs decreased cardiomyocyte apoptosis. Insulin-like growth factor-1 (IGF-1) levels were significantly higher in the conditioned medium of shPHD2-ADSCs versus ADSCs, and depletion of IGF-1 attenuated the cardioprotective effects of shPHD2-ADSC-conditioned medium. Nuclear factor-κB activation was induced by shPHD2 to induce IGF-1 secretion via binding to IGF-1 gene promoter. Conclusions: PHD2 silencing promotes ADSCs survival in infarcted hearts and enhances their paracrine function to protect cardiomyocytes. The prosurvival effect of shPHD2 on ADSCs is hypoxia-inducible factor-1α dependent, and the enhanced paracrine function of shPHD2-ADSCs is associated with nuclear factor-κB-mediated IGF-1 upregulation. PHD2 silencing in stem cells may be a novel strategy for enhancing the effectiveness of stem cell therapy after myocardial infarction. © 2013 American Heart Association, Inc.


Wu G.,Daping Hospital | Wu G.,Harvard University | Cai J.,Daping Hospital | Han Y.,Daping Hospital | And 18 more authors.
Circulation | Year: 2014

Background: Long noncoding RNAs (lncRNAs) have recently been implicated in many biological processes and diseases. Atherosclerosis is a major risk factor for cardiovascular disease. However, the functional role of lncRNAs in atherosclerosis is largely unknown. Methods and Results: We identified lincRNA-p21 as a key regulator of cell proliferation and apoptosis during atherosclerosis. The expression of lincRNA-p21 was dramatically downregulated in atherosclerotic plaques of ApoE-/-mice, an animal model for atherosclerosis. Through loss- and gain-of-function approaches, we showed that lincRNA-p21 represses cell proliferation and induces apoptosis in vascular smooth muscle cells and mouse mononuclear macrophage cells in vitro. Moreover, we found that inhibition of lincRNA-p21 results in neointimal hyperplasia in vivo in a carotid artery injury model. Genome-wide analysis revealed that lincRNA-p21 inhibition dysregulated many p53 targets. Furthermore, lincRNA-p21, a transcriptional target of p53, feeds back to enhance p53 transcriptional activity, at least in part, via binding to mouse double minute 2(MDM2), an E3 ubiquitin-protein ligase. The association of lincRNA-p21 and MDM2 releases MDM2 repression of p53, enabling p53 to interact with p300 and to bind to the promoters/enhancers of its target genes. Finally, we show that lincRNA-p21 expression is decreased in patients with coronary artery disease. Conclusions: Our studies identify lincRNA-p21 as a novel regulator of cell proliferation and apoptosis and suggest that this lncRNA could serve as a therapeutic target to treat atherosclerosis and related cardiovascular disorders.


Hao L.,No 324 Hospital Of Pla | Sun H.,Chongqing Medical University | Wang J.,Daping Hospital | Wang T.,Chongqing Medical University | And 2 more authors.
International Journal of Hematology | Year: 2012

Mesenchymal stromal cells (MSC) have attracted the attention of scientists and clinicians due to their self-renewal, capacity for multipotent differentiation, and immunomodulatory properties. Some essential problems remain to be solved before the clinical application of MSC. Platelet lysate (PL) has recently been used as a substitute for FBS in MSC amplification in vitro to achieve clinically applicable numbers of MSC. In addition to promising trials in regenerative medicine, such as in the treatment of major bone defects and myocardial infarction, MSC have shown therapeutic effect other than direct hematopoiesis support in hematopoietic reconstruction. It has been confirmed that MSC promote hematopoietic cell engraftment and immune recovery after allogeneic hematopoietic stem cell transplantation, probably through the provision of cytokines, matrix proteins, and cell-to-cell contacts. Their suppressive effects on immune cells, including T cells, B cells, NK cells and DC cells, suggest MSCs as a novel therapy for GVHD and other autoimmune disorders. These cells thus present as promising candidates for cellular therapy in the fields of regenerative medicine, allogeneic hematopoietic stem cell transplantation, and autoimmune disorders. © 2011 The Japanese Society of Hematology.


Tu Y.-J.,Daping Hospital | Tu Y.-J.,174th Hospital of PLA | Fan X.,Daping Hospital | Yang X.,Daping Hospital | And 2 more authors.
Oncology Reports | Year: 2013

Autophagy is a self-defense mechanism that provides nutrition and energy for cell survival by recycling the cytoplasm and organelles. Hence, chemotherapy is rendered less effective against cancer cells. Evodiamine is a previously described biological agent that possesses a cytotoxic activity in multiple cancer cells. However, little is known about evodiamine-induced autophagy in Lewis lung carcinoma (LLC) cells. In this study, LLC cells and a xenograft model were used. By use of a panel of techniques such as MTT assay, flow cytometry, western blotting, immunocytochemistry and TUNEL assay, the effects on the induction of apoptosis and autophagy were evaluated. We demonstrated that evodiamine inhibited LLC cell growth and induced apoptosis through caspase-independent manner in vitro and caspase-dependent pathway in vivo. In addition, we showed for the first time that evodiamine promoted autophagosome formation by enhancing the conversion of microtubule-associated protein 1 light chain 3 (LC3)-I to LC3-II and upregulating the expression of autophagy-specific genes (Atgs). Moreover, 3-methyladenine (3-MA), an autophagy inhibitor, attenuated evodiamine-induced autophagy through decreasing the conversion of LC3-I to LC3-II. The inhibition of autophagy was found to increase cell death and enhance evodiamine-induced apoptosis in vitro in a caspase-independent manner and in vivo in a caspase-dependent manner. In conclusion, evodiamine promoted autophagy in LLC cells and autophagy inhibition enhanced evodiamine-induced apoptosis in vitro and in vivo. These results demonstrate that evodiamine-induced autophagy plays a cytoprotective role in LLC cells and evodiamine combined with autophagy inhibitor therapy could increase the chemosensitivity of LLC cells.


Pi Y.,Daping Hospital | Zhang L.-L.,Daping Hospital | Li B.-H.,Daping Hospital | Guo L.,Daping Hospital | And 3 more authors.
Laboratory Investigation | Year: 2013

Reactive oxygen species (ROS) are associated with inflammation and vasculature dysfunction. This study aimed to investigate the potential role of the ROS on vascular Toll-like receptor 4 (TLR4)-mediated proinflammatory and proliferative phenotype of vascular smooth muscle cells (VSMCs). A wire-induced carotid injury model was used in male TLR4-deficient (TLR4-/-) and wild-type C57BL/6J mice to induce neointima formation. In the presence or absence of the ROS scavenger apocynin for 14 days, increased TLR4 and proinflammatory cytokines were observed in wire injury-induced carotid neointima and in platelet-derived growth factor-BB (PDGF-BB)-stimulated VSMCs. The TLR4-/- protected the injured carotid from neointimal formation and impaired the cellular proliferation and migration in response to PDGF-BB. Apocynin attenuated intimal hyperplasia. Pre-treatment with apocynin significantly inhibited intracellular ROS generation, accompanied by a significant suppression of TLR4 and proinflammatory cytokines expression, and VSMC proliferation and migration. However, the results were not obvious in TLR4-/- condition. These findings highlight the importance of ROS inhibition in TLR4-mediated proinflammatory and proliferative phenotype of VSMCs, and suggest ROS as an essential therapeutic target for TLR4-associated vascular inflammation and vascular diseases. © 2013 USCAP, Inc All rights reserved.


Li L.,Daping Hospital | Yin Z.,Daping Hospital | Liu J.,Daping Hospital | Li G.,Daping Hospital | And 3 more authors.
Journal of Neurology | Year: 2013

Studies of the relationship between Alzheimer's disease (AD) and single nucleotide polymorphism (SNP) T/C in intron 2 of the cholesterol-24S-hydroxylase gene (CYP46A1) have reported inconsistent results. To confirm the association between the CYP46A1 T/C polymorphism and AD risk, a meta-analysis containing 4,875 AD cases and 4,874 controls from 21 case-control studies was performed. There were 16 studies involving Europeans, four studies with Asians and one study with Africans. The combined results of overall analysis showed that the CYP46A1 T/C polymorphism increased the risk of AD significantly in recessive model [CC versus CT + TT, odds ratio (OR) = 1.20, 95 % confidence interval (CI) = 1.04-1.38, p = 0.01]. On subgroup analysis by ethnicity, similarly significant differences in recessive model were also found in Europeans. Another analysis of the synergistic effect of the CYP46A1 T/C polymorphism and the ε4 allele of the apolipoprotein E gene (APOE ε4) was performed in eight studies with available stratified information. The results revealed that the presence of APOE ε4 allele could strengthen the effect of CC genotype on AD risk, and the reverse was also true. In conclusion, our meta-analysis has successfully proved that CC genotype of the CYP46A1 T/C polymorphism could increase the risk of AD, and this effect would be weakened in APOE ε4 non-carriers and strengthened in APOE ε4 carriers. © 2012 Springer-Verlag Berlin Heidelberg.


Li T.,Daping Hospital | Liu Z.,Chongqing Medical University
Medical Hypotheses | Year: 2010

Benign prostatic hyperplasia (BPH) is a world-wide common disease in elderly male patients. A number of invasive physiotherapies have been used to replace prostatectomy. In this article we report our hypothesis of using microbubbles-mediated ultrasound cavitation effects to ablate prostatic tissues. Microbubble ultrasound contrast agent is widely used contrast media in ultrasonography, yet it is also found to act as cavitation nuclei or enhancer. Once excited by a high peak pressure ultrasound pulse, the mechanical effects, like shock wave and microstream, released from cavitation could produce a series of bioeffects, contributing to sonoporation, microvascular rupture and hematoma. BPH is known to have hyperplastic neovasculature and this make it possible to be disrupted by the physical effects of cavitation under existing microbubbles in circulation. Mechanical ablation of prostatic capillary or small vessels could result in pathological alterations such as thrombosis, micro-circulation blockage, prostatic necrosis and atrophia. Thereupon it could effectively treat BPH by nontraumatic ways. © 2009 Elsevier Ltd. All rights reserved.


Fu L.-Y.,Chongqing Medical University | Dai L.-M.,Chongqing Medical University | Li X.-G.,Daping Hospital | Zhang K.,Chongqing Medical University | Bai Y.,Chongqing Medical University
European Journal of Obstetrics Gynecology and Reproductive Biology | Year: 2014

Objectives To re-estimate the association between methylenetetrahydrofolate reductase gene (MTHFR) C677T polymorphism and polycystic ovary syndrome (PCOS) risk by critically reviewing, analyzing and updating the current evidence. MTHFR C677T polymorphism has been studied as a possible risk factor for a variety of common conditions including heart disease, stroke and hypertension. Its association with PCOS was negative in a previous meta-analysis which had possible shortcomings. More studies have now been done but their results remain inconclusive. Study design Available case-control studies containing genotype frequencies of MTHFR C677T were chosen, and odds ratio (OR) with 95% confidence interval (CI) was used to assess the strength of the association. Statistical analyses were performed using software Review Manager (Version 5. 2) and Stata (Version 11.0). Results Nine case-control studies including 638 PCOS and 759 healthy controls were identified. Meta-analysis showed a significant effect in the dominant model (TT+CT vs. CC: OR = 1.65, 95%CI = 1.28-2.12, P < 0.0001) and heterozygote comparison (CT vs. CC: OR = 1.83, 95%CI = 1.17-2.87, P = 0.008). In subgroup analysis stratified by ethnicity, MTHFR C677T variant was statistically significantly relevant to PCOS risk in European populations (TT+CT vs. CC: OR = 2.16, 95%CI = 1.50-3.12, P < 0.0001; CT vs. CC: OR = 2.11, 95%CI = 1.15-3.87, P = 0.02) but not in Asian populations (TT+CT vs. CC: OR = 1.29, 95%CI = 0.91-1.82, P = 0.15; CT vs. CC: OR = 1.31, 95%CI = 0.91-1.90, P = 0.15). Conclusions This meta-analysis indicates that the 677T allele increases PCOS susceptibility, and this relevance seems to be more intense in Europeans than in Asians. © 2013 Published by Elsevier Ireland Ltd.


Li Y.,Daping Hospital | Liu L.,Biowave Center | Wang B.,Daping Hospital | Wang J.,Daping Hospital | Chen D.,Daping Hospital
European Journal of Gastroenterology and Hepatology | Year: 2014

OBJECTIVES: Hematocrit levels are commonly elevated in patients with nonalcoholic fatty liver disease (NAFLD) and related to hypoxia and hyperlipidemia. AIM: This study was conducted to investigate the association between elevated hematocrit and liver histology in patients with NAFLD. PATIENTS AND METHODS: We examined 215 consecutive adults with biopsy-proven NAFLD (108 with steatosis alone, 107 with nonalcoholic steatohepatitis) and 110 controls. The stage of fibrosis was measured using a four-point scale. All underwent anthropometric and metabolic profiling. Hematocrit and related hematologic variables such as blood viscosity and red blood cell count were also measured. RESULTS: NAFLD morbidity was found to be positively correlated with hematocrit levels. After adjusting for age, smoking, diabetes, BMI, homeostasis model assessment of insulin resistance, triglycerides, and obstructive sleep apnea, patients with hematocrit levels in the highest quartile were seen to have had an odds ratio of 3.05 (95% confidence interval 2.12-4.36, P=0.015) for NAFLD in males. Hematocrit levels increased significantly (P<0.001) in steatosis (42.4±4.6%) compared with control groups (38.2±4.2%), and in nonalcoholic steatohepatitis (45.1±5.2%) compared with steatosis patients. On multivariate analysis, hematocrit levels were found to be strongly and independently associated with fibrosis (β=0.205, P=0.030). Moreover, hematocrit levels increased with the severity of hepatic fibrosis (P<0.05). CONCLUSION: Our results indicate that hematocrit levels are significantly increased and independently associated with fibrosis in NAFLD patients. Therefore, hematocrit levels may have potential interest as a clinical marker of NAFLD severity. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.

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