Mao J.,Xiangya Hospital |
Liu S.,Xiangya Hospital
Neuroscience Letters | Year: 2017
Purpose To investigate whether the different role of ocular dopamine was involved in the myopic development between spontaneous myopia (SM) and form deprivation myopia (FDM) in albino guinea pigs. Methods 55 myopic animals were randomly divided into SM, Levodapa (L-DOPA), L-DOPA + carbidopa and vehicle. 70 non-myopic animals were randomly divided into normal control, FDM, L-DOPA + FDM, L-DOPA + carbidopa + FDM and vehicle. Once per day, for 14 days, L-DOPA (10 mg/kg) was injected intraperitoneally, and carbidopa (1 μg) was injected at the same time into the peribulbar space of the right eye. Refractive parameters and dopamine content in neural retina and RPE/choroid complex were measured. Results In SM animals, high myopia was formed at 5 week of ages. L-DOPA treatment could reduce its myopic degree, and inhibit the increase of axial length and vitreous chamber depth with the increase of retinal dopamine in both eyes. Administration of carbidopa could prevent the increase of retinal dopamine induced by L-DOPA, but no influenced on its refractive state in the injected eyes. In non-SM animals, intraperitoneal L-DOPA could inhibit FDM, accompanied by the increase of retinal dopamine. Carbidopa treatment diminished the inhibition of FDM and prevented the increase in retinal dopamine by L-Dopa. Retinal dopamine was highly correlated with ocular refraction in FDM, but not in SM. There was no significant difference in dopamine content of RPE/choroid complex among all groups. Conclusions The role of retinal dopamine was different between SM and FDM in albino guinea pigs. Although systemic L-DOPA could inhibit the development of SM and FDM, retinal dopamine was only involved in the L-DOPA inhibition on FDM, but not on SM. © 2016 Elsevier Ireland Ltd
News Article | February 16, 2017
Scientists at Winship Cancer Institute of Emory University have mapped a vast spider web of interactions between proteins in lung cancer cells, as part of an effort to reach what was considered "undruggable." This approach revealed new ways to target cells carrying mutations in cancer-causing genes. As an example, researchers showed sensitivity to an FDA-approved drug, palbociclib, for a gene that is commonly mutated in lung cancer cells, which is now being tested in a clinical study. The results are published online in Nature Communications. Many genes that drive the growth of cancer cells don't have any drugs available against them. For "tumor suppressor" genes, researchers are often not sure how to go after them. When the tumor suppressors are gone, cells often become more deranged, but there's no bullseye left to target. Exploiting the cancer cells' derangement remains a daunting challenge, says senior author Haian Fu, PhD. "Our approach is to place tumor suppressors in the context of a network of cancer-associated proteins and link tumor suppressors to drugs through a known drug target protein," Fu says. "In this way, changes in a tumor suppressor may be linked with the response of the target to the connected drug." The study is part of a push by the National Cancer Institute's Cancer Target Discovery and Development (CTD2) network to translate genomics data into therapeutic strategies, he says. Emory is a member of the NCI CTD2 network. Fu holds the Winship Partner in Research endowed chair and is leader of Winship's Discovery and Developmental Therapeutics Program, director of the Emory Chemical Biology Discovery Center and professor of pharmacology and hematology and medical oncology. Co-corresponding author Fadlo Khuri, MD, maintains his professor appointment at Winship Cancer Institute and is now president of the American University of Beirut in Lebanon. Cancer researchers have been searching for ways to target mutations in the gene STK11/LKB1, found in 15 to 25 percent of non-small cell lung cancers. The tumor suppressor STK11/LKB11 encodes an enzyme that is thought to regulate cell migration and metabolism. One of the Winship team's newly identified interactions -- a "thread" in the spider web -- suggested that palbociclib, recently approved against metastatic breast cancer, may work against cells carrying mutations in LKB1, through LKB1's connection to CDK4, the target of palbociclib. That prediction was supported by genomic data analysis and cell culture experiments: lung cancer cells with LKB1 defects showed a tendency of increased sensitivity to palbociclib. Now a study led by Taofeek Owonikoko, MD, at Winship is using LKB1 status as a biomarker for interpreting the effect of palbociclib. If cells are complex machines, then a number of ways exist for figuring out how the machines' parts, dominated by proteins, fit together. Some of them involve multiple washing steps to remove nonspecific partners after breaking cells apart, but FRET (Förster resonance energy transfer) does not. If two fluorescent molecules with colors that are near on the spectrum are close enough (less than 10 nanometers), that proximity can be detected by FRET. Fu and his colleagues established a large-scale platform for tagging proteins with two different fluorescent molecules, introducing them into cancer cells, and then detecting interactions between the proteins. They call this network of cancer-associated proteins "OncoPPI." Starting with a set of 83 lung cancer-related proteins, the team detected more than 260 interactions that were not known previously. They tested the interactions several times, in different orientations, and in other lung cancer cell lines with selected interactions to establish reliability. More than 80 percent of the interactions the researchers detected could be confirmed by another method (GST pulldown). As an additional example to illustrate the utility of a protein interaction web, the team focused on the prominent oncoprotein Myc, which was also considered "undruggable." But the researchers could connect Myc indirectly through NSD3 to another protein called Brd4, against which inhibitors have been developed. Brd4 inhibitors are being currently tested in clinical trials. This finding revealed a new pathway Brd4-NSD3-Myc as potential targets for therapeutic intervention, Fu says. The OncoPPI research was supported by the National Cancer Institute Cancer Target Discovery and Development (CTD2) network (U01CA168449), lung cancer program project (P01CA116676) and Winship Cancer Institute (P30CA138292) and the Georgia Research Alliance, and the Emory University Research Committee. The clinical study of palbociclib is sponsored by Pfizer. Co-first authors are research associate Zenggang Li, PhD, now at Michigan State University, instructor Andrei Ivanov, PhD and Xiangya Hospital medical student Rina Su, now at Chao-yang Hospital, Capital Medical University in Beijing, China. Emory/Winship co-authors include Qi Qi, PhD, Philip Webber, PhD, Yuhong Du, PhD, Wei Zhou, PhD, Adam Marcus, PhD, Carlos Moreno, PhD, Lee Cooper, PhD and Margaret Johns, PhD, graduate students Valentina Gonzalez-Pecchi and Lauren Rusnak, and visiting medical student Songlin Liu. Collaborators from UT Southwestern contributed to the paper.
Wang R.-K.,Xiangya Hospital |
Zhang Q.-Q.,Xiangya Hospital |
Pan Y.-D.,Xiangya Hospital |
Guo Q.-L.,Xiangya Hospital
Experimental and Therapeutic Medicine | Year: 2013
In the present study, we examined the effect of etanercept on high mobility group box 1 (HMGB1) expression in dorsal root ganglion (DRG) neuron cells in a rat model of chronic constriction injury (CCI) of the sciatic nerve, with the aim of exploring the molecular mechanism underlying the therapeutic effect of etanercept on sciatica-related nociception and the potential interaction between tumor necrosis factor-α (TNF-α) and HMGB1 in DRG neuron cells. A rat CCI model was employed and the animals were randomly assigned to seven groups (n=20/group): untreated, sham only, sham/saline, sham/etanercept, CCI only, CCI/saline and CCI/etanercept. Our results revealed that compared with the sham/saline and sham/etanercept groups, thermal hyperalgesia and mechanical hyperalgesia, as well as HMGB1 expression at both the mRNA and protein levels in the DRG neuron cells, were induced by CCI, and were significantly inhibited by etanercept. Although etanercept showed no significant effect on the sham group, it significantly reduced the phosphorylated p38 mitogen-activated protein kinase (MAPK) levels induced by CCI in the DRG neuron cells. In conclusion, we demonstrated that etanercept significantly decreased the HMGB1 expression induced by CCI in the DRG neuron cells. This study not only explored the molecular mechanisms underlying the therapeutic effect of etanercept on sciatica-related nociception, but also provided indirect evidence for an interaction between TNF-α and HMGB1 in DRG neuron cells.
Li J.,Xiangya Hospital |
Cai Y.,Xiangya Hospital |
Cai Y.,Central South University
Acta Cardiologica | Year: 2015
Autophagy played a crucial role for survival when cells were sufiering from nutrient deprivation, as autophagy could engulf and degenerate macromolecules to provide new nutrients and energy. Autophagy also plays an essential role in maintaining cellular homeostasis, which was activated in response to the cellular stresses in hypertensive heart disease. Interestingly, many studies had proven that the baseline and up-regulation of autophagy played a beneficial role in myocardial hypertrophy while other studies found that up-regulated autophagy was associated with myopathies. In this review, we showed the signalling pathways which were involved in myocardial hypertrophy. Besides, we talked about the protective as well as harmful efiects of autophagy in myocardial hypertrophy. Finally, we proposed the possible reasons of dual efiects of autophagy in hypertrophy, including the degree of the activation, the stage of the disease and the signalling pathways responsible for the activation of autophagy, etc. © 2015, Acta Cardiologica. All rights reserved.
Leng A.,Xiangya Hospital
Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine | Year: 2011
The strategies for tumor-specific expression of suicide genes and target tumor angiogenesis have been tested in tumors. However, the anti-tumor efficacy of the combination of these two strategies, particularly, delivering suicide gene and anti-angiogenesis agent by nanoparticles, has not yet been evaluated in colon carcinoma. We constructed a cassette to silence VEGF-A expression and express a fused yCDglyTK gene driven by tumor-specific promoter (shVEGF-CDTK). The DNA carrying shVEGF-CDTK was delivered into colon carcinoma cells by calcium phosphate nanoparticles (CPNPs). Cell proliferation was measured by MTT assay, and apoptosis was detected by flow cytometry. The anti-tumor effect of the combined cassette was tested in xenograft animal model. With 5-fluorocytosine (5-FC), CPNP-delivered shVEGF-CDTK DNA (CPNP-shVEGF-CDTK) showed high expression of fused yCDglyTK gene and effectively silenced VEGF-A expression in vitro and in vivo, which significantly inhibited colon carcinoma cell proliferation and induced apoptosis in vitro. With 5-FC, the systemic delivery of CPNP-shVEGF-CDTK significantly inhibited tumor growth in the colon carcinoma xenograft animal model. The combined cassette is obviously effective in inhibiting tumor cell proliferation and inducing apoptosis in vitro and tumor growth in vivo than the CPNP-shVEGF or CPNP-CDTK alone. The combination of VEGF-A-silencing and tumor-specific expression of suicide gene is an effective strategy for colon carcinoma treatment.
Liu Y.,Central South University |
Lijian T.,Xiangya Hospital |
Fu X.,Xiangya Hospital |
Zhao Y.,Tulane University |
Xu X.,Xiangya Hospital
Molecular Medicine Reports | Year: 2013
Diabetic retinopathy (DR) is one of the most common diabetic eye diseases and a leading cause of blindness. It is characterized by changes in the blood vessels of the retina. The pathogenesis of DR is complex and to date, the precise mechanisms involved remain unclear. Previous studies have reported that DR is associated with neurodegeneration and that apoptosis may occur in diabetic retinas. In the present study, retinal neurons under conditions of hyperglycemia were used as a model to study apoptosis in diabetic retinas. Retinal neurons exposed to hyperglycemia exhibited high levels of apoptosis. Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, was effective in protecting retinal neurons from hyperglycemia in vitro. BDNF promoted neuronal cell survival in a concentration-dependent manner. In addition, BDNF was demonstrated to promote the expression of tropomyosin-related kinase B (TrkB) and elevate the phosphorylation levels of TrkB and ERK in retinal neurons exposed to hyperglycemia. The results of the present study demonstrated that BDNF may protect retinal neurons from hyperglycemia via the TrkB/ERK/MAPK pathway and provides novel insights into the pathogenesis of DR. Copyright © 2013 Spandidos Publications Ltd. All rights reserved.
Liu N.,Xiangya Hospital |
Zhou C.,Third Affiliated Hospital |
Zhao J.,Central South University |
Chen Y.,Central South University
Cancer Investigation | Year: 2012
The purpose of this study was to establish tumor tissue specific delivery of let-7i miRNA to reverse paclitaxel-induced chemoresistance. A chimera that combines MUC1 aptamer and let-7i miRNA was tested in OVCAR-3 ovarian cancer cells. Results demonstrated that the chimera can specifically be delivered into OVCAR-3 cells and the released let-7i significantly sensitized the role of paclitaxel in inhibiting cell proliferation, inducing cell apoptosis, and decreasing long-term cell survival. The chimera achieved reversal of chemoresistance through downregulation of cyclin D1, cyclin D2, Dicer 1, and PGRMC1 expressions. Our study indicated that this MUC1/let-7i chimera can specifically reverse chemoresistance to paclitaxel. © 2012 Informa Healthcare USA, Inc.
Gao N.,Central South University |
Qu X.,Central South University |
Yan J.,Third Xiangya Hospital |
Huang Q.,Xiangya Hospital |
And 2 more authors.
Molecular and Cellular Biochemistry | Year: 2010
Liver fatty acid-binding protein (L-FABP, FABP1) is a highly conserved key factor in lipid metabolism. This study was undertaken to verify whether the T94A mutation in the L-FABP gene affects fatty acid uptake and intracellular esterification into specific lipid pools. Candidate SNPs were recreated using site-directed mutagenesis and tested for physical function in stably transfected Chang liver cell lines. We found that the T94A mutant of L-FABP lowered FFA uptake but had no effect on FFA efflux. L-FABP T94A-expressing cells showed decreased triglyceride content and increased cholesterol accumulation compared to the wild-type control for cells incubated with an FFA mixture (oleate: palmitate, 2:1 ratio). In conclusion, our study provided additional indications of the functional relevance of the L-FABP T94A SNP in hepatic fatty acid and lipid metabolism in humans. © 2010 Springer Science+Business Media, LLC.
Sun Y.,Xiangya Hospital |
Long J.,Xiangya Hospital |
Zhou Y.,Central South University
Oncology Letters | Year: 2014
In the present study, the association between angiopoietin-like 4 (ANGPTL4) and aldolase A (ALDOA) in human melanoma cell invasion and survival was investigated. Overexpression and knockdown of ANGPTL4 were respectively performed in WM-115 and WM-266-4 cells. ALDOA expression at both the mRNA and the protein levels as well as the ALDOA gene promoter activities were increased and decreased in parallel with overexpression and knockdown of ANGPTL4 in the melanoma cells, which was blocked by selective protein kinase C (PKC) inhibitor and restored by PKC agonist, respectively. ANGPTL4 overexpression significantly increased cell invasion and matrix metalloproteinase-2 (MMP-2) expression and decreased cell apoptosis against cisplatin in WM-115 cells, which was reversed by knocking down ALDOA. In WM-266-4 cells, knockdown of ANGPTL4 decreased cell invasion and MMP-2 expression and increased cell apoptosis against cisplatin, which was reversed by overexpression of ALDOA. In conclusion, this study demonstrates that ANGPTL4 upregulates ALDOA expression in human melanoma cells at the ALDOA gene promoter/transcriptional level through a PKC-dependent mechanism, and that ALDOA is a critical mediator of the promoting effect of ANGPTL4 on melanoma cell invasion, likely through upregulating the MMP-2 expression. Additionally, our results suggest that ALDOA plays an important role in ANGPTL4-enhanced melanoma cell survival against apoptotic stress, which implicates ANGPTL4 and ALDOA in the development of melanoma chemoresistance.
Zhao J.,Central South University |
Zhang Q.,Central South University |
Wang Y.,Central South University |
Li Y.,Central South University |
Li Y.,Xiangya Hospital
Fertility and Sterility | Year: 2014
Result(s): In the analysis of pregnancy, 16 cohort studies (3,106 couples) were included. Of these, 14 studies (2,756 couples, 965 pregnancies) that also mentioned miscarriage were identified in the analysis of miscarriage. Meta-analysis showed that high-level sperm DNA fragmentation has a detrimental effect on outcome of IVF/ICSI, with decreased pregnancy rate and increased miscarriage rate. The stratified analysis by type of procedure (IVF vs. ICSI) indicated that high sperm DNA damage was related to lower pregnancy rates in IVF but not in ICSI cycles, whereas it was associated with higher miscarriage rates in both IVF and ICSI cycles.Conclusion(s): The results indicate that assays detecting sperm DNA damage should be recommended to those suffering from recurrent failure to achieve pregnancy. Selection of sperm without DNA damage for use may improve the clinical outcome of ART. The data also provide a rationale for conducting further research aimed at evaluating the underlying mechanism(s) responsible for the detrimental effect of high sperm DNA fragmentation and the potential therapy.Objective: To examine whether sperm DNA fragmentation has an effect on pregnancy and miscarriage after IVF and/or intracytoplasmic sperm injection (ICSI).Design: Systematic review and meta-analysis.Setting: University-affiliated teaching hospital.Patient(s): Infertility patient(s).Intervention(s): An exhaustive electronic literature search was conducted on MEDLINE, Google Scholar, and the Cochrane Library, from database inception to October 2013. We included clinical trials that examined the influence of sperm DNA damage on pregnancy and miscarriage of IVF/ICSI.Main Outcome Measure(s): The outcomes of interest were pregnancy rate and miscarriage rate. © 2014 American Society for Reproductive Medicine.