Tu Y.,Fourth Military Medical University |
Gao X.,Fourth Military Medical University |
Gao X.,Xian Medical University |
Gao X.,Shanghai Institute of Technology |
And 7 more authors.
Cancer Research | Year: 2013
Malignant gliomas are the most common central nervous system tumors and the molecular mechanism driving their development and recurrence is still largely unknown, limiting the treatment of this disease. Here, we show that restoring the expression of miR-218, a microRNA commonly downregulated in glioma, dramatically reduces the migration, invasion, and proliferation of glioma cells. Quantitative reverse transcription PCR and Western blotting analysis revealed that expression of the stem cell-promoting oncogene Bmi1 was decreased after overexpression of miR-218 in glioma cells. Mechanistic investigations defined Bmi1 as a functional downstream target of miR-218 through which miR-218 ablated cell migration and proliferation. We documented that miR-218 also blocked the self-renewal of glioma stem-like cells, consistent with the suggested role of Bmi1 in stem cell growth. Finally, we showed that miR-218 regulated a broad range of genes involved in glioma cell development, including Wnt pathways that suppress glioma cell stem-like qualities. Taken together, our findings reveal miR-218 as a tumor suppressor that prevents migration, invasion, proliferation, and stemlike qualities in glioma cells. © 2013 American Association for Cancer Research.
News Article | November 17, 2016
(Philadelphia, PA) - The inability of cells to eliminate damaged proteins and organelles following the blockage of a coronary artery and its subsequent re-opening with angioplasty or medications - a sequence known as ischemia/reperfusion - often results in irreparable damage to the heart muscle. To date, attempts to prevent this damage in humans have been unsuccessful. According to a new study by scientists at the Lewis Katz School of Medicine at Temple University (LKSOM), however, it may be possible to substantially limit reperfusion injury by increasing the expression of a protein known as Bcl-2-associated athanogene 3 (BAG3). "We found that BAG3 plays a pivotal role in protecting the heart from damage caused by reperfusion injury," explained the study's lead author, Feifei Su, MD, PhD, a postdoctoral fellow in the laboratory of Arthur M. Feldman, MD, PhD, Professor of Medicine at LKSOM. Ischemia impairs the function of cellular organelles including mitochondria, the cell's energy-producers, resulting in harmful effects that set the stage for a sudden burst in the generation of toxic oxidizing substances when oxygenated blood reenters the heart. The toxins lead to fundamental changes in the biology of the heart. Notably, they activate cell death pathways and decrease autophagy - the process by which cells remove malfunctioning proteins and organelles. Autophagy plays a critical role in removing damaged myocardial cells (the muscular tissue of the heart) and misfolded heart muscle fibers. The new work shows that BAG3 expression both inactivates cell death pathways, helping prevent the loss of heart cells triggered by ischemia, and activates autophagy, thereby enabling cells to clear out impaired components of the heart cell before they inflict extensive damage. The findings, published online November 17 in the journal JCI Insight, open the door to the investigation of BAG3 as a therapeutic target during reperfusion in heart attack patients. In initial work, the research group found that BAG3 promotes autophagy and inhibits programmed cell death (apoptosis) in cultured cardiac myocytes. Subsequently, they found that when heart cells were exposed to the stress of hypoxia/reoxygenation or when living mice were stressed with ischemia/reperfusion, they suffered dramatic reductions in BAG3 expression. Those paradoxical changes in BAG3 levels turned out to be directly associated with increases in biomarkers of autophagy and with decreases in biomarkers of apoptosis. By artificially knocking down BAG3 in mouse heart cells, the researchers were able to produce an apoptosis-autophagy biomarker phenotype nearly identical to that produced by hypoxia/reoxygenation. By contrast, BAG3 overexpression normalized apoptosis and autophagy. In a key experiment, the Temple team further showed that tissue damage sustained following ischemia/reperfusion could be substantially reduced by treating mice with BAG3 prior to vessel re-opening. BAG3 overexpression before the onset of ischemia/reperfusion also resulted in normalization in apoptosis and autophagy biomarkers. According to Dr. Feldman, the senior investigator on the project, his team's interest in the role of BAG3 in the heart has grown in recent years, owing to their discovery of a unique BAG3 mutation in a family with familial dilated cardiomyopathy, a genetic condition characterized by the development of heart failure between early and late adulthood. "After finding that a mutation in BAG3 caused heart failure in a Philadelphia family, we have been trying to figure out what the protein does in the heart," Dr. Feldman said. "Now that we have a better understanding of its role and what happens when its levels are increased, we can investigate the possibility of targeting BAG3 in human patients using gene therapy or a small molecule." Other researchers on the new study include Feifei Su in the Department of Medicine at LKSOM, Temple University, and the Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China; Valerie D. Myers in the Department of Medicine at LKSOM, Temple University; Tijana Knezevic, Farzaneh G. Tahrir, Manish K. Gupta, Jennifer Gordon, and Kamel Khalili in the Department of Neuroscience at LKSOM, Temple University; JuFang Wang, Ehre Gao, Muniswamy Madesh, Joseph Rabinowitz, Douglas G. Tilley, and Joseph Y. Cheung in the Center for Translational Medicine at LKSOM, Temple University; and Frederick V. Ramsey in the Department of Clinical Sciences at LKSOM, Temple University. The research was supported by National Institutes of Health grants P01 HL 091799-01 and R01 HL123093. Temple University Health System (TUHS) is a $1.6 billion academic health system dedicated to providing access to quality patient care and supporting excellence in medical education and research. The Health System consists of Temple University Hospital (TUH), ranked among the "Best Hospitals" in the region by U.S. News & World Report; TUH-Episcopal Campus; TUH-Northeastern Campus; Fox Chase Cancer Center, an NCI-designated comprehensive cancer center; Jeanes Hospital, a community-based hospital offering medical, surgical and emergency services; Temple Transport Team, a ground and air-ambulance company; and Temple Physicians, Inc., a network of community-based specialty and primary-care physician practices. TUHS is affiliated with the Lewis Katz School of Medicine at Temple University. The Lewis Katz School of Medicine (LKSOM), established in 1901, is one of the nation's leading medical schools. Each year, the School of Medicine educates approximately 840 medical students and 140 graduate students. Based on its level of funding from the National Institutes of Health, the Katz School of Medicine is the second-highest ranked medical school in Philadelphia and the third-highest in the Commonwealth of Pennsylvania. According to U.S. News & World Report, LKSOM is among the top 10 most applied-to medical schools in the nation. Temple Health refers to the health, education and research activities carried out by the affiliates of Temple University Health System (TUHS) and by the Katz School of Medicine. TUHS neither provides nor controls the provision of health care. All health care is provided by its member organizations or independent health care providers affiliated with TUHS member organizations. Each TUHS member organization is owned and operated pursuant to its governing documents.
PubMed | Xijing University, Fourth Military Medical University and PLA Fourth Military Medical University
Type: | Journal: Clinical cancer research : an official journal of the American Association for Cancer Research | Year: 2017
Purpose Chemo-resistance is the main cause of treatment failure in cancer and is associated with distant metastases and epithelial-to-mesenchymal transition (EMT). This study aimed to explore the mechanism of metastases and EMT in chemo-resistant gastric cancer (GC). Experimental Design A key molecular pathway was identified via gene profiling and a bioinformatic analysis in a chemo-resistant GC model. The roles of FOXL2, HMGA2 and ITGA2 were validated via loss-of-function and gain-of-function experiments in vitro and in an orthotopic GC animal model. The regulation of FOXL2 by HMGA2 was explored via immunoprecipitation and luciferase reporter assays. The expression of these proteins in GC tissues was examined by immunohistochemistry. Results HMGA2 and FOXL2 directly regulated the metastasis and EMT of chemo-resistant GC. The interaction between HMGA2 and pRb facilitated the transactivation of FOXL2 by E2F1, and ITGA2 was the downstream effector of the HMGA2-FOXL2 pathway. HMGA2, FOXL2 and ITGA2 were associated with the TNM classification and staging of GC and were increased in metastatic lymph nodes and distant metastases. Increased HMGA2, FOXL2 and ITGA2 levels were associated with reduced overall survival periods of GC patients. Conclusions This study demonstrated that the transactivation of FOXL2 driven by interactions between HMGA2 and pRb might exert critical effects on the metastases and EMT of chemo-resistant GC. Blocking the HMGA2-FOXL2-ITGA2 pathway could serve as a new strategy for GC treatment.
Wang M.-Q.,PLA Fourth Military Medical University |
He J.-J.,Fourth Military Medical University |
Chen C.-S.,Shaanxi University of Chinese Medicine |
Widmalm S.E.,Karolinska Institutet
Cranio - Journal of Craniomandibular Practice | Year: 2011
The aim of this study was to test the hypothesis that condylar and occlusion asymmetry are not associated. For each of 22 skulls, the asymmetry of condyles was graded by one examiner and the asymmetry of occlusion by another examiner, both blinded to each other's evaluation, as 0 = symmetrical, 1 = mild asymmetrical and 2 = severe asymmetrical. There were 18 condyles graded the same as to their occlusion, but in four, the grades differed by one degree. Nine were graded symmetrical, seven were mild, and six were graded severely asymmetrical condyles. The corresponding figures for occlusion were: 10 were graded symmetrical, seven were graded mildly asymmetrical, and five were graded severely asymmetrical occlusion. The relation between occlusion and condylar asymmetry was tested using Goodman-Kruskal's gamma and was found to be 0.970 (p<0.001). The null hypothesis was not supported. The results indicate that asymmetry of occlusion and condyles are associated, which indicates the need for further studies on larger samples, and in vivo studies.
Yang H.,PLA Fourth Military Medical University |
Gao L.-N.,PLA Fourth Military Medical University |
An Y.,PLA Fourth Military Medical University |
Hu C.-H.,PLA Fourth Military Medical University |
And 4 more authors.
Biomaterials | Year: 2013
Gingival tissue-derived mesenchymal stem cells (MSCs) were recently identified and characterized as having multipotential differentiation and immunomodulatory properties invitro and invivo, and they represent new postnatal stem cell types for cytotherapy and regenerative medicine. However, the utility of gingival MSCs (GMSCs) as alternatives to periodontal ligament stem cells (PDLSCs), which have been demonstrated to be effective but with limited cell availability and reduced clinical feasibility, for periodontal regeneration in a previously diseased/inflamed environment remains obscure. In this study, patient-matched human GMSCs and PDLSCs were evaluated in terms of their colony-forming ability, proliferative capacity, cell surface epitopes, multi-lineage differentiation potentials, and related gene expression when incubated in different designed culture conditions, with or without the presence of inflammatory cytokines. An invivo ectopic transplantation model using transplants from inflammatory cytokine-treated or untreated cells was applied to assess bone formation. We found that cells derived from both tissues expressed MSC markers, including CD146, CD105, CD90, CD29, and STRO-1. Both cells successfully differentiated under osteogenic, adipogenic, and chondrogenic microenvironments; PDLSCs displayed a more effective differentiation potential in all of the incubation conditions compared to GMSCs (P<0.01). Although inflammatory cytokine-treated GMSCs and PDLSCs are inferior to normally cultured, patient and tissue-matched cells in terms of their osteogenic capacity and regenerative potential (P<0.05), they retain the capacity for osteoblastic and adipose differentiation, as well as ectopic bone formation, similar to what has been demonstrated for other MSCs. Interestingly, GMSCs exhibited fewer inflammation-related changes in terms of osteogenic potential invitro and bone formation invivo compared to PDLSCs (P<0.01). These results suggest that both gingiva and PDL tissues are putative cell sources for future cytotherapeutic applications. Whether GMSCs act as an adjunctive or alternative cell source for cytotherapy of inflammatory periodontal disease warrants further investigation. © 2013 Elsevier Ltd.
PubMed | Fourth Military Medical University and PLA Fourth Military Medical University
Type: Journal Article | Journal: Journal of periodontology | Year: 2016
The activation of the unfolded protein response (UPR) has been demonstrated in periodontal diseases. However, the cellular and molecular mechanisms by which the UPR is induced in periodontitis remain unclear. In this study, the effects of lipopolysaccharide (LPS) on the induction of the UPR in human periodontal ligament fibroblasts (HPDLFs) in vitro are investigated.HPDLFs isolated from human PDLs were stimulated with various concentrations of Escherichia coli LPS (0.1, 1, and 10 g/mL) for the indicated time points (0, 3, 6, 9, 12, and 18 hours). The messenger RNA (mRNA) and protein levels of molecular markers associated with UPR activation, such as glucose-regulated protein 78 (GRP78), X-box binding protein 1 (XBP1), and C/EBP homologous protein (CHOP), were measured at different time points of LPS treatment. Apoptosis of HPDLFs was assessed by Annexin V-FITC and propidium iodide staining, followed by flow cytometry.LPS treatment of HPDLFs increased GRP78 mRNA and protein levels in a concentration-dependent manner. Additionally, LPS also induced the expression, splicing, and activation of XBP1 mRNA. Moreover, LPS-induced CHOP expression was concentration dependent: a lower concentration of LPS (0.1 g/mL) had no effect on CHOP mRNA levels, but higher concentrations of LPS (1 and 10 g/mL) markedly increased CHOP mRNA and protein expression without inducing apoptosis.The findings demonstrate that activating the Toll-like receptor-4 signaling pathway in HPDLFs using LPS triggers the UPR in vitro, warranting additional investigation into the precise mechanisms by which pathways promote this response under inflammatory conditions.
PubMed | Fourth Military Medical University, PLA Fourth Military Medical University and Nanjing University
Type: Journal Article | Journal: Journal of periodontology | Year: 2016
This study aims to evaluate the performance of chitosan/anorganic bovine bone (C/ABB) scaffold seeded with human jaw bone marrow-derived mesenchymal stem cells (hJBMMSCs) in supporting the healing/repair of 1-wall critical-size periodontal defects.Physical properties of the C/ABB scaffold were compared with those of the chitosan scaffold. hJBMMSCs were obtained from healthy human alveolar bone during the extraction of third molar impacted teeth. One-wall (7 4 mm) infrabony defects were surgically created at the bilateral mandibular third premolars and first molars in six beagles. The defects were randomly assigned to six groups and implanted with different scaffolds: 1) chitosan (C) scaffold; 2) C scaffold with hJBMMSCs (C + cell); 3) C/ABB scaffold (C/ABB); 4) C/ABB scaffold with hJBMMSCs (C/ABB + cell); 5) ABB scaffold (ABB); and 6) open flap debridement (control). The animals were euthanized 8 weeks after surgery for histologic analysis.The C/ABB scaffold had a porous structure and increased compressive strength. Both C/ABB and C/ABB + cell exhibited the newly formed cellular mixed-fiber cementum, woven/lamellar bone, and periodontal ligament. Cementum formation was significantly greater in group C/ABB + cell than in group C/ABB (2.64 0.50 mm versus 0.91 0.55 mm, P <0.05). For new bone (NB) height, group C/ABB + cell and C/ABB showed mean SD values of 2.83 0.29 mm and 2.65 0.52 mm and for NB area 8.89 1.65 mm and 8.73 1.94 mm(2), respectively. For NB (height and area), there was no significant difference between the two groups.The combination of hJBMMSCs and C/ABB scaffolds could promote periodontal repair. Future studies are expected to further optimize the combination and lead to an ideal periodontal regeneration.
PubMed | Fourth Military Medical University and PLA Fourth Military Medical University
Type: Journal Article | Journal: Pain physician | Year: 2015
Clinical studies have been previously carried out on the efficacy of systemic magnesium to minimize postoperative pain, however, with controversial results. A quantitative meta-analysis was performed to evaluate the analgesic efficacy and safety of systemic magnesium on post-operative pain.Comprehensive systematic review of all relevant, publsished randomized controlled trials.A search was conducted of published literature in MEDLINE, PsycINFO, Scopus, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL) databases from inception to Sep-Oct 2014. Randomized controlled trials (RCTs) that compared magnesium with placebo were identified. Effects were summarized using standardized mean differences (SMDs), weighed mean differences (WMD), or odds ratio (OR) with suitable effect model.Twenty-seven RCTs involving 1,504 patients were included. In total, peri-operative magnesium significantly reduced the pain score at rest (SMD, -1.43, 95% CI, -2.74 to -0.12, < 0.01). Magnesium significantly reduced analgesic consumption (SMD, -1.72, 95% CI, -3.21 to -0.23) in patients undergoing urogenital, orthopaedic, and cardiovascular surgeries, but was inconclusive for patients receiving gastrointestinal surgeries. The obvious analgesia of systemic magnesium was observed on reducing the pain score during movement at 24 hours after operation (SMD, -0.05, 95% CI, -0.43 to 0.32). Moreover, magnesium administration showed a beneficial effect with regard to intra-operative hemodynamics and reduced extubation time in the cardiovascular surgery patients (WMD, -29.34 min, 95% CI, -35.74 to -22.94, P < 0.01).Focused only on the quality of analgesia on postoperative pain with regards to surgery type.Our study suggests that systemic magnesium during general anesthesia significantly decreases post-operative pain scores without increasing adverse events. It should be noted that since there are 18 ongoing RCTs without published data, it is still premature to draw conclusions on the long-term analgesic effects of magnesium as well as potential gender or age difference.
Wei J.,Xian Railway Central Hospital |
Zhao J.,Xian Railway Central Hospital |
Long M.,Fourth Military Medical University |
Han Y.,Fourth Military Medical University |
And 5 more authors.
BMC Cancer | Year: 2010
Background: Non-small-cell lung carcinomas (NSCLCs) exhibit poor prognosis and are usually resistant to conventional chemotherapy. Absence of p21WAF1/CIP1, a cyclin-dependent kinase (cdk) inhibitor, has been linked to drug resistance in many in vitro cellular models. RNA activation (RNAa) is a transcriptional activation phenomena guided by double-strand RNA (dsRNA) targeting promoter region of target gene.Methods: In this study, we explored the effect of up-regulation of p21 gene expression on drug-resistance in A549 non-small-cell lung carcinoma cells by transfecting the dsRNA targeting the promoter region of p21 into A549 cells.Results: Enhanced p21 expression was observed in A549 cells after transfection of dsRNA, which was correlated with a significant growth inhibition and enhancement of chemosensitivity to cisplatin in A549 cells in vitro. Moreover, in vivo experiment showed that saRNA targeting the promoter region of p21 could significantly inhibit A549 xenograft tumor growth.Conclusions: These results indicate that p21 plays a role in lung cancer drug-resistance process. In addition, this study also provides evidence for the usage of saRNA as a therapeutic option for up-regulating lower-expression genes in lung cancer. © 2010 Wei et al; licensee BioMed Central Ltd.