Sui J.,Chongqing Medical University |
Li H.,Chengdu Military General Hospital |
Fang Y.,Southwest Hospital |
Liu Y.,Chengdu Medical College |
And 5 more authors.
Arthritis and Rheumatism | Year: 2012
Objective The inflammasome-related protein NLRP1/NALP1 has been implicated in the onset and progression of some autoimmune diseases. This study was undertaken to determine whether a polymorphism in the NLRP1 gene is associated with susceptibility to rheumatoid arthritis (RA) in Han Chinese and to assess the functional implications of this association. Methods RA patients (n = 190) and matched healthy controls (n = 190) residing in the city of Chengdu were genotyped for the NLRP1 promoter polymorphisms rs6502867 and rs878329. Genotyping for rs878329 was performed in a second set of subjects (n = 1,514) residing in the city of Chongqing. The effect of each polymorphism on NLRP1 transcription was evaluated by dual-luciferase assay, while the effect on DNA protein interaction was determined by electrophoretic mobility shift assay. Differential expression of NLRP1 in individuals with different genotypes was investigated by real-time quantitative polymerase chain reaction. Results The polymorphism rs878329, but not rs6502867, was associated with RA (odds ratio [OR] 0.83, P = 0.02 for the C allele; OR 0.42, P = 0.01 for the CC genotype). The GG genotype of rs878329 was the risk genotype for RA (OR 2.38) and had a runt-related transcription factor 1 binding site that up-regulated NLRP1 transcription. Individuals with the RA risk genotype GG had significantly higher NLRP1 messenger RNA levels than those with the CC genotype among the Han Chinese population. Conclusion Our findings indicate that NLRP1 is associated with RA in Han Chinese. The G allele of rs878329 in the NLRP1 promoter up-regulates gene transcription and confers the risk of RA. Copyright © 2012 by the American College of Rheumatology.
News Article | March 2, 2017
(Philadelphia, PA) - Mitochondria - the energy-generating powerhouses of cells - are also a site for oxidative stress and cellular calcium regulation. The latter two functions have long been suspected of being linked mechanistically, and now new research at the Lewis Katz School of Medicine at Temple University (LKSOM) shows precisely how, with the common connection centering on a protein complex known as the mitochondrial Ca2+ uniporter (MCU). "MCU had been known for its part in driving mitochondrial calcium uptake for cellular energy production, which protects cells from bioenergetic crisis, and for its role in eliciting calcium overload-induced cell death," explained senior investigator on the study, Muniswamy Madesh, PhD, Professor in the Department of Medical Genetics and Molecular Biochemistry and Center for Translational Medicine at LKSOM. "Now, we show that MCU has a functional role in both calcium regulation and the sensing of levels of reactive oxygen species (ROS) within mitochondria." The study, published online March 2 in the journal Molecular Cell, is the first to identify a direct role for MCU in mitochondrial ROS-sensing. In previous work, Dr. Madesh and colleagues were the first to show how the MCU protein complex comes together to effect mitochondrial calcium uptake. "We know from that work, and from existing work in the field, that as calcium accumulates in mitochondria, the organelles generate increasing amounts of ROS," Dr. Madesh said. "Mitochondria have a way of dealing with that ROS surge, and because of the relationship between mitochondrial calcium uptake and ROS production, we suspected ROS-targeting of MCU was involved in that process." In the new study, Dr. Madesh and colleagues employed advanced biochemical, cell biological, and superresolution imaging to examine MCU oxidation in the mitochondrion. Critically, they discovered that MCU contains several cysteine molecules in its amino acid structure, only one of which, Cys-97, is capable of undergoing an oxidation-induced reaction known as S-glutathionylation. Structural analyses showed that oxidation-induced S-glutathionylation of Cys-97 triggers conformational changes within MCU. Those changes in turn regulate MCU activity during inflammation, hypoxia, and cardiac stimulation. They also appear to be relevant to cell survival - elimination of ROS-sensing via Cys-97 mutation resulted in persistent MCU channel activity and an increased rate of calcium-uptake, with cells eventually dying from calcium overload. Importantly, Dr. Madesh and colleagues found that S-glutathionylation of Cys-97 is reversible. "Reversible oxidation is essential to the regulation of protein function," Dr. Madesh explained. When switched on by oxidation, Cys-97 augments MCU channel activity that perpetuates cell death. Oxidation reverses when the threat has subsided. The findings could have implications for the understanding of metabolic disorders and neurological and cardiovascular diseases. "Abnormalities in ion homeostasis are a central feature of metabolic disease," Dr. Madesh said. "We plan next to explore the functional significance of ROS and MCU activity in a mouse model using genome editing technology, which should help us answer fundamental questions about MCU's biological functions in mitochondrial ROS-sensing." Other researchers involved in the study include Zhiwei Dong, Santhanam Shanmughapriya, Dhanendra Tomar, Neeharika Nemani, Sarah L. Breves, Aparna Tripathi, Palaniappan Palaniappan, Massimo F. Riitano, Alison Worth, Ajay Seelam, Edmund Carvalho, Ramasamy Subbiah, Fabia?n Jan?a, and Sudarsan Rajan, Department of Medical Genetics and Molecular Biochemistry and the Center for Translational Medicine at LKSOM; Jonathan Soboloff, Department of Medical Genetics and Molecular Biochemistry at LKSOM; Xueqian Zhang and Joseph Y. Cheung, Center for Translational Medicine at LKSOM; Naveed Siddiqui and Peter B. Stathopulos, Department of Physiology and Pharmacology, Western University, London, Ontario, Canada; Solomon Lynch and Jeffrey Caplan, Department of Biological Sciences, Delaware Biotechnology Institute, University of Delaware; Suresh K. Joseph, MitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia; Yizhi Peng and Zhiwei Dong, Institute of Burn Research, Southwest Hospital, Third Military Medical University, Chongqing, People's Republic of China. The research was supported in part by National Institutes of Health grants R01GM109882, R01HL086699, R01HL119306, 1S10RR027327, P01 DA037830, and RO1DK103558. 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.
Zhu B.,Chongqing University |
Zhou X.,Southwest Hospital
Chinese Journal of Lung Cancer | Year: 2011
PI3K/AKT signal pathway is an important intracellular signal transduction pathway. It plays important roles in cell apoptosis and survival by affecting the activity of downstream effector molecules, and it is closely associated with the development and progression of human tumors. Recent researches of PI3K/AKT indicate that this pathway plays important roles in tumor cells proliferation, blood vessel neogenesis, tumor metastasis and resistance to chemotherapy and radiotherapy. The profound research of PI3K/AKT is beneficial to the prevention of tumor and to the finding of potential targets for new drugs. This article reviewed the composition, function and regulation of PI3K/AKT signal pathway, and its effect in metastasis and drug resistance of lung cancer.
Huang G.,Chongqing Medical University |
Wen Q.,Affiliated Hospital of Guiyang Medical College |
Zhao Y.,Southwest Hospital |
Gao Q.,Chongqing Medical University |
Bai Y.,Chongqing Medical University
PLoS ONE | Year: 2013
CD274, one of two co-stimulatory ligands for programmed death 1 and widely expressed in the mononuclear phagocyte system (MPS), may co-stimulate T cells and regulates inflammatory responses. However, changes in CD274 gene expression and the underlying molecular mechanism are poorly understood during inflammatory responses. Therefore, delineation of the complex mechanisms regulating CD274 expression is critical to understand this immunoregulatory system during inflammatory responses. The purpose of this study was to assess the molecular mechanisms regulating CD274 expression in an in vitro monocyte model of inflammatory response. Firstly, CD274 expression levels in human primary monocytes after lipopolysaccharide (LPS) treatment were observed and correlated with NF-κB activation. Secondly, based on the distribution of putative NF-κB binding sites, 5′ truncated human CD274 promoter reporters were constructed, transfected into U937 cells and critical promoter regions for basal (nt -570 to +94) and LPS-induced (nt -1735 to -570) transcription were identified by dual luciferase assays. Finally, a key NF-κB binding site (nt -610 to -601) for LPS-inducible CD274 transcriptional activity was characterized by point mutation analysis and chromatin immunoprecipitation analysis assays (ChIP). Thus, the present study establishes a molecular basis to understand the mechanisms governing CD274 expression in certain infections and inflammatory disorders. © 2013 Huang et al.
Guo L.,Southwest Hospital |
Yang L.,Southwest Hospital |
Briard J.L.,Center Medico Chirurgical du Cedre |
Duan X.,Southwest Hospital |
Wang F.,Southwest Hospital
Knee Surgery, Sports Traumatology, Arthroscopy | Year: 2012
Purpose: Clinical factors related to cruciate-retaining knee arthroplasty failure in a long-term follow-up are yet unclear. The study was designed to evaluate the long-term survival rate of cruciate-retaining arthroplasty and clinical factors that may contribute to its failure. Methods: A total of 162 patients (188 knees) who received cruciate-retaining press-fit condylar arthroplasty from June 1993 to May 1994 were followed up. All patients were assessed clinically and radiographically. Revision for any reason was regarded as failure of arthroplasty. Results: A total of 120 patients (138 knees) were successfully followed up. Survivorship over 17 years was 92. 5%. Fourteen knees were revised. Tibial varus angle of the operated knee in the unrevised patient group was greater than in revised group. There was statistical difference between these two groups (P < 0. 05). Conclusion: Long-term survivorship of cruciate-retaining arthroplasty was fair. Varus and valgus deformity of the unoperated contralateral knee and tibial varus deformity of the operated knee could be important factors related to arthroplasty failure. Clinical relevance: This long-term follow-up result of Press-Fit Condylar cruciate-retaining arthroplasty was good considering it was an old design. The alignment of the operated knee and deformity of the unoperated contralateral knee are important clinical factors that should be paid attention to avoid unexpected arthroplasty failure. Level of evidence: IV. © 2011 Springer-Verlag.
Yang B.,Chongqing Medical University |
Guo H.,Chongqing Medical University |
Zhang Y.,Chongqing Medical University |
Zhang Y.,Chengdu Military General Hospital |
And 3 more authors.
PLoS ONE | Year: 2011
Chondrogenic differentiation of mesenchymal stem cells (MSCs) is accurately regulated by essential transcription factors and signaling cascades. However, the precise mechanisms involved in this process still remain to be defined. MicroRNAs (miRNAs) regulate various biological processes by binding target mRNA to attenuate protein synthesis. To investigate the mechanisms for miRNAs-mediated regulation of chondrogenic differentiation, we identified that miR-145 was decreased during transforming growth factor beta 3 (TGF-β3)-induced chondrogenic differentiation of murine MSCs. Subsequently, dual-luciferase reporter gene assay data demonstrated that miR-145 targets a putative binding site in the 3′-UTR of SRY-related high mobility group-Box gene 9 (Sox9) gene, the key transcription factor for chondrogenesis. In addition, over-expression of miR-145 decreased expression of Sox9 only at protein levels and miR-145 inhibition significantly elevated Sox9 protein levels. Furthermore, over-expression of miR-145 decreased mRNA levels for three chondrogenic marker genes, type II collagen (Col2a1), aggrecan (Agc1), cartilage oligomeric matrix protein (COMP), type IX collagen (Col9a2) and type XI collagen (Col11a1) in C3H10T1/2 cells induced by TGF-β3, whereas anti-miR-145 inhibitor increased the expression of these chondrogenic marker genes. Thus, our studies demonstrated that miR-145 is a key negative regulator of chondrogenic differentiation by directly targeting Sox9 at early stage of chondrogenic differentiation. © 2011 Yang et al.
Zhou X.,Arizona State University |
Zhou X.,Chonqing University |
Ye J.,Arizona State University |
Feng Y.,Southwest Hospital
IEEE Transactions on Biomedical Engineering | Year: 2011
Tuberculosis (TB) is a major global health concern, causing nearly ten million new cases and over one million deaths every year. The early detection of possible epidemic is the first and important defense line against TB. However, traditional surveillance approaches, e.g., U.S. Centers for Disease Control and Prevention (CDC), publish the TB morbidity surveillance results on a quarterly basis, with months of reporting lag. Moreover, in some developing countries, where most infections occur, there may not be enough medical resources to build traditional surveillance systems. To improve early detection of TB outbreaks, we developed a syndromic approach to estimate the actual number of TB cases using Google search volume. Specifically, the search volume of 19 TB-related terms, obtained from January 2004 to April 2009, were examined for surveillance purpose. Contemporary TB surveillance data were extracted from the CDCs reports to build and evaluate the syndromic system. We estimate the actual TB occurrences using a nonstationary dynamic system. Respective models are built to monitor both national-level and state-level TB activities. The surveillance results of the syndromic system can be updated every day, which is 12 weeks ahead of CDCs reports. © 2011 IEEE.
Li D.,Southwest Hospital |
Zhou K.,Chongqing Medical University |
Wang S.,Southwest Hospital |
Shi Z.,Chongqing Medical University |
Yang Z.,Chongqing Medical University
Cancer Science | Year: 2010
Numerous lines of evidence have shown that angiogenesis plays a pivotal role in the development of tumors. Therefore anti-angiogenesis therapy represents a potentially promising approach to cancer therapy. Recently, a new inhibitor called vasohibin was discovered to operate as an intrinsic and highly specific feedback inhibitor in the process of angiogenesis. However, to date, reports on the antitumor and anti-angiogenic properties of vasohibin have been very limited. To explore the potential of vasohibin as an anti-angiogenesis therapeutic, we constructed a recombinant adenovirus encoding vasohibin. Our data showed that the recombinant adenovirus encoding vasohibin could prevent tumor angiogenesis and tumor growth. Notably, angiogenesis in the tumors was prevented without any apparent side-effects. Therefore, the findings suggested that the recombinant adenovirus encoding vasohibin might be valuable as a potential strategy for antitumor angiogenesis therapy in the clinic. © 2009 Japanese Cancer Association.
Yan G.-N.,Southwest Hospital |
Yang L.,Southwest Hospital |
Lv Y.-F.,Southwest Hospital |
Shi Y.,Southwest Hospital |
And 8 more authors.
Journal of Pathology | Year: 2014
Microenvironmental regulation of cancer stem cells (CSCs) strongly influences the onset and spread of cancer. The way in which glioma cells interact with their microenvironment and acquire the phenotypes of CSCs remains elusive. We investigated how communication between vascular endothelial cells and glioma cells promoted the properties of glioma stem cells (GSCs). We observed that CD133+ GSCs were located closely to Shh+ endothelial cells in specimens of human glioblastoma multiforme (GBM). In both in vitro and in vivo studies, we found that endothelial cells promoted the appearance of CSC-like glioma cells, as demonstrated by increases in tumourigenicity and expression of stemness genes such as Sox2, Olig2, Bmi1 and CD133 in glioma cells that were co-cultured with endothelial cells. Knockdown of Smo in glioma cells led to a significant reduction of their CSC-like phenotype formation in vitro and in vivo. Endothelial cells with Shh knockdown failed to promote Hedgehog (HH) pathway activation and CSC-like phenotype formation in co-cultured glioma cells. By examination of glioma tissue specimens from 65 patients, we found that the survival of glioma patients was closely correlated with the expression of both Shh by endothelial cells and Gli1 by perivascular glioma cells. Taken together, our study demonstrates that endothelial cells in the tumour microenvironment provide Shh to activate the HH signalling pathway in glioma cells, thereby promoting GSC properties and glioma propagation. © 2014 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. © 2014 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Ming L.,Southwest Hospital
Journal of Spinal Cord Medicine | Year: 2010
Background/Objective: Spinal intramedullary tuberculoma is rare, accounting for 2/100,000 of cases of tuberculosis and only 2% of all cases of tuberculosis of the central nervous system. Diagnostic imaging is essential to improving diagnosis and management of this disease. Methods: The clinical profile, radiological data, and histological slides of 2 cases of intramedullary tuberculomas confirmed by pathologic examinations were reviewed. Results: In 2 cases, magnetic resonance imaging (MRI) showed thickening of the spinal cord and oval lesions with a low T1-weighted image signal and a typical "target sign" T2-weighted image signal. After gadopentetate dimeglumine administration, the lesion's rim shape was enhanced, showing uneven wall thickness and sharp margins. Conclusions: MRI findings of spinal intramedullary tuberculoma were specific, and accurate diagnosis could be obtained. MRI is the optimal measure because it shows location, size, and number of lesions and the presence of degeneration and necrosis. © 2010 by the American Paraplegia Society.