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211.
Uncontrolled systemic activation of the immune system is an early initiating event that leads to development of acute fulminant liver failure (FLF) in mice after treatment with agonistic Fas mAb. In this study, we demonstrate that treatment of mice with N-acetylcysteine (NAC), an ROS scavenger and glutathione (GSH) precursor, almost completely abolished Fas mAb-induced FLF through suppression of Vα14iNKT cell activation, IFN-γ signaling, apoptosis and nitrotyrosine formation in liver. In addition, enrichment of the liver with GSH due to Vα14iNKT cells deficiency, induced an anti-inflammatory response in the liver of Jα18(-/-) mice that inhibited apoptosis, nitrotyrosine formation, IFN-γ signaling and effector functions. In summary, we propose a novel and previously unrecognized pro-inflammatory and pro-apoptotic role for endogenous ROS in stimulating Th1 signaling in Vα14iNKT cells to promote the development of FLF. Therefore, our study provides critical new insights into how NAC, a ROS scavenger, regulates Th1 signaling in intrahepatic Vα14iNKT cells to impact inflammatory and pathological responses. 相似文献
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Jei‐Wen Chang Hsin‐Lin Tsai Chang‐Wei Chen Hui‐Wen Yang An‐Hang Yang Ling‐Yu Yang Paulus S. Wang Yee‐Yung Ng Teng‐Lung Lin Oscar K. Lee 《Journal of cellular and molecular medicine》2012,16(12):2935-2949
Mesenchymal stem cells (MSCs) have been shown to improve the outcome of acute renal injury models; but whether MSCs can delay renal failure in chronic kidney disease (CKD) remains unclear. In the present study, the were cultured in media containing various concentrations of basic fibroblast growth factor, epidermal growth factor and ascorbic acid 2‐phosphate to investigate whether hepatocyte growth factor (HGF) secretion could be increased by the stimulation of these growth factors. Then, TGF‐β1‐treated renal interstitial fibroblast (NRK‐49F), renal proximal tubular cells (NRK‐52E) and podocytes were co‐cultured with conditioned MSCs in the absence or presence of ascorbic acid 2‐phosphate to quantify the protective effects of conditioned MSCs on renal cells. Moreover, male Sprague‐Dawley rats were treated with 1 × 106 conditioned MSCs immediately after 5/6 nephrectomy and every other week through the tail vein for 14 weeks. It was found that basic fibroblast growth factor, epidermal growth factor and ascorbic acid 2‐phosphate promoted HGF secretion in MSCs. Besides, conditioned MSCs were found to be protective against TGF‐β1 induced epithelial‐to‐mesenchymal transition of NRK‐52E and activation of NRK‐49F cells. Furthermore, conditioned MSCs protected podocytes from TGF‐β1‐induced loss of synaptopodin, fibronectin induction, cell death and apoptosis. Rats transplanted with conditioned human MSCs had a significantly increase in creatinine clearance rate, decrease in glomerulosclerosis, interstitial fibrosis and increase in CD4+CD25+Foxp3+ regulatory T cells counts in splenocytes. Together, our studies indicated that conditioned MSCs preserve renal function by their anti‐fibrotic and anti‐inflammatory effects. Transplantation of conditioned MSCs may be useful in treating CKD. 相似文献
214.
Susan H. Yee Patricia Bradley William S. Fisher Sally D. Perreault James Quackenboss Eric D. Johnson Justin Bousquin Patricia A. Murphy 《EcoHealth》2012,9(4):411-426
The U.S. Environmental Protection Agency has recently realigned its research enterprise around the concept of sustainability. Scientists from across multiple disciplines have a role to play in contributing the information, methods, and tools needed to more fully understand the long-term impacts of decisions on the social and economic sustainability of communities. Success will depend on a shift in thinking to integrate, organize, and prioritize research within a systems context. We used the Driving forces–Pressures–State–Impact–Response (DPSIR) framework as a basis for integrating social, cultural, and economic aspects of environmental and human health into a single framework. To make the framework broadly applicable to sustainability research planning, we provide a hierarchical system of DPSIR keywords and guidelines for use as a communication tool. The applicability of the integrated framework was first tested on a public health issue (asthma disparities) for purposes of discussion. We then applied the framework at a science planning meeting to identify opportunities for sustainable and healthy communities research. We conclude that an integrated systems framework has many potential roles in science planning, including identifying key issues, visualizing interactions within the system, identifying research gaps, organizing information, developing computational models, and identifying indicators. 相似文献
215.
Sim SB Mattsson M Feder JL Cha DH Yee WL Goughnour RB Linn CE Feder JL 《Journal of evolutionary biology》2012,25(5):961-971
Prezygotic isolation due to habitat choice is important to many models of speciation-with-gene-flow. Habitat choice is usually thought to occur through positive preferences of organisms for particular environments. However, avoidance of non-natal environments may also play a role in choice and have repercussions for post-zygotic isolation that preference does not. The recent host shift of Rhagoletis pomonella (Diptera: Tephritidae) from downy hawthorn, Crataegus mollis, to introduced apple, Malus domestica, in the eastern United States is a model for speciation-with-gene-flow. However, the fly is also present in the western United States where it was likely introduced via infested apples ≤ 60 years ago. R. pomonella now attacks two additional hawthorns in the west, the native C. douglasii (black hawthorn) and the introduced C. monogyna (English ornamental hawthorn). Flight tunnel tests have shown that western apple-, C. douglasii- and C. monogyna-origin flies all positively orient to fruit volatile blends of their respective natal hosts in flight tunnel assays. Here, we show that these laboratory differences translate to nature through field-trapping studies of flies in the state of Washington. Moreover, western R. pomonella display both positive orientation to their respective natal fruit volatiles and avoidance behaviour (negative orientation) to non-natal volatiles. Our results are consistent with the existence of behaviourally differentiated host races of R. pomonella in the west. In addition, the rapid evolution of avoidance behaviour appears to be a general phenomenon for R. pomonella during host shifts, as the eastern apple and downy hawthorn host races also are antagonized by non-natal fruit volatiles. 相似文献
216.
Jun Zhu Serguei Stepaniants Chunsheng Zhang Qingying Meng Mette Peters Yudong He Chester Ni Deborah Slipetz Michael A Crackower Hani Houshyar Christopher M Tan Ernest Asante‐Appiah Gary O'Neill Mingjuan Jane Luo Rolf Thieringer Jeffrey Yuan Chi‐Sung Chiu Pek Yee Lum John Lamb Yves Boie Hilary A Wilkinson Eric E Schadt Hongyue Dai Christopher Roberts 《Molecular systems biology》2012,8(1)
Common inflammatome gene signatures as well as disease‐specific signatures were identified by analyzing 12 expression profiling data sets derived from 9 different tissues isolated from 11 rodent inflammatory disease models. The inflammatome signature significantly overlaps with known drug targets and co‐expressed gene modules linked to metabolic disorders and cancer. A large proportion of genes in this signature are tightly connected in tissue‐specific Bayesian networks (BNs) built from multiple independent mouse and human cohorts. Both the inflammatome signature and the corresponding consensus BNs are highly enriched for immune response‐related genes supported as causal for adiposity, adipokine, diabetes, aortic lesion, bone, muscle, and cholesterol traits, suggesting the causal nature of the inflammatome for a variety of diseases. Integration of this inflammatome signature with the BNs uncovered 151 key drivers that appeared to be more biologically important than the non‐drivers in terms of their impact on disease phenotypes. The identification of this inflammatome signature, its network architecture, and key drivers not only highlights the shared etiology but also pinpoints potential targets for intervention of various common diseases. 相似文献
217.
Venturi V Chin HY Price DA Douek DC Davenport MP 《Journal of immunology (Baltimore, Md. : 1950)》2008,181(4):2597-2609
In some epitope-specific responses, T cells bearing identical TCRs occur in many MHC-matched individuals. The sharing of public TCRs is unexpected, given the enormous potential diversity of the TCR repertoire. We have previously studied the sharing of TCR beta-chains in the CD8(+) T cell responses to two influenza epitopes in mice. Analysis of these TCRbeta repertoires suggests that, even with unbiased V(D)J recombination mechanisms, some TCRbetas can be produced more frequently than others, by a process of convergent recombination. The TCRbeta production frequency was shown to be a good predictor of the observed sharing of epitope-specific TCRbetas between mice. However, this study was limited to immune responses in an inbred population. In this study, we investigated TCRbeta sharing in CD8(+) T cell responses specific for the immunodominant Mamu-A*01-restricted Tat-SL8/TL8 and Gag-CM9 epitopes of SIV in rhesus macaques. Multiple data sets were used, comprising a total of approximately 6000 TCRbetas sampled from 20 macaques. We observed a spectrum in the number of macaques sharing epitope-specific TCRbetas in this outbred population. This spectrum of TCRbeta sharing was negatively correlated with the minimum number of nucleotide additions required to produce the sequences and strongly positively correlated with the number of observed nucleotide sequences encoding the amino acid sequences. We also found that TCRbeta sharing was correlated with the number of times, and the variety of different ways, the sequences were produced in silico via random gene recombination. Thus, convergent recombination is a major determinant of the extent of TCRbeta sharing. 相似文献
218.
The hypoxia-inducible factor 1α (HIF-1α) is the master regulator of the cellular response to hypoxia. A key regulator of HIF-1α is von Hippel-Lindau protein (pVHL), which mediates the oxygen-dependent, proteasomal degradation of HIF-1α in normoxia. Here, we describe a new regulator of HIF-1α, the hypoxia-associated factor (HAF), a novel E3-ubiquitin ligase that binds HIF-1α leading to its proteasome-dependent degradation irrespective of cellular oxygen tension. HAF, a protein expressed in proliferating cells, binds and ubiquitinates HIF-1α in vitro, and both binding and E3 ligase activity are mediated by HAF amino acids 654 to 800. Furthermore, HAF overexpression decreases HIF-1α levels in normoxia and hypoxia in both pVHL-competent and -deficient cells, whereas HAF knockdown increases HIF-1α levels in normoxia, hypoxia, and under epidermal growth factor stimulation. In contrast, HIF-2α is not regulated by HAF. In vivo, tumor xenografts from cells overexpressing HAF show decreased levels of HIF-1α accompanied by decreased tumor growth and angiogenesis. Therefore, HAF is the key mediator of a new HIF-1α-specific degradation pathway that degrades HIF-1α through a new, oxygen-independent mechanism. 相似文献
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220.
Toh GT Kang P Lee SS Lee DS Lee SY Selamat S Mohd Taib NA Yoon SY Yip CH Teo SH 《PloS one》2008,3(4):e2024