Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatic ischemia/reperfusion injury (HIRI) is a major cause of liver dysfunction and even liver failure after liver transplantation and hepatectomy. One of the critical mechanisms that lead to HIRI is an acidic microenvironment, which develops due to the accumulation of high acid-like substances such as lactic acid and ketone bodies. Previous studies have shown that the adoptive transfer of induced regulatory T cells (iTregs) attenuates HIRI; however, little is known about the function of Tregs in the acidic microenvironment of a HIRI model. In the present study, we examined the effect of acidic microenvironment on Tregs in vitro and in vivo. Here, we report that microenvironment acidification and dysfunction of the liver is induced during HIRI in humans and mice and that an acidic microenvironment can inhibit the generation and function of CD4+CD25+Foxp3+ iTregs via the PI3K/Akt/mTOR signaling pathway. By contrast, the reversal of the acidic microenvironment restored Foxp3 expression and iTreg function. In addition, the results of cell culture in vitro indicated that the proton pump inhibitor omeprazole improves decreased iTreg differentiation caused by the acidic microenvironment, suggesting the potential clinical use of proton pump inhibitors as immunoregulatory therapy in the treatment of HIRI. Furthermore, our findings demonstrate that buffering the acidic microenvironment to attenuate HIRI in mice has an inseparable relationship with Tregs. Thus, an acidic microenvironment is a key regulator in HIRI, involved in modulating the generation and function of Tregs.
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PMID:Acidic Microenvironment Regulates the Severity of Hepatic Ischemia/Reperfusion Injury by Modulating the Generation and Function of Tregs via the PI3K-mTOR Pathway. 3199 87

Inflammatory response regulation is a mechanism through which human umbilical cord mesenchymal stem cells (HUCMSCs) improve myocardial ischemia reperfusion injury (IRI); however, the timing of HUCMSC delivery to achieve maximum effectiveness is controversial. To investigate the effects of HUCMSC delivery on the acute inflammatory stage of IRI, we transplanted HUCMSCs or HUCMSCs with cyclosporin A (CsA) through the coronary artery simultaneously during ischemia reperfusion in pigs. Ferumoxytol-labeled HUCMSCs (HUCMSC), HUCMSCs with cyclosporin A (HUCMSC+CsA), and PBS (control) groups were investigated to evaluate the homing of transplanted cells and changes in infarct features, cardiac activity, and inflammatory response at three time points post-transplantation. Animals were sacrificed 2 weeks later for histological analysis of the hearts. We detected Prussian blue-dyed granules distributed around T lymphocyte clusters in the infarct area in the HUCMSC group. Infarct size and collagen deposition in the infarct area were lower in the HUCMSC group than in the control and HUCMSC+CsA groups. Cardiac function was mildly impaired in both the control and HUCMSC groups, whereas added CsA had a more severe impact. The levels of proinflammatory markers were lower in the HUCMSC group than in the control group at 24-h follow-up, and the difference was more significant after adding CsA. There were more CD3+ T lymphocytes and Foxp3+ Tregs in the HUCMSC group infarct area than in the other two groups. Proliferation rate of T lymphocytes was higher in the HUCMSC group than in the other two groups. Indirect co-culture experiments in vitro showed that MSCs promoted the generation of CD4+CD25+ Foxp3+Tregs through a paracrine mechanism. These results indicate that immediate intracoronary delivery of HUCMSCs after ischemia reperfusion can reduce acute myocardial IRI and promote myocardial repair, mainly through T lymphocyte interactions to regulate the intense inflammatory response during the acute inflammatory stage.
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PMID:Immediate Intracoronary Delivery of Human Umbilical Cord Mesenchymal Stem Cells Reduces Myocardial Injury by Regulating the Inflammatory Process Through Cell-Cell Contact with T Lymphocytes. 3276 86

Ethyl pyruvate (EP), a stable form of pyruvate, has shown beneficial effects in animal models of shock, ischemia/reperfusion injury, and sepsis due to its potent anti-oxidant and anti-inflammatory properties. Our recent study demonstrated that EP application prevented the clinical manifestation of type 1 diabetes in mice by augmenting regulatory T cell (Treg) number and function. Our present study shows that EP increases Treg proliferation and suppressive function (perforin and IL-10 expression) during in vitro differentiation from conventional CD4+CD25- T cells. Enhanced expansion of Treg after EP treatment correlated with increased ATP levels and relied on increased glycolysis. Inhibition of oxidative phosphorylation did not attenuate EP stimulatory effects, suggesting that this metabolic pathway was not mandatory for EP-driven Treg proliferation. Moreover, EP lowered the expression of carnitine palmitoyltransferase I, an enzyme involved in fatty acid oxidation. Further, the stimulatory effect of EP on Treg proliferation was not mediated through inhibition of the mTOR signaling pathway. When given in vivo either intraperitoneally or orally to healthy C57BL/6 mice, EP increased the number of Treg within the peritoneal cavity or gut-associated lymphoid tissue, respectively. In conclusion, EP promotes in vitro Treg proliferation through increased glycolysis and enhances Treg proliferation when administered in vivo.
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PMID:Ethyl Pyruvate Promotes Proliferation of Regulatory T Cells by Increasing Glycolysis. 3291 80


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