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)

Hydrogen sulfide (H2S) is a novel gaseous mediator produced by cystathionine-beta-synthase and cystathionine-gamma-lyase in the cardiovascular system, including the heart. Using a rat model of regional myocardial ischemia/reperfusion, we investigated the effects of an H2S donor (sodium hydrogen sulfide [NaHS]) on the infarct size and apoptosis caused by ischemia (25 min) and reperfusion (2 h). Furthermore, we investigated the potential mechanism(s) of the cardioprotective effect(s) afforded by NaHS. Specifically, we demonstrate that NaHS (1) attenuates the increase in caspase 9 activity observed in cardiac myocytes isolated from the area at risk (AAR) of hearts subjected in vivo to regional myocardial I/R and (2) ameliorates the decrease in expression of Bcl-2 within the AAR obtained from rat hearts subjected to regional myocardial I/R. The cardioprotective effects of NaHS were abolished by 5-hydroxydeconoate, a putative mitochondrial adenosine triphosphate-sensitive potassium channel blocker. Furthermore, NaHS attenuated the increase in the I/R-induced (1) phosphorylation of p38 mitogen-activated protein kinase and Jun N-terminal kinase, (2) translocation from the cytosol to the nucleus of the p65 subunit of nuclear factor-kappaB, (3) intercellular adhesion molecule 1 expression, (4) polymorphonuclear leukocyte accumulation, (5) myeloperoxidase activity, (6) malondialdehyde levels, and (7) nitrotyrosine staining determined in the AAR obtained from rat hearts subjected to regional myocardial I/R. In conclusion, we demonstrate that the cardioprotective effect of NaHS is secondary to a combination of antiapoptotic and anti-inflammatory effects. The antiapoptotic effect of NaHS may be in part due to the opening of the putative mitochondrial adenosine triphosphate-sensitive potassium channels.
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PMID:Anti-apoptotic and anti-inflammatory effects of hydrogen sulfide in a rat model of regional myocardial I/R. 1863 44

We investigated the effect of the p38 mitogen-activated protein kinase inhibitor SB239063 on inflammation and neurogenesis after ischemia in organotypic hippocampal slice cultures. Our study shows that after oxygen-glucose deprivation, the p38 mitogen-activated protein kinase (MAPK) and the extracellular-signal-regulated kinase 1/2 (ERK1/2) are strongly activated. The p38 MAPK phosphorylation returned to basal levels within 1 h after oxygen-glucose deprivation, whereas the ERK1/2 phosphorylation reached the basal level only after 24 h. Treatment with 20 microM and 100 microM SB239063 strikingly reduced cell death after oxygen-glucose deprivation and significantly diminished microglia activation in the cornu ammonis (CA-region), but not in the area dentata. Levels of the pro-inflammatory cytokine IL-1beta were reduced by 84% after treatment with SB239063 whereas the cytokines IL-6 and TNF-alpha were not affected. After 6 days, neurogenesis was significantly increased in the posterior periventricle. Based on these findings, our study shows that anti-inflammatory treatment with SB239063 reduces cell death, inflammation and microglia activation and, at high concentrations, enhances the oxygen-glucose deprivation-induced neurogenesis in the posterior periventricle.
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PMID:Anti-inflammatory treatment with the p38 mitogen-activated protein kinase inhibitor SB239063 is neuroprotective, decreases the number of activated microglia and facilitates neurogenesis in oxygen-glucose-deprived hippocampal slice cultures. 1863 72

Glaucoma is a visual disorder characterized by progressive loss of retinal ganglion cells (RGCs), which is often associated with high intraocular pressure. However, mechanisms of RGC death in glaucoma still remain a mystery. Two theories have been proposed as pathogeneses of glaucoma: mechanical and vascular. We demonstrate that glutamate excitotoxicity triggered by overactivation of the N-methyl-D-aspartate (NMDA)-type glutamate receptors may contribute according to both theories to RGC death in glaucoma and other retinal diseases such as ischemia. From a therapeutic standpoint, NMDA receptors and downstream signaling pathways, triggered by p38 mitogen-activated protein kinase (MAPK) and caspases, are potential targets of intervention to prevent RGC death. Glutamate, however, mediates synaptic transmission essential for normal function of the nervous system. Hence, complete blockade of NMDA receptor activity causes unacceptable side effects. Studies in our laboratory have shown that an open-channel blocker of the NMDA receptors, memantine, blocks only excessive NMDA receptor activity while leaving normal function relatively intact. This characteristic endows memantine with clinical tolerability, as demonstrated by its approval for treatment of Alzheimer's disease and vascular dementia, and clinical trials for glaucoma. In this review, we discuss improved memantine derivatives, p38 MAPK, and caspase inhibitors as plausible therapeutics to prevent RGC death.
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PMID:Targeting excitotoxic/free radical signaling pathways for therapeutic intervention in glaucoma. 1892 30

We examined whether angiotensin (Ang) II receptor antagonists could be considered a therapeutic strategy in steatotic and nonsteatotic livers in conditions of partial hepatectomy under ischemia-reperfusion (I/R), which is commonly applied in clinical practice to reduce blood loss. We report that Ang II type I receptor (AT1R) antagonist, but not Ang II type II receptor (AT2R) antagonist, increased regeneration in nonsteatotic livers. In the presence of steatosis, both AT1R and AT2R antagonists increased liver regeneration. This effect was stronger when the two were combined. Neither of the Ang II receptor antagonists protected nonsteatotic livers against damage. Only the AT1R antagonist, through nitric oxide inhibition, reduced damage in steatotic livers. The combination of the AT1R and AT2R antagonists in steatotic livers conferred a similar degree of protection to AT1R antagonist alone. Herein, we show that p38 mitogen-activated protein kinase (p38) was a key mechanism in the regeneration induced by the Ang II receptor antagonists in both liver types because when this signaling pathway was inhibited, the beneficial effects of the Ang II receptor antagonists on liver regeneration disappeared, regardless of hepatocyte growth factor or transforming growth factor beta-hepatic levels. In conclusion, in conditions of partial hepatectomy under I/R, the AT1R antagonist for nonsteatotic livers and the AT1R and AT2R antagonists for steatotic livers improved regeneration in the remnant liver through p38 activation. In addition, the combination of the AT1R and AT2R antagonists in steatotic livers led to stronger liver regeneration than either antagonists used separately and also provided the same protection against damage as that afforded by AT1R antagonist alone.
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PMID:Are angiotensin II receptor antagonists useful strategies in steatotic and nonsteatotic livers in conditions of partial hepatectomy under ischemia-reperfusion? 1911 69

Hydrogen sulfide (H(2)S) is one of three endogenous gases, along with carbon monoxide (CO) and nitric oxide (NO), that exert a variety of important vascular actions in vivo. Although it has been demonstrated that CO or NO can trigger the development of a preconditioned phenotype in postischemic tissues, it is unclear whether H(2)S may also induce protection in organs subsequently exposed to ischemia-reperfusion (I/R). In light of these observations, we postulated that preconditioning with the exogenous H(2)S donor sodium hydrosulfide (NaHS-PC) would inhibit leukocyte rolling (LR) and adhesion (LA) induced by I/R. We used intravital microscopic techniques to demonstrate that NaHS-PC 24 h, but not 1 h, before I/R causes postcapillary venules to shift to an anti-inflammatory phenotype in wild-type (WT) mice such that these vessels fail to support LR and LA during reperfusion. The protective effect of NaHS-PC on LR was largely abolished by coincident pharmacological inhibition of NO synthase (NOS) in WT animals and was absent in endothelial NOS-deficient (eNOS(-/-)) mice. A similar pattern of response was noted in WT mice treated concomitantly with NaHS plus p38 mitogen-activated protein kinase (MAPK) inhibitors (SB 203580 or SK-86002). Whereas the reduction in LA induced by antecedent NaHS was attenuated by pharmacological inhibition of NOS or p38 MAPK in WT mice, the antiadhesive effect of NaHS was still evident in eNOS(-/-) mice. Thus NaHS-PC prevents LR and LA by triggering the activation of an eNOS- and p38 MAPK-dependent mechanism. However, the role of eNOS in the antiadhesive effect of NaHS-PC was less prominent than its effect to reduce LR.
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PMID:Hydrogen sulfide triggers late-phase preconditioning in postischemic small intestine by an NO- and p38 MAPK-dependent mechanism. 1916 23

Farnesoid X receptor (FXR), a member of the nuclear receptor superfamily, has been shown to play pivotal roles in bile acid homeostasis by regulating the biosynthesis, conjugation, secretion and absorption of bile acids. Accumulating data suggest that FXR signaling is involved in the pathogenesis of liver and metabolic disorders. Here we show that FXR expression is significantly suppressed in HepG2 cells exposed to hypoxia. Concomitantly, the expression of the bile salt export pump, known as an FXR target gene product and responsible for the excretion of bile acids from the liver, is also decreased under hypoxia. Overexpression of hypoxia-inducible factor (HIF)-1alpha does not mimic the suppressive effect of hypoxia on FXR expression. Furthermore, simultaneous knockdown of HIF-1alpha, HIF-2alpha and HIF-3alpha fails to restore the FXR expression level under hypoxia, indicating that HIF is not involved in hypoxia-evoked FXR downregulation. Instead, we demonstrate that p38 mitogen-activated protein kinase is an indispensable factor for FXR downregulation under hypoxia. Thus, we propose a novel liver disorder model in which two signaling molecules, p38 mitogen-activated protein kinase and FXR, may contribute to the linkage of two pathogenic conditions, i.e. ischemia, a condition accompanying hypoxia, and cholestasis, a condition with intrahepatic accumulation of cytotoxic bile acids.
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PMID:Hypoxia downregulates farnesoid X receptor via a hypoxia-inducible factor-independent but p38 mitogen-activated protein kinase-dependent pathway. 1918 29

Type 2 diabetes is associated with insulin resistance, endothelial dysfunction and accelerated atherosclerotic diseases. Though underlying mechanisms remain to be unraveled, p38 mitogen-activated protein kinase (MAPK) appears to play important roles in their pathogenesis. As a member of the MAPK family, it regulates the activities of many transcription factors and proteins/enzymes and thus has a wide-spectrum of biological effects. Patients with insulin resistance and/or type 2 diabetes have high levels of plasma free fatty acids, inflammatory cytokines, and/or glucose, and over-activation of the cardiovascular renin-angiotensin system, all are capable of activating p38 MAPK. p38 MAPK plays a central role in hepatic glucose and lipid metabolism, leading to increased hepatic glucose production and decreased hepatic lipogenesis. The roles of p38 MAPK in insulin-mediated glucose uptake in skeletal muscle and adipose tissue remain controversial. p38 MAPK also mediates inflammatory processes and cell apoptosis. Recent evidence suggests that p38 MAPK may be the key node linking cardiovascular insulin resistance, endothelial dysfunction and the pathogenesis of atherosclerotic diseases through its influences on monocytes/macrophages, vascular endothelial cells, and vascular smooth muscle cells in type 2 diabetes. In addition, p38 MAPK also contributes significantly to cardiac injury during ischemia-reperfusion.
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PMID:p38 mitogen-activated protein kinase: a critical node linking insulin resistance and cardiovascular diseases in type 2 diabetes mellitus. 1927 80

Increases in cell death by programmed (i.e., apoptosis, autophagy) or nonprogrammed mechanisms (i.e., necrosis) occur during tissue injury and may contribute to the etiology of several pulmonary or vascular disease states. The low-molecular-weight stress protein heme oxygenase-1 (HO-1) confers cytoprotection against cell death in various models of lung and vascular injury by inhibiting apoptosis, inflammation, and cell proliferation. HO-1 serves a vital metabolic function as the rate-limiting step in the heme degradation pathway and in the maintenance of iron homeostasis. The transcriptional induction of HO-1 occurs in response to multiple forms of chemical and physical cellular stress. The cytoprotective functions of HO-1 may be attributed to heme turnover, as well as to beneficial properties of its enzymatic reaction products: biliverdin-IXalpha, iron, and carbon monoxide (CO). Recent studies have demonstrated that HO-1 or CO inhibits stress-induced extrinsic and intrinsic apoptotic pathways in vitro. A variety of signaling molecules have been implicated in the cytoprotection conferred by HO-1/CO, including autophagic proteins, p38 mitogen-activated protein kinase, signal transducer and activator of transcription proteins, nuclear factor-kappaB, phosphatidylinositol 3-kinase/Akt, and others. Enhanced HO-1 expression or the pharmacological application of HO end-products affords protection in preclinical models of tissue injury, including experimental and transplant-associated ischemia/reperfusion injury, promising potential future therapeutic applications.
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PMID:Heme oxygenase-1, a critical arbitrator of cell death pathways in lung injury and disease. 1936 44

The mechanisms of cell death induced by hypoxia or ischemia are not yet fully understood. We have previously demonstrated that cell death induced by hypoxia occurs independently of caspases, and is mediated by phospholipase A(2) (PLA(2)). Here, we show that p38 mitogen-activated protein kinase is activated under hypoxia. A selective inhibitor of p38 or decrease in the p38alpha protein level prevents hypoxia-induced cell death. The p38 inhibitor abolishes PLA(2) activation by hypoxia, indicating that p38 acts upstream of PLA(2). The antioxidant N-acetyl-cysteine inhibits activation of p38 and cell death induced by hypoxia, indicating that reactive oxygen species (ROS) are responsible for p38 activation. These results demonstrate that the ROS/p38/PLA(2) signaling axis has a crucial role in caspase-independent cell death induced by hypoxia.
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PMID:Essential role of p38 MAPK in caspase-independent, iPLA(2)-dependent cell death under hypoxia/low glucose conditions. 1939 51

This review addresses the complexity of coronary collateral growth from the aspect of redox signaling and introduces the concept of a "redox window" in the context of collateral growth. In essence, the redox window constitutes a range in the redox state of cells, which not only is permissive for the actions of growth factors but also amplifies their actions. The interactions of redox-dependent signaling with growth factors are well established through the actions of many redox-dependent kinases (e.g., Akt and p38 mitogen-activated protein kinase). The initial changes in cellular redox can be induced by a variety of events, from the oxidative burst during reperfusion after ischemia, to recruitment of various types of inflammatory cells capable of producing reactive oxygen species. Any event that "upsets" the normal redox equilibrium is capable of amplifying growth. However, extremes of the redox window, oxidative and reductive stresses, are associated with diminished growth-factor signaling and reduced activation of redox-dependent kinases. This concept of a redox window helps to explain why the clinical trials aimed at stimulating coronary collateral growth, the "therapeutic angiogenesis trials," failed. However, understanding of redox signaling in the context of coronary collateral growth could provide new paradigms for stimulating collateral growth in patients.
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PMID:Redox-dependent mechanisms in coronary collateral growth: the "redox window" hypothesis. 1941 57


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