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

The precise role of microglia in stroke and cerebral ischemia has been the subject of debate for a number of years. Microglia are capable of synthesizing numerous soluble and membrane-bound biomolecules, some known to be neuroprotective, some neurotoxic, whereas others have less definitive bioactivities. The molecular mechanisms through which microglia activate these molecules have thus become an important area of ischemia research. Here we provide a survey review that summarizes the key actions of microglial factors in cerebral ischemia including complement proteins, chemokines, pro-inflammatory cytokines, neurotrophic factors, hormones, and proteinases, as well several important messenger molecules that play a part in how these factors respond to extracellular signals during ischemic injuries. We also provide some new perspectives on how microglial intracellular signaling may contribute to the seemingly contradictory roles of several microglial effector molecules.
 ...
PMID:Microglia in cerebral ischemia: molecular actions and interactions. 1684 90

NADH:ubiquinone oxidoreductase (complex I) from bovine heart mitochondria is a highly complicated, membrane-bound enzyme. It is central to energy transduction, an important source of cellular reactive oxygen species, and its dysfunction is implicated in neurodegenerative and muscular diseases and in aging. Here, we describe the effects of Zn2+ on complex I to define whether complex I may contribute to mediating the pathological effects of zinc in states such as ischemia and to determine how Zn2+ can be used to probe the mechanism of complex I. Zn2+ inhibits complex I more strongly than Mg2+, Ca2+, Ba2+, and Mn2+ to Cu2+ or Cd2+. It does not inhibit NADH oxidation or intramolecular electron transfer, so it probably inhibits either proton transfer to bound quinone or proton translocation. Thus, zinc represents a new class of complex I inhibitor clearly distinct from the many ubiquinone site inhibitors. No evidence for increased superoxide production by zinc-inhibited complex I was detected. Zinc binding to complex I is mechanistically complicated. During catalysis, zinc binds slowly and progressively, but it binds rapidly and tightly to the resting state(s) of the enzyme. Reactivation of the inhibited enzyme upon the addition of EDTA is slow, and inhibition is only partially reversible. The IC50 value for the Zn2+ inhibition of complex I is high (10-50 microm, depending on the enzyme state); therefore, complex I is unlikely to be a major site for zinc inhibition of the electron transport chain. However, the slow response of complex I to a change in Zn2+ concentration may enhance any physiological consequences.
 ...
PMID:The inhibition of mitochondrial complex I (NADH:ubiquinone oxidoreductase) by Zn2+. 1698 Mar 8

The interleukin-1 receptor-like protein ST2 exists in both membrane-bound (ST2L) and soluble form (sST2). ST2L has been found to play an important regulatory role in Th2-type immune response, but the function of soluble form of ST2 remains to be elucidated. In this study, we report the protective effect of soluble ST2 on warm hepatic ischemia/reperfusion injury. We constructed a eukaryotic expression plasmid, psST2-Fc, which expresses functional murine soluble ST2-human IgG1 Fc (sST2-Fc) fusion protein. The liver damage after ischemia/reperfusion was significantly attenuated by the expression of this plasmid in vivo. sST2-Fc remarkably inhibited the activation of Kupffer cells and the production of proinflammatory mediators TNF-alpha and IL-6. Furthermore, the levels of TLR4 mRNA and the nuclear translocation of NF-kappaB were also suppressed by pretreatment with sST2-Fc. These results thus identified soluble ST2 as a negative regulator in hepatic I/R injury, possibly via ST2-TLR4 pathway.
 ...
PMID:Pretreatment with soluble ST2 reduces warm hepatic ischemia/reperfusion injury. 1709 7

In view of the high incidence of heart failure and sudden cardiac death, efforts in the development of compounds which target-specific mechanisms such as a reduced expression of SERCA2, the Ca2+ pump of sarcoplasmic reticulum, of hypertrophied cardiomyocytes of pressure-overloaded or infarcted hearts should be strengthened. Lead compounds for correcting a dysregulated gene expression are the carnitine palmitoyltransferase-1 (CPT-1) inhibitors etomoxir and oxfenicine. Since bypassing the CPT-1 inhibition by a medium-chain fatty acid diet had a lesser effect on myosin V1 proportion than on lipid droplet number, one has to infer also other mechanisms such as PPARalpha activation (FOXIB/PPARalpha). In view of the intricate interrelationship between depressed pump function and malignant arrhythmias, stimulation of endogenous antiarrhythmogenic mechanisms linked to an enhanced production of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) could potentially provide alternatives to the administration of 1 g EPA and DHA ethyl esters (minimum 84% EPA + DHA) for secondary prevention of myocardial infarction. The apparently greater efficacy of omega-3 fatty acids in post-myocardial infarction patients (GISSI-Prevention study) compared with ICD patients (SOFA study) can be attributed to the greater ischemia-induced release of membrane-bound EPA and DHA and a better compliance (one vs. four capsules daily).
 ...
PMID:Acute heart failure--basic pathomechanism and new drug targets. 1714 74

The relationships among regional (ischemic and nonischemic) myocardial extracellular (coronary venous) potassium concentration, potassium-sodium concentration ratio, acid-base balance, and metabolism of glucose and lactate were evaluated in 14 anesthetized dogs in which ischemia was produced by transitory left anterior descending coronary artery (LAD) occlusion. Coronary blood samples were obtained from the specific regions by using coronary arterial and venous catheters placed directly into the vessel supplying (or draining) that region. During ischemia, in coronary venous blood sampled from the ischemic area, pH decreased, and PCO2, base deficit, potassium concentration, and the potassium-sodium ratio increased. In LAD venous blood samples obtained during LAD occlusion, the percentage change in potassium concentration was inversely related to the percentage change in PCO2 (r = -0.634, P < 0.05), but not to the percentage change in hydrogen ion concentration (r = -0.339, P > 0.05). During ischemia, arteriovenous O2 content difference in the LAD region increased from 8.54 +/- 0.73 vol % to 10.71 +/- 0.73 vol %; lactate extraction became negative (indicating net production), values decreasing from 27.76 +/- 4.49% to -138.10 +/- 16.81% (P < 0.05); and glucose extraction increased from 14.57 +/- 2.88% to 19.01 +/- 6.06% (0.05 < P < 0.1). These observations indicate that efflux of potassium from the myocardium during ischemia is linked to tissue hypoxia, increased glucose extraction, lactate production, and extracellular acidosis. A further contributor to potassium release, failure of the normal membrane-bound, energy-requiring ion pump, cannot be excluded by these data. With the model used in this study, blood can be sampled from discrete regions of the heart, which enables the study of interactions between pharmacologic agents, such as anesthetics, and the metabolic abnormalities produced by acute ischemia.
 ...
PMID:Regional myocardial metabolism and electrolyte balance during acute ischemia in dogs. 1717 57

This review aims at presenting state-of-the-art knowledge on the composition and functions of the endothelial glycocalyx. The endothelial glycocalyx is a network of membrane-bound proteoglycans and glycoproteins, covering the endothelium luminally. Both endothelium- and plasma-derived soluble molecules integrate into this mesh. Over the past decade, insight has been gained into the role of the glycocalyx in vascular physiology and pathology, including mechanotransduction, hemostasis, signaling, and blood cell-vessel wall interactions. The contribution of the glycocalyx to diabetes, ischemia/reperfusion, and atherosclerosis is also reviewed. Experimental data from the micro- and macrocirculation alludes at a vasculoprotective role for the glycocalyx. Assessing this possible role of the endothelial glycocalyx requires reliable visualization of this delicate layer, which is a great challenge. An overview is given of the various ways in which the endothelial glycocalyx has been visualized up to now, including first data from two-photon microscopic imaging.
 ...
PMID:The endothelial glycocalyx: composition, functions, and visualization. 1725 54

Hydroxymethyl glutaryl (HMG)-coenzyme A (CoA) reductase inhibitors (statins) protect the myocardium against ischemia-reperfusion injury via a mechanism unrelated to cholesterol lowering. Statins may inhibit isoprenylation and thereby prevent activation of proteins such as RhoA. We hypothesized that statins protect the myocardium against ischemia-reperfusion injury via a mechanism involving inhibition of geranylgeranyl pyrophosphate synthesis and translocation of RhoA to the plasma membrane. Sprague-Dawley rats were given either the HMG-CoA reductase inhibitor rosuvastatin, geranylgeranyl pyrophosphate dissolved in methanol, the combination of rosuvastatin and geranylgeranyl pyrophosphate, rosuvastatin and methanol, or distilled water (control) by intraperitoneal injection for 48 h before ischemia-reperfusion. Animals were anesthetized and either subjected to 30 min of coronary artery occlusion followed by 2 h of reperfusion where at infarct size was determined, or the expression of RhoA protein was determined in cytosolic and membrane fractions of nonischemic myocardium. There were no significant differences in hemodynamics between the control group and the other groups before ischemia or during ischemia and reperfusion. The infarct size was 80 +/- 3% of the area at risk in the control group. Rosuvastatin reduced infarct size to 64 +/- 2% (P<0.001 vs. control). Addition of geranylgeranyl pyrophosphate (77 +/- 2%, P<0.01 vs. rosuvastatin) but not methanol (65 +/- 2%, not significant vs. rosuvastatin) abolished the cardioprotective effect of rosuvastatin. Geranylgeranyl pyrophosphate alone did not affect infarct size per se (84 +/- 2%). Rosuvastatin increased the cytosol-to-membrane ratio of RhoA protein in the myocardium (P<0.05 vs. control). These changes were abolished by addition of geranylgeranyl pyrophosphate. We conclude that the cardioprotection and the increase of the RhoA cytosol-to-membrane ratio induced by rosuvastatin in vivo are blocked by geranylgeranyl pyrophosphate. The inhibition of geranylgeranyl pyrophosphate formation and subsequent modulation of cytosol/membrane-bound RhoA are of importance for the protective effect of statins against myocardial ischemia-reperfusion injury.
 ...
PMID:Cardioprotective effect of rosuvastatin in vivo is dependent on inhibition of geranylgeranyl pyrophosphate and altered RhoA membrane translocation. 1732 12

Recent studies suggest a possible link between calcification and ischemia-reperfusion injury following liver transplantation. Histological staining, immunolabeling, and biochemical and electron microscopy analyses were applied to assess the possible mechanism(s) of calcification in liver tissue. Although light microscopy studies did not reveal the presence of large necrotic or apoptotic areas, electron microscopy showed the presence of membrane-bound vacuolar structures in hepatocytes, indicative of cell damage. Myofibroblasts were abundant in regions surrounding and within calcification. In these precalcified and calcified areas, myofibroblasts expressed bone-specific matrix proteins, such as osteopontin, type 1 collagen and bone sialoprotein. In addition, transforming growth factor beta (TGFbeta)-1 and BMP2, two growth factors implicated in osteoblast differentiation, and Runx2 and Msx2, two transcription factors targets of TGFbeta-1 and BMP2, were also expressed in these myofibroblasts. These data suggest that liver calcification following transplantation may be a consequence of precipitation of hydroxylapatite emanating from necrotic or apoptotic hepatocytes associated with proliferation of myofibroblasts expressing bone-specific matrix proteins.
 ...
PMID:Cellular and molecular mechanisms of abnormal calcification following ischemia-reperfusion injury in human liver transplantation. 1733 30

This study was designed to investigate the protective effect of oleanolic acid (OA) against isoproterenol-induced myocardial ischemia in rat myocardium. Wistar strain rats were pretreated with OA (20, 40, and 60 mg/kg, s.c) for 7 days and then intoxicated with isoproterenol (ISO, 85 mg/kg, sc for 2 consecutive days). Heart were excised from the experimental animals and assessed for the activities of marker enzymes [alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and creatine phosphokinase (CPK)], the levels of lipid peroxide products [thiobarbituric acid reactive substances (TBARS), lipid hydroperoxides (HP) and conjugated dienes (CD)], myeloperoxidase (MPO), lipid profiles [total cholesterol (TC), free cholesterol, ester cholesterol, triglycerides (TG), free fatty acids (FFA) and phospholipids (PL)], and membrane-bound ATPase enzymes (total ATPase, Na(+)K(+) ATPase, Ca(2 +) ATPase, and Mg(2 +) ATPase). Troponin T and I were estimated in plasma. Leakage of cardiac markers, elevated lipid peroxidation with increased lipid profiles and decreased activities of membrane-bound ATPase enzymes were confirmed the severe myocardial damage occurring as a consequence of isoproterenol-induced ischemia, and they also showed the significant improvement effected by oleanolic acid pretreatment. These findings provided evidence that oleanolic acid was found to be protecting rat myocardium against ischemic insult and the protective effect could attribute to its anti-oxidative, anti-hyperlipedemic, and anti-arrhythmic properties as well as its membrane-stabilizing action.
 ...
PMID:Cardioprotective effect of oleanolic acid on isoproterenol-induced myocardial ischemia in rats. 1745 91

Proteolytic enzymes constitute around 2% of the human genome and are involved in many stages of cell development from fertilization to death (apoptosis). The identification of many novel proteases from genome-sequencing programs has suggested them as potential new therapeutic targets. In addition, several well-characterized metallopeptidases were recently shown to possess new biological roles in neuroinflammation and neurodegeneration. As a result of these studies, metabolism of the neurotoxic and inflammatory amyloid peptide (Abeta) is considered as a physiologically relevant process with several metallopeptidases being suggested for the role of amyloid-degrading enzymes. These include the neprilysin (NEP) family of metalloproteinases (including its homologue endothelin-converting enzyme), insulin-degrading enzyme, angiotensin-converting enzyme, plasmin, and, possibly, some other enzymes. NEP also has a role in metabolism of sensory and inflammatory neuropeptides such as tachykinins and neurokinins. The existence of natural enzymatic mechanisms for removal of amyloid peptides has extended the therapeutic avenues in Alzheimer's disease (AD) and neurodegeneration. The proteolytic events underlying AD are highly compartmentalized in the cell and formation of amyloid peptide from its precursor molecule APP (amyloid precursor protein) takes place both within intracellular compartments and in the plasma membrane, especially in lipid raft domains. Degradation of amyloid peptide by metallopeptidases can also be both intra- and extracellular depending on the activity of membrane-bound enzymes and their soluble partners. Soluble forms of proteases can be secreted or released from the cell surface through the activity of "sheddases"-another group of proteolytic enzymes involved in key cellular regulatory functions. The activity of proteases involved in amyloid metabolism depends on numerous factors (e.g., genetic, environmental, age), and some conditions (e.g., hypoxia and ischemia) shift the balance of amyloid metabolism toward accumulation of higher concentrations of Abeta. In this regard, regulation of the activity of amyloid-degrading enzymes should be considered as a viable strategy in neuroprotection.
 ...
PMID:New insights into the roles of metalloproteinases in neurodegeneration and neuroprotection. 1767 58


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>