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)

The current lack of suitable probes has limited the in vivo imaging of reactive oxygen/nitrogen species (ROS/RNS). ROS/RNS are often generated by ischemia-induced inflammation; defining the extent of tissue involvement or ROS/RNS-related damage would have a significant clinical impact. We present the preparation and demonstration of a fluorogenic sensor for monitoring peroxynitrite (ONOO(-)) and myeloperoxidase (MPO) mediated hypochlorous acid (HOCl/OCl(-)) production. The sensor consists of a long circulating biocompatible nanoparticle that targets phagocytic cells in vivo and is coated with approximately 400 quenched oxazine fluorophores that are released by reaction with HOCl or ONOO(-) but are stable toward oxidants such as hydroxyl radical, hydrogen peroxide, and superoxide. MPO-dependent probe activation is chloride ion dependent and is negated in flow cytometry studies of MPO inhibitor treated neutrophils. Fluorescence reflectance imaging and microscopic fluorescence imaging in mouse hearts after myocardial infarction showed probe release into neutrophil-rich ischemic areas, making this ROS/RNS sensor a novel prognostic indicator.
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PMID:Oxazine conjugated nanoparticle detects in vivo hypochlorous acid and peroxynitrite generation. 1981 43

Hippocampal CA1 pyramidal neurons are selectively vulnerable to ischemia, while adjacent CA3 neurons are relatively resistant. Although glutamate receptor-mediated mitochondrial Ca(2+) overload and dysfunction is a major component of ischemia-induced neuronal death, no direct relationship between selective neuronal vulnerability and mitochondrial dysfunction has been demonstrated in intact brain preparations. Here, we show that in organotypic slice cultures NMDA induces much larger Ca(2+) elevations in vulnerable CA1 neurons than in resistant CA3. Consequently, CA1 mitochondria exhibit stronger calcium accumulation, more extensive swelling and damage, stronger depolarization of their membrane potential, and a significant increase in ROS generation. NMDA-induced Ca(2+) and ROS elevations were abolished in Ca(2+)-free medium or by NMDAR antagonists, but not by zinc chelation. We conclude that Ca(2)(+) overload-dependent mitochondrial dysfunction is a determining factor in the selective vulnerability of CA1 neurons.
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PMID:Differential NMDA receptor-dependent calcium loading and mitochondrial dysfunction in CA1 vs. CA3 hippocampal neurons. 1987 59

Reactive oxygen and nitrogen species (ROS and RNS) are produced by metabolism of normal cells. However, in liver diseases, redox is increased thereby damaging the hepatic tissue; the capability of ethanol to increase both ROS/RNS and peroxidation of lipids, DNA, and proteins was demonstrated in a variety of systems, cells, and species, including humans. ROS/RNS can activate hepatic stellate cells, which are characterized by the enhanced production of extracellular matrix and accelerated proliferation. Cross-talk between parenchymal and nonparenchymal cells is one of the most important events in liver injury and fibrogenesis; ROS play an important role in fibrogenesis throughout increasing platelet-derived growth factor. Most hepatocellular carcinomas occur in cirrhotic livers, and the common mechanism for hepatocarcinogenesis is chronic inflammation associated with severe oxidative stress; other risk factors are dietary aflatoxin B(1) consumption, cigarette smoking, and heavy drinking. Ischemia-reperfusion injury affects directly on hepatocyte viability, particularly during transplantation and hepatic surgery; ischemia activates Kupffer cells which are the main source of ROS during the reperfusion period. The toxic action mechanism of paracetamol is focused on metabolic activation of the drug, depletion of glutathione, and covalent binding of the reactive metabolite N-acetyl-p-benzoquinone imine to cellular proteins as the main cause of hepatic cell death; intracellular steps critical for cell death include mitochondrial dysfunction and, importantly, the formation of ROS and peroxynitrite. Infection with hepatitis C is associated with increased levels of ROS/RNS and decreased antioxidant levels. As a consequence, antioxidants have been proposed as an adjunct therapy for various liver diseases.
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PMID:Role of free radicals in liver diseases. 1994 Nov 70

Since its discovery in 2000, neuroglobin (Nb) has been demonstrated to have an essential and conserved function in vertebrates with the consequential discovery of a neuroprotective role. Nb is a member of the globin superfamily and is predominantly expressed in neurons of the central and peripheral nervous system. Thorough studies have been performed to elucidate the molecular structure of Nb and its ligand binding characteristics. The precise physiological function and mechanism of action of Nb is beginning to be established, with a number of hypotheses having been put forward. While Nb shares an intrinsic affinity for low-molecular weight diatomic gases similar to other globins, the relatively low level of Nb expression in cerebral neurons places limitations on its potential to function as a reservoir for oxygen, especially during periods of acute ischemia. In vitro studies have suggested that the neuroprotective role of Nb may be due to its ability to scavenge reactive oxygen (ROS) and nitrogen (RNS) species. However other studies have proposed Nb as being part of a signalling chain that transmits the redox state of the cell that is protective against oxidative stress or that inhibits apoptosis. This review is intended to summarize the structural, genomic and functional data on neuroglobin to date, thereby providing perspectives for future research on these molecules that may have substantial biomedical implications.
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PMID:The significance of neuroglobin in the brain. 2072 63

A series of amidine, thiourea, and guanidine derivatives of 2-amino-6-(trifluoromethoxy)benzothiazole termed 2, 3, and 4, respectively, and structurally related to riluzole, a neuroprotective drug in many animal models of brain disease, have been synthesized. The biological activity of compounds 2a-e, 3a-f, and 4a,b was preliminarily tested by means of an in vitro protocol of ischemia/reperfusion injury. The results demonstrated that 2c and 3a-d significantly attenuated neuronal injury. Selected for testing of their antioxidant properties, compounds 3a-d were shown to be endowed with a direct ROS scavenging activity. Compounds 3b and 3d were also evaluated for their activity on voltage-dependent Na(+) and Ca(2+) currents in neurons from rat piriform cortex. At 50 microM, compound 3b inhibited the transient Na(+) current to a much smaller extent than riluzole, whereas 3d was almost completely ineffective.
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PMID:Synthesis and biological evaluation of amidine, guanidine, and thiourea derivatives of 2-amino(6-trifluoromethoxy)benzothiazole as neuroprotective agents potentially useful in brain diseases. 1995 Sep 3

In the past few years, a growing interest has been given to the possible antioxidant functions of a natural acid, synthesized in human tissues: alpha-lipoic acid (ALA). Both the oxidized (disulfide) and reduced (dithiol: dihydrolipoic acid, DHLA) forms of ALA show antioxidant properties. ALA administered in the diet accumulates in tissues, and a substantial part is converted to DHLA via a lipoamide dehydrogenase. Commercial ALA is usually a racemic mixture of the R and S forms. Chemical studies have indicated that ALA scavenges hydroxyl radicals, hypochlorous acid, and singlet oxygen. ALA exerts antioxidant effects in biological systems not only through direct ROS quenching but also via transition metal chelation. ALA has been shown to possess a number of beneficial effects both in the prevention and treatment of diabetes in experimental conditions. ALA presents beneficial effects in the management of symptomatic diabetic neuropathy and has been used in this context in Germany for more than 30 years. In cardiovascular disease, dietary supplementation with ALA has been successfully employed in a variety of in vivo models: ischemia-reperfusion, heart failure, and hypertension. More mechanistic and human in vivo studies are needed to determine whether optimizing the dietary intake of ALA can help to decrease cardiovascular diseases. A more complete understanding of cellular biochemical events that influence oxidative damage is required to guide future therapeutic advances.
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PMID:Antioxidant properties of an endogenous thiol: Alpha-lipoic acid, useful in the prevention of cardiovascular diseases. 1999 23

Reactive oxygen/nitrogen species (ROS/RNS) have been increasingly recognized as important mediators and play a number of critical roles in cell injury, metabolism, disease pathology, diagnosis, and clinical treatment. Electron paramagnetic resonance (EPR) spectroscopy enables the spectral information at certain spatial position, and, from the observed line-width and signal intensity, the localized tissue oxygenation, and tissue redox status can be determined. We applied in vivo EPR oximetry and redoximetry technique and implemented its physiological/pathophysiological applications, along with the use of biocompatible lithium pthalocyanine (liPc) and nitroxide redox sensitive probes, on in vivo tissue oxygenation and redox profile of the ischemic and reperfused heart in living animals. We have observed that the hypoxia during myocardial ischemia limited mitochondrial respiration and caused a shift of tissue redox status to a more reduced state. ROS/RNS generated at the beginning of reperfusion not only caused a shift of redox status to a more oxidized state which may contribute to the postischemic myocardial injury, but also a marked suppression of in vivo tissue O(2) consumption in the postischemic heart through modulation of mitochondrial respiration based on alterations in enzyme activity and mRNA expression of NADH dehydrogenase (NADH-DH) and cytochrome c oxidase (CcO). In addition, ischemic preconditioning was found to be able to markedly attenuate postischemic myocardial hyperoxygenation with less ROS/RNS generation and preservation of mitochondrial O(2) metabolism, due to conserved NADH-DH and CcO activities. These studies have demonstrated that EPR oximetry and redoximetry techniques have advanced to a stage that enables in-depth insight in the process of ischemia reperfusion injury.
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PMID:Electron paramagnetic resonance oximetry and redoximetry. 2007 11

Sauchinone, a biologically active lignan isolated from Saururus chinensis, has been reported to show cytoprotective, anti-inflammatory and anti-apoptotic effects. However, little study has been done of the anti-ischemic/hypoxic effect of sauchinone. The present study investigates the anti-ischemic/hypoxic effect of sauchinone by using ischemia/hypoxia-sensitive neuronal cells. We found that sauchinone significantly prevented cortical neurons from oxygen-glucose deprivation (OGD) followed by re-oxygenation. Sauchinone did not inhibit both NMDA-induced cell membrane depolarization and intracellular calcium influx. We further found that sauchinone cannot directly scavenge reactive oxygen and nitrogen species such as H2O2 and peroxynitrite. Sauchinone, however, greatly reduced the formation of reactive oxygen and nitrogen species in neurons exposed to OGD/reoxygenation and inhibited the depolarization of mitochondrial transmembrane potential induced by OGD/reoxygenation. In accordance with diminishment of endogenous ROS production, sauchinone restored the decreased activities of antioxidant enzymes catalase and SOD evoked by OGD/reoxygenation. Specifically, sauchinone up-regulated the activity of catalase, indicating that sauchinone could be a useful cytoprotectant.
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PMID:Sauchinone reduces oxygen-glucose deprivation-evoked neuronal cell death via suppression of intracellular radical production. 2009 Dec 74

TLRs are recognized as promoters of tissue damage, even in the absence of pathogens. TLR binding to damage-associated molecular patterns (DAMPs) released by injured host cells unleashes an inflammatory cascade that amplifies tissue destruction. However, whether TLRs possess the reciprocal ability to curtail the extent of sterile inflammation is uncertain. Here, we investigated this possibility in mice by studying the role of conventional DCs (cDCs) in liver ischemia/reperfusion (I/R) injury, a model of sterile inflammation. Targeted depletion of mouse cDCs increased liver injury after I/R, as assessed by serum alanine aminotransferase and histologic analysis. In vitro, we identified hepatocyte DNA as an endogenous ligand to TLR9 that promoted cDCs to secrete IL-10. In vivo, cDC production of IL-10 required TLR9 and reduced liver injury. In addition, we found that inflammatory monocytes recruited to the liver via chemokine receptor 2 were downstream targets of cDC IL-10. IL-10 from cDCs reduced production of TNF, IL-6, and ROS by inflammatory monocytes. Our results implicate inflammatory monocytes as mediators of liver I/R injury and reveal that cDCs respond to DAMPS during sterile inflammation, providing the host with protection from progressive tissue damage.
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PMID:Conventional DCs reduce liver ischemia/reperfusion injury in mice via IL-10 secretion. 2009 75

The adipocytokine apelin and its G protein-coupled APJ receptor were initially isolated from a bovine stomach and have been detected in the brain and cardiovascular system. Recent studies suggest that apelin can protect cardiomyocytes from ischemic injury. Here, we investigated the effect of apelin on apoptosis in mouse primary cultures of cortical neurons. Exposure of the cortical cultures to a serum-free medium for 24 h induced nuclear fragmentation and apoptotic death; apelin-13 (1.0-5.0 nM) markedly prevented the neuronal apoptosis. Apelin neuroprotective effects were mediated by multiple mechanisms. Apelin-13 reduced serum deprivation (SD)-induced ROS generation, mitochondria depolarization, cytochrome c release and activation of caspase-3. Apelin-13 prevented SD-induced changes in phosphorylation status of Akt and ERK1/2. In addition, apelin-13 attenuated NMDA-induced intracellular Ca(2+) accumulation. These results indicate that apelin is an endogenous neuroprotective adipocytokine that may block apoptosis and excitotoxic death via cellular and molecular mechanisms. It is suggested that apelins may be further explored as a potential neuroprotective reagent for ischemia-induced brain damage.
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PMID:Neuroprotective effect of the endogenous neural peptide apelin in cultured mouse cortical neurons. 2015 32


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