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 calcium-sensing receptor (CaR) is a seven-transmembrane G-protein coupled receptor, which activates intracellular effectors, for example, it causes inositol phosphate (IP) accumulation to increase the release of intracellular calcium. Although intracellular calcium overload has been implicated in the cardiac ischemia/reperfusion (I/R)-induced apoptosis, the role of CaR in the induction of apoptosis has not been fully understood. This study tested the hypothesis that CaR is involved in I/R cardiomyocyte apoptosis by increasing [Ca2+]i. The isolated rat hearts were subjected to 40-min ischemia followed by 2 h of reperfusion, meanwhile GdCl3 was added to reperfusion solution. The expression of CaR increased at the exposure to GdCl3 during I/R. By laser confocal microscopy, it was observed that the intracellular calcium was significantly increased and exhibited a Deltapsim, as monitored by 5,5',6,6'-tetrachloro-1,1',3,3'- tetraethylbenzimidazolcarbocyanine iodide (JC-1) during reperfusion with GdCl3. Furthermore, the number of apoptotic cells was significantly increased as shown by TUNEL assay. Typical apoptotic cells were observed with transmission electron microscopy in I/R with GdCl3 but not in the control group. The expression of cytosolic cytochrome c and activated caspase-9 and caspase-3 was significantly increased whereas the expression of mitochondrial cytochrome c significantly decreased in I/R with GdCl3 in comparison to the control. In conclusion, these results suggest that CaR is involved in the induction of cardiomyocyte apoptosis during ischemia/reperfusion through activation of cytochrome c-caspase-3 signaling pathway.
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PMID:Involvement of calcium-sensing receptor in ischemia/reperfusion-induced apoptosis in rat cardiomyocytes. 1685 39

Hypoxia is a critical factor for cell death or survival in ischemic stroke, but the pathological consequences of combined ischemia-hypoxia are not fully understood. Here we examine this issue using a modified Levine/Vannucci procedure in adult mice that consists of unilateral common carotid artery occlusion and hypoxia with tightly regulated body temperature. At the cellular level, ischemia-hypoxia produced proinflammatory cytokines and simultaneously activated both prosurvival (eg, synthesis of heat shock 70 protein, phosphorylation of ERK and AKT) and proapoptosis signaling pathways (eg, release of cytochrome c and AIF from mitochondria, cleavage of caspase-9 and -8). However, caspase-3 was not activated, and very few cells completed the apoptosis process. Instead, many damaged neurons showed features of autophagic/lysosomal cell death. At the tissue level, ischemia-hypoxia caused persistent cerebral perfusion deficits even after release of the carotid artery occlusion. These changes were associated with both platelet deposition and fibrin accumulation within the cerebral circulation and would be expected to contribute to infarction. Complementary studies in fibrinogen-deficient mice revealed that the absence of fibrin and/or secondary fibrin-mediated inflammatory processes significantly attenuated brain damage. Together, these results suggest that ischemia-hypoxia is a powerful stimulus for spontaneous coagulation leading to reperfusion deficits and autophagic/lysosomal cell death in brain.
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PMID:Cerebral ischemia-hypoxia induces intravascular coagulation and autophagy. 1703 24

Cold ischemia--warm reperfusion (CI/WR) injury of liver transplantation involves hepatocyte cell death, the nature and underlying mechanisms of which remain unclear. Isolated hepatocytes and isolated perfused livers were used to determine the prevalence of necrosis and apoptosis as well as mitochondrial dysfunction. In isolated cells, propidium iodide and Hoechst 33342 staining showed a cold-storage, time-dependent increase in necrosis, whereas apoptosis was minimal even after 48 h of hypothermia. Nonetheless, a progressive loss of mitochondrial membrane potential was observed. Translocation of mitochondrial cytochrome c toward microsomes occurred within 24 h of CI/WR, with cytochrome c reaching the cytosol later. Mitochondria isolated from whole livers subjected to CI/WR also display reduced metabolic parameters and increased susceptibility to swelling. These events are associated with increased activity of major initiator (caspase 9) and effector (caspase 3) caspases. The results demonstrate that CI/WR induces mitochondrial dysfunction in isolated cells and in the whole organ; only in the latter is that sufficient to trigger the classical mitochondrial pathway of apoptosis. Our study also provides evidence for the involvement of endoplasmic reticulum stress in CI/WR hepatocyte injury. Combined protection of mitochondria and endoplasmic reticulum may thus represent an innovative therapeutic avenue to enhance liver graft viability and functional integrity.
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PMID:Implication of mitochondrial dysfunction and cell death in cold preservation--warm reperfusion-induced hepatocyte injury. 1690

Tetramethylpyrazine (TMP), a compound purified from Rhizoma Ligustici, is a widely used active ingredient in Chinese herbal medicine to treat cardiovascular diseases on account of its vasodilatory actions and antiplatelet activity. Studies have shown that TMP can remove oxygen free radicals and protect rat kidney from ischemia-reperfusion injury. In addition, adriamycin-induced nephrosis in rats is commonly used in pharmacological studies of human chronic renal diseases. Apoptosis of renal tubular cells has been reported in adriamycin-treated rats. To examine the therapeutic potential of TMP on chronic progressive renal diseases, adriamycin-induced injury in rat renal tubular cells NRK-52E has been used to monitor its protective effect. In TUNEL staining, TMP showed a dose-dependent protective effect against adriamycin-induced apoptosis in NRK-52E cells. Pretreatment of the cells with 10 or 100 microM of TMP effectively decreased the reactive oxygen species (ROS) formation induced by adriamycin, as measured in fluorescent assays. TMP was found to reduce the adriamycin-stimulated activities of caspase-3, caspase-8 and caspase-9, inhibit adriamycin-induced release of cytochrome C, and elevate the expression of Bcl-x (L). TMP was also able to inhibit the death receptor signaling pathway and suppress the activation of transcription factor NF-kappaB in adriamycin-treated NRK-52E cells. Based on the results of this study, we suggest that TMP can attenuate adriamycin-induced oxidative stress and apoptotic injury in NRK-52E cells, and that it may have therapeutic potential for patients with renal diseases. TMP: tetramethylpyrazine LDH: lactate dehydrogenase ROS: reactive oxygen species DCF: 2',7'-dichlorofluorescein TNF-alpha: tumor necrosis factor-alpha TUNEL: terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling.
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PMID:Tetramethylpyrazine attenuates adriamycin-induced apoptotic injury in rat renal tubular cells NRK-52E. 1690 63

In animal models of severe ischemia, it has not been uniformly observed that anesthetics are protective. However, anesthetics have not been evaluated in the presence of a mild excitotoxic insult. We hypothesized that in the presence of a mild excitotoxic insult, 3 microm N-methyl-D-aspartate (NMDA), isoflurane may prevent apoptotic cell death. Primary mixed neuronal/glial cultures were prepared from fetal rat brains. Mature cultures were exposed to dissolved isoflurane [0 mM, 0.4 mM (1.8 minimum alveolar concentration) or 1.6 mM (7 minimum alveolar concentration)] or dizocilpine (10 microM), and NMDA (0 or 3 microM) at 37 degrees C for 30 minutes. Apoptosis was assessed using terminal-deoxy-nucleotidyl end-nick labeling oligonucleosomal DNA fragmentation enzyme-linked immunosorbent assay, and caspases-3 and -9 activation assays. NMDA (3 muM) induced apoptosis in mixed neuronal/glial cell cultures. Apoptosis induced by 3 microm NMDA was caspase-3 but not caspase-9 mediated. In the presence of a mild excitotoxic insult, this investigation showed an attenuation of apoptotic cell death by dizocilpine, but not isoflurane.
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PMID:NMDA-induced apoptosis in mixed neuronal/glial cortical cell cultures: the effects of isoflurane and dizocilpine. 1700 21

Nitric oxide (NO) is associated with many pathophysiology of the central nervous system including brain ischemia, neurodegeneration and inflammation. Epigallocatechin gallate (EGCG) is a major compound of green tea polyphenol that has shown the protective activity against neuronal diseases. This study examined the effect of EGCG on NO-induced cell death in PC12 cells. The administration of sodium nitroprusside (SNP), a NO donor, decreased the cell viability and induced apoptosis showing characterization such as cell shrinkage and chromatin condensation as well as subG1 fraction of cell cycles. EGCG inhibited the cytotoxicity and apoptotic morphogenic changes induced by SNP. EGCG attenuated the production of reactive oxygen species (ROS) by SNP, and ameliorated the SNP-induced Bax to Bcl-2 expression ratio leading to apoptosis. In addition, EGCG prevented the release of cytochrome c from the mitochondria into the cytosol as well as the upregulation of the voltage-dependent anion channel (VDAC), a cytochrome c releasing channel, in the mitochondria of SNP-treated cells. EGCG abrogated the activation of caspase-9, caspase-8 and caspase-3 induced by SNP. These results demonstrate that EGCG has a protective effect against SNP-induced apoptosis in PC12 cells by scavenging ROS and modulating the signal molecules associated with cytochrome c, caspases, VDAC and the Bcl-2 family. These findings suggest that EGCG might be a natural neuroprotective substance.
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PMID:Epigallocatechin gallate inhibits nitric oxide-induced apoptosis in rat PC12 cells. 1711 66

High temperature requirement A2 (HtrA2)/Omi is a mitochondrial serine protease that is released into the cytosol from mitochondria and in turn promotes caspase activation by proteolyzing inhibitor of apoptosis proteins. Here we asked whether treatment with an HtrA2/Omi inhibitor, 5-[5-(2-nitrophenyl)furfuryliodine]-1,3-diphenyl-2-thiobarbituric acid (UCF-101), restores heart dysfunction following ischemia/reperfusion injury in vivo. Rats underwent a 30-min ischemia by occluding the left anterior descending artery, followed by 24 h reperfusion. UCF-101 (0.75 or 1.5 micromol/kg, i.p.) was administered 10 min before reperfusion. UCF-101 treatment significantly recovered the mean arterial blood pressure and ameliorated contractile dysfunction of the left ventricle 72 h after reperfusion with concomitant reduction of infarct size. Cardio-protection mediated by UCF-101 was correlated with reduced X-linked inhibitor of apoptosis protein (XIAP) degradation and inhibition of Caspase-9, Caspase-3, and Caspase-7 processing. Furthermore, UCF-101 prevented loss of membrane integrity by inhibiting fodrin breakdown in cardiomyocytes. UCF-101-induced cytoprotection was also correlated with reduced Fas ligand expression and inhibition of FLIP degradation following ischemia/reperfusion. These results suggest that UCF-101 rescues cardiomyocytes from ischemia/reperfusion injury by inhibiting XIAP degradation and Fas/Fas-ligand-induced apoptosis, thereby ameliorating ischemia/reperfusion-induced myocardial dysfunction.
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PMID:Inhibition of HtrA2/Omi ameliorates heart dysfunction following ischemia/reperfusion injury in rat heart in vivo. 1718 30

Ischemia-reperfusion (IR) of the testis results in germ-cell-specific apoptosis (GCA) and a reduction in daily sperm production. This has been correlated with and is dependent upon neutrophil recruitment to the testis. In a rat model of testicular IR, this has also been correlated with an increase in reactive oxygen species (ROS). We have investigated ROS in the mouse testis after IR and determined whether the observed GCA is mediated via a mitochondrial caspase-9-dependent pathway involving the upstream mediators caspase 2 and BAX. Mice were subjected to a 2-h period of testicular ischemia followed by reperfusion. An accumulation of 8-isoprostane, a marker of oxidative stress, occurred 4 h after reperfusion. Activation of a mitochondrial dependent pathway to GCA after testicular IR was determined based on the observations that both BAX and caspase 2 translocated to the mitochondria, and that an increase occurred in cytoplasmic cytochrome c. Moreover, microinfusion of a specific caspase 9 inhibitor significantly reduced active caspase 3 after testicular IR and the number of apoptotic germ cells. These results suggest that oxidative stress products accumulate in the testis following IR and demonstrate that the observed GCA is stimulated through a mitochondrial caspase-9-dependent pathway. The identification of the germ-cell apoptotic pathway induced after testicular IR, including the key players in the pathway subsequent to ROS (BAX, caspase 9, and caspase 2), aids our understanding of IR injury in the testis and provides a wider background for the development of therapeutic interventions to rescue testis function.
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PMID:Caspase-9-dependent pathway to murine germ cell apoptosis: mediation by oxidative stress, BAX, and caspase 2. 1726 69

Taurine is a sulphur-containing amino acid abundant in the nervous system. It protects cells from ischemia-induced apoptosis, but the mechanism underlying this is not well established. The aim of our study was to explore the effects of taurine on two main pathways of apoptosis induced by ischemia: receptor-mediated and mitochondrial cell death. Brain slices containing the supraoptic (SON) and paraventricular (PVN) nuclei of the hypothalamus were incubated in vitro under control and simulated ischemic (oxygen-glucose deprivation for 30 min) conditions in the absence and presence of 20 mM taurine. Brain slices were harvested after the 180-min "postischemic" period and fixed in 4% paraformaldehyde. To estimate apoptosis, immunostaining was done for caspase-8 and caspase-9 in paraffin-embedded sections. Immunoreactive caspase-8 and caspase-9 cells were observed in SON and PVN in all experimental groups, but in the "ischemic" group the expression of caspase-8 and caspase-9 and the number of immunoreactive cells was significantly increased in both hypothalamic nuclei. Addition of taurine (20 mM) to the incubation medium induced a marked decrease in caspase-8 and caspase-9 immunoreactivity after ischemia in SON and PVN when compared with the taurine-untreated "ischemic" group. Taurine reduces ischemia-induced caspase-8 and caspase-9 expression, the key inductors of apoptosis in SON and PVN.
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PMID:Taurine reduces caspase-8 and caspase-9 expression induced by ischemia in the mouse hypothalamic nuclei. 1729 64

The present study aims to investigate the potential therapeutic role of interleukin-10 (IL-10) in small-for-size liver transplantation. A syngenic rat orthotopic liver transplantation model was performed using either whole or 40% liver volume of Lewis rats as grafts according to the experimental design. IL-10 was given to the 40% grafts right after reperfusion, and also at 24 and 48 hours after transplantation. When no treatment was given, less than 40% of the small-for-size grafts survived indefinitely, whereas IL-10 treatment could increase the long-term survival rate of the small-for-size grafts to 80%. The 40% grafts presented with extensive areas of necrosis and increased number of apoptotic cells at the early phases after reperfusion. In addition, upregulation of plasma protein carbonyl content (PCC) levels was also detected in the 40% graft group. IL-10 treatment suppressed the upregulation of allograft inflammatory factor-1 (AIF-1) on macrophages in the 40% grafts, and at the same time, decreased the levels of plasma PCC, and improved the histology and function of the 40% grafts. The expression of inducible nitric oxide synthase (iNOS), tumor necrosis factor (TNF)-alpha, and caspase 9 in the 40% grafts were upregulated after reperfusion, whereas the augmentation could be suppressed by the administration of IL-10. Finally, IL-10 culture could block AIF-1-mediated NO production and downregulate the expression of iNOS and TNF-alpha in a macrophage cell line. In conclusion, IL-10 rescued the small-for-size liver grafts by its antiinflammatory properties, through inhibition of AIF-1 mediated proinflammatory and proapoptotic activities of the macrophages during the early period after ischemia/reperfusion.
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PMID:Antiinflammatory properties of IL-10 rescue small-for-size liver grafts. 1739 54


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