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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Reperfusion of ischemic myocardium results in apoptotic cell death, which can be blocked by adapting the heart to ischemic stress induced by cyclic episodes of brief periods of ischemia and reperfusion. In concert, the antiapoptotic gene bcl-2 is decreased by ischemia/reperfusion, but increased in the ischemically adapted myocardium. To examine if bcl-2 plays a crucial role in cardioprotection, adaptive cardioprotection was further examined in the hearts treated with antisense bcl-2 oligodeoxynucleotides (ODN). Isolated Langendorff-perfused rat hearts were divided into three groups: control (perfused with Krebs-Henseleit bicarbonate buffer for 210 min); 30-min ischemia followed by 2-h reperfusion; ischemic adaptation followed by 30-min ischemia and 2-h reperfusion. The last (adapted heart) group was subdivided into another two groups: one was transfected 48 h earlier with antisense bcl-2 ODN, whereas the other group was transfected with sense bcl-2 ODN. Cardioprotection was examined by determining cardiomyocyte death due to necrosis and apoptosis. Antisense gene therapy almost completely abolished bcl-2 protein expression in the hearts. Bcl-2 mRNA was down-regulated in the ischemic/reperfused heart, but up-regulated in the adapted myocardium. Adapted myocardium showed decreased infarct size and reduced number of apoptotic cardiomyocytes. Ischemia/reperfusion resulted in increased oxidative stress as evidenced by increased malonaldehyde formation. Adapted myocardium had a reduced amount of malonaldehyde. Antisense bcl-2 ODN completely abolished the cardioprotective effects of adaptation by eliminating the antideath signal of bcl-2. In concert, reduced oxidative stress in the adapted myocardium no longer persisted. The results suggest an antioxidant role of bcl-2 that appeared to be essential for the cardioprotection achieved by ischemic adaptation.
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PMID:An essential role of the antioxidant gene Bcl-2 in myocardial adaptation to ischemia: an insight with antisense Bcl-2 therapy. 1149 53

Neuronal nitric oxide-I is constitutively expressed in approximately 2% of cortical interneurons and is co-localized with gamma-amino butric acid, somatostatin or neuropeptide Y. These interneurons additionally express high amounts of glutamate receptors which mediate the glutamate-induced hyperexcitation following cerebral injury, under these conditions nitric oxide production increases contributing to a potentiation of oxidative stress. However, perilesional nitric oxide synthase-I containing neurons are known to be resistant to ischemic and excitotoxic injury. In vitro studies show that nitrosonium and nitroxyl ions inactivate N-methyl-D-aspartate receptors, resulting in neuroprotection. The question remains of how these cells are protected against their own high intracellular nitric oxide production after activation. In this study, we investigated immunocytochemically nitric oxide synthase-I containing cortical neurons in rats after unilateral, cortical photothrombosis. In this model of focal ischemia, perilesional, constitutively nitric oxide synthase-I containing neurons survived and co-expressed antioxidative enzymes, such as manganese- and copper-zinc-dependent superoxide dismutases, heme oxygenase-2 and cytosolic glutathione peroxidase. This enhanced antioxidant expression was accompanied by a strong perinuclear presence of the antiapoptotic Bcl-2 protein. No colocalization was detectable with upregulated heme oxygenase-1 in glia and the superoxide and prostaglandin G(2)-producing cyclooxygenase-2 in neurons. These results suggest that nitric oxide synthase-I containing interneurons are protected against intracellular oxidative damage and apoptosis by Bcl-2 and several potent antioxidative enzymes. Since nitric oxide synthase-I positive neurons do not express superoxide-producing enzymes such as cyclooxygenase-1, xanthine oxidase and cyclooxygenase-2 in response to injury, this may additionally contribute to their resistance by reducing their internal peroxynitrite, H(2)O(2)-formation and caspase activation.
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PMID:Nitric oxide synthase-I containing cortical interneurons co-express antioxidative enzymes and anti-apoptotic Bcl-2 following focal ischemia: evidence for direct and indirect mechanisms towards their resistance to neuropathology. 1152 39

Female rodents producing endogenous estrogens are protected from stroke damage in comparison with male counterparts. This natural protection is lost after ovariectomy or reproductive senescence. The aim of this study is to determine whether estrogen reduces early neuronal injury and cell loss after ischemia by increasing the expression of Bcl-2. Male, intact female, ovariectomized, and estrogen-repleted ovariectomized rats were subjected to middle cerebral artery occlusion, and 22 hr later the level and localization of Bcl-2 mRNA and protein were determined. The levels of post-ischemic bcl-2 mRNA and protein were increased exclusively in neurons within the peri-infarct region. Intact females and estrogen-treated castrates demonstrated increased bcl-2 mRNA and protein expression compared with males and estrogen-deficient females, accompanied by a decrease in infarct size. To test the hypothesis that the neuroprotective mechanism of estrogen functions via Bcl-2, we compared ischemic outcome in male, female, and ovariectomized wild-type mice and mice overexpressing Bcl-2 exclusively in neurons. Wild-type female mice sustained smaller infarcts compared with males. Bcl-2 overexpression reduced infarct size in males, but provided no added protection in the female. Moreover, ovariectomy exacerbated infarction in wild-type females, but had no effect in Bcl-2 overexpressors. These data indicate that overexpression of Bcl-2 simulates the protection against ischemic injury conferred by endogenous female sex steroids. We concluded that estrogen rescues neurons after focal cerebral ischemia by increasing the level of Bcl-2 in peri-infarct regions and that estrogen-induced bcl-2 gene expression is an important downstream component of neuronal protection in female stroke.
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PMID:Estrogen and Bcl-2: gene induction and effect of transgene in experimental stroke. 1156 44

We studied neuronal cell body, axonal, and terminal degeneration in brains from 7-day-old rat pups recovered for 0, 1.5, 3, 6, 24, 48, 72 h, and 6 days following hypoxia-ischemia and identified proteins involved in the delayed neurodegeneration in the thalamus. We found that injury is biphasic with initial necrosis in the ipsilateral forebrain by 3 h following hypoxia-ischemia, in contrast to more delayed and apoptotic-like injury in the ventral-basal thalamus, brainstem, and other remote non-forebrain regions. Prior to the appearance of large numbers of apoptotic profiles in the ventral-basal thalamus, expression of Fas death receptor protein, activated forms of caspase 8 and caspase 3, and pro-apoptotic Bcl-2 proteins are increased. This manuscript combines our data on hypoxic-ischemic injury in the developing brain and presents evidence for at least two forms of neurodegeneration, namely, acute necrosis in the forebrain and delayed neurodegeneration in the thalamus, which is death-receptor-mediated programmed cell death.
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PMID:Neurodegeneration in the thalamus following neonatal hypoxia-ischemia is programmed cell death. 1159 18

Mild hypothermia protects the brain against experimental ischemia, but the reasons are not well known. We examined whether the protective effects of mild hypothermia could be correlated with alterations in expression of Bcl-2, an anti-apoptotic protein in a rat model of transient global ischemia. Following 10 min of forebrain ischemia, hippocampal neurons were examined 72 h later for survival, expression of Bcl-2 family proteins and apoptosis. Intraischemic mild hypothermia was applied for 3 h (33 degrees C, isch-33) or normal body temperature was maintained (37 degrees C, isch-37). Survival of CA1 neurons was significantly improved in the isch-33 group compared to the isch-37 group (90 vs. 53% survival; P<0.01). The proportion of Bcl-2-positive cells among surviving CA1 neurons in the isch-33 group was increased compared to that of sham and isch-37 groups (P<0.01). Bax expression in CA1 was no different between sham and isch-33 groups, but was significantly decreased in isch-37 (P<0.05). TUNEL staining was positive in many isch-37 CA1 neurons, but absent in isch-33. Utilizing electron microscopy, more cells meeting criteria for apoptosis were observed in the isch-37 than isch-33. These data suggest that mild hypothermia attenuates apoptotic death, and that this protection may be related to increases in Bcl-2.
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PMID:Mild hypothermia increases Bcl-2 protein expression following global cerebral ischemia. 1168 78

Our previous work in cultured cells has shown that the maintenance of mitochondrial Ca(2+) homeostasis is essential for cell survival, and that the anti-apoptotic protein Bcl-2 is able to maintain a threshold level of mitochondrial Ca(2+) by the inhibition of permeability transition. To test whether Bcl-2 also affects the mitochondrial Na(+)-Ca(2+) exchange (NCE), a major efflux pathway for mitochondrial Ca(2+), studies using transgenic mice that overexpress Bcl-2 in the heart have been performed. NCE activity was determined as the Na(+)-dependent Ca(2+) efflux in the isolated mitochondria. Overexpression of Bcl-2 led to a significant reduction of NCE activity as well as increased resistance to permeability transition in the mitochondria of transgenic heart. This was accompanied by increased matrix Ca(2+) level, enhanced formation of NADH and enhanced oxidation of pyruvate, an NAD(+)-linked substrate. Furthermore, there was induction of cellular Ca(2+) transport proteins including the Na(+)-Ca(2+) exchanger of the sarcolemma (NCX). Bcl-2 not only stimulates NCX expression in the sarcolemma but also attenuates the Na(+)-Ca(2+) exchange in the mitochondria. These results are consistent with the protection by Bcl-2 against apoptosis in heart following ischemia/reperfusion.
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PMID:Regulation of sodium-calcium exchange and mitochondrial energetics by Bcl-2 in the heart of transgenic mice. 1173 55

Dysregulated polymorphonuclear leukocyte (PMN) apoptosis and PMN-mediated organ damage have been associated with several medical conditions such as systemic inflammatory response syndrome (SIRS), acute respiratory distress syndrome (ARDS), and ischemia/reperfusion injury. IL-1beta and IL-8 are two cytokines that are elevated under similar conditions. Therefore, we hypothesized that PMN exposed to these cytokines would secrete factors that could affect PMN apoptosis in a cell contact-independent manner. We have previously shown that media conditioned by IL-1beta-stimulated PMN (CM-IL1beta) for 2 h suppressed spontaneous PMN apoptosis. Data presented here demonstrate that media conditioned by IL-8-stimulated PMN (CM-IL8) also have the ability to suppress spontaneous, as well as FasL- and TNF-alpha-induced apoptosis. In contrast, CM-IL1beta was able to suppress FasL-induced, but not TNF-alpha-induced, apoptosis. To elucidate the mechanisms these media use to elicit their effects, we examined the expression and function of several apoptosis-related proteins. Experimental results demonstrate that both CM-IL1beta and CM-IL8 have the ability to delay caspase activation, but have no effect on the expression of their upstream activator, Fas, or its ligand, FasL. Examination of several Bcl-2 family members revealed a selective regulation by each media: CM-IL1beta up-regulated Bcl-X(L), while CM-IL8 down-regulated Bak expression. Additionally, CM-IL1beta, but not CM-IL8, promoted the activation of NF-kappaB, which has anti-apoptotic activity. Together, we can conclude that IL-1beta- and IL-8-stimulated PMN have the ability to suppress PMN apoptosis in a paracrine manner, and that the extent and mechanism of suppression is specific for each.
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PMID:Paracrine suppression of apoptosis by cytokine-stimulated neutrophils involves divergent regulation of NF-kappaB, Bcl-X(L), and Bak. 1179 69

Islet transplantation is a promising method for restoring normoglycemia and alleviating the long term complications of diabetes. Widespread application of islet transplantation is hindered by the limited supply of human islets and requires a large increase in the availability of suitable insulin secreting tissue as well as robust quality assessment methodologies that can ensure safety and in vivo efficacy. We explore the application of nuclear magnetic resonance (NMR) spectroscopy in two areas relevant to beta cell engineering and islet transplantation: (1) the effect of genetic alterations on glucose metabolism, and (2) quality assessment of islet preparations prior to transplantation. Results obtained utilizing a variety of NMR techniques demonstrate the following: (1) Transfection of Rat1 cells with the c-myc oncogene (which may be involved in cell proliferation and cell cycle regulation) and overexpression of Bcl-2 (which may protect cells from stresses such as hypoxia and exposure to cytokines) introduce a wide array of alterations in cellular biochemistry, including changes in anaerobic and oxidative glucose metabolism, as assessed by 13C and 31P NMR spectroscopy. (2) Overnight incubation of islets and beta cells in the bottom of centrifuge tubes filled with medium at room temperature, as is sometimes done in islet transportation, exposes them to severe oxygen limitations that may cause cell damage. Such exposure, leading to reversible or irreversible damage, can be observed with NMR-detectable markers using conventional 13C and 31P NMR spectroscopy of extracts. In addition, markers of irreversible damage (as well as markers of hypoxia) can be detected and quantified without cell extraction using high-resolution magic angle spinning 1H NMR spectroscopy. Finally, acute ischemia in a bed of perfused beta cells leads to completely reversible changes that can be followed in real time with 31P NMR spectroscopy.
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PMID:NMR spectroscopy in beta cell engineering and islet transplantation. 1179 99

Mild hypothermia protects the brain from ischemia, but the underlying mechanisms of this effect are not well known. The authors previously found that hypothermia reduces the density of apoptotic cells, but it is not certain whether temperature alters associated biochemical events. Mitochondrial release of cytochrome c has recently been shown to be a key trigger in caspase activation and apoptosis via the intrinsic pathway. Using a model of transient focal cerebral ischemia, the authors determined whether mild hypothermia altered expression of Bcl-2 family proteins, mitochondrial release of cytochrome c, and caspase activation. Mild hypothermia significantly decreased the amount of cytochrome c release 5 hours after the onset of ischemia, but mitochondrial translocation of Bax was not observed until 24 hours. Mild hypothermia did not alter Bcl-2 and Bax expression, and caspase activation was not observed. The present study provides the first evidence that intraischemic mild hypothermia attenuates the release of cytochrome c in the brain, but does not appear to affect other biochemical aspects of the intrinsic apoptotic pathway. They conclude that necrotic processes may have been interrupted to prevent cytochrome c release, and that the ameliorative effect of mild hypothermia may be a result of maintaining mitochondrial integrity. Furthermore, the authors show it is unlikely that mild hypothermia alters the intrinsic apoptotic pathway.
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PMID:Mild hypothermia attenuates cytochrome c release but does not alter Bcl-2 expression or caspase activation after experimental stroke. 1180 91

This study examined the protective effects of cilostazol on cerebral infarcts produced by subjecting rats to 2-h occlusion of the left middle cerebral artery followed by 24-h reperfusion. The ischemic cerebral infarct consistently involved the cortex and striatum. The infarct size was significantly reduced, when rats received 10 mg/kg cilostazol intravenously 5 min or 1 h after the completion of 2-h ischemia. Cyclic AMP level was significantly elevated in the cortex of 4- and 12-h reperfusion (P < 0.01) following treatment with cilostazol (10 mg/kg, 5 min after 2-h ischemia) accompanied by decreased tumor necrosis factor-alpha level. Samples from the regions corresponding to the penumbra showed markedly reduced Bcl-2 protein level and, in contrast, high levels of Bax protein and cytochrome c release. Cilostazol decreased Bax protein and cytochrome c release and increased the levels of Bcl-2 protein. Cilostazol (10(-7)-10(-5) M) potently and concentration dependently scavenged hydroxyl and peroxyl radicals. In conclusion, cilostazol treatment decreases ischemic brain infarction in association with inhibition of apoptotic and oxidative cell death.
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PMID:Neuroprotective effect of cilostazol against focal cerebral ischemia via antiapoptotic action in rats. 1186 82


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