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)

A novel chrono-autoradiographic technique (sequential double label autoradiography) was established in order to evaluate regional cerebral blood flow (CBF) changes utilizing N-isopropyl-p-123I-iodoamphetamine (123I-IMP) and 14C-iodoantipyrine (14C-IAP). With sequential administration of 123I-IMP and 14C-IAP, two CBF images were obtained from the same brain section. By applying this method to focal cerebral ischemia, two sequential CBF images, one during ischemia and one after recirculation, were obtained. These results show that this method is useful in topographical evaluation of CBF changes. From a pathophysiological point of view, the result demonstrates a heterogeneous tissue perfusion after a transient ischemic insult.
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PMID:Sequential cerebral blood flow study by chrono-autoradiography. 373 11

This overviews recent understanding of the mechanisms of apoptosis on ischemia-induced neuronal cell death. Apoptosis is a prominent feature of the developing nervous system. Several lines of evidence suggest that apoptosis is also an important mechanism of cell death in adult brain in acute or chronic diseases such as stroke and Alzheimer's disease. In animal models of stroke, markers of apoptosis such as cytoplasmic and nuclear condensation and DNA fragmentation appear in neurons. A variety of physiological and pathological stimuli can activate signal-transduction pathways that result in the sequential proteolytic activation of caspase family members. The activation of caspases can be inhibited by several molecules, including peptide aldehydes (caspase-1 and or caspase-3 inhibitors) and crmA that target the active-site cysteine of caspase family members, Bcl-2, IAP (inhibitor of apoptosis protein) and NAIP (neuronal apoptosis inhibitory protein). Once activated, caspase-1 protease can activate the caspase family members and hydrolyze a discrete set of cellular targets. Poly (ADP-ribose)polymerase (PARP), which appears to facilitate apoptosis, was recognized as a substrate of activated caspase-3. These results suggest that caspase family, bcl-2 family, IAP family and substrates such PARP contribute to mechanisms of cell death in ischemic brain injury. Inhibition of the caspase family, particularly by non-peptide inhibitors that cross the blood-brain barrier and easily penetrate neurons and glia, could provide novel treatments for stroke and other forms of brain and spinal cord injury in humans.
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PMID:[Involvement of caspase on apoptosis in ischemia-induced neuronal cell death: usefulness of caspase inhibitors for stroke therapy]. 1020 84

Hypoxia is a key determinant of tissue pathology during tumor development and organ ischemia. However, little is known regarding hypoxic regulation of genes that are directly involved in cell death or death resistance. Here we report the striking induction by severe hypoxia of the anti-apoptotic protein IAP-2. Hypoxic cells with IAP-2 up-regulation became resistant to apoptosis. IAP-2 was induced by hypoxia per se rather than by the secondary effects of hypoxia, including ATP depletion and cell injury. The inductive response did not relate to alterations of cellular redox status or arrest of mitochondrial respiration. On the other hand, IAP-2 induction was attenuated by actinomycin D, suggesting a role for gene transcription. In vitro nuclear run-on assays demonstrated specific increases in IAP-2 transcriptional activity after hypoxia exposure. HIF-1, the primary transcription factor that is responsible for multiple gene activation under hypoxia, does not have a role in IAP-2 expression. HIF-1 and IAP-2 were induced by different degrees of hypoxia; severe hypoxia or anoxia was required for IAP-2 induction. Moreover, cobalt chloride and desferrioxamine activated HIF-1 but not IAP-2. Finally, IAP-2 was induced by severe hypoxia in mouse embryonic stem cells that were deficient of HIF-1. Thus, this study not only provides the first demonstration of hypoxic regulation of an anti-apoptotic gene but also suggests the participation of novel hypoxia-responsive transcription mechanisms.
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PMID:Up-regulation of apoptosis inhibitory protein IAP-2 by hypoxia. Hif-1-independent mechanisms. 1127 85

Many factors contribute to the severity of neuronal cell death and the functional outcome in stroke. We describe an embolic model of focal cerebral ischemia in the rat that does not require craniotomy and is compatible with continuous measurement of regional CBF using multichannel laser Doppler flow (LDF) technique. Either a 22 microliters (large lesion) or 11 microliters (small lesion) bolus of viscous silicone was injected cephalad into the internal carotid artery. Upon injection, LDF decreased abruptly, most severely in the parietal cortex (-74% +/- 5%) in the large lesion and in the occipital cortex (-69% +/- 10%) in the small lesion model. Over the first hour, post-embolization LDF improved in most areas (e.g. -48% +/- 9% parietal, large lesion) but declined in the small lesion group in the occipital region (-81% +/- 8%). CBF measured by [C]14-IAP autoradiography 1 h post-embolization in the large lesion model demonstrated near-hemispheric ischemia (70% of hemisphere) with sparing of cingulate cortex. Autoradiography demonstrated that ischemia in the small lesion was largely cortical. Light microscopy of brains embolized with 11 microliters of dyed silicone showed filling of pial vessels with no silicone in the Circle of Willis or parenchyma. No animals in the large lesion group survived 24 h. Thirteen of 15 animals in the small lesion group survived for two weeks with resolution of initial hemiplegia, ocular asymmetry and weight loss. Hematoxylin-eosin staining two weeks post-embolization showed signs of severe hypoxia and infarction. In conclusion, the intracarotid silicone embolization technique produces a titrable, reproducible permanent ischemic injury by blocking perfusion in the pial circulation, and is amenable to multisite monitoring with laser Doppler flowmetry. The smaller embolus produces cortical infarction with high rate of survival and neurological recovery.
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PMID:Focal cerebral ischemia in rats produced by intracarotid embolization with viscous silicone. 1187 3

Cardiac myocytes undergo apoptosis under condition of ischemia. Little is known, however, about the molecular pathways that mediate this response. We show that serum deprivation and hypoxia, components of ischemia in vivo, resulted in apoptosis of rat ventricular myoblast cells H9c2. Hypoxia alone did not induce significant apoptosis for at least 48 h, but largely increased the proapoptotic action of serum deprivation. H9c2 cells apoptosis is evidenced by an increase in terminal (TdT)-mediated dUTP nick end-labeling-positive nuclei and by activation of caspases 3, 6, 7 and 9, and loss of mitochondrial functions. In this model of simulated ischemia, represented by serum deprivation plus hypoxia, cardiomyoblasts apoptosis was associated with a p53-independent Bax accumulation and with a down-regulation of Bcl-xL, whereas the levels of cIAP-1, cIAP-2 and X-IAP proteins did not change. Phorbol-12-myristate-13-acetate significantly reduced the induction of apoptosis, inhibiting caspase 3 cleavage, Bax accumulation, Bcl-xL down-regulation as well as restoring cell viability.
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PMID:H9c2 cardiac myoblasts undergo apoptosis in a model of ischemia consisting of serum deprivation and hypoxia: inhibition by PMA. 1258 43

Focal ischemia by middle cerebral artery occlusion (MCAO) results in necrosis at the infarct core and activation of complex signal pathways for cell death and cell survival in the penumbra. Recent studies have shown activation of the extrinsic and intrinsic pathways of caspase-mediated cell death, as well as activation of the caspase-independent signaling pathway of apoptosis in several paradigms of focal cerebral ischemia by transient MCAO to adult rats and mice. The extrinsic pathway (cell-death receptor pathway) is initiated by activation of the Fas receptor after binding to the Fas ligand (Fas-L); increased Fas and Fas-L expression has been shown following focal ischemia. Moreover, focal ischemia is greatly reduced in mice expressing mutated (nonfunctional) Fas. Increased expression of caspase-1, -3, -8, and -9, and of cleaved caspase-8, has been observed in the penumbra. Activation of the intrinsic (mitochondrial) pathway following focal ischemia is triggered by Bax translocation to and competition with Bcl-2 and other members of the Bcl-2 family in the mitochondria membrane that is followed by cytochrome c release to the cytosol. Bcl-2 over-expression reduces infarct size. Cytochrome c binds to Apaf-1 and dATP and recruits and cleaves pro-caspase-9 in the apoptosome. Both caspase-8 and caspase-9 activate caspase-3, among other caspases, which in turn cleave several crucial substrates, including the DNA-repairing enzyme poly(ADP-ribose) polymerase (PARP), into fragments of 89 and 28 kDa. Inhibition of caspase-3 reduces the infarct size, further supporting caspase-3 activation following transient MCAO. In addition, caspase-8 cleaves Bid, the truncated form of which has the capacity to translocate to the mitochondria and induce cytochrome c release. The volume of brain infarct is greatly reduced in Bid-deficient mice, thus indicating activation of the mitochondrial pathway by cell-death receptors following focal ischemia. Recent studies have shown the mitochondrial release of other factors; Smac/DIABLO (Smac: second mitochondrial activator of caspases: DIABLO: direct IAP binding protein with low pI) binds to and neutralizes the effects of the X-linked inhibitor of apoptosis (XIAP). Finally, apoptosis-inducing factor (AIF) translocates to the mitochondria and the nucleus following focal ischemia and produces peripheral chromatin condensation and large-scale DNA strands, thus leading to the caspase-independent cell death pathway of apoptosis. Delineation of the pro-apoptotic and pro-survival signals in the penumbra may not only increase understanding of the process but also help to rationalize strategies geared to reducing brain damage targeted at the periphery of the infarct core.
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PMID:Signaling of cell death and cell survival following focal cerebral ischemia: life and death struggle in the penumbra. 1272 25

Cardiomyocytes are post-mitotic, long-lived cells until disruptions to pro-survival factors occur after myocardial ischemia. To gain an understanding of the factors involved with ischemic injury, we examined expression changes in pro-survival and opposing pro-apoptotic signals at early and chronic periods of ischemia using an in vivo murine model. Alterations of pro-survival proteins such as the inhibitor of apoptosis protein on chromosome X (xIAP) and the apoptotic repressor protein (ARC) have not been evaluated in a murine model of cardiac ischemia. Early ischemia (1 day) resulted in a 50% reduction in ARC protein levels relative to sham-operated left ventricles, without significant changes in the expression of xIAP or other pro-survival factors. In contrast, a deficiency of xIAP expression was found in cardiac infarcts starting after 1 week, concomitant with significant evidence of apoptotic cell death and an up-regulation of pro-apoptotic signals including Bax, tumor necrosis factor-a, and caspase-8 activation. Chronic ischemia (after 2 weeks) was associated with elevated levels of other pro-survival factors such as Bcl-xL and the phosphorylated form of Akt, as part of the adaptive remodeling of the myocardium. Altogether, these findings suggest that strategies to increase IAP expression may promote myocyte survival after chronic ischemia.
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PMID:Ischemia elicits a coordinated expression of pro-survival proteins in mouse myocardium. 1280 54

Oxidative stress may cause apoptosis of cardiomyocytes in ischemia-reperfused myocardium, and heat shock pretreatment is thought to be protective against ischemic injury when cardiac myocytes are subjected to ischemia or simulated ischemia. However, the detailed mechanisms responsible for the protective effect of heat shock pretreatment are currently unclear. The aim of this study was to determine whether heat shock pretreatment exerts a protective effect against hydrogen peroxide(H2O2)-induced apoptotic cell death in neonatal rat cardiomyocytes and C2C12 myogenic cells and whether such protection is associated with decreased release of second mitochondria-derived activator of caspase-direct IAP binding protein with low pl (where IAP is inhibitor of apoptosis protein) (Smac/DIABLO) from mitochondria and the activation of caspase-9 and caspase-3. After heat shock pretreatment (42 +/- 0.3 degrees C for 1 hour, recovery for 12 hours), cardiomyocytes and C2C12 myogenic cells were exposed to H2O2 (0.5 mmol/L) for 6, 12, 24, and 36 hours. Apoptosis was evaluated by Hoechst 33258 staining and DNA laddering. Caspase-9 and caspase-3 activities were assayed by caspase colorimetric assay kit and Western analysis. Inducible heat shock proteins (Hsp) were detected using Western analysis. The release of Smac/DIABLO from mitochondria to cytoplasm was observed by Western blot and indirect immunofluorescence analysis. (1) H2O2 (0.5 mmol/L) exposure induced apoptosis in neonatal rat cardiomyocytes and C2C12 myogenic cells, with a marked release of Smac/DIABLO from mitochondria into cytoplasm and activation of caspase-9 and caspase-3, (2) heat shock pretreatment induced expression of Hsp70, Hsp90, and alphaB-crystallin and inhibited H2O2-mediated Smac/DIABLO release from mitochondria, the activation of caspase-9, caspase-3, and subsequent apoptosis. H2O2 can induce the release of Smac/DIABLO from mitochondria and apoptosis in cardiomyocytes and C2C12 myogenic cells. Heat shock pretreatment protects the cells against H2O2-induced apoptosis, and its mechanism appears to involve the inhibition of Smac release from mitochondria.
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PMID:Heat shock pretreatment inhibited the release of Smac/DIABLO from mitochondria and apoptosis induced by hydrogen peroxide in cardiomyocytes and C2C12 myogenic cells. 1618 70

The abdominal compartment syndrome (ACS) is defined a situation of high degrade abdominal hypertension (IAH) with clinicals signs of multiorganic dysfunction. It's observed like in the intensive care, in particular surgycals and postraumatics, there is ever a bigger frequence of complications presented by criticals patients. The various trials remark a changeable incidence, but the common factor is characterized by a particular severity of scores. All the possibles mechanicals, haemorragicals, infiammatories, and postraumatics causes act, but don't enable the stability among abdominal content, abdominal compliance and parietal tension. The initial triad of effects is constitued by the elevation of diaphragm and the visceral and vascular compression; after this triad provoke a pathophysiologic system that, through various levels, bring to a respiratory, renal and cardiocirculatory dysfunction and to a parietal, hepatic and intestinal ischemia with consequent bacterical translation: sepsis and MOF. The Burch's classification (1996) report four levels of gravity by the slight (< 15 mmHg) to the heavyest (> 35 mmHg): the firsts two levels are of intensivistic competence and for the detention are used conservatives metodics and pharmacological approach; instead in the lasts two levels it's necessary to foresee a surgycal treatment of laparotomy, washing and drainage with following temporary paret's closure. The mortality is now very elevated (29-62%) especially when it's already established a multiorganical dysfunction; therefore it's necessary forward its appearance through the monitorization of abdominal pression (IAP) with the measurement of vescical pression in alls criticals patients at the aim to treat immediately the firsts signs of IAH.
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PMID:[Pathophysiological and clinical trials of the abdominal compartment syndrome]. 1734 91

Although changes of cerebral blood flow (CBF) in and around traumatic contusions are well documented, the role of CBF for the delayed death of neuronal cells in the traumatic penumbra ultimately resulting in secondary contusion expansion remains unclear. The aim of the current study was therefore to investigate the relationship between changes of CBF and progressive peri-contusional cell death following traumatic brain injury (TBI). CBF and contusion size were measured in C57Bl6 mice under continuous on-line monitoring of (ETp)CO2 before, and at 15 min and 24 h following controlled cortical impact by 14C-iodoantipyrine autoradiography (IAP-AR; n = 5-6 per group) and by Nissl staining, respectively. Contused and ischemic (CBF < 10%) tissue volumes were calculated and compared over time. Cortical CBF in not injured mice varied between 69 and 93 mL/100mg/min depending on the anatomical location. Fifteen minutes after trauma, CBF decreased in the whole brain by approximately 50% (39 +/- 18 mL/100mg/min; p < 0.05), except in contused tissue where it fell by more than 90% (3 +/- 2 mL/100mg/min; p < 0.001). Within 24 h after TBI, CBF recovered to normal values in all brain areas except the contusion where it remained reduced by more than 90% (p < 0.001). Contusion volume expanded from 24.9 to 35.5 mm3 (p < 0.01) from 15 min to 24 h after trauma (+43%), whereas the area of severe ischemia (CBF < 10%) showed only a minimal (+13%) and not significant increase (22.3 to 25.1 mm3). The current data therefore suggest that the delayed secondary expansion of a cortical contusion following traumatic brain injury may not be caused by a reduction of CBF alone.
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PMID:Changes of cerebral blood flow during the secondary expansion of a cortical contusion assessed by 14C-iodoantipyrine autoradiography in mice using a non-invasive protocol. 1862 53


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