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)

Stroke is a devastating disease with limited treatment options. Recently, we found that the peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists troglitazone and pioglitazone reduce injury and inflammation in a rat model of transient cerebral ischemia. The mechanism of this protection is unclear, as these agents can act through PPAR-gamma activation or through PPAR-gamma-independent mechanisms. Therefore, we examined PPAR-gamma expression, DNA binding and transcriptional activity following stroke. In addition, we used a PPAR-gamma antagonist, T0070907, to determine the role of PPAR-gamma during ischemia. Using immunohistochemical techniques and real-time PCR, we found low levels of PPAR-gamma mRNA and PPAR-gamma immunoreactivity in nonischemic brain; however, PPAR-gamma expression dramatically increased in ischemic neurons, peaking 24 h following middle cerebral artery occlusion. Interestingly, we found that in both vehicle- and agonist-treated brains, DNA binding was reduced in the ischemic hemisphere relative to the contralateral hemisphere. Expression of a PPAR-gamma target gene, lipoprotein lipase, was also reduced in ischemic relative to nonischemic brain. Both DNA binding and lipoprotein lipase expression were increased by the addition of the PPAR-gamma agonist rosiglitazone. Finally, we found that rosiglitazone-mediated protection after stroke was reversed by the PPAR-gamma antagonist T0070907. Interestingly, infarction size was also increased by T0070907 in the absence of PPAR-gamma agonist, suggesting that endogenous PPAR-gamma ligands may mitigate the effects of cerebral ischemia.
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PMID:Altered PPARgamma expression and activation after transient focal ischemia in rats. 1700 29

Mitochondrial dysfunction is a common consequence of ischemia-reperfusion and drug injuries. For example, sublethal injury of renal proximal tubular cells (RPTCs) with the model oxidant tert-butylhydroperoxide (TBHP) causes mitochondrial injury that recovers over the course of six days. Although regeneration of mitochondrial function is integral to cell repair and function, the signaling pathway of mitochondrial biogenesis following oxidant injury has not been examined. A 10-fold overexpression of the mitochondrial biogenesis regulator PPAR-gamma cofactor-1alpha (PGC-1alpha) in control RPTCs resulted in a 52% increase in mitochondrial number, a 27% increase in respiratory capacity, and a 30% increase in mitochondrial protein markers, demonstrating that PGC-1alpha mediates mitochondrial biogenesis in RPTCs. RPTCs sublethally injured with TBHP exhibited a 50% decrease in mitochondrial function and increased mitochondrial autophagy. Compared with the controls, PGC-1alpha levels increased 12-fold on days 1, 2, and 3 post-injury and returned to base line on day 4 as mitochondrial function returned. Inhibition p38 MAPK blocked the up-regulation of PGC-1alpha following oxidant injury, whereas inhibition of calcium-calmodulin-dependent protein kinase, calcineurin A, nitric-oxide synthase, and phosphoinositol 3-kinase had no effect. The epidermal growth factor receptor (EGFR) was activated following TBHP exposure, and the EGFR inhibitor AG1478 blocked the up-regulation of PGC-1alpha. Additional inhibitor studies revealed that the sequential activation of Src, p38 MAPK, EGFR, and p38 MAPK regulate the expression of PGC-1alpha following oxidant injury. In contrast, although Akt was activated following oxidant injury, it did not play a role in PGC-1alpha expression. We suggest that mitochondrial biogenesis following oxidant injury is mediated by p38 and EGFR activation of PGC-1alpha.
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PMID:Signaling of mitochondrial biogenesis following oxidant injury. 1711 59

Cell death from mitochondrial dysfunction and compromised bioenergetics is common after ischemia-reperfusion injury and toxicant exposure. Thus, promoting mitochondrial biogenesis is therapeutically attractive for sustaining oxidative phosphorylation and maintaining ATP-dependent cellular functions. Here, we evaluated increased mitochondrial biogenesis prior to or after oxidant exposure in primary cultures of renal proximal tubular cells (RPTC). Over-expression of the mitochondrial biogenesis regulator PPAR-gamma cofactor-1 alpha (PGC-1alpha) in control RTPC increased basal and uncoupled cellular respiration, ATP, and mitochondria. Increasing mitochondrial number/function prior to oxidant exposure did not preserve mitochondrial function, but potentiated dysfunction and cell death. However, increased mitochondrial biogenesis after oxidant injury accelerated recovery of mitochondrial function. In oxidant treated RPTC, mitochondrial protein expression was reduced by 50%. Also, ATP and cellular respiration decreased 48 h after oxidant exposure, whereas mitochondrial function in injured RPTC over-expressing PGC-1alpha returned to control values. Thus, up-regulation of mitochondrial biogenesis after oxidant exposure accelerates recovery of mitochondrial and cellular functions.
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PMID:PGC-1alpha over-expression promotes recovery from mitochondrial dysfunction and cell injury. 1730 37

Two groups of rats were used to examine the effect of pioglitazone, a peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, on rat hearts using an in vivo model of ischemia-reperfusion (I/R) to elucidate potential mechanisms. One group was the 30-min reperfusion group, which was further subdivided into sham (n=5), vehicle (n=6) and pioglitazone (3 mg x kg(-1), n=7) treatment groups with 30 min ischemia followed by 30 min reperfusion to detect data related to cardiac function and the area of myocardial infarction. The other group was the 120-min reperfusion group, subdivided into sham (n=5), vehicle (n=6), and pioglitazone 0.3 mg x kg(-1) (n=6), 1 mg x kg(-1) (n=7) and 3 mg x kg(-1) (n=6) treatment groups. Immunohistochemistry, in situ hybridization, terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) and DNA agarose gel electrophoresis were performed to detect apoptosis and expressions of Bax, Bcl-2, caspase 3, MMP-2 and PPARgamma protein, and MMP-2 and PPARgamma mRNA. We found that, after acute treatment with pioglitazone, the ratio of necrosis to area at risk decreased by 28% (p<0.01) and that of necrosis to left ventricle was reduced by 32% (p<0.01), compared with the vehicle group. Heart rate and +dp/dt(max), representing the cardiac systolic function, as well as -dp/dt(max), the indicator of cardiac diastolic function, improved significantly at 1 and 30 min after reperfusion (p<0.05-0.01). Furthermore, myocardial apoptosis was significantly suppressed by acute treatment with pioglitazone as evidenced by the decreased number of TUNEL-positive myocytes and DNA ladder, enhanced Bcl-2 protein expression, reduced Bax and caspase 3 protein expression in a dose-dependent manner compared with vehicle-treated rats. In addition, acute treatment with pioglitazone dose-dependently increased PPARgamma expression and decreased MMP-2 expression at protein and mRNA levels. Our findings demonstrate that a PPARgamma agonist may protect the heart from I/R injury. The protective effect is likely to occur by reducing cardiomyocyte apoptosis and inhibiting MMP-2.
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PMID:Effect of pioglitazone, a peroxisome proliferator-activated receptor gamma agonist, on ischemia-reperfusion injury in rats. 1735 10

Angiotensin II exerts its central nervous system effects primarily via its receptors AT1 and AT2, and it participates in the pathogenesis of ischemia via AT1. The selective AT1 receptor blocker (ARB) is used in the hypertension treatment, and it exerts a variety of pleiotropic effects, including antioxidative, antiapoptotic, and anti-inflammatory effects. In this study, we investigated the therapeutic effect of the ARB telmisartan in experimental intracerebral hemorrhage (ICH) in normotensive rats. ICH was induced via the collagenase infusion or autologous blood injection. Either telmisartan at 30 mg/kg/dose or phosphate-buffered saline was orally administered 2 h after ICH induction. We evaluated hemorrhage volume, brain water content, and functional recovery, and we performed the histological analysis for terminal deoxynucleotidyl transferase dUTP nick-end labeling, leukocyte infiltration, and microglia activation. A variety of intracellular signals, in terms of oxidative stress, apoptotic molecules, and inflammatory mediators, were also measured. Telmisartan reduced hemorrhage volume, brain edema, and inflammatory or apoptotic cells in the perihematomal area. Telmisartan was noted to induce the expression of endothelial nitric-oxide synthase and peroxisome proliferator-activated receptor gamma and decrease oxidative stress, apoptotic signal, tumor necrosis factor-alpha, and cyclooxygenase-2 expression. The telmisartan-treated rats exhibited less pronounced neurological deficits and recovered better. Thus, telmisartan seems to offer neural protection, including antiapoptosis, anti-inflammatory, and antioxidant benefits in the intracerebral hemorrhage rat model.
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PMID:Blockade of AT1 receptor reduces apoptosis, inflammation, and oxidative stress in normotensive rats with intracerebral hemorrhage. 1753 8

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors of the nuclear hormone receptor superfamily. The 3 PPAR isoforms (alpha, delta/beta and gamma) are known to control many physiological functions including glucose absorption, lipid balance, and cell growth and differentiation. Of interest, PPAR-gamma activation was recently shown to mitigate the inflammation associated with chronic and acute neurological insults. Particular attention was paid to test the therapeutic potential of PPAR agonists in acute conditions like stroke, spinal cord injury (SCI) and traumatic brain injury (TBI), in which massive inflammation plays a detrimental role. While 15d-prostaglandin J2 (15d PGJ2) is the natural ligand of PPAR-gamma, the thiazolidinediones (TZDs) are potent exogenous agonists. Due to their insulin-sensitizing properties, 2 TZDs rosiglitazone and pioglitazone are currently FDA-approved for type-2 diabetes treatment. Recent studies from our laboratory and other groups have shown that TZDs induce significant neuroprotection in animal models of focal ischemia and SCI by multiple mechanisms. The beneficial actions of TZDs were observed to be both PPAR-gamma-dependent as well as -independent. The major mechanism of TZD-induced neuroprotection seems to be prevention of microglial activation and inflammatory cytokine and chemokine expression. TZDs were also shown to prevent the activation of pro-inflammatory transcription factors at the same time promoting the anti-oxidant mechanisms in the injured CNS. This review article discusses the multiple mechanisms of TZD-induced neuroprotection in various animal models of CNS injury with an emphasis on stroke.
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PMID:Mechanisms of anti-inflammatory and neuroprotective actions of PPAR-gamma agonists. 1798 70

Previous studies have demonstrated that pioglitazone, a peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, inhibits ischemia-induced injury in various tissues including neural tissue. Pioglitazone has also been shown to reduce matrix metalloproteinase (MMP) activity. Because MMP is known to play a major role in the pathophysiology of brain ischemia, the present study was undertaken to test whether pioglitazone attenuates ischemic neuronal damage through MMP inhibition. C57BL/6 mice were subjected to global brain ischemia for 20 min. Animals were killed 72 h after ischemia. Oral pioglitazone (40 mg/kg/day, as a suspension in 0.5% carboxymethylcellulose) was administered to mice twice daily for 3 days before ischemia and twice daily after ischemia until the animals were killed. We investigated gelatinase activity by zymography and laminin immunohistochemistry. Histological analysis was also performed to test the protective effect of pioglitazone on neuronal damage. Mice treated with pioglitazone had attenuated gelatinase activity. Gelatin gel and in situ zymography showed up-regulation of gelatinase activity after ischemia. Pioglitazone significantly inhibited ischemia-induced elevation of the active form of MMP-9. Pioglitazone also reduced up-regulation of in situ gelatinase activity and laminin breakdown induced by ischemia in the hippocampus. There was marked neuronal damage in the CA1 and CA2 areas after ischemia. Neuronal damage in mice was significantly decreased by pioglitazone treatment, compared with vehicle-treated mice. Pioglitazone also inhibited TdT-mediated dUTP nick end labeling staining in CA1 and CA2 areas. Pioglitazone, a PPARgamma agonist, reduces delayed neuronal damage induced by global ischemia through inhibition of MMP-9 activity.
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PMID:PPARgamma agonist pioglitazone reduces [corrected] neuronal cell damage after transient global cerebral ischemia through matrix metalloproteinase inhibition. 1821 32

Early enteral nutrition supplemented with glutamine, arginine, omega-3 fatty acids, and nucleotides has been shown to decrease infection complications in critically injured patients. Concern has been raised, however, that under conditions of hyperinflammation, these diets may be injurious through the induction of inducible NO synthase by enteral arginine. In a rodent model of gut ischemia/reperfusion, inflammation and injury are intensified by enteral arginine and abrogated by glutamine. These findings correlate with the degree of metabolic stress imposed upon the gut by hypoperfusion. Glutamine is metabolized by the gut and therefore, can contribute back energy in the form of ATP, whereas arginine is a nonmetabolizable nutrient, using but not contributing energy. Recent data suggest that one of the molecular mechanisms responsible for the gut-protective effects of enteral glutamine is the activation of peroxisome proliferator-activated receptor gamma. This anti-inflammatory transcription factor belongs to the family of nuclear receptors, plays a key role in adipocyte development and glucose homeostasis, and has been recognized as an endogenous regulator of intestinal inflammation. Preliminary clinical studies support the use of enteral glutamine in patients with gut hypoperfusion.
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PMID:Enteral glutamine: a novel mediator of PPARgamma in the postischemic gut. 1839 Sep 29

Thiadiazolidinones (TDZDs) are small molecules that inhibit glycogen synthase kinase 3-beta (GSK3-beta) activity in a non competitive manner to ATP. NP00111, a new TDZD, besides causing inhibition of GSK-3beta, has also shown to be an agonist of PPARgamma . Since phosphorylation and consequent inhibition of GSK-3beta by PI-3K/Akt and agonism of PPARgamma have shown to afford neuroprotection in several in vitro and in vivo models, we have studied the potential neuroprotective effect of NP00111 in an "in vitro" model of ischemia-reperfusion. NP00111, at the concentration of 10 microM, significantly protected adult rat hippocampal slices subjected to oxygen and glucose deprivation (OGD) for 1 h followed by 3 h re-oxygenation, measured as lactic dehydrogenase (LDH) released to the extracellular media. The protective effects of NP00111 were more pronounced during the re-oxygenation period in comparison to the OGD period. Other GSK-3beta inhibitors like lithium or AR-A014418 did not afford protection in this model. However, the PPARgamma agonist rosiglitazone was protective at 3 microM. Protection afforded by NP00111 and rosiglitazone were prevented by the PPARgamma antagonist GW9662, suggesting that both NP00111 and rosiglitazone were preventing cell death caused by oxygen-glucose deprivation via activation of PPARgamma. NP00111 increased by two fold phosphorylation of ERK1/2 and its protective effects were lost when the hippocampal slices were co-incubated with the mitogen-activated protein kinase (MAPK) inhibitor PD98059. In conclusion, the novel TDZD NP00111 was protective against OGD in rat hippocampal slices by a mechanism related to phosphorylation of ERK1/2 via activation of PPARgamma.
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PMID:Neuroprotective effect of the new thiadiazolidinone NP00111 against oxygen-glucose deprivation in rat hippocampal slices: implication of ERK1/2 and PPARgamma receptors. 1847 12

The peroxisome proliferator-activated receptor gamma (PPAR-gamma) is a regulator of anti-inflammatory genes. One of its agonists, rosiglitazone-widely used in the treatment of type 2 diabetes mellitus-has recently been reported to increase the risk for myocardial infarction. In contrast, various studies provide evidence for a rosiglitazone-induced cardioprotection in different models of acute myocardial I/R. Here, we report that this protection can still be observed after 28 days of reperfusion in a murine model even when treatment commenced after the period of ischemia (reperfusion therapy). In vitro, cells from the rat cardiomyoblast cell line H9c2(2-1) are protected against oxidative stress by incubation with rosiglitazone, which can be abrogated by dexamethasone or cycloheximide. The antioxidant enzyme heme oxygenase 1 is up-regulated in these cells after rosiglitazone treatment. Our data provide further evidence that rosiglitazone exerts protective effects during myocardial I/R and might contribute to the reevaluation of the approved drug rosiglitazone.
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PMID:Rosiglitazone is cardioprotective in a murine model of myocardial I/R. 1856 25


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