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)

Epithelial-to-mesenchymal transition (EMT) of tubular epithelial cells (TECs) may participate in the pathogenesis of renal fibrosis. We performed a prospective study of EMT markers in protocol biopsies obtained 3 months after engraftment from 56 patients who received deceased donor kidneys and who had stable renal function. The presence of EMT was examined, and quantified by immunohistochemical staining for vimentin and translocation of beta-catenin to the cytoplasm. EMT status was defined as the presence of EMT markers in > or = 10% of TECs. EMT features were virtually absent in implantation biopsies, whereas 41% of the grafts were EMT-positive in the absence of advanced chronic allograft nephropathy. Thirteen patients (23%) had borderline changes or acute rejection. EMT features were more frequent in these patients than in those with normal kidney grafts (vimentin expression, p = 0.003; beta-catenin translocation, p = 0.002). EMT in grafts corresponded with elevated serum creatinine of the donor before the recovery of kidney (p = 0.02) and longer cold ischemia time (p = 0.02). In contrast, the donor age had no influence on the expression of EMT markers. These results suggest that EMT is an early and frequent phenomenon in kidney transplants that could be triggered by immunological and/or ischemic tubular injury.
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PMID:Risk factors for early epithelial to mesenchymal transition in renal grafts. 1706 92

Cilostazol is a selective inhibitor of cyclic nucleotide phosphodiesterase 3 (PDE3), which induces a vasodilatoric antiplatelet effect. In the present study, we investigated the impact of cilostazol on the blood-brain barrier (BBB), while focusing on the actin cytoskeleton (F-actin), the permeability of endothelial cells, and the junctional proteins under hypoxia/reoxygenation (H/R). Cilostazol was thus found to inhibit the cytoskeletal reorganization under H/R, in which F-actin decrease at the cell periphery. Accordingly, cilostazol was able to attenuate the hyperpermeability of endothelial cells in H/R to the level of the permeability in normoxia. However, the adherens junction (AJ) protein VE-cadherin was not preserved in the presence of cilostazol under H/R. On the other hand, beta-catenin was slightly retained by cilostazol. In contrast to the redistribution of these proteins, immunoblotting demonstrated the total amount of AJ and tight junction (TJ) proteins (occludin, ZO-1 and ZO-2) to not show any significant change under H/R stress in either the presence or absence of cilostazol. Taken together, cilostazol potently displayed a protective effect against acute ischemia by preventing an increase in the endothelial permeability through the preservation of the actin cytoskeleton and the redistribution of junctional proteins.
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PMID:Cilostazol inhibits the redistribution of the actin cytoskeleton and junctional proteins on the blood-brain barrier under hypoxia/reoxygenation. 1715 25

Hypercholesterolemia (HC) is a common health problem that significantly increases risk of cardiovascular disease. Both statin (S) and resveratrol (R) demonstrated cardioprotection through nitric oxide-dependent mechanism. Therefore, the present study was undertaken to determine whether combination therapy with statin and resveratrol is more cardioprotective than individual treatment groups in ischemic rat heart model. The rats were fed with 2% high cholesterol diet and after 8 weeks of high cholesterol diet the animals were treated with statin (1 mg/kg bw/day) and resveratrol (20 mg/kg bw/day) for 2 weeks. The rats were assigned to: (1) Control (C), (2) HC, (3) HCR, (4) HCS and (5) HCRS. The hearts, subjected to 30-min global ischemia followed by 120-min reperfusion were used as experimental model. The left ventricular functional recovery (+dp/dt(max)) was found to be significantly better in the HCRS (1926+/-43), HCR (1556+/-65) and HCS (1635+/-40) compared to HC group (1127+/-16). The infarct sizes in the HCRS, HCS and HCR groups were 37+/-3.6, 43+/-3.3 and 44+/-4.2 respectively compared to 53+/-4.6 in HC. The lipid level was found to be decreased in all the treatment groups when compared to HC more significantly in HCS and HCRS groups when compared to HCR. Increased phosphorylation of Akt and eNOS was also observed in all the treatment groups resulting in decreased extent of cardiomyocyte apoptosis but the extent of reduction in apoptosis was more significant in HCRS group compared to all other groups. In vivo rat myocardial infarction (MI) model subjected to 1 week of permanent left descending coronary artery (LAD) occlusion documented increased capillary density in HCR and HCRS treated group when compared to HCS treatment group. We also documented increased beta-catenin translocation and increased VEGF mRNA expression in all treatment groups. Thus, we conclude that the acute as well as chronic protection afforded by combination treatment with statin and resveratrol may be due to pro-angiogenic, anti-hyperlipidemic and anti-apoptotic effects and long-term effects may be caused by increased neo-vascularization of the MI zone leading to less ventricular remodeling.
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PMID:Statin and resveratrol in combination induces cardioprotection against myocardial infarction in hypercholesterolemic rat. 1722 64

Recombinant human erythropoietin (rhEPO), a neurovascular protective agent, therapeutically supports angiogenesis after stroke by enhancing endogenous up-regulation of vascular endothelial growth factor (VEGF). Increased VEGF expression has been characterized to negatively impact the integrity of the blood brain barrier (BBB), causing brain edema and secondary injury. The present study investigated the rhEPO-induced BBB protection after stroke and how it might be achieved by affecting VEGF pathway. rhEPO treatment (5,000 U/kg, i.p., 30 min before stroke and once a day for three days after stroke) reduced Evans blue leakage and brain edema after ischemia. The expression of the BBB integrity markers, occludin, alpha-catenin and beta-catenin, in the brain was preserved in animals received rhEPO. rhEPO up-regulated VEGF expression; however, the expression of VEGF receptor-2 (fetal liver kinase receptor, Flk-1) was significantly reduced in rhEPO-treated animals three days after stroke. We propose that, disregarding increased VEGF levels, rhEPO protects against ischemia-induced BBB damage at least partly by down-regulating Flk-1 expression and the response to VEGF signaling in the acute phase after stroke.
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PMID:Erythropoietin prevents blood brain barrier damage induced by focal cerebral ischemia in mice. 1756 65

Although ischemia is associated with disruption of cadherin-mediated adhesion in renal cell lines, the impact of decreased cadherin function on the transcriptional activity of beta-catenin remains poorly defined. In these studies, we used a simulated ischemia model in normal rat kidney (NRK) cells to disrupt cadherin function. Cell viability; cadherin/catenin expression, function, and localization; and beta-catenin-mediated transcriptional activity were assessed during ischemia/reperfusion. Following 6 hr of ischemia, a decrease in the expression of E- and N-cadherin was seen that correlated with altered cell morphology indicative of decreased intercellular adhesion. While ischemia was associated with activation of glycogen synthase kinase 3 beta (GSK-3beta), this did not correlate with increased phosphorylation of beta-catenin as assessed by Western blots using phosphoryl-specific antibodies. beta-Catenin was not localized to the nucleus by immunofluorescence in ischemic NRK cells, but rather a strong perinuclear signal was seen in reperfused cells. This was consistent with the finding that neither ischemia nor reperfusion activated the transcriptional activity of beta-catenin as assessed by the TCF-optimal promoter (TOPFlash) construct. However, NRK cells possess a competent Wnt pathway, as challenge with lithium chloride elicited a ten-fold increase in luciferase activity. These results suggest that ischemia-induced disruption of cadherin/catenin complexes is not sufficient to stimulate beta-catenin transcriptional activity in NRK cells.
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PMID:Ischemia-induced cleavage of cadherins in NRK cells is not sufficient for beta-catenin transcriptional activity. 1795 28

We previously reported that ischemic postconditioning with a series of mechanical interruptions of reperfusion reduced infarct volume 2 days after focal ischemia in rats. Here, we extend this data by examining long-term protection and exploring underlying mechanisms involving the Akt, mitogen-activated protein kinase (MAPK) and protein kinase C (PKC) signaling pathways. Post-conditioning reduced infarct and improved behavioral function assessed 30 days after stroke. Additionally, postconditioning increased levels of phosphorylated Akt (Ser473) as measured by western blot and Akt activity as measured by an in vitro kinase assay. Inhibiting Akt activity by a phosphoinositide 3-kinase inhibitor, LY294002, enlarged infarct in postconditioned rats. Postconditioning did not affect protein levels of phosphorylated-phosphatase and tensin homologue deleted on chromosome 10 or -phosphoinositide-dependent protein kinase-1 (molecules upstream of Akt) but did inhibit an increase in phosphorylated-glycogen synthase kinase 3beta, an Akt effector. In addition, postconditioning blocked beta-catenin phosphorylation subsequent to glycogen synthase kinase, but had no effect on total or non-phosphorylated active beta-catenin protein levels. Furthermore, postconditioning inhibited increases in the amount of phosphorylated-c-Jun N-terminal kinase and extracellular signal-regulated kinase 1/2 in the MAPK pathway. Finally, postconditioning blocked death-promoting deltaPKC cleavage and attenuated reduction in phosphorylation of survival-promoting epsilonPKC. In conclusion, our data suggest that postconditioning provides long-term protection against stroke in rats. Additionally, we found that Akt activity contributes to postconditioning's protection; furthermore, increases in epsilonPKC activity, a survival-promoting pathway, and reductions in MAPK and deltaPKC activity; two putative death-promoting pathways correlate with postconditioning's protection.
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PMID:The Akt signaling pathway contributes to postconditioning's protection against stroke; the protection is associated with the MAPK and PKC pathways. 1818 53

Dephosphorylated and activated glycogen synthase kinase (GSK) 3beta hyperphosphorylates beta-catenin, leading to its ubiquitin-proteosome-mediated degradation. beta-catenin-knockdown increases while beta-catenin overexpression prevents neuronal death in vitro; in addition, protein levels of beta-catenin are reduced in the brain of Alzheimer's patients. However, whether beta-catenin degradation is involved in stroke-induced brain injury is unknown. Here we studied activities of GSK 3beta and beta-catenin, and the protective effect of moderate hypothermia (30 degrees C) on these activities after focal ischemia in rats. The results of Western blot showed that GSK 3beta was dephosphorylated at 5 and 24 h after stroke in the normothermic (37 degrees C) brain; hypothermia augmented GSK 3beta dephosphorylation. Because hypothermia reduces infarction, these results contradict with previous studies showing that GSK 3beta dephosphorylation worsens neuronal death. Nevertheless, hypothermia blocked degradation of total GSK 3beta protein. Corresponding to GSK 3beta activity in normothermic rats, beta-catenin phosphorylation transiently increased at 5 h in both the ischemic penumbra and core, and the total protein level of beta-catenin degraded after normothermic stroke. Hypothermia did not inhibit beta-catenin phosphorylation, but it blocked beta-catenin degradation in the ischemic penumbra. In conclusion, moderate hypothermia can stabilize beta-catenin, which may contribute to the protective effect of moderate hypothermia.
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PMID:Hypothermia blocks beta-catenin degradation after focal ischemia in rats. 1824 48

Beta-catenin, a protein that functions in both cell adhesion and Wnt signaling, plays vital roles in mammalian neural development. To investigate the roles of beta-catenin in stroke-induced neurogenesis, we injected beta-catenin siRNA into ipsilateral ischemic lateral ventricle. We found that inactivation of beta-catenin by siRNA caused the decline of beta-catenin in the ischemic striatum, enlarged stroke-induced infarct volume, reduced SVZ expansion, and inhibited striatal neurogenesis in adult rat brain following a transient middle cerebral artery occlusion (tMCAO). These results show that beta-catenin-mediated transcriptional activation functions in the decision of subventricular zone precursors to proliferate or differentiate during stroke-induced striatal neurogenesis, and suggest that the signaling activity of beta-catenin may control the production of newborn neurons and thus regulate the autonomous repair in the striatum after ischemia.
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PMID:Beta-catenin siRNA inhibits ischemia-induced striatal neurogenesis in adult rat brain following a transient middle cerebral artery occlusion. 1834 78

beta-Catenin, the downstream target of glycogen synthase kinase-3beta (GSK-3beta), plays a vital role in ischemic preconditioning (IP)-mediated cardioprotection. In the present study, we investigated the mechanism of IP-mediated cardioprotection through suppression of beta-catenin expression by intramyocardial injection of adeno-sh-RNA against beta-catenin (BCT) (4 x 10(8) pfu). Adeno-LacZ (LZ) was used as control. The rats were randomized into (a) LZ + ischemia-reperfusion (IR); (b) LZIPIR; (c) BCTIR; and (d) BCTIPIR. Isolated hearts from each group were subjected to 30 min of I followed by 2 h of R. Both IPIR group hearts were subjected to IP (5 min I + 10 min R; four cycles) before IR. Significant reduction in left ventricular functional recovery (78 vs. 88 mm Hg), dp/dt(max) (1,802 vs. 2,189 mm Hg/sec), and aortic flow (4 vs. 9 ml/min) was observed in BCTIPIR compared with LZIPIR at 120 min of reperfusion. Increased infarct size (42 vs. 24%) and apoptotic cardiomyocytes (122 vs. 58 counts/60 HPF) were observed in BCTIPIR compared with LZIPIR. Realtime PCR and Western blot analysis showed significant downregulation in mRNA and protein expression of VEGF, Bcl-2, and survivin in BCTIPIR compared with LZIPIR. These findings indicated for the first time that silencing beta-catenin abolished IP-mediated cardioprotection, probably through inhibition of VEGF-Bcl-2 and survivin.
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PMID:Adeno-sh-beta-catenin abolishes ischemic preconditioning-mediated cardioprotection by downregulation of its target genes VEGF, Bcl-2, and survivin in ischemic rat myocardium. 1840 48

Endothelial cells control the passage of plasma constituents and circulating cells from blood to the underlying tissues. This specialized function is lost or impaired in several pathological conditions - including inflammation, sepsis, ischemia and diabetes - which leads to severe, and sometimes fatal, organ dysfunction. Endothelial permeability is regulated in part by the dynamic opening and closure of cell-cell adherens junctions (AJs). In endothelial cells, AJs are largely composed of vascular endothelial cadherin (VE-cadherin), an endothelium-specific member of the cadherin family of adhesion proteins that binds, via its cytoplasmic domain, to several protein partners, including p120, beta-catenin and plakoglobin. Endogenous pathways that increase vascular permeability affect the function and organization of VE-cadherin and other proteins at AJs in diverse ways. For instance, several factors, including vascular endothelial growth factor (VEGF), induce the tyrosine phosphorylation of VE-cadherin, which accompanies an increase in vascular permeability and leukocyte diapedesis; in addition, the internalization and cleavage of VE-cadherin can cause AJs to be dismantled. From the knowledge of how AJ organization can be modulated, it is possible to formulate several pharmacological strategies to control the barrier function of the endothelium. We discuss the possible use of inhibitors of SRC and other kinases, of agents that increase cAMP levels, and of inhibitors of lytic enzymes as pharmacological tools for decreasing endothelial permeability.
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PMID:The role of adherens junctions and VE-cadherin in the control of vascular permeability. 1856 24


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