Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

L-Glutamine (Gln) is known to have protective effect on the small intestine under deleterious stressful condition. Although the mechanism by which Gln confers intestinal cellular protection remains unclear, its potential role may be mediated via signal transduction including stress response genes and anti-apoptotic genes. Herein, we examined a possible role of stress response genes in warm ischemically injured small intestines. We measured mRNA and protein expression of heme oxygenase (HO)-1, Bcl-2 and Bax at different time points after Gln administration. Warm ischemia model was made by clamping of the superior mesenteric artery for 60 min. After reperfusion, tissue samples were taken for end labeling of nuclear DNA fragments (TdT-mediated d-uridine triphosphate biotin nick end labeling; TUNEL) and hematoxylin-eosin staining. In Gln-treated group, the substantial expression of HO-1 mRNA peaked at 3 h and reduced thereafter, while HO-1 protein synthesis was noted within 3 h and reached plateau thereafter. NO-1-positive components were markedly detected in the villus epithelial cells and crypts. The ratios of Bcl-2/Bax mRNA expression after Gln administration peaked at 3 h and reduced thereafter until 24 h. Bcl-2 immunoreactive protein was enhanced in Gln group, whereas Bax was faintly detected. Following reperfusion, less TUNEL-positive staining of the top of the villi and more prompt recovery of denuded villus epithelial cells were noted in Gln group, compared with those in untreated and lactated Ringer-treated control groups. In conclusion, a concomitant expression of anti-oxidative HO-1 and anti-apoptotic Bcl-2 molecules induced by non-toxic amino acid, Gln, may alleviate or even prevent intestinal warm ischemia and reperfusion injury, attenuating programmed cell death and promoting its reepithelialization.
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PMID:[Impact of stress response genes induced by L-glutamine on warm ischemia and reperfusion injury in the rat small intestine]. 1196 53

It is well known that hyperthermia causes a transient tolerance of cells to a second heat challenge (acquired thermotolerance). The present study addresses the question of whether hyperthermic pre-treatment also increases the tolerance against heat- and hydrogen peroxide-induced apoptosis in rat IPC-81 leukaemia cells. This cell line exhibits an aberrant heat shock response which is characterized by a lack of the inducible Hsp70 isoform, even under conditions of heat or hydrogen peroxide stress, while the constitutively expressed Hsc70 and the inducible isoform of hemoxygenase (HO-1) are strongly enhanced by heat stress (43.5 degrees C; 30 min). In spite of this Hsp70 deficiency, hyperthermic pre-treatment protects IPC-81 leukaemia cells against apoptotic cell death induced by heat or hydrogen peroxide, but is less effective against necrosis induced by higher doses of the applied stressors. Addition of hydrogen peroxide (25 microM) enhances the amount of bax mRNA, while the level of bcl-2 mRNA remains unchanged. No increase of bax mRNA, in contrast, could be detected in heat shock-primed IPC-81 cells when treated with hydrogen peroxide after a 12h recovery. These results indicate that hyperthermic pre-treatment may exert its anti-apoptotic function not only by enhanced expression of constitutive as well as inducible HSPs but also by lowering the level of bax transcripts and thereby increasing the Bcl-2/Bax ratio.
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PMID:Hyperthermic pre-treatment protects rat IPC-81 leukaemia cells against heat- and hydrogen peroxide-induced apoptosis. 1207 89

Liver injury caused by ischemia/reperfusion (I/R) insult represents the major problem following orthotopic liver transplantation (OLT). I/R damage has been linked to Th1-like cytokine producers. This study evaluates putative cytoprotective effects/mechanisms of Th2-type IL-13 gene transfer. IL-13 overexpression prevented hepatic insult in a rat model of 24 h cold ischemia followed by OLT, as assessed: (i) profoundly decreased hepatocellular damage (sGOT levels), and ameliorated histological signs of I/R injury (Suzuki criteria), consistent with long-term OLT survival; (ii) prevented hepatic apoptosis (TUNEL stains) and up-regulated expression of antiapoptotic (A20, Bcl-2/Bcl-xl)/antioxidant (HO-1) genes. However, inhibition of HO-1 with tin protoporphyrin reversed cytoprotective/antiapoptotic effects of IL-13. In conclusion, cytoprotection rendered by virally induced IL-13 against hepatic I/R injury in this clinically relevant rat hepatic cold I/R injury model was accomplished via decreased apoptosis and induction of antiapoptotic/antioxidant molecules. HO-1 neutralization studies suggest that HO-1 represents one of putative IL-13 downstream effectors. This study provides the rationale for novel approaches to maximize organ donor pool through the safer use of OLTs despite prolonged periods of cold ischemia.
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PMID:Cytoprotective and antiapoptotic effects of IL-13 in hepatic cold ischemia/reperfusion injury are heme oxygenase-1 dependent. 1291 86

Liver injury induced by ischemia/reperfusion (I/R) is the prime factor in delayed or loss graft function following transplantation. CD4+ T lymphocytes are key cellular mediators of antigen-independent inflammatory response triggered by I/R. We attempted to modulate rat liver I/R injury by targeted gene therapy with CD40Ig, which blocks the CD40-CD154 costimulation pathway. One hundred percent of Ad-CD40Ig-pretreated orthotopic liver transplants (OLTs) subjected to 24 h of cold (4 degrees C) ischemia survived > 14 days (vs 50% in untreated/Ad-beta-gal groups). Ad-CD40Ig treatment decreased sGOT levels and depressed neutrophil infiltration, compared with controls. These functional data correlated with histological Suzuki's grading of hepatic injury, which in untreated/Ad-beta-gal groups showed severe necrosis (> 60%) and moderate to severe sinusoidal congestion; the Ad-CD40Ig-pretreated group revealed minimal sinusoidal congestion/necrosis. Unlike in controls, OLT expression of mRNA coding for IL-2/IFN-gamma remained depressed, whereas that of IL-4/IL-13 reciprocally increased in the Ad-CD40Ig group. Ad-CD40Ig reduced frequency of TUNEL+ cells and pro-apoptotic Caspase-3, but enhanced antioxidant HO-1 and anti-apoptotic Bcl-2/Bcl-xl expression. Thus, prolonged blockade of CD40-CD154 by CD40Ig exerts potent cytoprotection against hepatic I/R injury. These results provide the rationale for a novel gene therapy approach to maximize the organ donor pool through the safer use of liver transplants exposed to prolonged cold ischemia.
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PMID:Gene therapy for liver transplantation using adenoviral vectors: CD40-CD154 blockade by gene transfer of CD40Ig protects rat livers from cold ischemia and reperfusion injury. 1474 76

Heme oxygenase (HO) is well known as the rate-limiting enzyme in the oxidative degradation of heme to biliverdin, carbon monoxide (CO), and iron. Based on recent evidence that overexpression of HO-1 confers protection against various types of cell and tissue injury by regulating apoptotic cell death or cytokine expression profiles, the present study was performed to examine whether the transfer of exogenous HO-1 cDNA in the lung would provide therapeutic effect in a murine model of lung inflammation induced by Pseudomonas aeruginosa. HO-1 overexpression clearly attenuated neutrophil influx and decreased numbers of apoptotic bronchial epithelial cells. Interestingly, the overexpression of Bcl-2, a known antiapoptotic factor, was observed and thought to be the mechanism that inhibits bronchial epithelial cellular apoptosis. It is thus suggested that HO-1 overexpression is useful for treating P. aeruginosa-associated lung inflammation by attenuating neutrophil influx and apoptotic cell death.
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PMID:Pseudomonas aeruginosa-induced neutrophilic lung inflammation is attenuated by adenovirus-mediated transfer of the heme oxygenase 1 cDNA in mice. 1501 36

Peri-operative tissue injury triggers the development of Transplant Coronary Artery Disease (TCAD). Animal studies have shown that induction of heme oxygenase (HO)-1 protects the donor organ from the development of TCAD. To investigate the role of HO-1 in TCAD after clinical heart transplantation, we measured intragraft mRNA expression of HO-1, HIF-1alpha, TGF-beta, FLIP, and the Bcl-2/Bax balance. Immunohistochemical staining of HO-1 was performed to determine its origin. Myocardial biopsies taken at the end of the transplantation procedure (time 0), at 1 week and at 10 months after transplantation were studied from recipients with or without angiographic signs of accelerated TCAD, diagnosed after 1 year. At time 0, no differences in mRNA expression for any of the measured parameters were found between TCAD positive and negative patients. At 1 week, mRNA expression of HO-1 and TGF-beta was higher in grafts that developed accelerated TCAD (p=0.001 and p=0.0002). These higher mRNA levels were accompanied by a pro-apoptotic shift in Bcl-2/Bax (p=0.02), suggesting proneness for apoptosis via the mitochondrial pathway. Immunohistochemical staining showed that HO-1 was mainly produced by infiltrating macrophages. At 10 months, again HO-1 and TGF-beta levels were high in TCAD positive patients (p=0.02 and p=0.05), but the expression of apoptotic markers was comparable at this time point. Our results suggest that a higher HO-1 by macrophages in our patient population might be an adaptive response to tissue injury and inflammation, reflecting damage due to the transplantation procedure that finally results in TCAD.
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PMID:Intragraft heme oxygenase-1 and coronary artery disease after heart transplantation. 1558 39

We examined the contribution of apoptosis- and oxidative stress-associated genes to apoptosis induction in trophoblast cells of human fetal membrane tissues undergoing apoptosis during in vitro incubation. RT-PCR analyses demonstrated an increased level of HO-1, Mn-SOD, Cox-2, iNOS, TNFalpha, TNFR1, IL-1beta, IL-6, Bax, Bak, and Bad gene expression, while Bcl-2 mRNA expression level decreased. Western blot analyses demonstrated an increase in iNOS, Cox-2, and HO-1 protein levels; a decrease in pro-caspase-3 and 9, proform-PARP, and Apaf-1 protein levels; a leakage of cytochrome c from the mitochondria. An antioxidative reagent, general and selective Cox-2 inhibitors, and an iNOS inhibitor suppressed in vitro progression of the apoptosis. Furthermore, an NO donor reagent induced apoptosis in primary cultured trophoblast cells. Therefore, we concluded that the induction of apoptosis in the smooth chorion trophoblasts is mediated through oxidative stress induction followed by mitochondria damage, suggesting that iNOS and Cox-2 play an important role in the apoptosis induction in trophoblasts of human fetal membrane tissues.
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PMID:Contribution of inducible nitric oxide synthase and cyclooxygenase-2 to apoptosis induction in smooth chorion trophoblast cells of human fetal membrane tissues. 1644

Heme oxygenase-1 can play a protective role against cellular stress. In colon cancer cells, these effects would be relevant to oncogenesis and resistance to chemotherapy. The aim of the study was to examine the effects of heme oxygenase-1 induction on cell survival in a human colon cancer cell line, Caco-2. Serum deprivation induced apoptosis, reduced Akt and p38 phosphorylation, and increased p21(Cip/WAF1) levels. Heme oxygenase-1 induction by treatment with cobalt protoporphyrin IX resulted in resistance to apoptosis, activation of Akt, reduction in p21(Cip/WAF1) levels and modification of bcl2/bax ratio towards survival. Indomethacin reduced apoptosis but in contrast to heme oxygenase-1, arrested cells in G0/G1. Apoptosis was also inhibited by the heme oxygenase metabolites bilirubin and biliverdin but the CO donor tricarbonyldichlororuthenium(II) dimer did not exert significant effects. Protection against apoptosis in cells treated with cobalt protoporphyrin IX was reverted by incubation with heme oxygenase-1 small interfering RNA. This study shows an antiapoptotic effect of heme oxygenase-1 in colon cancer cells which could be mediated by the formation of bilirubin and biliverdin. Our results support an antiapoptotic role for HO-1 in these cells and provide a mechanism by which overexpression of HO-1 may promote tumor resistance to stress in conditions of limited nutrient supply. We have extended these observations by demonstrating that these effects are independent of p38 but are mediated via Akt pathway.
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PMID:Heme oxygenase-1 inhibits apoptosis in Caco-2 cells via activation of Akt pathway. 1669 92

Pharmacological modulation of heme oxygenase (HO) gene expression may have significant therapeutic potential in oxidant-induced disorders, such as ischemia reperfusion (I/R) injury. Higenamine is known to reduce ischemic damages by unknown mechanism(s). The protective effect of higenamine on myocardial I/R-induced injury was investigated. Ligation of rat left anterior descending coronary artery for 30 min under anesthesia was done and followed by 24 h reperfusion before sacrifice. I/R-induced myocardial damages were associated with mitochondria-dependent apoptosis as evidenced by the increase of cytochrome c release and caspase-3 activity. Administration of higenamine (bolus, i.p) 1 h prior to I/R-injury significantly decreased the release of cytochrome c, caspase-3 activity, and Bax expression but up-regulated the expression of Bcl-2, HO-1, and HO enzyme activity in the left ventricles, which were inhibited by ZnPP IX, an enzyme inhibitor of HO-1. In addition, DNA-strand break-, immunohistochemical-analysis, and TUNEL staining also supported the anti-apoptotic effect of higenamine in I/R-injury. Most importantly, administration of ZnPP IX inhibited the beneficial effect of higenamine. Taken together, it is concluded that HO-1 plays a core role for the protective action of higenamine in I/R-induced myocardial injury.
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PMID:Higenamine reduces apoptotic cell death by induction of heme oxygenase-1 in rat myocardial ischemia-reperfusion injury. 1670 64

Apoptosis has been shown to contribute to the development of acute and chronic renal failure. The antiapoptotic action of the heme oxygenase (HO) system may represent an important protective mechanism in kidney pathology. We examined whether the lack of HO-1 would influence apoptosis in clipped kidneys of two-kidney, one-clip (2K1C) rats. Five-day-old Sprague-Dawley rats were injected in the left ventricle with approximately 5 x 10(9) colony-forming units/ml of retrovirus containing rat HO-1 antisense (LSN-RHO-1-AS) or control retrovirus (LXSN). After 3 mo, a 0.25-mm U-shaped silver clip was placed around the left renal artery. Animals were killed 3 wk later. Clipping the renal artery in LSN-RHO-1-AS rats did not result in increased HO-1 expression. In contrast to LXSN animals, 2K1C LSN-RHO-1-AS rats showed increased expression of cyclooxygenase 2 (COX-2) and higher 3-nitrotyrosine (3-NT) content as well as increased expression of the proapoptotic protein Apaf-1 and caspase-3 activity. Clipping the renal artery in LXSN rats resulted in increased expression of the antiapoptotic proteins Bcl-2 and Bcl-xl, while clipping the renal artery in LSN-RHO-1-AS rats did not change Bcl-2 levels and decreased the levels of Bcl-xl. Treatment of LSN-RHO-1-AS rats with cobalt protoporphyrin resulted in induction of renal HO-1, which was accompanied by decreases in blood pressure, COX-2, 3-NT, and caspase-3 activity, and increased expression of anti-apoptotic molecules (Bcl-2, Bcl-xl, Akt and p-Akt) in the clipped kidneys. These findings underscore the prominent role of HO-1 in counteracting apoptosis in this 2K1C renovascular hypertension model.
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PMID:Genetic suppression of HO-1 exacerbates renal damage: reversed by an increase in the antiapoptotic signaling pathway. 1694 May 61


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