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)

The role of oxidative stress in mercuric chloride (HgCl2)-induced nephrotoxicity is uncertain and controversial. We demonstrate that I.L.C-PK1 cells, exposed to HgCl2, generate massive amounts of hydrogen peroxide, the latter completely quenched by the hydrogen peroxide scavenger, pyruvate. HgCl2 exerts a dose-dependent cytotoxicity which is attenuated by pyruvate and catalase. Cellular generation of hydrogen peroxide arises, at least in part, from mitochondria since mitochondrial rates of generation of hydrogen peroxide increase in response to HgCl2; HgCl2 also provokes a shift in absorbance spectra in rhodamine 123 loaded-mitochondria and stimulates mitochondrial state 4 respiration. HgCl2, applied for one hour, impairs cellular vitality as demonstrated by the MTT assay, an assay dependent in part on mitochondrial function. HgCl2 impairs function in other organelles such as lysosomes that maintain a transmembrane proton gradient; these latter effects are partially attenuated by pyruvate. We complement these in vitro findings with in vivo evidence demonstrating that HgCl2 stimulates renal generation of hydrogen peroxide. The functional significance of such generation of hydrogen peroxide was evaluated in rats deficient in selenium and vitamin E, a nutrient deficiency that impairs the scavenging of hydrogen peroxide and promotes the toxicity of this oxidant. In these rats serum creatinine values were significantly higher on sequential days following the administration of HgCl2. To probe the renal response to oxidative stress induced by HgCl2, we examined hydrogen peroxide-scavenging enzymes and redox-sensitive genes. Catalase activity was unaltered whereas glutathione peroxidase activity was decreased, effects that may contribute to the net renal generation of hydrogen peroxide. The redox sensitive enzyme, heme oxygenase, was markedly up-regulated in the kidney in response to HgCl2. HgCl2 also induced members of the bcl family, bcl2 and bclx, genes that protect against apoptosis and oxidant injury. In another model of oxidant-induced renal injury, the glycerol model, bcl2 mRNA was not induced at 6 and 24 hours after the administration of glycerol. In summary, we demonstrate that HgCl2 potently stimulates renal generation of hydrogen peroxide in vitro and in vivo and such generation of peroxide contributes to renal dysfunction in vitro and in vivo. We also demonstrate that in response to HgCl2, redox sensitive genes are expressed including heme oxygenase and members of the bcl family.
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PMID:Renal oxidant injury and oxidant response induced by mercury. 887 81

We examined the effect of broad spectrum UVA (320-380 nm) and UVB (290-320 nm) radiation on the induction of apoptosis in the rat 6 fibroblast cell line (R6). UVA, but not UVB, induces apoptosis in this cell line. The morphological changes and DNA ladders associated with apoptosis occurred within the first 4 h after UVA irradiation, a phenomenon referred to as "immediate" apoptosis. From previous studies, it is known that Bcl-2 inhibits most types of apoptotic cell death. Overexpression of mouse Bcl-2 in the R6 fibroblasts inhibited the UVA-induced immediate apoptosis. The induction of the heme oxygenase 1 (HO-1) gene by UVA is a general response to oxidative stress. As a marker of oxidative stress, we monitored the effect of Bcl-2 overexpression on the level of HO-1 mRNA accumulation after UVA irradiation. The results showed that the overexpression of Bcl-2 in the R6 fibroblasts strongly reduces the level of HO-1 induction from 12.5- to 4.9-fold. We propose that Bcl-2 expression inhibits UVA-induced immediate apoptosis via an antioxidant pathway, suppressing either the generation or effects of specific UVA-mediated reactive oxygen species.
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PMID:Overxpression of Bcl-2 inhibits UVA-mediated immediate apoptosiinrat 6 fibroblasts: evidence for the involvement of Bcl-2 as an antioxidant. 910 35

Recent studies have indicated that glial cells such as astrocytes and microglia are activated in an early and delayed episode after brain damage. However, the mechanism and function of glial activation are still unclear. I examined whether the induction of inducible nitric oxide synthase (iNOS), heme oxygenase-1 (HO-1) and major histocompatibility complex (MHC) antigen was involved in the glial activation. The microinjection of interferon-gamma and lipopolysaccharide into rat hippocampus induced MHC class II and iNOS in microglia. The iNOS induction may be involved in the activation of tyrosine kinases and transcription factors such as signal transducer and activator of transcription-1 (STAT1) and nuclear factor-kappa B (NF-kappa B). Subsequently, neuronal cell death occurred in the hippocampus, but cell death was undetectable in both microglia and astrocytes that expressed HO-1. Thus, induction of iNOS and HO-1 in glial cells may be involved in hippocampal neurodegeneration and resistance to oxidative stress in glial cells, respectively. In Alzheimer's disease (AD) brains, iNOS expression was at a very low level, although STAT1 and NF-kappa B were significantly increased. Also, Bcl-2, Bcl-x, Bak, Bad and p53 were increased in AD brains. These observations suggest that oxidative stress and glial activation without iNOS induction may be involved in neurodegeneration of AD brains.
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PMID:[Functional activation of glial cells in early and delayed episodes of the brain damage]. 958 78

Nitric oxide (NO.), a potentially toxic molecule, has been implicated in a wide range of diverse (patho)physiological processes. It is appreciated that the production of NO. from L-arginine is important for nonspecific host defense, helping to kill tumors and intracellular pathogens. Cytotoxicity as a result of a massive NO.-formation is now established to initiate apoptosis. Apoptotic cell death in RAW 264.7 macrophages and several other systems as a result of inducible NO-synthase activation comprises upregulation of the tumor suppressor p53, activation of caspases, chromatin condensation, and DNA fragmentation. The involvement of NO was established by blocking adverse effects by NO-synthase inhibition. Overexpression of the antiapoptotic protein Bcl-2 rescued cells from apoptosis by blocking signal propagation downstream of p53 and upstream of caspase activation. As the wide variety of NO.-effects is achieved through its interactions with targets via redox and additive chemistry, the biological milieu, as a result of internal and external stimuli, may modulate toxicity. Therefore, transducing pathways of NO. are not only adopted to cytotoxicity but also refer to cell protection. NO.-signaling during protection from apoptosis is in part understood by the requirement of gene transcription and protein synthesis. NO.-formation causes upregulation of protective proteins such as heat shock proteins, cyclooxygenase-2, or heme oxygenase-1 which in a cell specific way may attenuate apoptotic cell death. Alternatively, protection may result as a consequence of a diffusion controlled NO./O2- (superoxide) interaction. The NO./O2--interaction redirects the apoptotic initiating activity of either NO. or O2- towards protection as long as reduced glutathione compensates the resultant oxidative stress. Protective principles may further arise from cyclic GMP formation or thiol modification. NO shares with other toxic molecules such as tumor necrosis factor-alpha the unique ability to initiate and to block apoptosis, depending on multiple variables that are being elucidated. The crosstalk between cell destructive and protective signaling pathways, their activation or inhibition under the modulatory influence of NO. will determine the role of NO in apoptotic cell death.
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PMID:Nitric oxide and its role in apoptosis. 972 Oct 17

Our group recently reported that cultured sheep pulmonary artery endothelial cells (SPAECs) became resistant to lipopolysaccharide (LPS)-induced apoptosis several days after constitutive synthesis of nitric oxide (NO) after adenoviral (Ad) transfer of inducible NO synthase (iNOS) or exposure to the NO donor S-nitroso-N-acetylpenicillamine (SNAP) (E. Tzeng, Y.-M. Kim, B. R. Pitt, A. Lizonova, I. Kovesdi, and T. R. Billiar. Surgery 122: 255-263, 1997). In the present study, we confirmed this observation by establishing stable transfectants after retroviral gene transfer [replication-deficient retrovirus (DFG)] of human iNOS (DFG-iNOS) SPAECs and then used all three approaches (Ad, DFG, and SNAP) to determine underlying mechanisms of this phenomenon. Continuous endogenous production of NO in itself did not cause apoptosis as assessed by phase-contrast microscopy, nuclear morphology, and internucleosomal DNA fragmentation. Prolonged (72-96 h) synthesis of NO, however, after DFG- or replication-deficient adenovirus (Ad. CMV)-iNOS or SNAP (100 microM, 96 h) inhibited LPS-induced apoptosis. The kinetics of such protection suggested that NO may be inducing other gene products. Ad-mediated transfer of manganese superoxide dismutase (MnSOD) decreased the sensitivity of wild-type SPAECs to LPS-induced apoptosis. MnSOD, however, was not induced in an NG-monomethyl-L-arginine (L-NMMA)-sensitive time-dependent fashion after Ad.CMV-iNOS. Other inducible genes that may be affected by NO and that may protect against potential oxidant-mediated LPS-induced apoptosis including 70-kDa heat shock protein, heme oxygenase-1, metallothionein, and Bcl-2 also were not elevated in an L-NMMA-sensitive, time-dependent fashion. Although the candidate gene product underlying NO-induced protection remains unclear, we did note that prolonged synthesis of NO inhibited LPS-induced activation of an interleukin-1beta-converting enzyme-like cysteine protease (cysteine protease protein-32-like) in a dithiothreitol-sensitive fashion, suggesting that S-nitrosylation of an important downstream target of convergence of apoptotic signals may contribute to the sensitivity of SPAECs to LPS.
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PMID:Nitric oxide inhibits lipopolysaccharide-induced apoptosis in pulmonary artery endothelial cells. 975 4

Acute lung injury is an unfortunate consequence of oxygen therapy. Increasing evidence suggests that pulmonary dysfunction resulting from acute oxygen toxicity is at least in part due to the injury and death of lung cells. Studies using morphological and biochemical analyses revealed that hyperoxia-induced pulmonary cell death is multimodal, involving not only necrosis, but also apoptosis. A correlative relationship between the severity of hyperoxic acute lung injury and increased apoptosis has been supported by numerous studies in a variety of animal models, although future experiments are necessary to determine whether it is an actual causal relationship. Altered expression of several apoptotic regulatory proteins, such as p53 and Bcl-2, and DNA damage-induced proteins is associated with hyperoxic cell death and lung injury. Stress-responsive proteins, such as heme oxygenase (HO)-1, have been shown to protect animals against hyperoxic cell injury and death. Redox-sensitive transcription factors and mitogen-activated protein kinase signal transduction pathways may play important roles in regulating the expression of stress-responsive and apoptotic regulatory genes. A better understanding of signal transduction pathways leading to hyperoxic cell death may provide new approaches to the treatment of hyperoxia-induced lung injury.
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PMID:Signal transduction pathways in hyperoxia-induced lung cell death. 1100 28

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

Hypertrophy is one mechanism of pancreatic beta-cell growth and is seen as an important compensatory response to insulin resistance. We hypothesized that the induction of protective genes contributes to the survival of enlarged (hypertrophied) beta-cells. Here, we evaluated changes in stress gene expression that accompany beta-cell hypertrophy in islets from hyperglycemic rats 4 weeks after partial pancreatectomy (Px). A variety of protective genes were upregulated, with markedly increased expression of the antioxidant genes heme oxygenase-1 and glutathione peroxidase and the antiapoptotic gene A20. Cu/Zn-superoxide dismutase (SOD) and Mn-SOD were modestly induced, and Bcl-2 was modestly reduced; however, several other stress genes (catalase, heat shock protein 70, and p53) were unaltered. The increases in mRNA levels corresponded to the degree of hyperglycemia and were reversed in Px rats by 2-week treatment with phlorizin (treatment that normalized hyperglycemia), strongly suggesting the specificity of hyperglycemia in eliciting the response. Hyperglycemia in Px rats also led to activation of nuclear factor-kappaB in islets. The profound change in beta-cell phenotype of hyperglycemic Px rats resulted in a reduced sensitivity to the beta-cell toxin streptozotocin. Sensitivity to the toxin was restored, along with the beta-cell phenotype, in islets from phlorizin-treated Px rats. Furthermore, beta-cells of Px rats were not vulnerable to apoptosis when further challenged in vivo with dexamethasone, which increases insulin resistance. In conclusion, beta-cell adaptation to chronic hyperglycemia and, hence, increased insulin demand is accompanied by the induction of protective stress genes that may contribute to the survival of hypertrophied beta-cells.
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PMID:Increased expression of antioxidant and antiapoptotic genes in islets that may contribute to beta-cell survival during chronic hyperglycemia. 1181 49

Most viral gene delivery syslems utilized to date have demonstrated significant limitations in practicality and safety due to the level and duration of recombinant transgene expression as well as their induction of host immunogenicity to vector proteins. Recombinant adeno-associated virus (rAAV) vectors appear to offer a vehicle for safe, long-term therapeutic gene transfer; factors afforded through the propensity of rAAV to establish long-term latency without deleterious effects on the host cell and the relative non-immunogenicity of the virus or viral expressed transgenes. The principal historical limitation of this vector system, efficiency of rAAV-mediated transduction, has recently observed a dramatic increase as the titer, purity, and production capacity of rAAV preparations have improved. In terms of systems that could benefit from such improvements, rAAV gene therapy to enhance solid organ transplantation would appear an obvious choice with islet transplantation forming a promising candidate due to the ability to perform viral transductions ex vivo. Currently, islet transplantation can be used to treat type 1 diabetes yet persisting alloimmune and autoimmune responses represent major obstacles to the clinical success for this procedure. The delivery of transgenes capable of interfering with antigenic recognition and/or cell death [e.g., Fas ligand (FasL), Bcl-2, Bcl-XL] as well as imparting tolerance/immunoregulation [e.g., interleukin(IL)-4, IL-10, transforming growth factor (TGF)-beta], or cytoprotection [e.g., heme oxygenase-1 (HO-1), catalase, manganese superoxide dismutase (MnSOD)] may prevent recurrent type 1 diabetes in islet transplantation and offer a promising form of immunotherapy. Research investigations utilizing such systems may also provide information vital to understanding the immunoregulatory mechanisms critical to the development of both alloimmune and autoimmune islet cell rejection mechanisms and recurrent type 1 diabetes.
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PMID:Adeno-associated virus (AAV) as a vehicle for therapeutic gene delivery: improvements in vector design and viral production enhance potential to prolong graft survival in pancreatic islet cell transplantation for the reversal of type 1 diabetes. 1189 74

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


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