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)

To understand the expression of inducible nitric oxide synthase (iNOS) and its possible association with apoptosis in human lupus nephritis, 48 renal tissue samples from patients with lupus nephritis were investigated immunohistochemically and by the terminal-deoxynucleotidyl-transferase-mediated dUTP nick end labeling method for the detection of iNOS and apoptosis, respectively. Modulation of apoptosis by p53 and Bcl-2 was also evaluated. This study showed immunohistochemical evidence of iNOS expression, predominantly in the glomerular and tubulointerstitial cells of class-IV lupus nephritis. The frequency of iNOS+ glomeruli was significantly correlated with that of apoptosis+ glomeruli, and the frequency of the latter was also significantly correlated with that of the glomeruli showing p53 overexpression. Bcl-2 was predominantly expressed in the cellular and fibrocellular crescents. This study suggests that induction of iNOS, and thus nitric oxide production, plays a role in the occurrence of apoptosis in the glomeruli of lupus nephritis; and the occurrence of apoptosis might in part be modulated by p53 and Bcl-2-related pathways. The expression of Bcl-2 in predominantly cellular and fibrocellular crescents suggests that Bcl-2 may participate in persistent proliferation of the crescentic cells.
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PMID:Expression of inducible nitric oxide synthase and apoptosis in human lupus nephritis. 943 61

Apoptosis plays an important role in the development of the organism but also under various pathological conditions. Nitric oxide exhibits contradictory effects in the regulation of apoptosis. Both pro- and antiapoptotic effects have been demonstrated. The proapoptotic effects seem to be linked to pathophysiological conditions, where high amounts of NO are produced by the inducible nitric oxide synthase. In contrast, the continuous release of endothelial NO inhibits apoptosis and may contribute to the antiatherosclerotic function of NO. The present article summarizes these effects and provides insights into the role of NO in apoptotic signal transduction, with special regard to the Bcl-2 homologous proteins, the protease family of caspases and heat shock proteins.
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PMID:Nitric oxide and apoptosis: another paradigm for the double-edged role of nitric oxide. 944 99

In human neuroblastoma SH-SY5Y cells, S-nitroso-N-acetylpenicillamine (SNAP), a nitric oxide (NO)-donor, caused cell death accompanying p53 expression, nucleosomal DNA fragmentation and cell death. In addition, SNAP-induced cell death and DNA fragmentation were enhanced by pretreatment for 4 days with N6,2'-O-dibutyryl cyclic AMP (diBu-cAMP) or staurosporine, while those were not changed by pretreatment with phorbol 12-myristate 13-acetate (PMA). Protein level of Bcl-2 was decreased by pretreatment with diBu-cAMP or staurosporine, and, on the contrary, the level was increased by pretreatment with PMA. However, these pretreatments did not change Bax protein level and SNAP-induced p53 expression. However, SNAP-treatment did not change protein levels of Bcl-2 and Bax. These results suggest that SNAP-induced p53-sensitive apoptosis is enhanced by Bcl-2 reduction, and that Bcl-2 and Bax may act downstream of p53 in SH-SY5Y cells.
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PMID:Nitric oxide donor-induced p53-sensitive cell death is enhanced by Bcl-2 reduction in human neuroblastoma cells. 946 Jul 7

Previously we have shown that nitric oxide (NO) donors induced apoptosis in vascular smooth muscle cells (VSMCs). However, the mechanisms by which NO induced apoptosis in VSMCs are entirely unknown. In the present study, we intended to identify the mechanism by which NO donors induce apoptosis in VSMCs. First, we evaluated the expression of c-Myc, P53, and Bcl-2 proteins in VSMCs treated by NO donors. c-Myc and P53 protein expression increased after VSMCs were incubated with NO donors for 6 hr and reached a maximum level at 24 hr, while Bcl-2 protein decreased after 12 hr incubation. Next we investigated to see whether the CPP32 protease activation was involved in NO donors-induced apoptosis. In VSMCs treated by NO donors, the increase of CPP32 protease activity was observed and specific inhibition of CPP32 activity significantly prevented apoptosis induced by NO donors in a dose-dependent manner. These results suggest that NO donors induced apoptosis through proto-oncoprotein expression and CPP32-like protease activation.
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PMID:No induced apoptosis accompanying the change of oncoprotein expression and the activation of CPP32 protease. 948 2

While a high rate of cell loss is tolerated and even required to model the developing nervous system, an increased rate of cell death in the adult nervous system underlies neurodegenerative disease. Evolutionarily conserved mechanisms involving proteases, Bcl-2-related proteins, p53, and mitochondrial factors participate in the modulation and execution of cell death. In addition, specific death mechanisms, based on specific neuronal characteristics such as excitability and the presence of specific channels or enzymes, have been unraveled in the brain. Particularly important for various human diseases are excessive nitric oxide (NO) production and excitotoxicity. These two pathological mechanisms are closely linked, since excitotoxic stimulation of neurons may trigger enhanced NO production and exposure of neurons to NO may trigger the release of excitotoxins. Depending on the experimental situation and cell type, excitotoxic neuronal death may either be apoptotic or necrotic.
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PMID:Apoptosis, excitotoxicity, and neuropathology. 952 37

Mononuclear cell infiltration into the islets of the pancreas (insulitis) is characteristic of autoimmune diabetes. T lymphocytes are the predominant subpopulation seen in insulitis, and are involved in the autoimmune process. Insulin-producing beta cells are thought to be destroyed by cytotoxic T cells, cytokines or nitric oxide, and beta-cell death occurs, at least partly, via apoptosis. Beta-cell death induced by cytokines is inhibited by Bcl-2, suggesting its potential as a tool for gene therapy. The Fas/Fas-ligand system plays a critical role in inducing insulitis and overt diabetes in nonobese diabetic (NOD) mice, a model of autoimmune diabetes. T-cell receptor gene usage in infiltrating T cells is not restricted in NOD mice, but there are some observations indicating relative restriction in human IDDM patients. Preventive strategies might be developed by focusing on these molecules involved in beta-cell destruction. The establishment of screening techniques for detecting prediabetic patients is also necessary to allow successful intervention.
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PMID:Molecular mechanisms of pancreatic beta-cell destruction in autoimmune diabetes: potential targets for preventive therapy. 955 16

Nitric oxide (NO) inhibits the respiration of mitochondria and enteric bacteria, particularly under low O2 concentration, and induces apoptosis of various types of cells. To gain insight into the molecular role of NO in the intestine, we examined its effects on the respiration, Ca2+ status, and expression of Bcl-2 in cultured intestinal epithelial cells (IEC-6). NO reversibly inhibited the respiration of IEC-6 cells, especially under physiologically low O2 concentration. Although NO elevated cytosolic Ca2+ as determined by the fura 2 method, the cells were fairly resistant to NO. Kinetic analysis revealed that prolonged exposure to NO elevated the levels of Bcl-2 and suppressed the NO-induced changes in Ca2+ status of the cells. Because Bcl-2 possesses antiapoptotic function, toxic NO effects might appear minimally in enterocytes enriched with Bcl-2. Thus NO might effectively exhibit its antibacterial action in anaerobic intestinal lumen without inducing apoptosis of Bcl-2-enriched mucosal cells.
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PMID:Nitric oxide regulates energy metabolism and Bcl-2 expression in intestinal epithelial cells. 961 58

Nitric oxide (NO) promotes apoptotic cell death in the mouse macrophage cell line RAW 264.7 and in the human promyelocytic leukaemia cell line U937, which exemplifies p53-dependent and p53-independent executive death pathways. Here, we followed the cleavage of two caspase substrates during NO-intoxication, assaying poly(ADP-ribose) polymerase and U1-70kDa small ribonucleoprotein (U1-70kDa) degradation. By using pharmacological inhibitors, we found that Z-aspartyl-2,6-dichlorobenzoyloxymethylketone (Z-Asp-CH2-DCB; 100 microM), a caspase-like protease inhibitor, completely blocked S-nitrosoglutathione (GSNO)-induced apoptosis in both RAW 264.7 and U937 cells (IC50 = 50 microM for RAW 264.7 macrophages vs. IC50 = 33 microM for U937 cells). Notably, a characterized caspase-3 (Ac-DEVD-CHO) inhibitor left NO-induced DNA fragmentation and the appearance of an apoptotic morphology unaltered, although completely blocking caspase-3 activity. However, Z-Asp-CH2-DCB suppressed protease-mediated U1-70kDa cleavage and DNA fragmentation in parallel. In contrast, poly(ADP-ribose) polymerase cleavage in U937 cells was only delayed by Z-Asp-CH2-DCB, while poly(ADP-ribose) polymerase digestion in RAW 264.7 macrophages proceeded unaltered. We further compared U1-70kDa and poly(ADP-ribose) polymerase cleavage in stably Bcl-2 transfected RAW 264.7 macrophages. Rbcl2-2, a Bcl-2 overexpressing clone, suppressed DNA fragmentation and U1-70kDa digestion in response to GSNO, although allowing delayed but complete poly(ADP-ribose) polymerase degradation. Conclusively, poly(ADP-ribose) polymerase cleavage not causatively coincided with the appearance of other apoptotic parameters. Our results suggest that NO-induced apoptosis demands a Z-Asp-CH2-DCB inhibitable caspase activity, most likely distinct from caspase-3 and caspase-1. NO-mediated executive apoptotic signaling results in U1-70kDa and poly(ADP-ribose) polymerase cleavage. Whereas U1-70kDa digestion closely correlates to the occurrence of apoptotic parameters such as DNA fragmentation or an apoptotic morphology, poly(ADP-ribose) polymerase-breakdown does not.
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PMID:Protease activation during nitric oxide-induced apoptosis: comparison between poly(ADP-ribose) polymerase and U1-70kDa cleavage. 967 Nov 15

Polymorphonuclear leukocytes (PMN) isolated from the oral cavity of healthy human volunteers, spontaneously generated superoxide, nitric oxide (NO) and other reactive oxygen species (ROS) which exhibited strong luminol chemiluminescence (LCL). To understand the physiological roles of oral PMN (OPMN), biochemical properties of the cells were analyzed. Biochemical analysis revealed that OPMN were already primed under physiological conditions. Western blot analysis revealed that they strongly expressed the inducible type of NO synthase (NOS II) and exhibited the activity to catalyze tyrosine phosphorylation of various proteins including a 115 kDa protein (cbl product). OPMN also generated H2O2 and .OH by some superoxide dismutase (SOD)-sensitive mechanism and released myeloperoxidase (MPO). Kinetic analysis using specific inhibitors revealed that OCl- generated by OPMN was predominantly responsible for the enhanced LCL. During the incubation under standard culture conditions, OPMN underwent apoptosis which proceeded more rapidly than that of the circulating PMN (CPMN). Immunochemical analysis revealed that expression of apoptosis-related gene products, such as Bcl-2, Bcl-xL and Bax, was below detectable levels with both cell types. However, caspase-3 but not caspase-1 was markedly activated in OPMN. These results indicate that the primed OPMN spontaneously generate ROS and play an important role in the defense mechanism in the oral cavity and that the generated ROS activate caspase-3 thereby inducing apoptosis of the cells.
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PMID:Biochemical properties of human oral polymorphonuclear leukocytes. 970 29

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


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