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 clinical use of dendritic cells (DC) as tumor vaccines is very much dependent on their survival potential. Members of the tumor necrosis factor (TNF) receptor superfamily and their ligands are involved in the regulation of cell death. Fas (CD95) is a representative protein that promotes apoptosis. The Bcl-2 family of proteins functions as an integrator of diverse pro- and anti-apoptotic signals. It has been found that DC maturation facilitates their survival, and thus has an anti-apoptotic function. However, little is known about the underlying mechanisms. We investigated the effects of TNF-alpha and lipopolysaccharide (LPS) on the expression of apoptotic molecules during differentiation and maturation of DC under serum-free conditions, and correlated this to the sensitivity to apoptosis by the Fas-mediated pathway. Indeed, DC activation effectively inhibited DC apoptosis, which was predominantly accompanied by the upregulation of Bcl-X(L) and to a lesser extent Bcl-2, while Bax and FLICE inhibitory protein (FLIP) remained unchanged. In contrast, in the presence of serum FLIP was also upregulated. We conclude that under serum-free conditions, Bcl-X(L) rather than FLIP plays the main role in protection against DC apoptosis.
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PMID:Mature dendritic cells are protected from Fas/CD95-mediated apoptosis by upregulation of Bcl-X(L). 1194 52

Bcl-2 protein family members are among the key regulators of the apoptosis effector phase. Therefore, we investigated the ability of synthetic peptides derived from proteins of the Bcl-2 family, namely, the NH2-terminal region of Bcl-2 (Bcl2_syn), a central domain of Bax (Bax_syn), and a central domain of Bak (Bak_syn) to interfere with the apoptotic process in LLC-PK1 cells. Apoptosis was induced by tacrolimus or lipopolysaccharide treatment, and microinjection of Bcl2_syn into stimulated LLC-PK1 cells significantly reduced the percentage of apoptotic cells detected within 4 h after the treatment. Microinjection of Bax_syn or Bax_syn, in contrast, induced apoptosis in otherwise untreated LLC-PK1 cells during the same period of time. A random sequence control peptide (Control_syn), which served as a negative control, as well as FITC-labeled dextran, which was coinjected in all experiments for visualization, were ineffective in either preventing or inducing apoptosis. These results suggest that synthetic peptides mimicking the functional domains of proteins of the Bcl-2 family are capable of regulating apoptosis when microinjected into LLC-PK1 cells in vivo. Analogs to these regulatory peptides could therefore provide valuable lead compounds in the therapeutical context.
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PMID:Effects of microinjection of synthetic Bcl-2 domain peptides on apoptosis of renal tubular epithelial cells. 1206 Jun 1

The production of nitric oxide (NO) is an essential determinant in auto- and paracrine signaling. NO is generated under inflammatory conditions and may serve as a cytotoxic molecule to produce cell demise along an apoptotic or necrotic pathway. NO also gained attention as a regulator of immune function and a death inhibitor. Cytotoxicity because of substantial NO-formation is established to initiate apoptosis, characterized by upregulation of the tumor suppressor p53, changes in the expression of pro- and antiapoptotic Bcl-2 family members, cytochrome c relocation, activation of caspases, and DNA fragmentation. However, NO-toxicity is not a constant value and NO may protect several cell types from entering programmed cell death. Preactivation of macrophages with a nontoxic dose of S-nitrosoglutathione (200 microM) or lipopolysaccharide/interferon-gamma/N(G)-monomethyl-L-arginine for 15 hours attenuated death in response to various agonists, suppressed p53 accumulation, and abrogated caspase activation. Prestimulation of macrophages with cytokines or low-level NO activated the transcription factor NF-kappaB as well as AP-1 and promoted immediate early gene expression of cyclooxygenase-2 (COX-2). NF-kappaB activation comprised p50/p65-heterodimer formation, IkappaB degradation, and activation of a luciferase reporter construct, that contained four copies of the NF-kappaB-site derived from the murine COX-2 promoter. A NF-kappaB decoy approach (oligonucleotides directed against NF-kappaB) or transfection of a dominant-negative c-Jun mutant (TAM67) abrogated not only the COX-2 expression but also the inducible protection. Blocking NO- or cytokine-mediated inducible protection at the level of NF-kappaB and/or AP-1 restored the occurrence of apoptotic features. Our experiments underscore the role of COX-2 in attenuating natural occurring cell death (i.e., apoptosis).
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PMID:The role of nitric oxide and cyclooxygenase-2 in attenuating apoptosis. 1208 96

In this lipopolysaccharide (LPS)-induced endotoxemia model, the effects of 3-aminobenzamide (3-AB), a poly(ADP-ribose) synthetase (PARS) inhibitor, on ileal apoptosis were evaluated by light microscopy and M30 cell death staining. Moreover, the relationship between Bcl-2, iNOS expression, and serum nitrate (NO(3)(-)) levels were investigated. Thirty-two male Wistar rats, weighing 180-220g were randomly divided into four groups. The group I (control; n=8) received saline and group II (sepsis; n=8) received 10 mg kg(-1) LPS intraperitoneally. 3-AB was given to the group IV (S+3-AB; n=8) 20 min before giving LPS and to the group III (C+3-AB; n=8) 20 min before giving saline. Six hours later, blood and ileum samples were taken. Endotoxemic group exhibited significant apoptosis in intestinal epithelial cells and the immunohistochemical examination with M30 was demonstrated that the 3-AB reduced the LPS-induced intestinal apoptosis. Serum NO(3)(-) level was increased in endotoxemic group, whereas the elevation of NO(3)(-) level was prevented in LPS+3-AB group (P<0.05). The increased iNOS expression observed in the LPS group was also prevented by 3-AB. Compared with the endotoxemic group, ileal epithelial columnar cells from LPS+3-AB group had a dense Bcl-2 staining which was almost identical with control. In conclusion, 3-AB decreases LPS-induced apoptosis in ileum by preventing LPS-induced depletion of Bcl-2 and blocking iNOS gene. Modification of Bcl-2 expression by PARS inhibitors should further be investigated as a new therapeutic alternatives in septic states.
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PMID:The role of poly(ADP-ribose) synthetase inhibition in preventing endotoxemia-induced intestinal epithelial apoptosis. 1222 Sep 50

Immature dendritic cells (DCs) reside in interstitial tissues (int-DC) or in the epidermis, where they capture antigen and, thereafter, mature and migrate to draining lymph nodes (LNs), where they present processed antigen to T cells. We have identified int-DCs that express both TRANCE (tumor necrosis factor-related activation-induced cytokine) and RANK (receptor activator of NF-kappaB) and have generated these cells from CD34(+) human progenitor cells using macrophage colony-stimulating factor (M-CSF). These CD34(+)-derived int-DCs, which are related to macrophages, are long-lived, but addition of soluble RANK leads to significant reduction of cell viability and Bcl-2 expression. This suggests that constitutive TRANCE-RANK interaction is responsible for CD34(+)-derived int-DC longevity. Conversely, CD1a(+) DCs express only RANK and are short-lived. However, they can be rescued from cell death either by recombinant soluble TRANCE or by CD34(+)-derived int-DCs. CD34(+)-derived int-DCs mature in response to lipopolysaccharide (LPS) plus CD40 ligand (L) and become capable of CCL21/CCL19-mediated chemotaxis and naive T-cell activation. Upon maturation, they lose TRANCE, making them, like CD1a(+) DCs, dependent on exogenous TRANCE for survival. These findings provide evidence that TRANCE and RANK play important roles in the homeostasis of DCs.
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PMID:Long-lived immature dendritic cells mediated by TRANCE-RANK interaction. 1239 86

Emodin (1,3,8-trihydroxy-6-methylanthraquinone) is an active constituent of Rheum palmatum, and showed inhibitory activity on lipopolysaccharide-induced NO production in our previous study. However, the apoptosis-inducing activity of emodin has remained undefined. Among three structurally related anthraquinones, including emodin, physcion, and chrysophanol, emodin showed the most potent cytotoxic effects on HL-60 cells, accompanied by the dose- and time-dependent appearance of characteristics of apoptosis including an increase in DNA ladder intensity, morphological changes, appearance of apoptotic bodies, and an increase in hypodiploid cells. Emodin at apoptosis-inducing concentrations causes rapid and transient induction of caspase 3/CPP32 activity, but not caspase 1 activity, according to cleavage of caspase 3 substrates poly(ADP-ribose) polymerase and D4-GDI proteins, the appearance of cleaved caspase 3 fragments being detected in emodin- but not physcion- or chrysophanol-treated HL-60 cells. A decrease in the anti-apoptotic protein, Mcl-1, was detected in emodin-treated HL-60 cells, whereas other Bcl-2 family proteins including Bax, Bcl-2, Bcl-XL, and Bad remained unchanged. The caspase 3 inhibitor, Ac-DEVD-CHO, but not the caspase 1 inhibitor, Ac-YVAD-CHO, attenuated emodin-induced DNA ladders, associated with the blockage of PARP and D4-GDI cleavage. Free radical scavenging agents including NAC, catalase, SOD, ALL, DPI, L-NAME and PDTC showed no preventive effect on emodin-induced apoptotic responses, whereas NAC, CAT and PDTC prevented HL-60 cells from ROS (H(2)O(2))-induced apoptosis through inhibition of caspase 3 cascades. Induction of catalase, but not SOD, activity was detected in emodin-treated HL-60 cells by in gel activity assays, and H(2)O(2)-induced intracellular peroxide level was significantly reduced by prior treatment of emodin in HL-60 cells. Our experiments provide evidence that emodin is an effective apoptosis inducer in HL-60 cells through activation of the caspase 3 cascade, but that it is independent of ROS production.
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PMID:Emodin induces apoptosis in human promyeloleukemic HL-60 cells accompanied by activation of caspase 3 cascade but independent of reactive oxygen species production. 1244 60

Dendritic cells (DCs) are the most important antigen-presenting cells. Many recent studies have compared the function of immature DCs (iDCs) and mature DCs (mDCs), but there have been few reports of the molecular changes that occur in DCs during maturation. Here, we report on differential gene expression in iDCs generated from peripheral blood monocytes compared with mDCs. Gene expression was evaluated using the differential display method after activation of iDCs with a low concentration of lipopolysaccharide (LPS) to induce maturation. Proteasome subunit alpha type 3 (PSMA3), transcription factor EC (TFEC) isoform and BTK region clone 2f10-rpi were transiently upregulated. Tryptophanyl-tRNA synthetase and CD63 antigen were upregulated for at least 24 h. Neuronal apoptosis inhibitory protein (NAIP) and transforming growth factor-beta-induced 68 kDa protein were downregulated. This is the first report of NAIP expression in human DCs. By comparing the expression of NAIP with that of other members of the inhibitor of apoptosis protein (IAP) family and the Bcl-2 family, only NAIP was found to be strongly expressed in iDCs before stimulation by LPS. PSMA3 was also induced in the DCs stimulated with immune complex. These findings might contribute to our understanding of DC maturation and the effectiveness of DC-based vaccines.
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PMID:Analysis of gene expression during maturation of immature dendritic cells derived from peripheral blood monocytes. 1247 71

Nitric oxide (NO), in excess, behaves as a cytotoxic substance mediating the pathological processes that cause neurodegeneration. The NO-induced dopaminergic cell loss causing Parkinson's disease (PD) has been postulated to include the following: an inhibition of cytochrome oxidase, ribonucleotide reductase, mitochondrial complexes I, II, and IV in the respiratory chain, superoxide dismutase, glyceraldehyde-3-phosphate dehydrogenase; activation or initiation of DNA strand breakage, poly(ADP-ribose) synthase, lipid peroxidation, and protein oxidation; release of iron; and increased generation of toxic radicals such as hydroxyl radicals and peroxynitrite. NO is formed by the conversion of L-arginine to L-citrulline by NO synthase (NOS). At least three NOS isoforms have been identified by molecular cloning and biochemical studies: a neuronal NOS or type 1 NOS (nNOS), an immunologic NOS or type 2 NOS (iNOS), and an endothelial NOS or type 3 NOS (eNOS). The enzymatic activities of eNOS or nNOS are induced by phosphorylation triggered by Ca(2+) entering cells and binding to calmodulin. In contrast, the regulation of iNOS seems to depend on de novo synthesis of the enzyme in response to a variety of cytokines, such as interferon-gamma and lipopolysaccharide. The evidence that NO is associated with neurotoxic processes underlying PD comes from studies using experimental models of this disease NOS inhibitors can prevent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity. Furthermore, NO fosters dopamine depletion, and the said neurotoxicity is averted by nNOS inhibitors such as 7-nitroindazole working on tyrosine hydroxylase-immunoreactive neurons in substantia nigra pars compacta. Moreover, mutant mice lacking the nNOS gene are more resistant to MPTP neurotoxicity when compared with wild-type littermates. Selegiline, an irreversible inhibitor of monoamine oxidase B, is used in PD as a dopaminergic function-enhancing substance. Selegiline and its metabolite, desmethylselegiline, reduce apoptosis by altering the expression of a number of genes, for instance, superoxide dismutase, Bcl-2, Bcl-xl, NOS, c-Jun, and nicotinamide adenine nucleotide dehydrogenase. The selegiline-induced antiapoptotic activity is associated with prevention of a progressive reduction of mitochondrial membrane potential in preapoptotic neurons. As apoptosis is critical to the progression of neurodegenerative disease, including PD, selegiline or selegiline-like compounds to be discovered in the future may be efficacious in treating PD.
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PMID:Peroxynitrite and mitochondrial dysfunction in the pathogenesis of Parkinson's disease. 1288 Apr 86

The silencer of death domains (SODD) has been proposed to prevent constitutive signaling of tumor necrosis factor receptor 1 (TNFR1) in the absence of ligand. Besides TNFR1, death receptor 3 (DR3), Hsp70/Hsc70, and Bcl-2 have been characterized as binding partners of SODD. In order to investigate the in vivo role of SODD, we generated mice congenitally deficient in expression of the sodd gene. No spontaneous inflammatory infiltrations were observed in any organ of these mice. Consistent with this finding, in the absence of SODD no alteration in the activation patterns of nuclear factor kappaB (NF-kappaB), stress kinases, or ERK1 or -2 was observed after stimulation with tumor necrosis factor (TNF). Activation of NF-kappaB by DR3 was also unchanged. The extents of DR3- and TNF-induced apoptosis were comparable in gene-deficient and wild-type cells. Protection of cells against heat shock as mediated by the Hsp70 system and against staurosporine-induced apoptosis was independent of SODD. Furthermore, resistance to high-dose lipopolysaccharide (LPS) injections, LPS-D-GalN injections, and infection with listeriae was similar in wild-type and gene-deficient mice. In conclusion, our data do not support the concept of a unique, nonredundant role of SODD for the functions of TNFR1, Hsp70, and DR3.
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PMID:Apparently normal tumor necrosis factor receptor 1 signaling in the absence of the silencer of death domains. 1294 86

Gut epithelial apoptosis is increased in human studies and animal models of noninfectious inflammation and sepsis. Elevated intestinal cell death appears to be physiologically significant in sepsis. Previous studies demonstrate that overexpression of the antiapoptotic protein Bcl-2 in the gut epithelium of transgenic mice is associated with improved survival from Pseudomonas aeruginosa pneumonia and cecal ligation and puncture. The functional significance of elevated gut apoptosis in noninfectious inflammation has not been examined. We hypothesized that intestinal apoptosis would be detrimental to survival in noninfectious critical illness. To address this issue, acute lung injury (ALI) was induced with intratracheal injection of lipopolysaccharide (LPS, 800 microg) in wild-type (WT) FVB/N mice and transgenic mice that overexpress Bcl-2 in their intestinal epithelium. Guts were harvested at 12, 24, 48, and 72 h and assessed for apoptosis by both hematoxylin and eosin and active caspase-3 staining in 100 contiguous crypts. ALI increased gut epithelial apoptosis 12 h after LPS instillation compared with shams (P < 0.01), whereas overexpression of Bcl-2 decreased intestinal apoptosis compared with WT animals with ALI when assayed by active caspase-3 (P < 0.05). Plasma levels of tumor necrosis factor alpha, interleukin (IL)-6, and IL-10 were similar between WT and transgenic animals with ALI, both of which had elevated IL-10 levels at 12 h and elevated IL-6 levels at 24 h compared with sham animals. In a separate experiment, transgenic and WT animals with ALI were followed for mortality to determine whether gut overexpression of Bcl-2 conferred a survival advantage. Survival at 10 days was 73% in WT animals (n = 33) and 65% in Bcl-2 animals (n = 23, P = ns). These results indicate that while gut epithelial apoptosis is elevated in multiple models of critical illness, prevention of intestinal cell death by overexpression of Bcl-2 is associated with a disparate survival effect between sepsis and noninfectious inflammation.
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PMID:Bcl-2 inhibits gut epithelial apoptosis induced by acute lung injury in mice but has no effect on survival. 1456 Jan 8


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