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

The mechanism of injury and death of muscle cells in the inflammatory myopathies (dermatomyositis, polymyositis, and inclusion body myositis) remains obscure. We and others have not detected apoptosis in the muscle biopsies from patients with myositis despite clear evidence of cell damage and loss. We provide evidence in this study that Fas ligand (FasL) as well as Fas is present on muscle cells and inflammatory cells in myositis biopsies: Fas is present on most muscle cells and lymphocytes, and FasL is present on degenerating muscle cells and many infiltrating mononuclear cells. The expression of both Fas and FasL in the inflamed tissue makes the absence of apoptosis more striking. To address the mechanisms of this resistance to classical apoptosis in muscle cells, we have investigated the expression of the antiapoptotic molecule FLICE (Fas-associated death domain-like IL-1-converting enzyme)-inhibitory protein (FLIP) in muscle biopsies of myositis patients and in cultured human skeletal muscle cells. Using laser capture microscopy, we have shown that FLIP is expressed in the muscle fibers and on infiltrating lymphocytes of myositis biopsies. Furthermore, we have shown that FLIP, but not Bcl-2, is expressed in cultured human skeletal muscle cells stimulated with proinflammatory cytokines, and inhibition of FLIP with antisense oligonucleotides promotes significant cleavage of poly(ADP-ribose) polymerase autoantigen, a sensitive indicator of apoptosis. These studies strongly suggest that the resistance of muscle to Fas-mediated apoptosis is due to the expression of FLIP in muscle cells in the inflammatory environment in myositis.
 ...
PMID:The inhibition of apoptosis in myositis and in normal muscle cells. 1079 13

Apert syndrome is an autosomal dominant disorder characterized by premature cranial ossification resulting from fibroblast growth factor receptor-2 (FGFR-2)-activating mutations. We have studied the effects of the prominent S252W FGFR-2 Apert mutation on apoptosis and the underlying mechanisms in human mutant osteoblasts. In vivo analysis of terminal deoxynucleotidyl transferase-mediated nick-end labeling revealed premature apoptosis of mature osteoblasts and osteocytes in the Apert suture compared to normal coronal suture. In vitro, mutant osteoblasts showed increased apoptosis, as demonstrated by terminal deoxynucleotidyl transferase-mediated nick-end labeling analysis, trypan blue staining, and DNA fragmentation. Mutant osteoblasts also showed increased activity of caspase-8 and effector caspases (-3, -6, -7) constitutively. This was related to protein kinase C activation because the selective protein kinase C inhibitor calphostin C inhibited caspase-8, effector caspases, and apoptosis in mutant osteoblasts. Apert osteoblasts also showed increased expression of interleukin (IL)-1alpha, IL-1beta, Fas, and Bax, and decreased Bcl-2 levels. Specific neutralizing anti-IL-1 antibody reduced Fas levels, Bax expression, effector caspases activity, and apoptosis in mutant cells. Thus, the Apert S252W FGFR-2 mutation promotes apoptosis in human osteoblasts through activation of protein kinase C, overexpression of IL-1 and Fas, activation of caspase-8, and increased Bax/Bcl-2 levels, leading to increased effector caspases and DNA fragmentation. This identifies a complex FGFR-2 signaling pathway involved in the premature apoptosis induced by the Apert S252W FGFR-2 mutation in human calvaria osteoblasts.
 ...
PMID:Increased osteoblast apoptosis in apert craniosynostosis: role of protein kinase C and interleukin-1. 1133 81

Similar to solid tumors, growth of leukemias may also be angiogenesis dependent. Furthermore, tyrosine kinase receptors specific to endothelial cells are expressed on certain subsets of leukemias. We have previously demonstrated the existence of a VEGF/VEGFR-2 autocrine loop on leukemic cells that supports their growth and migration. Here, we demonstrate that in response to leukemia-derived proangiogenic and proinflammatory cytokines such as basic fibroblast growth factor and IL-1, endothelial cells release increasing amounts of another vascular endothelial growth factor (VEGF) family member, VEGF-C. In turn, interaction of VEGF-C with its receptor VEGFR-3 (FLT-4) promotes leukemia survival and proliferation. We demonstrate in 2 cell lines and 5 FLT-4(+) leukemias that VEGF-C and a mutant form of the molecule that lacks the KDR-binding motif induce receptor phosphorylation, leukemia proliferation, and increased survival, as determined by increased Bcl-2/Bax ratios. Moreover, VEGF-C protected leukemic cells from the apoptotic effects of 3 chemotherapeutic agents. Because most leukemic cells release proangiogenic as well as proinflammatory cytokines, our data suggest that the generation of a novel paracrine angiogenic loop involving VEGF-C and FLT-4 may promote the survival of a subset of leukemias and protect them from chemotherapy-induced apoptosis. These results identify the VEGF-C/FLT-4 pathway as a novel therapeutic target for the treatment of subsets of acute leukemia.
 ...
PMID:Vascular endothelial growth factor (VEGF)-C signaling through FLT-4 (VEGFR-3) mediates leukemic cell proliferation, survival, and resistance to chemotherapy. 1187 95

Fumonisin B1 (FB1) is a naturally occurring mycotoxin produced primarily by Fusarium verticillioides and related fungi, common contaminants of corn throughout the world. FB1 is a carcinogen and causative agent of several lethal animal diseases, including equine leukoencephalomalacia and porcine pulmonary edema. Liver is the primary target organ in mice. In vivo and vitro, cells exposed to FB1 undergo a mixture of necrotic and apoptotic cell death. Our previous studies showed gender differences in hepatotoxicity caused after 5 day FB1 treatment. Gene alterations in cytokine network and apoptosis signaling molecules were also observed after an acute single dose of FB1. To further investigate the gene alterations after a subchronic FB1 exposure and its correlation to observed gender differences, male and female BALB/c mice (five per group) were injected subcutaneously with either saline or 2.25 mg/kg per day of FB1 for 5 days. FB1 caused increased expression of tumor necrosis factor alpha (TNFalpha), interleukin (IL)-1alpha, IL-1beta, IL-1 receptor antagonist (IL-1Ra), IL-6, IL-10, IL-12 p40, IL-18 and interferon gamma (IFNgamma) in male liver, with a similar increase in females except for IL-1beta and IL-18. Control females showed higher basal levels of IL-1alpha, IL-1Ra, IL-10, IL-12 p40 and IFNgamma compared with males. Expression of TNF receptor 55 and TNF receptor associated death domain (TRADD) was increased, with no changes in Fas signaling molecules, Fas, Fas ligand (FasL), Fas associated death domain (FADD) and Fas-associated protein factor (FAF). Expression of oncogenic transcription factors, c-Myc, B-Myc, Max and Mad, and apoptotic genes, namely Bcl-2, Bax and Bad, was increased after FB1 treatment. FB1 caused an activation of cytokine network in liver, particularly the TNFalpha signaling pathway, suggesting its involvement in hepatotoxic mechanisms. Induction of IL-1Ra and oncogenes is a likely mechanism for the cancer promoting properties of FB1, through a mechanism involving apoptotic necrosis, oncotic necrosis and consequent regeneration.
 ...
PMID:Modulation of selected cell signaling genes in mouse liver by fumonisin B1. 1187 19

The nuclear self-Ags targeted in systemic lupus erythematosus translocate to the cell membrane of UV-irradiated apoptotic keratinocytes and may represent an important source of self-immunization. It is hard to understand how the noninflammatory milieu accompanying most apoptosis might provoke an immunogenic response leading to autoantibodies. We have found that the precise amount of keratinocyte UV exposure is crucial in determining the rate of apoptosis, the amount of inflammatory cytokine production, and the degree of autoantigen translocation. Low doses of UVB (</=15 mJ/cm(2)) promptly induced a normal, caspase-dependent apoptosis, while intermediate doses of UV-B (35 mJ/cm(2)) caused apoptosis with altered morphology, slower DNA fragmentation, and poly(ADP-ribose) polymerase degradation accompanied by increased Bcl-2. High doses of UVB (80 mJ/cm(2)) induced instead necrosis. We observed IL-1 production upon intermediate and high UVB doses. Nuclear Ag redistribution was also markedly UV dose dependent: at low doses, Sm, Ku, and DNA translocated to the surfaces of early apoptotic cells. At intermediate doses, these Ags concentrated on the cell membrane when the nucleus was still visible. At high doses, these autoantigens diffused into the cytoplasm and were released into the supernatant. Taken together, the results show that low-dose UVB induces prompt noninflammatory apoptosis. In contrast, intermediate and high doses of UVB induce proinflammatory apoptosis and necrosis, where the production of inflammatory cytokines is accompanied by exposure and release of autoantigens. The key importance of the UV dose on the fate of apoptotic keratinocytes and on their potential immunogenicity should help clarify the role of UVB in inducing systemic lupus erythematosus autoimmunity.
 ...
PMID:Ultraviolet B radiation-induced cell death: critical role of ultraviolet dose in inflammation and lupus autoantigen redistribution. 1463 86

Blast cell survival in suspension culture is associated with chemoresistance in acute myeloid leukaemia (AML). Autonomous production of IL-1beta by AML blasts is linked with a proliferative response, although its role in survival and hence apoptosis-resistance has not been examined in this disease. Cells that secreted more than 19.7 pg/ml IL-1beta were significantly more resistant to spontaneous apoptosis in 48-h culture than those that produced less than 19.7 pg/ml IL-1beta (P=0.008). Exogenous rhIL-1beta significantly enhanced 48-h survival in 25/29 blast cell samples (P=0.0001). IL-1 receptor ligation is known to activate at least three survival pathways: those mediated by PI-3 kinase, IL-1 receptor-associated kinase (IRAK) and ceramidase. In apoptosis-sensitive AML blasts with a strong survival response to rhIL-1beta, inhibitors of all three pathways down-modulated an IL-1beta-mediated increase in blast survival, but only the inhibition of all three pathways totally eliminated viable blasts. In apoptosis-resistant and apoptosis-sensitive primary AML samples, the three inhibitors all increased apoptosis in vitro after 48 h. Exogenous rhIL-1beta induced the hyperphosphorylation of Bcl-2. It also increased the activation of NF-kappaB in 5/15 blast samples. IL-1beta-mediated survival pathways may be a factor in apoptosis-resistance in primary AML blasts, and may therefore contribute to chemoresistance.
 ...
PMID:Interleukin-1beta maintains an apoptosis-resistant phenotype in the blast cells of acute myeloid leukaemia via multiple pathways. 1530 22

Using indirect inmunohistochemical method, the expression of Bcl-XL and Bax, anti- and proapoptotic proteins of Bcl-2 family, as well as of cytokine IL-1beta were studied to demonstrate the role of these substances in apoptosis regulation of sensory neurons of different subpopulations after the severance of their peripheral processes. For comparison of the capacity of these neurons to survive after central and peripheral axotomy, the expression of high-molecular component of neurofilament triplet NF200 and isolectin B4 (IB4) binding were studied. At day 30 after central axotomy, the total number of neurons in LIV-LV ganglia of rat was not changed, but the number of NF200+ neurons was decreased. In mouse Lv dorsal root, proapoptotic BaX protein was demonstrated in the nuclei of 46% of small neurons that accounts for 20% of the total neuronal number in this ganglion. By day 30 after the nerve crush separate Bax expression was found in the nuclei of 30% and in the cytoplasm of 20% of neurons. In intact animals, dorsal root ganglion antiapoptotic Bcl-XL protein was expressed in the cytoplasm of 30% of small neurons, as well as in satellite cells surrounding large and intermediate neurons. At day 30 after the nerve crush Bcl-XL expression in LV ganglion was not detected. IL-1beta was present in the cytoplasm of 17% of neurons belonging predominantly to the subpopulations of large and intermediate neurons. By day 30 after the nerve crush IL-1(+-neurons were not found.
 ...
PMID:[Survival and phenotypic characterisctic of axotomized dorsal root ganglion neurons]. 1535 93

Resveratrol, trans-3,5,4'-trihydroxystilbene, was first isolated in 1940 as a constituent of the roots of white hellebore (Veratrum grandiflorum O. Loes), but has since been found in various plants, including grapes, berries and peanuts. Besides cardioprotective effects, resveratrol exhibits anticancer properties, as suggested by its ability to suppress proliferation of a wide variety of tumor cells, including lymphoid and myeloid cancers; multiple myeloma; cancers of the breast, prostate, stomach, colon, pancreas, and thyroid; melanoma; head and neck squamous cell carcinoma; ovarian carcinoma; and cervical carcinoma. The growth-inhibitory effects of resveratrol are mediated through cell-cycle arrest; upregulation of p21Cip1/WAF1, p53 and Bax; down-regulation of survivin, cyclin D1, cyclin E, Bcl-2, Bcl-xL and clAPs; and activation of caspases. Resveratrol has been shown to suppress the activation of several transcription factors, including NF-kappaB, AP-1 and Egr-1; to inhibit protein kinases including IkappaBalpha kinase, JNK, MAPK, Akt, PKC, PKD and casein kinase II; and to down-regulate products of genes such as COX-2, 5-LOX, VEGF, IL-1, IL-6, IL-8, AR and PSA. These activities account for the suppression of angiogenesis by this stilbene. Resveratrol also has been shown to potentiate the apoptotic effects of cytokines (e.g., TRAIL), chemotherapeutic agents and gamma-radiation. Phamacokinetic studies revealed that the target organs of resveratrol are liver and kidney, where it is concentrated after absorption and is mainly converted to a sulfated form and a glucuronide conjugate. In vivo, resveratrol blocks the multistep process of carcinogenesis at various stages: it blocks carcinogen activation by inhibiting aryl hydrocarbon-induced CYP1A1 expression and activity, and suppresses tumor initiation, promotion and progression. Besides chemopreventive effects, resveratrol appears to exhibit therapeutic effects against cancer. Limited data in humans have revealed that resveratrol is pharmacologically quite safe. Currently, structural analogues of resveratrol with improved bioavailability are being pursued as potential therapeutic agents for cancer.
 ...
PMID:Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. 1551 85

We have reported that caspase cascade accompanied by the regulation of Bax/Bcl-2 and MAPK signaling were involved in evodiamine-induced A375-S2 cell death. In this study, pretreatment with interleukin 1 (IL-1) receptor antagonist (IL-1Ra) rescued the cell viability loss and reversed the ratio of terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL)-positive cells induced by evodiamine. IL-1Ra was capable of attenuating the expression of Fas-ligand (Fas-L) and the cleavage of procaspas-8 and -3 caused by evodiamine. Subsequently, IL-1Ra reduced evodiamine-induced DNA degradation, p53 activation and up-regulation of Bax/Bcl-2 ratio. However, IL-1Ra attenuated the enhanced phosphorylation level of p38 mitogen-activated protein kinase (p38 MAPK) without affecting extracellular signal-regulated protein kinase (ERK) inactivation induced by evodiamine. In conclusion, IL-1-induced death cascade in melanoma A375-S2 cell might be one of the targets for natural product evodiamine, and increased Fas-L expression via IL-1 mediated pathway stands at the initiation phase, leading to consequent events that culminate in the death of the cells.
 ...
PMID:Evodiamine induced human melanoma A375-S2 cell death partially through interleukin 1 mediated pathway. 1593 Jul 31

In osteoarthritis (OA) a time or age dependent process leads to aberrant cartilage structure which is characterized by reduced number of chondrocytes, loss of existing cartilage extracellular matrix, the production of matrix with abnormal composition and pathologic matrix calcification. Because chondrocyte matrix synthesis and mineralization are modulated by the balance between ATP generation and consumption, the mechanism by which chondrocytes generate energy have been a topic of interest. The analysis of mitochondrial respiratory chain (MRC) activity in OA chondrocytes shows a significant decrease in complexes II and III compared to normal chondrocytes. On the other hand, mitochondrial mass is increased in OA, as demonstrated by a significant rise in CS activity. Furthermore, OA cells show a reduction in the mitochondrial membrane potential (deltapsim) as demonstrated by using the fluorescent probe JC-1. OA cartilage contains high number of apoptotic chondrocytes, and mitochondria play a key role in apoptosis. Interestingly, OA cartilages show markedly elevated Bcl-2 and caspasa-3 expression. This expression is also correlated with chondrocyte apoptosis and OA lesions. The pathogenesis of OA includes elaboration of increased amounts of NO as a consequence of up-regulation of chondrocyte-inducible NO synthase induced by IL-1, TNF-alpha and other factors. NO reduces chondrocyte survival and induces cell death with morphologic changes characteristic of chondrocyte apoptosis. NO reduces the activity of complex IV and decreases the deltapsim as measured as the ratio of red/green fluorescence. Furthermore, NO induces the mRNA expression of caspase-3 and -7, and it reduces the expression of mRNA bcl-2 and the bcl-2 protein synthesis. Some studies suggest that the chondrocyte mitochondria are specialized for calcium transport and are important in the calcification of the extracellular matrix. Mineral formation has been demonstrated in matrix vesicles (MV) and within mitochondria. Direct suppression of mitochondrial respiration promoted MV-mediated mineralization in chondrocytes. Regulation of MRC may be one of the signaling pathways by which NO modulates articular cartilage matrix biosynthesis and pathologic mineralization. After age 40, the incidence of OA in humans increases progressively with increasing age. Studies show a trend to statistic significance between the age and the reduction of complex I activity of human normal chondrocytes. However, the study of relation between age and deltapsim in normal chondrocytes do not demonstrate any significant correlation. It has been reported that as the number of population doublings increased, mitochondrial DNA was degraded and the number of mitochondria per chondrocyte decline. One approach for determining the role of mitochondria in OA is to determine the effects of the MRC inhibition and to compare them with the findings in OA. Inhibition of MRC with antimycin prevents the normal ability of TGFbeta to increase excretion of Pi, thereby worsening deposition of pathologic HA crystals. In chondrocytes, the inhibition of complex IV with NaN3 modified both the deltapsim and the survival of cells inducing apoptosis. Inhibition of complex I with rotenone increases the expression and synthesis of Bcl-2 and Cox-2, both effects are similar effects to produced by IL-1 in human chondrocytes.
 ...
PMID:Mitochondrial dysfunction in osteoarthritis. 1612 Apr 27


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>