Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Our recent work demonstrated functional Fas expression on human osteoblasts, and the histologic examination of the periarticular osteoporosis region in patients with rheumatoid arthritis (RA) showed apoptosis in osteoblasts. High concentrations of interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), and IL-6--which are thought to increase bone resorption--have been determined in RA synovium. We investigated the effect of these cytokines on the Fas-mediated apoptosis of human osteoblasts. The human osteoblastic cell line MG63 and human primary osteoblast-like cells from bone biopsy specimens were used as human osteoblasts. Fas expression on these cells was examined by flow cytometry, and Fas-mediated apoptosis induced by anti-Fas immunoglobulin M (IgM) was determined by a chromium 51 release assay, the presence of cells with hypodiploid DNA, staining with Hoechst 33258 dye, and the detection of DNA fragmentation on agarose gel electrophoresis. The proliferation of osteoblasts was analyzed by a tritiated thymidine incorporation assay. Spontaneous apoptosis was not found on cultured osteoblasts. The apoptosis of human osteoblasts was not induced by TNF-alpha, IL-1beta, or IL-6 alone in the absence of anti-Fas IgM. In addition, proliferation of the cells was not affected by these cytokines. Fas was constitutively expressed on unstimulated osteoblasts, and treatment of these cells with IL-1beta or TNF-alpha significantly augmented Fas expression. Human osteoblasts were committed to apoptosis with anti-Fas IgM, and the treatment of both IL-1beta and TNF-alpha markedly increased Fas-mediated apoptosis. TNF-alpha augmented both Fas expression and Fas-mediated apoptosis more efficiently than did IL-1beta. In addition, an additive effect on both Fas expression and Fas-mediated apoptosis was demonstrated when TNF-alpha and IL-1beta were added to osteoblasts. IL-6 influenced neither Fas expression nor the Fas-mediated apoptosis of osteoblasts. Furthermore, no synergistic effect of IL-6 with IL-1beta or TNF-alpha was observed. IL-1beta, TNF-alpha, or IL-6 did not change Bcl-2 expression. Our results suggest that IL-1beta and TNF-alpha regulate osteoblast cell number by up-regulating the Fas-mediated apoptosis of osteoblasts, one of the putative mechanisms inducing periarticular osteoporosis in patients with RA.
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PMID:Tumor necrosis factor-alpha and interleukin-1beta increase the Fas-mediated apoptosis of human osteoblasts. 1048 2

Vitamin K2 is used for the treatment of osteoporosis, but the precise mode of action is still not clear. We investigated the effects of vitamin K2 on apoptosis of human osteoblasts. Human osteoblastic cell line MG63 cells and human primary osteoblast-like cells obtained from bone fragments in corrective surgery were used as human osteoblasts. Cells were cultured with or without various concentrations of vitamin K2 and tumor necrosis factor-alpha (TNF-alpha). We then determined the proliferative response, expression of Fas and Bcl-2-related proteins, and Fas-mediated apoptosis of these cells induced by anti-Fas immunoglobulin M (IgM). In addition, the effect of vitamin K2 in osteoblast apoptosis induced by Z-Leu-Leu-Leu-aldehyde (LLL-CHO), etoposide, or staurosporine was also examined. Human osteoblasts did not show spontaneous apoptosis in culture, even in the presence of vitamin K2 or TNF-alpha. Furthermore, proliferation of the cells was not influenced by vitamin K2 or TNF-alpha. Fas was functionally expressed on human osteoblasts, and the treatment with TNF-alpha significantly enhanced both Fas expression and Fas-mediated apoptosis of osteoblasts. The addition of vitamin K2 to the culture resulted in a dose-dependent inhibition of functional Fas expression on osteoblasts, in the presence or absence of TNF-alpha. Treatment of human osteoblasts with vitamin K2 clearly suppressed Bax expression of the cells, although the expression of Bcl-2 was not influenced by vitamin K2. Fas ligand (FasL) cDNA transformants were cytotoxic against osteoblasts, and the cytotoxicity was increased when osteoblasts were treated with TNF-alpha. The addition of vitamin K2 to osteoblasts significantly decreased the cytotoxic effects of FasL cDNA transformants. Furthermore, apoptosis of human osteoblasts induced by LLL-CHO, etoposide, or staurosporine was also clearly suppressed in vitamin K2-treated osteoblasts. Our results suggest that vitamin K2 inhibits apoptotic cell death of osteoblasts and maintains the number of osteoblasts. These actions may explain the therapeutic efficacy of vitamin K2 in osteoporosis.
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PMID:Effect of vitamin K2 on osteoblast apoptosis: vitamin K2 inhibits apoptotic cell death of human osteoblasts induced by Fas, proteasome inhibitor, etoposide, and staurosporine. 1098 96

Over the past decade, our understanding of apoptosis, or programmed cell death, has increased greatly, with the identification of some of the major components of the apoptotic program and the processes regulating their activation. Although apoptosis is an intrinsic process present in all cells, it can be regulated by extrinsic factors, including growth factors, cell surface receptors, cellular stress and hormones. Apoptotis plays an important role in autoimmune diseases. Normal thyrocytes could induce apoptosis of infiltrating activated T cells and protect against attack by such cells, i.e., the normal thyroid tissues act as an immune privileged site. In Hashimoto's thyroiditis (HT), Fas-mediated apoptosis of thyrocytes in a section of tissues is due to at least two separate mechanisms, the first by infiltrating activated T cells, and the other by FasL-positive thyrocytes in a suicidal or fratricidal fashion. A common feature of autoimmune diseases such as systemic lupus erythematosus (SLE) is the breakdown of tolerance of self antigens, a consequence of which is the production of autoantibodies reactive with multiple self proteins. Evidence is accumulating that modifications of autoantigens during apoptosis lead to the development of autoantibodies by bypassing the normal mechanisms of tolerance. Tissue homeostasis is maintained through a balance between cell proliferation and apoptotic cell death. Rheumatoid arthritis (RA) is characterized by pronounced hyperplasia of the synovial tissue, cell infiltration and periarticular osteoporosis. Enhanced Bcl-2 expression and NF-kappaB nuclear translocation of synovial cells are induced by inflammatory cytokines and/or growth factors. These synovial cells become resistant toward apoptosis triggered by various stimuli. The infiltrated cells which are defect in activation-induced cell death can cause autoimmunity by allowing the survival of autoreactive T and B cells. These data suggest that apoptosis might be implicated with the pathogenesis of autoimmunity, whereas the mechanisms might be distinct in each autoimmune disease.
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PMID:Apoptosis in autoimmune diseases. 1133 84

Selective estrogen receptor modulator is a proven agent for chemoprevention and chemotherapy of cancer. Raloxifene, a mixed estrogen agonist/antagonist, was developed to prevent osteoporosis and potentially reduce the risk of breast cancer. In this study, we examined the effect of raloxifene on the TSU-PR1 cell line. This cell line was originally reported to be a prostate cancer cell line, but recently it has been shown to be a human bladder transitional cell carcinoma cell line. The TSU-PR1 cell line contains high levels of estrogen receptor beta. Following treatment with raloxifene, evidence of apoptosis, including change in nuclear morphology, DNA fragmentation, and cytochrome c release, was observed in a dose-dependent manner in the TSU-PR1 cells (10(-9) to 10(-6) m range). We observed no detectable change in the steady-state levels of Bax, Bcl-2, and Bcl-X(L) following raloxifene treatment. However, raloxifene induced caspase-dependent cleavage of BAD to generate a 15-kDa truncated protein. Overexpression of a double mutant BAD resistant to caspase 3 cleavage blocked raloxifene-induced apoptosis. These results demonstrate that raloxifene induces apoptosis through the cleavage of BAD in TSU-PR1 cells. This molecular mechanism of apoptosis suggests that raloxifene may be a therapeutic agent for human bladder cancer.
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PMID:Raloxifene, a mixed estrogen agonist/antagonist, induces apoptosis through cleavage of BAD in TSU-PR1 human cancer cells. 1208 14

Pamidronate belongs to the class of nitrogen-containing bisphosphonates that are potent inhibitors of bone resorption frequently used for the treatment of osteoporosis and cancer-induced osteolysis. The inhibition of osteoclasts' growth has been suggested as the main mechanism of the inhibitory effect of pamidronate on bone metastases. Recent findings indicated that bisphosphonates also have a direct apoptotic effect on other types of tumour cells. Nitrogen-containing bisphosphonates were shown to inhibit farnesyl diphosphate synthase, thus blocking the synthesis of higher isoprenoids. By this mechanism they inactivate monomeric G-proteins of the Ras and Rho families for which prenylation is a functional requirement. On the background of the known key role of G-proteins in tumorigenesis, we investigated a possible beneficial use of pamidronate in the treatment of malignant melanoma. Our results indicate that pamidronate inhibits the cell growth and induces apoptosis in human melanoma cells in vitro. Susceptibility to pamidronate did not correlate to CD95 ligand sensitivity or p53 mutational status. Furthermore it is interesting to note that overexpression of bcl-2 did not abolish pamidronate-induced apoptosis. These data suggests that pamidronate has a direct anti-tumour effect on malignant melanoma cells, independently of the Bax/Bcl-2 level.
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PMID:The bisphosphonate pamidronate induces apoptosis in human melanoma cells in vitro. 1217 10

Osteoporosis (OP) and atherosclerotic-cardiovascular diseases (and possibly dementia) constitute emerging age-related co-morbidity states that might share risk factors. Blood-born lipids, like LDL involved in atherosclerosis and apolipoprotein-E4 (ApoE4) involved in dementia, may also be implicated in development of OP. We examined osteoblast cell lines as a culture model for OP by exposure to lipoproteins. ApoE expression in Saos2 and U2OS osteoblasts was confirmed by PCR. ApoE4 did decrease cell counts relatively to ApoE3, especially in Saos2 cells in which it was less selective for cells with higher alkaline phosphatase (ALP, an osteoblast marker) activity than ApoE3. This associates with ApoE4, being a risk factor for both dementia and OP. Saos2, but not U2OS, showed a decrease in cell counts after 48 h exposure to native LDL (NLDL). Both cell lines had decreased cell counts already after 24 h when exposed to oxidized-LDL (OxLDL) for which Saos2 also showed a higher sensitivity than U2OS. Exposure of Saos2 to both, OxLDL at low concentration (5 microg/ml) and NLDL revealed a shrunken size cell fraction of 17-23% on the fluorescence-activated cell sorter (FACS) analysis. Such shrunken cell fraction was not seen when Saos2 cells were exposed to 50 microg/ml of OxLDL or to OxLDL combined with 10 nM dexamethasone (DEX, a stimulator of osteoprogenitor differentiation). DEX treatment has lysed the cells earlier than 24 h post exposure and has selected more resistant cells that did not show apoptotic shrinkage in the FACS analysis done after 24 h. We interpret this as a failure to detect the apoptotic cell fraction due to their lysis prior to the FACS analysis. Western blots performed at different time points (10 min, 30 min, 4 h, 24 h, and 48 h) under OxLDL + DEX revealed a fall in the positive regulator of pp60Src-kinase phosphotyrosine (pY)418 relative to the DEX controls during the first 4 h. This is consistent with DEX osteogenic induction, known to be negatively regulated by c-Src, although the pY418/pY529 ratios (negative/positive kinase regulation) fell only at the 10 min time point. Contrarily the pY418/pY529 ratio increased, relative to untreated controls, under 5 microg/ml and 50 microg/ml of NLDL at the 4 h time point and under 50 microg/ml NLDL only at the 10 min time point, being consistent with the ability of a higher dose of LDL to antagonize osteoblast differentiation. This could be even more acceptable if the NLDL would have become minimally oxidized during its long purification procedure. Under NLDL, the Bcl-2/Bax ratio was pro-apoptotic at 10 min, 30 min, and 4 h only under 50 microg/ml, whereas under OxLDL + DEX it was pro-apoptotic only after 4 h suggesting that additional pathways contribute to cell death. These results indicate that lipid effects on human osteoblast lines in culture may be used as a model to identify molecular targets shared between OP and atherosclerosis for intervention in this co-morbidity.
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PMID:Cell death in cultured human Saos2 osteoblasts exposed to low-density lipoprotein. 1293 55

Menopause marks the start of a new phase in a woman's life that is associated with a decrease in circulating estrogen levels. Although the average age of women has increased from 50 to nearly 85 years, the average age at menopause has remained essentially constant at 50 years. Thus, women now spend nearly a third of their lives in an estrogen deficient state. This normal aging process in women is associated with increasing health problems such as osteoporosis, cardiovascular disease, neurodegenerative diseases, and cancer. Estrogen replacement therapy (ERT) has been shown to play an important beneficial role in the health and well being of postmenopausal women. Several estrogen preparations are available and among these conjugated equine estrogens (CEE) are most frequently used. The drug CEE, is a complex natural urinary extract of pregnant mare's urine and contains at least 10 estrogens in their sulfate ester form and these are the ring B saturated estrogens: estrone (E(1)), 17beta-estradiol (17beta-E(2)), 17alpha-estradiol (17alpha-E(2)), and the ring B unsaturated estrogens equilin (Eq), 17beta-dihydroequilin (17beta-Eq), 17alpha-dihydroequilin (17alpha-Eq), equilenin (Eqn), 17beta-dihydroequilenin (17beta-Eqn), 17alpha-dihydroequilenin (17alpha-Eqn), and Delta(8)-estrone (Delta(8)-E(1)). All of these estrogens in their unconjugated form are biologically active and can interact with recombinant human estrogen receptor alpha (ERalpha) and beta (ERbeta) with 17beta-estradiol and 17beta-dihydroequilin having the highest affinity for both receptors. A number of the ring B unsaturated estrogens had nearly twofold higher affinity for the ERbeta. The pharmacokinetics of these estrogens in postmenopausal women indicate that the unconjugated estrogens compared to their sulfated forms are cleared more rapidly. The 17-keto estrogens are metabolized to the more potent 17beta-reduced products which are cleared at a slower rate. In postmenopausal women, the extent of 17beta-activation is much higher with the ring B unsaturated estrogens than with ring B saturated estrogens. Oxidized LDL and oxidative stress are thought to contribute to both atherosclerosis and neurodegenerative disorders. Neurons in particular are at a high risk from damage resulting from oxidative stress. In vivo and in vitro studies indicate that the oxidation of LDL isolated from postmenopausal women was inhibited differently by various estrogens and other antioxidants. The unique ring B unsaturated estrogens were the most potent while the red wine component t-resveratrol was the least potent. Studies were designed to explore the cellular and molecular mechanisms that may be involved in the neuroprotective effects of CEE components. The data indicate that the neurotoxic effects of oxidized LDL and glutamate can be inhibited by various estrogens, with the ring B unsaturated estrogens being the most active. These effects are involved in the inhibition of DNA fragmentation and up-regulation of anti-apoptotic protein Bcl-2 and down-regulation of pro-apoptotic protein Bax. These combined data suggest that some of the neuroprotective benefits associated with long-term estrogen therapy may occur by the above mechanism(s). Because estrogens such as the Delta(8)-estrogens are relatively less feminizing than the classical estrogen 17beta-estradiol, they may be important in the development of more neuro-specific estrogens that will be useful in the prevention of neurodegenerative diseases, such as Alzheimer's and Parkinson disease, in both men and women.
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PMID:Estrogens and menopause: pharmacology of conjugated equine estrogens and their potential role in the prevention of neurodegenerative diseases such as Alzheimer's. 1294 38

It is believed that bisphosphonates (BPs) induce apoptosis in cells such as myeloma cells, as they inhibit prenylation of G-proteins. However, the details of the apoptosis-inducing mechanism remain obscure. In the present study, we attempted to clarify the mechanism by which YM529, a new bisphosphonate, induces apoptosis. YM529 induced cell deaths in HL60 cells in a concentration-dependent manner. At that time, we observed an increase in Caspase-3 activity and morphological fragmentation of the nuclei. We could confirm that these cell deaths were evidence of apoptosis. The apoptosis induced by YM529 was not inhibited by the addition of farnesyl pyrophosphate (FPP), but was by the addition of geranylgeranyl pyrophosphate (GGPP). When we examined the survival signals at the time of apoptotic induction, we also observed that the administration of YM529 caused a remarkable decrease in the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2). However, other survival signals such as nuclear factor kappa B (NF-kappaB), protein kinase B (Akt), and p38 mitogen-activated protein kinase (p38) exhibited no change. In addition, no quantitative change was observed in Bcl-2, which is an anti-apoptosis protein. It was also observed that apoptosis was induced when U0126, an MEK inhibitor, was added to the cells to inhibit ERK. These results suggest that YM529, the new bisphosphonate, induced apoptosis when inhibit GGPP synthase and consequently decreased the levels of phosphorylated ERK, which is a survival signal; moreover, during this process, there is no influence on NF-kappaB, Akt, p38, and Bcl-2. The results of this study also suggest that YM529 can be used as an anticancer agent, in addition to its use as a therapeutic agent to treat osteoporosis.
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PMID:A new bisphosphonate, YM529 induces apoptosis in HL60 cells by decreasing phosphorylation of single survival signal ERK. 1367 34

Glucocorticoids have marked effects on bone metabolism, and continued exposure of skeletal tissue to excessive amounts of these steroids results in osteoporosis. Therefore, in the present proteomic study, we characterized the potential effects of glucocorticoids on protein expression in human osteoblastic cells. Using two-dimensional gel electrophoresis and mass spectrometry, we identified an increased expression of glutamine synthetase (GS) in dexamethasone (Dex)-treated human MG-63 osteosarcoma cells. GS is an enzyme catalyzing the conversion of glutamate and ammonia to glutamine. Intracellular and extracellular glutamate levels may be important in cell signalling mediated by glutamate transporters and receptors which have recently been found in bone cells. The induction of GS protein by Dex was accompanied by an increase in mRNA level and enzyme activity. Dex induction of GS was also mediated by glucocorticoid receptors (GRs) because it was blocked by the GR antagonist RU-38486. In addition, Dex induction of GS expression was partially blocked by cyclohexamide indicating that it at least partly required new protein synthesis. GS induction by Dex was not associated with apoptosis as determined by Bax/Bcl-2 ratio and DNA staining. In addition to MG-63 cells, Dex induction of GS was also observed in human G-292 osteosarcoma cells as well as conditionally immortalized human preosteoblastic (HOB-03-C5) and mature osteoblastic (HOB-03-CE6) cells. However, in two other human osteosarcoma cell lines, SaOS-2 and U2-OS, GS expression was not affected by Dex. This observation may be explained by the lower levels of GR protein in these cells. In summary, this is the first report of the regulation of GS expression by glucocorticoids in bone cells. The role of GS in bone cell metabolism and glucocorticoid action on the skeleton is not yet known, but as a modulator of intracellular glutamate and glutamine levels, it may have an important role in these processes.
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PMID:Glucocorticoids induce glutamine synthetase expression in human osteoblastic cells: a novel observation in bone. 1496 10

Chemotherapy-induced bone growth arrest and osteoporosis are significant problems in paediatric cancer patients, and yet how chemotherapy affects bone growth remains unclear. This study characterised development and resolution of damage caused by acute chemotherapy with antimetabolite 5-fluorouracil (5-FU) in young rats in the growth plate cartilage and metaphyseal bone, two important tissues responsible for bone lengthening. In metaphysis, 5-FU induced apoptosis among osteoblasts and preosteoblasts on days 1-2. In growth plate, chondrocyte apoptosis appeared on days 5-10. Interestingly, Bax was induced prior to apoptosis and Bcl-2 was upregulated during recovery. 5-FU also suppressed cell proliferation on days 1-2. While proliferation returned to normal by day 3 in metaphysis, it recovered partially on day 3, overshot on days 5-7 and normalised by day 10 in growth plate. Histologically, growth plate heights decreased by days 4-5 and returned normal by day 10. In metaphysis, primary spongiosa height was also reduced, mirroring changes in growth plate thickness. In metaphyseal secondary spongiosa, a reduced bone volume was observed on days 7-10 as there were fewer but more separated trabeculae. Starting from day 4, expression of some cartilage/bone matrix proteins and growth factors (TGF-beta1 and IGF-I) was increased. By day 14, cellular activity, histological structure and gene expression had returned normal in both tissues. Therefore, 5-FU chemotherapy affects bone growth directly by inducing apoptosis and inhibiting proliferation at growth plate cartilage and metaphyseal bone; after the acute damage, bone growth mechanism can recover, which is associated with upregulated expression of matrix proteins and growth factors.
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PMID:Damage and recovery of the bone growth mechanism in young rats following 5-fluorouracil acute chemotherapy. 1688 18


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