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)

Immunostaining of Bcl-2 protein which represses apoptosis was performed on 178 biopsied human pathologic muscles and 10 control muscles by the ABC method using two monoclonal anti-Bcl-2 antibodies. Bcl-2 in control muscles was positive mainly in nuclear membrane and cytoplasm in type 2 fibers (especially type 2B fibers), and negative in type 1 fibers. In myopathies, it was not expressed in type 2C (regenerating) fibers, and its expression in atrophic fibers such as forming pyknotic nuclear clumps was strong. In inflammatory myopathies, expression was observed in infiltrating lymphocytes, and especially in dermatomyositis in atrophic fibers facing perimysium. In mitochondrial myopathies, the positivity was observed only in type 2 ragged-red fibers. In muscles of neurogenic disorders, both small angulated fibers and atrophic grouped fibers were strongly positive. Western blot analysis using anti-Bcl-2 antibody showed a single band at 26 kDa in control and diseased skeletal muscles. Compared to immunostaining of Fas antigen in serial sections, both Bcl-2 and Fas were expressed in same atrophic fibers in distal myopathy with rimmed vacuoles. In myotonic dystrophy, they were often expressed in type 2 fibers containing internal nucleus. In carriers of Duchenne dystrophy, Fas-positive but Bcl-2 negative fibers were observed in same dystrophin-negative fibers. In conclusion, expression of Bcl-2 in skeletal muscles might suggest that Bcl-2 plays a role on surviving muscle fibers.
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PMID:[Immunostaining of anti-Bcl-2 antibody in diseased human muscles]. 893 93

Expression of the Fas 'death receptor', Fas (CD95/APO-1) renders cells susceptible to programmed cell death ('apoptosis'), whereas Bcl-2 protects cells from apoptosis. Using fluorescence immunohistochemistry, we analysed Fas and Bcl-2 expression in muscle from five patients with polymyositis (PM), four patients with inclusion body myositis (IBM), three patients with dermatomyositis (DM), three patients with Duchenne muscular dystrophy (DMD) and three nonmyopathic controls. Fas (CD95) and Bcl-2 were not detected in control muscle, but expressed in muscle fibres and inflammatory cells in PM, IBM, DM and DMD. The proportion of Fas+ muscle fibres ranged from < 1 to 50%, and was higher in PM and IBM than in DM and DMD. On average, the Fas+ muscle fibres were smaller (median diameter, 10 microns; range, 7-32 microns) than the Fas- fibres (median, 36 microns; range, 10-60 microns). Less than 10% of the Fas+ muscle fibres co-expressed the regeneration marker CD56 (neural cell adhesion molecule N-CAM). In PM and IBM, the proportion of Fas+ muscle fibres was higher among fibres invaded or contacted by T cells than among fibres not contacted by T cells (P < 0.01). The proportion of Fas+ fibres co-expressing Bcl-2 was 76 +/- 16% in PM, 100% in IBM and 63 +/- 23% in DM. Fas and Bcl-2 expression was also noted in inflammatory cells in PM, IBM, DM and DMD. Using the terminal deoxytransferase-catalysed DNA nick end labelling technique for detection of nuclear DNA fragmentation, none of myonuclei, and < 0.1% of inflammatory cell nuclei, showed signs of apoptosis. Our results suggest that, although Fas expression confers susceptibility to Fas-mediated apoptosis, Fas-expressing muscle fibres and inflammatory cells are protected by the anti-apoptotic protein Bcl-2.
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PMID:Cytotoxic mechanisms in inflammatory myopathies. Co-expression of Fas and protective Bcl-2 in muscle fibres and inflammatory cells. 921 78

Several recent studies suggest the isolation of stem cells in skeletal muscle, but the functional properties of these muscle-derived stem cells is still unclear. In the present study, we report the purification of muscle-derived stem cells from the mdx mouse, an animal model for Duchenne muscular dystrophy. We show that enrichment of desmin(+) cells using the preplate technique from mouse primary muscle cell culture also enriches a cell population expressing CD34 and Bcl-2. The CD34(+) cells and Bcl-2(+) cells were found to reside within the basal lamina, where satellite cells are normally found. Clonal isolation and characterization from this CD34(+)Bcl-2(+) enriched population yielded a putative muscle-derived stem cell, mc13, that is capable of differentiating into both myogenic and osteogenic lineage in vitro and in vivo. The mc13 cells are c-kit and CD45 negative and express: desmin, c-met and MNF, three markers expressed in early myogenic progenitors; Flk-1, a mouse homologue of KDR recently identified in humans as a key marker in hematopoietic cells with stem cell-like characteristics; and Sca-1, a marker for both skeletal muscle and hematopoietic stem cells. Intramuscular, and more importantly, intravenous injection of mc13 cells result in muscle regeneration and partial restoration of dystrophin in mdx mice. Transplantation of mc13 cells engineered to secrete osteogenic protein differentiate in osteogenic lineage and accelerate healing of a skull defect in SCID mice. Taken together, these results suggest the isolation of a population of muscle-derived stem cells capable of improving both muscle regeneration and bone healing.
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PMID:Clonal isolation of muscle-derived cells capable of enhancing muscle regeneration and bone healing. 1097 97

Reports concerning the influence of exercise loading and steroid administration on dystrophinopathy are inconsistent. To investigate the effect of muscle exercise in Duchenne muscular dystrophy (DMD), 15 control and 15 mdx mice, an animal model of DMD, were divided into free-living (n = 6), exercise (n = 6), and immobilization (n = 3) groups. Free-living and exercise groups were further divided into steroid-treated and sham-treated groups to evaluate the effect of steroid administration. We measured apoptotic changes by in situ DNA nick-end labeling (TUNEL), DNA fragmentation assay, and Western blotting for Bcl-2 and BAX. Apoptosis was most prominent in the sham-treated exercise group, and it was significantly reduced in the steroid-treated exercise group. The steroid-treated free-living group showed a higher rate of apoptotic change than the sham-treated free-living group. Apoptosis was minimized in the free-living condition, whereas exercise loading and immobilization caused apoptotic change in this muscular dystrophy animal model. Steroid administration induced apoptosis in muscle of free-living mice, but alleviated the apoptotic damage caused by exercise loading in mdx mice. These findings suggest that steroid administration may be effective in preventing a postexercise deterioration of skeletal muscle in animal models of DMD.
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PMID:Effects of exercise and steroid on skeletal muscle apoptosis in the mdx mouse. 1537 34

Duchenne muscular dystrophy (DMD) is a lethal disease caused by the lack of the cytoskeletal protein dystrophin. Altered calcium homoeostasis and increased calcium concentrations in dystrophic fibres may be responsible for the degeneration of muscle occurring in DMD. In the present study, we used subsarcolemmal- and mitochondrial-targeted aequorin to study the effect of the antiapoptotic Bcl-2 protein overexpression on carbachol-induced near-plasma membrane and mitochondrial calcium responses in myotubes derived from control C57 and dystrophic (mdx) mice. We show that Bcl-2 overexpression decreases subsarcolemmal and mitochondrial calcium overload that occurs during activation of nicotinic acetylcholine receptors in dystrophic myotubes. Moreover, our results suggest that overexpressed Bcl-2 protein may prevent near-plasma membrane and mitochondrial calcium overload by inhibiting IP3Rs (inositol 1,4,5-trisphosphate receptors), which we have shown previously to be involved in abnormal calcium homoeostasis in dystrophic myotubes. Most likely as a consequence, the inhibition of IP3R function by Bcl-2 also inhibits calcium-dependent apoptosis in these cells.
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PMID:Bcl-2 overexpression prevents calcium overload and subsequent apoptosis in dystrophic myotubes. 1639 38

Phosphatidylinositol 3-kinase (PI3K)/Akt and nuclear factor-kappa B (NF-kappaB) signaling pathways play a critical role in mediating survival signals. In this study we have investigated how loss of dystrophin (the primary cause of Duchenne muscular dystrophy) modulates the activation of PI3K/Akt and NF-kappaB signaling pathways in skeletal muscle in response to mechanical stimulation. Activation of Akt was significantly higher in diaphragm muscle from dystrophin-deficient mdx mice compared to normal mice at both prenecrotic and necrotic states. Higher activation of Akt was also observed in cultured dystrophin-deficient primary myotubes differentiated in vitro. Application of passive mechanical stretch ex vivo synergistically increased the activation of Akt in diaphragm of mdx mice. Stretch-induced activation of PDK-1 and PI3K were also higher in diaphragm of mdx mice compared to normal mice. Pretreatment of diaphragm with PI3K inhibitor LY294002 blocked the activation of Akt in normal and mdx mice. Higher activation of Akt was associated with increased phosphorylation of its downstream targets glycogen synthase kinase 3beta (GSK3beta), FKHR, and mammalian target of rapamycin (mTOR). Treatment of diaphragm muscle with LY294002 inhibited the stretch-induced activation of IkappaB (IkappaB) kinase (IKK) and NF-kappaB transcription factor in normal and mdx mice. Mechanical stretch also reduced the interaction of HDAC1 with RelA subunit of NF-kappaB in diaphragm muscle. Finally, cellular levels of Bcl-2, cIAP1, and integrin beta1 and activation of integrin linked kinase were higher in diaphragm muscle of mdx mice compared to normal mice. Taken together, our data suggest that loss of dystrophin and/or mechanical stretch results in the up-regulation of P13K/Akt and NF-kappaB signaling pathways in skeletal muscle.
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PMID:Regulation of phosphatidylinositol 3-kinase (PI3K)/Akt and nuclear factor-kappa B signaling pathways in dystrophin-deficient skeletal muscle in response to mechanical stretch. 1674 26

The unique absence of major histocompatibility complex class I antigen (MHC-I) expression in normal muscle is one possible mechanism protecting striated muscle. In order to define their possible involvement in protection of normal muscle, we investigated the expression of molecules involved in muscle fibre death and survival mechanisms (Bcl-2, Fas, Fas-ligand and TRAIL), focusing on disorders with possible involvement of cytotoxic T cells. We studied muscle biopsies from 20 healthy volunteers, from 10 patients affected by polymyositis and 10 by Duchenne muscular dystrophy. By using immunohistochemistry, Western blot and real-time PCR we detected a constitutional expression of Bcl-2 in healthy muscle, whereas the expression was weaker in disease processes. Fas-L and TRAIL were not detected in muscle fibres, and Fas only in muscle affected by disease. Our findings indicate that the major apoptotic protein Bcl-2 might have a hitherto unrecognized role in the protection of normal muscle.
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PMID:Expression of apoptosis related proteins in normal and diseased muscle: a possible role for Bcl-2 in protection of striated muscle. 1947 29

Dystrophin deficiency associated with Duchenne muscular dystrophy (DMD) results in chronic inflammation and severe skeletal muscle degeneration, where the extent of muscle fibrosis contributes to disease severity. The microenvironment of dystrophic muscles is associated with variation in levels of markers of degeneration and regeneration. Since in dystrophic muscle apoptosis precedes necrosis, markers of apoptosis can be used as indicators of degeneration, while regeneration can be measured in terms of cytokines and growth factor expression"; and then throughout the text use "markers of apoptosis/degeneration. The present study is an attempt to evaluate the extent of degeneration and regeneration in DMD patient blood. Subjects were 24 boys with DMD diagnosed at the molecular level versus 20 age and socioeconomic matching healthy boys. In their blood, levels of Fas and FasL and Bax/Bcl-2 and plasma DNA fragmentation were measured as markers of apoptosis. The cytokine tumor necrosis factor alfa (TNF-alpha), and the growth factors: basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) were measured as markers of regeneration. Plasma DNA fragmentation (0.38% +/- 0.12 vs. 0.2% +/- 0.15) and Fas (9.9 +/- 2.8 vs. 2 +/- 0.1, p < 0.001) together with FasL mRNA expression in circulating lymphocytes (0.47 +/- .09 vs. 0.24 +/- .04, p < 0.001) were significantly increased in DMD patients compared to controls. There was a significant increase in Bax (0.19 +/- 0.7 vs. 0.05 +/- 0.1, p < 0.00001) expression and a significant decrease in Bcl-2 protein (6.4 +/- 1.6 vs 10 +/- 2.8, p < 0.00001) as compared to controls. Among markers of regeneration, TNF- alpha (30.2 +/- 9.5 vs. 3.6 +/- 0.9) and bFGF (21.7 +/- 10.3 vs. 4.75 +/- 2.2) were significant increased while VEGF was significantly decreased (190 +/- 115 vs. 210 +/- 142.) in blood of DMD patients compared to controls. Our results indicate that Fas/FasL and Bax/Bcl-2 are involved in muscle atrophy and degeneration in DMD patients, while regeneration process does not cope with the degeneration.
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PMID:Markers of degeneration and regeneration in Duchenne muscular dystrophy. 2047 68

Dystrophin lack in DMD causes neuronal nitric oxide synthase (nNOS) membrane delocalization which in turn promotes functional muscle ischemia, and exacerbates muscle injury. Apoptosis and the exhaustion of muscle regenerative capacity are implicated in Duchenne muscular dystrophy (DMD) pathogenesis and therefore are relevant therapeutic targets. Genistein has been reported to have pro-proliferative effects, promoting G1/S cell phase transition through the induction of cyclin D1, and anti-apoptotic properties. We previously showed that genistein could reduce muscle necrosis and enhance regeneration with an augmented number of myogenin-positive satellite cells and myonuclei, ameliorating muscle function in mdx mice. In this study we evaluated the underlying mechanisms of genistein effect on muscle specimens of mdx and wild type mice treated for five weeks with genistein (2 mg/kg/i.p. daily) or vehicle. Western blot analysis show that genistein increased cyclin D1 and nNOS expression; and showed an antiapoptotic effect, modulating the expression of BAX and Bcl-2. Our results suggest that this isoflavone might enhance the regenerative spurt in mdx mice muscle restoring nNOS, promoting G1/S phase transition in muscle cell, and inhibiting apoptosis. Further studies with longer time treatment or using different experimental approaches are needed to better investigate the underlying mechanisms of such results.
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PMID:Modulation of neuronal nitric oxide synthase and apoptosis by the isoflavone genistein in Mdx mice. 2633 24

Dp71 is one of the most ubiquitously expressed isoforms of dystrophin, the pathological genes of DMD. In order to find whether the alteration of Dp71 can affect the phenotypes of cell other than PC12, an A549 cell line with stably transfected Dp71 siRNA plasmids was set up and named A549-Dp71AS cell. It is demonstrated for the first time that the A549-Dp71AS cell line displayed decreased invasion capabilities, reduced migration ability, decreased proliferation rate, and lessened clonogenic formation. Cisplatin-induced apoptosis was also increased in A549-Dp71AS cell line via enhancing the Caspase 3, Caspase 8, and Caspase 9 activities. Knocking down Dp71 expression can significantly inhibit the A549 xenograft tumor growth in nude mice. The A549-Dp71AS cells and xenograft tumor tissues displayed reduced lamin B1, Bcl-2, and MMP2 protein expression, which accounts for the reduced malignancy of A549-Dp71AS cells in vivo and in vitro.
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PMID:Knocking down Dp71 expression in A549 cells reduces its malignancy in vivo and in vitro. 2669 28


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