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)

Human neuroblastoma cells, SH-SY5Y, contain relatively low levels of thioredoxin (Trx); thus, they serve favorably as a model for studying oxidative stress-induced apoptosis (Andoh, T., Chock, P. B., and Chiueh, C. C. (2001) J. Biol. Chem. 277, 9655-9660). When these neurotrophic cells were subjected to nonlethal 2-h serum deprivation, their neuronal nitric oxide synthase and Trx were up-regulated, and the cells became more tolerant of oxidative stress, indicating that NO may protect cells from serum deprivation-induced apoptosis. Here, the mechanism by which NO exerts its protective effects was investigated. Our results reveal that in SH-SY5Y cells, NO inhibits apoptosis through its ability to activate guanylate cyclase, which in turn activates the cGMP-dependent protein kinase (PKG). The activated PKG is required to protect cells from lipid peroxidation and apoptosis, to inhibit caspase-9 and caspase-3 activation, and to elevate the levels of Trx peroxidase-1 and Trx, which subsequently induces the expression of Bcl-2. Furthermore, active PKG promotes the elevation of c-Jun, phosphorylated MAPK/ERK1/2, and c-Myc, consistent with the notion that PKG enhances the expression of Trx through its c-Myc-, AP-1-, and PEA3-binding motifs. Elevation of Trx and Trx peroxidase-1 and Mn(II)-superoxide dismutase would reduce H(2)O(2) and O(2)(), respectively. Thus, the cytoprotective effect of NO in SH-SY5Y cells appears to proceed via the PKG-mediated pathway, and S-nitrosylation of caspases plays a minimal role.
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PMID:Cyclic GMP-dependent protein kinase regulates the expression of thioredoxin and thioredoxin peroxidase-1 during hormesis in response to oxidative stress-induced apoptosis. 1241 92

Esophageal adenocarcinoma arising on a background of Barrett's esophagus is increasing in incidence. A molecular understanding of both the progression of Barrett's esophagus and the factors determining the response of adenocarcinoma to neoadjuvant therapy is required, and this study focused on the role of proteins regulated by the bcl-2 family of genes, which are important regulators of programmed cell death (apoptosis). In total, 48 patients (36 men, 12 women) with Barrett's adenocarcinoma were studied. All patients received preoperative chemoradiotherapy followed by surgery. Bcl-2, bax and bcl-x protein expression were detected by standard avidin-biotin peroxidase method. Bcl-2, bax and bcl-x expression were detected in 84%, 80%, and 76%, respectively, of normal squamous mucosa. An increasing degree of dysplasia in Barrett's mucosa both before and after chemoradiotherapy was significantly associated with a reduction of bcl-2 expression (P = 0.03 and 0.009, respectively). Bcl-2 expression was significantly associated with tumor differentiation (P = 0.03) and a trend towards earlier T stage (P = 0.08), but not with nodal status. Pre-therapeutic bcl-2, bax and bcl-x protein expression (27%, 75%, and 87.5%, respectively) were not associated with tumor response or resistance to therapy. Bcl-2-positive patients had a significantly improved survival compared with bcl-2-negative tumors. A significant reduction of bcl-2 expression is associated with the progression of Barrett's mucosa to adenocarcinoma. Bcl-2 expression was associated with improved survival. Preoperative chemoradiotherapy induces expression of bax and bcl-x protein. The pretreatment expression of bcl-2 and related proteins did not predict response or resistance to neoadjuvant chemoradiotherapy, suggesting that regulators of apoptosis alone do not determine the response of Barrett's adenocarcinoma to neoadjuvant therapy.
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PMID:Loss of Bcl-2 expression in Barrett's dysplasia and adenocarcinoma is associated with tumor progression and worse survival but not with response to neoadjuvant chemoradiation. 1258 Dec 49

Hepatoblastoma, a childhood tumor of the liver, is composed of epithelial and mesenchymal elements in varying proportions and at various stages of differentiation. The epithelial element recapitulates the stages of hepatocyte development from the primitive blastema through embryonal hepatocytes to fetal hepatocytes. The blastemal or undifferentiated cells have been postulated to represent neoplastic hepatocyte progenitor cells. In this study, we examine the immunophenotype of the various epithelial cells of hepatoblastoma with special emphasis on the small undifferentiated cell component and compare it with that of adult hepatocytes and hepatic stem (oval) cells. Putative stem cells in the liver can express all of the following markers: alpha-feto protein, CK19 (OV-6), chromogranin A, Bcl-2, HepPar-1, and alpha1 microglobulin. The latter, like alpha-feto protein, is a plasma protein synthesized by hepatocytes. Both alpha1 microglobulin and HepPar-1 are expressed in fetal liver cells as early as 7 weeks of intrauterine life. They are also expressed in hepatocellular carcinoma and in hepatocytic cell lines derived from normal fetal or adult liver. Formalin-fixed, paraffin-embedded archival tissues from 10 predominantly epithelial hepatoblastomas were immunostained with antibodies directed against CD 34, alpha1 microglobulin, Bcl-2, HepPar 1, and CK19 using the avidin-biotin-peroxidase method. The undifferentiated small cell component did not express any of the markers studied, namely, Bcl-2, HepPar-1, alpha(1) microglobulin, CD34, or CK19. Hepatocyte-like cells were alpha1 microglobulin- and HepPar-1-positive, with the intensity of staining correlating with the degree of hepatocytic differentiation. Bcl-2 expression was restricted to areas of ductular differentiation. CK19 was detected in foci that showed duct formation. The small cells of hepatoblastoma did not express HepPar-1, Bcl-2, CK19, alpha1 microglobulin, or CD34, markers that characterize the immunophenotype of hepatic stem cells ("oval" cells). Thus, this observation raises the following questions: (1) is "hepatoblastoma" a misnomer? (2) is the expression of tumor antigens dysregulated in hepatoblastoma? (3) does the liver have two different types of progenitor cells, oval cells and blastemal cells, with differing immunophenotypes? and (4) do the blastemal cells, rather than oval cells, represent the more primitive progenitor cells of the liver?
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PMID:Small cells in hepatoblastoma lack "oval" cell phenotype. 1367 57

Excessive apoptosis has a central role in ineffective hematopoiesis in myelodysplastic syndrome (MDS). The aim of the study was to quantify apoptosis and Bcl-2 expression in patients with MDS and to use these parameters in the evaluation of treatment efficacy with compounds modulating proapoptotic cytokines. Bone marrow (BM) samples from eight MDS patients were studied: four with refractory anemia and four with refractory anemia with ringed sideroblasts. Two patients with Hodgkin disease without BM determination were studied for control. Therapy consisted in administration of pentoxyphylline, dexamethasone and ciprofloxacin. Biochemical assay of apoptosis and Bcl-2 was performed using annexin V-biotin conjugate antibody and anti-human Bcl-2 antibody respectively, followed by streptavidine-peroxidase conjugate, and peroxidase substrate. Ultrastructural investigation of BM samples was performed with standard electron microscopy techniques. Most of BM hematopoietic cells in the MDS patients had ultrastructural features of various stages of apoptosis including chromatin condensation and margination, cytoplasm condensation and budding of nuclear and plasma membranes to produce apoptotic bodies. Bcl-2 expression showed an inverse correlation with the rate of the apoptotic process. Periodic evaluation of these two parameters has shown an increase of Bcl-2 expression and a decrease of apoptotic rate in patients who had responded to the treatment. Response to the treatment was appreciated in accordance with their transfusion needs. Treatment efficiency diminished in time. The rate of apoptosis was inversely correlated with the level of Bcl-2 expression. These results confirm the importance of the apoptotic process evaluation in monitoring MDS treatment.
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PMID:Apoptotic rate in patients with myelodisplastic syndrome treated with modulatory compounds of pro-apoptotic cytokines. 1459 56

3-nitropropionic acid (3-NPA), a complex II inhibitor of the electron transport chain, causes Huntington disease-like symptoms after administration into animals. However, primary mechanisms of cell death are not clearly understood. This study tested the hypothesis that 3-NPA leads to the generation of reactive oxygen species (ROS), mitochondrial DNA damage, and loss of mitochondrial function. Amplex red and horseradish peroxidase were used to accurately measure the amount of H2O2, and showed that PC12 cells treated with 3-NPA (4 mM) lead to the production of hydrogen peroxide (1 nmol/10(6) cells/h). This amount of 3-NPA also leads to a rapid decline of ATP levels. There was time- and dose-dependent mitochondrial DNA damage following 3-NPA treatment. Overexpression of the proto-oncogene bcl-2 protects cells from apoptosis induced by various stimuli. Overexpression of Bcl-2 leads to almost threefold higher levels of ATP and also decreased the 3-NPA-mediated induction of hydrogen peroxide by over 50%. Bcl-2-overexpressing PC12 cells were also protected from mitochondrial DNA damage. These data show that ROS production followed by mitochondrial DNA damage is the primary event in 3-NPA toxicity, and Bcl-2 protects PC12 cells from 3-NPA toxicity by preventing mitochondrial DNA damage.
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PMID:3-nitropropionic acid-induced hydrogen peroxide, mitochondrial DNA damage, and cell death are attenuated by Bcl-2 overexpression in PC12 cells. 1571 Feb 38

Apoptosis is a process associated with development and progression of breast cancer. The association between connexins and programmed cell death has only been demonstrated in a few studies. The aim of the present study was the evaluation of Cx26 and Cx43 expression in breast cancer in correlation with Bcl-2 and Bak proteins as well as with selected clinicopathological features. Tissue samples from 71 women were examined by immunohistochemistry, using the streptavidin-biotin-peroxidase complex technique for Cx26, Cx43, Bak and Bcl-2. Cytoplasmic expression of Cx26 and Cx43 was detected in 34 (47.9%) and 61 (85.9%) of breast cancers, respectively. Bcl-2 and Bak expression was found in 59 (83%) and 50 (70%) of studied cases, respectively. We found a positive correlation between Cx26 and Bak expression (r=0.541, p<0.0001) as well as between Cx43 and Bak (r=0.589, p<0.0001), but not between the studied connexins and Bcl-2. The expression of Cx26 was not associated with age, tumor size, lymph node status or histological grade. However, we observed an association between Cx43 expression and histological grade G3 (p<0.04). Cytoplasmic localization of evaluated connexins supports the concept of alterations in connexins expression in breast cancer cells. The associations of evaluated connexins with Bak protein could suggest that connexins localized in the cytoplasm may participate in signaling apoptotic pathways.
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PMID:Connexins 26 and 43 correlate with Bak, but not with Bcl-2 protein in breast cancer. 1601 10

Beclin 1 was originally identified as a novel Bcl-2-interacting protein, but co-immunoprecipitation studies suggest that the major physiological partner for Beclin 1 is the mammalian class III phosphatidylinositol 3-kinase (PI 3-kinase) Vps34. Beclin 1 has been proposed to function as a tumor suppressor by promoting cellular macroautophagy, a process that is known to depend on Vps34. However, an alternative role for Beclin 1 in modulating normal Vps34-dependent protein trafficking pathways has not been ruled out. This possibility was examined in U-251 glioblastoma cells. Immunoprecipitates of endogenous Beclin 1 contained human Vps34 (hVps34), but not Bcl-2. Suppression of Beclin 1 expression by short interfering (si)RNA-mediated gene silencing blunted the autophagic response of the cells to nutrient deprivation or C2-ceramide. However, other PI 3-kinase-dependent trafficking pathways, such as the post-endocytic sorting of the epidermal growth factor receptor (EGFR) or the proteolytic processing of procathepsin D en route from the trans-Golgi network (TGN) to lysosomes, were not affected. Depletion of Beclin 1 did not reduce endocytic internalization of a fluid phase marker (horseradish peroxidase, HRP) or cause swelling of late endosomal compartments typically seen in cells where the function of hVps34 is impaired. These findings argue against a role for Beclin 1 as an essential chaperone or adaptor for hVps34 in normal vesicular trafficking, and they support the hypothesis that Beclin 1 functions mainly to engage hVps34 in the autophagic pathway.
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PMID:Functional specificity of the mammalian Beclin-Vps34 PI 3-kinase complex in macroautophagy versus endocytosis and lysosomal enzyme trafficking. 1639 Aug 69

Acceleration of blood leukocyte apoptosis in major depression has been described. The present studies have been undertaken to estimate the level of apoptosis of blood leukocytes in patients with depression and to examine the mechanisms leading to apoptosis. Blood was taken from 29 patients with depression (age 48.2+/-11.2, 14 males, 15 females) and 30 healthy controls (age 41.3+/-4.1, 15 males, 15 females), and apoptosis was estimated by the cytometric method by measurements of annexin V binding, mitochondrial membrane potential (DeltaPsi), bcl-2, bax, and Fas (CD95) expression in CD4+, CD8+ and CD14+ cells. The amounts of cytochrome c released from mitochondria to cytosol of peripheral blood mononuclear cells (PBMCs) and polymorphonuclear cells (PMNs) were also measured. The levels of reactive oxygen species (ROS) released from PMNs were examined as was the serum activity of superoxide dismutase (SOD), catalase (CAT), and total peroxidase (PER). Additionally, serum levels of the tumor necrosis factor (TNF-alpha) and interleukin-6 (IL-6) were estimated. Our experiments indicated accelerated apoptosis of CD4+ T lymphocytes and CD14+ cells (mainly neutrophils) of depressed patients as well as a significant increase in the percent of Fas-expressing cells. Bcl-2 and bax expression was higher in cells of depressed patients than in control, however, bcl-2/bax ratio was significantly decreased in CD14+ cells of depressed patients. PMNs isolated from the blood of the patients produced more ROS spontaneously and after induction with phorbol ester (PMA) than PMNs of the healthy control. A significant increase in serum activity of SOD, CAT and PER was also detected. Overproduction of superoxide anion correlated positively with the level of PMNs apoptosis (measured by cytochrome c release), suggesting that superoxide anion might be an important factor inducing apoptotic death of blood cells. The result of our experiment indicated that apoptosis of immune cells may affect patient's susceptibility to different infections and application of antioxidants in medication of patients with depression will be beneficial for them. The increased level of IL-6 in sera of the depressed patients did not correlate with overproduction of ROS, suggesting that this cytokine is not involved in oxidative stress and apoptosis of leukocytes.
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PMID:Accelerated apoptosis of blood leukocytes and oxidative stress in blood of patients with major depression. 1808 80

The present study was conducted to investigate the possible protective effects of lycopene (LP) and ellagic acid (EA) on aroclor (AR) 1254-induced testicular and spermatozoal toxicity associated with the oxidative stress and apoptosis in male rats. The control group was treated with placebo. LP (10 mg/kg/every other day), EA (2 mg/kg/every other day) and AR (2 mg/kg/day) groups were given alone LP, EA and AR respectively. One of the last two groups received AR + LP, and the other treated with AR + EA. Body and reproductive organ weights, epididymal sperm characteristics, testicular tissue lipid peroxidation levels, antioxidant enzyme activities, histopathological changes and apoptosis via Bax and Bcl-2 genes were investigated. AR administration caused statistically significant decreases in body-weight, epididymal sperm concentration, testicular superoxide dismutase activity, diameters of seminiferous tubules, germinal cell layer thickness and Johnsen's testicular score, and increases in relative weights of testis, epidydimis and seminal vesicles, rates of abnormal sperm and apoptotic cell expression along with degeneration, desquamation and disorganization in spermatogenic cells, and interstitial oedema and congestion in testicular tissue. LP and EA treatments to AR-treated rats markedly decreased abnormal sperm rates, testicular thiobarbituric acid reactive substances level, and increased the glutathione (GSH) level, GSH-peroxidase, catalase activities and epidiymal sperm concentration as compared with the alone AR group. Additionally, the AR-induced histopathological damages were totally or partially recovered by LP or EA administrations respectively. AR damages the testicular tissue and spermatozoa by impairing the oxidant/antioxidant balance and by increasing the apoptotic spermatogenic cell rates. However, both LP and EA have modulator effects on AR-induced reproductive dysfunction in male rats.
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PMID:Modulatory effects of lycopene and ellagic acid on reproductive dysfunction induced by polychlorinated biphenyl (Aroclor 1254) in male rats. 2007 68

Diethylcarbamazine (DEC) is the main drug used against lymphatic filariasis but it is only microfilaricidal. Hence there is an urgent need for adulticidal drug. Aspirin is known nonsteroidal anti-inflammatory drugs which can inhibit prostaglandin H synthase and also induces apoptosis. Studies presented in this paper demonstrated that exposure of worms to the combination of DEC plus aspirin (DEC + A) at 100 microM concentration irreversibly paralyzed adult worms as well as microfilariae within 2 h. Some of the apoptosis markers viz; DNA fragmentation with accompanying ladder formation, upregulation of Bax expression and decrease in Bcl-2 have suggested that the parasite may be killed due to mitochondrial mediated apoptosis. The levels of several apoptosis regulating proteins and enzymes have also shown to be altered. DEC + A treated worms showed significant decrease in prostaglandin H synthase activity (PGHS) and increase in the level of nitric oxide (NO) and cysteine proteases while glutathione (GSH) and peroxidase level was found to be decreased. NO is known inducer of mitochondrial mediated apoptosis and acts by increasing the permeability of mitochondrial membrane through Bax and allowing cytochrome c to release in cytosol, inducing caspases leading to apoptosis. The DEC + A concentration used in this study is much lower than recommended dose so its intake is safe. Here we report for the first time that combination of DEC and aspirin is more effective and could be used as an adulticidal for control of human filarial infections.
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PMID:Combination of DEC plus aspirin induced mitochondrial mediated apoptosis in filarial parasite Setaria cervi. 2036 29


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