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)

Asthma is characterized by airway inflammation, which can be now assessed by the analysis of induced sputum. Ten patients with asthma were investigated during acute exacerbation for the quantification of apoptosis, for Bcl-2 and Fas expression, in induced sputum lymphocytes. They were compared to 12 patients with chronic obstructive pulmonary disease (COPD), and 10 healthy controls. Spontaneous apoptosis was determined by staining nuclei with propidium iodide, and analyzed with a FACScan. Bcl-2 was measured by Western blotting, and results were obtained by densitometric scanning, done by the gel proanalyser. The investigation of Fas was performed using the streptavidin-biotin preroxidase-complex method. Patients with asthma and patients with COPD exhibited a significant increase of cellularity, percentage of neutrophils, eosinophils and lymphocytes when compared to healthy controls. Apoptosis in induced sputum mononuclear cells was found decreased in patients with asthma compared to COPD patients and healthy controls. The quantification of apoptosis was measured after exposure to anti-cytokine antibodies. Anti-TNF-alpha antibody blocked the apoptosis in both patients groups and healthy controls, suggesting that TNF-alpha acted as an inducer of apoptosis. Anti-IL-10 blocked apoptosis completely exclusively in patients with asthma. Bcl-2 expression was found to be increased in induced sputum mononuclear cells from patients with asthma, compared to healthy controls and patients with COPD. Expression of Fas could be detected in patients with asthma, at a lower level than COPD patients and healthy controls. Distinct mechanisms of apoptosis were found in patients with asthma and patients with COPD, characterized by different levels of Bcl-2 and Fas expression. Induction of apoptosis should be a beneficial process in allergic inflammation traduced in induced sputum mononuclear cells. The apoptosis process is assumed by two different mechanisms in asthma and COPD. Our findings indicated that in asthmatic patients, activated lymphocytes accumulate in the bronchi; because of their prolonged survival that maintains inflammation.
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PMID:Lymphocytes apoptosis in patients with acute exacerbation of asthma. 1070 78

Cisplatin is in common use in ovarian cancer therapy, although it is also implicated in cytotoxicity in normal tissue. We have examined the effect of cisplatin alone and in combination with theophylline, a phoshodiesterase inhibitor, on modulation of Bcl-2/Bax expression and induction of apoptosis in human granulosa cells transformed by stable transfection with mutant p53 plus Ha-ras. Theophylline elicited cell death only at relatively high concentrations with an EC50 of 200 microg/ml. Cisplatin exerted its lethal effect with an EC50 of 7 microM. In the presence of 15 or 50 microg/ml of theophylline (in the range used against asthma in humans), the EC50 for cisplatin was reduced to 2 microM or 1.2 microM, respectively. Using fluorescence-activated cell sorting analysis of DNA stained cells and the terminal deoxy-nucleotide tranferase-mediated dUTP nick end-labeling method, we found that even at concentrations of 0. 3 and 1 microM cisplatin, theophylline at 15 and 50 microg/ml increased the incidence of apoptosis in these cells by 3-5-fold, while theophylline alone induced extremely low apoptosis. Neither drug had any measurable effect on Bax protein expression. In contrast Bcl-2 protein expression levels were markedly reduced by theophylline and cisplatin in a dose-dependent manner. The combination of theophylline and cisplatin resulted in a further dramatic reduction in Bcl-2, under-scoring the pronounced synergy of these two drugs. These observations suggest that suppression of Bcl-2 expression may play an important role in mediating the synergistic effect of cisplatin and theophylline on induction of apoptosis in ovarian cancer cells.
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PMID:Theophylline and cisplatin synergize in down regulation of BCL-2 induction of apoptosis in human granulosa cells transformed by a mutated p53 (p53 val135) and Ha-ras oncogene. 1089 29

Eosinophils play a major role in the onset and maintenance of bronchial inflammation and tissue injury in asthma. Like other leukocytes, eosinophils present in excessive numbers in inflamed tissues are removed by apoptosis. This phenomenon, also called 'programmed cell death', allows elimination of dangerous or redundant cells, thereby ensuring maintenance of tissue homeostasis. It has been suggested that a defect in eosinophil apoptosis would participate in the development and persistence of allergic airways inflammation in asthma. Eosinophil apoptosis, as well as the expression and function of various molecules determining this process, are closely regulated by various stimuli, including cytokines, lipid mediators and growth factors released by various cell types and by the eosinophil itself, as well as exogenous molecules, such as glucocorticoids. These stimuli have been shown to alter the expression and function of different molecules involved in the cascade of events characterising the apoptotic process, particularly Bcl-2 family proteins and the pro-apoptotic membrane glycoprotein, Fas. These observations, together with a better understanding of the mechanisms underlying eosinophil apoptosis, will help to more clearly define the molecular events involved in accumulation of these cells in blood and tissues and to identify potential new targets for the treatment of allergic diseases.
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PMID:[Eosinophil apoptosis in asthma]. 1096 36

Apoptosis of eosinophils is of increasingly important value in modulating allergic inflammatory airway diseases, such as asthma, and is suppressed by interleukin-5 (IL-5) in in vitro culture. In this study, we examined the effects of theophylline on survival/apoptosis, intracellular cAMP concentration, and Bcl-2 protein expression. Treatment with theophylline protected eosinophils against IL-5-mediated inhibition of apoptosis with a simultaneous suppression of survival in a dose-dependent manner. Theophylline caused an increase in the intracellular cAMP levels of IL-5-stimulated eosinophils. Enhancement of eosinophil apoptosis was consistent with an increase in DNA fragmentation in eosinophils treated with theophylline. On the other hand, the Bcl-2 protein appeared to be expressed constitutively in freshly isolated eosinophils. Bcl-2 expression was augmented by IL-5 stimulation, yet it was considerably inhibited by theophylline treatment. These data suggest that intracellular cAMP levels and Bcl-2 expression are involved in the suppression of eosinophil survival by theophylline.
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PMID:The downregulation of Bcl-2 expression is necessary for theophylline-induced apoptosis of eosinophil. 1100 7

A variety of studies have stressed the importance of the control of inflammatory cell longevity and the balance of pro-survival and pro-apoptotic signalling. Recently, asthma was found to be associated with reduced apoptosis of inflammatory cells in lung tissue. The aim of the study was to investigate the systemic activation of apoptosis pathways using cDNA array technology in atopy and asthma. Eighteen atopic asthmatics (AA), eight atopic non-asthmatic (AN) and 14 healthy control subjects (C) were included in the study. Peripheral blood mononuclear cells were separated with gradient centrifugation, mRNA purified and the reverse-transcribed probes hybridized to cDNA arrays. The signals were compared by standardizing to the 100 most expressed genes and group differences assessed with the Mann-Whitney U-test. We found a concerted up-regulation of several pro-survival cytokines and growth factors in AN and AA. FAS and FASL were not differentially expressed, but FAST kinase was over-expressed in AN and AA. The tumour necrosis factor pathway was activated in AN and AA with increased cytokine and receptor levels and increased TRAF2, an intracellular signalling product. There were indications of a down-regulated p53 system. In contrast, the Bcl-2 family of genes showed a net pro-apoptotic profile in AN and AA. The group of caspases showed a constant gene expression pattern in all groups. In conclusion, significant differences in the expression of apoptosis-related genes were found in peripheral blood of atopic individuals with and without asthma. cDNA array technology proved to be useful and may be complementary to DNA-based studies in order to analyse interactive and multidimensional pathways as shown here for apoptosis.
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PMID:Apoptosis signals in atopy and asthma measured with cDNA arrays. 1120 46

B cell chronic lymphocytic leukemia (B-CLL) is an incurable clonal disease which shows initial responsiveness to a number of chemotherapeutic drugs. However, in most patients the disease becomes resistant to treatment. Rolipram, a specific inhibitor of phosphodiesterase (PDE) type 4, the PDE predominantly expressed in B-CLL cells, has been shown to induce cAMP-dependent apoptosis in these cells. In the present study, we demonstrate that the extent of rolipram-induced apoptosis is similar to fludarabine-induced apoptosis in vitro. The combination of rolipram and fludarabine results in an enhancement in the number of apoptotic cells compared to apoptosis induced by either agent alone. Second, rolipram suppresses the expression of anti-apoptotic members of the Bcl-2 family and induces the pro-apoptotic protein Bax, thereby shifting the balance between pro- and anti-apoptotic members of the Bcl-2 family towards a pro-apoptotic direction. Finally rolipram-induced apoptosis is caspase-dependent. PDE 4 inhibitors are currently under investigation for chronic obstructive pulmonary disease and asthma in phase III clinical trials showing promising results with tolerable side-effects. In conclusion, by inducing apoptosis, by enhancing apoptosis induced by fludarabine, by suppressing Bcl-2, Bcl-X and by inducing Bax expression, PDE 4 inhibitors may add a new therapeutic option for patients with B-CLL.
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PMID:Phosphodiesterase type 4 inhibitor suppresses expression of anti-apoptotic members of the Bcl-2 family in B-CLL cells and induces caspase-dependent apoptosis. 1158 14

Damage to the airway epithelium is one prominent feature of chronic asthma. Corticosteroids induce apoptosis in inflammatory cells, which in part explains their ability to suppress airway inflammation. However, corticosteroid therapy does not necessarily reverse epithelial damage. We hypothesized that corticosteroids may induce airway epithelial cell apoptosis as one potential explanation for persistent damage. We tested this hypothesis in cultured primary central airway epithelial cells and in the cell line 1HAEo(-). Treatment with dexamethasone, beclomethasone, budesonide, or triamcinolone each elicited a time-dependent and concentration-dependent cell death. This cell death was associated with cleavage of nuclear chromatin, mitochondrial depolarization, cytochrome c extrusion, activation of caspase-9, and expression of phosphatidylserine on the outer cell membrane. Inhibitors of caspase activity blocked apoptotic cell death, as did overexpression of the apoptosis regulators Bcl-2 or Bcl-x(L). We demonstrated that CD95 ligation is not essential for the corticosteroid-induced apoptosis in airway epithelial cells. These data demonstrate that corticosteroids induce apoptotic cell death of airway epithelium. This raises the possibility that at least one of the major components of chronic airway damage in asthma, epithelial shedding and denudation, may in part result from a major therapy for the disease.
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PMID:Apoptosis of airway epithelial cells induced by corticosteroids. 1240

Elimination of the eosinophils from the airways by selective induction of apoptosis represents a therapeutic approach for asthma. Here we report on a possible target molecule, the surface receptor CD69. To simulate an asthmatic response, segmental allergen challenge in mild asthmatics was performed. Eosinophil numbers increased in bronchoalveolar lavage (BAL) at 18 h. In contrast to blood cells, BAL eosinophils expressed the activation marker CD69. Purified blood eosinophils stimulated with granulocyte/macrophage colony-stimulating factor (GM-CSF) or interferon-gamma (IFN-gamma) expressed CD69 and showed prolonged viability. Only IFN-gamma enhanced constitutive CD95 expression. Coincubation with anti-CD69 or anti-CD95 monoclonal antibody (MoAb) induced apoptosis, as revealed by propidium iodide incorporation, membrane blebbing and nuclear fragmentation. Additionally, both anti-CD69 and anti-CD95 MoAb reduced cytokine-enhanced Bcl-2 expression. In conclusion, CD69 transduces a Bcl-2-dependent death signal when ligated by a specific antibody. As, in contrast to the ubiquitous death-inducer CD95, the function of CD69 appears to be restricted to activated eosinophils, it represents an ideal target for therapeutic intervention in asthma.
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PMID:Bcl-2-mediated regulation of CD69-induced apoptosis of human eosinophils: identification and characterization of a novel receptor-induced mechanism and relationship to CD95-transduced signalling. 1223 63

The two principal features of airway goblet cells are rapid secretion of mucin onto the airway surface and increase in number (hyperplasia) with chronic inhaled 'insult'. The first is associated with homeostasis, the latter with pathophysiology. Myristoylated alanine-rich C kinase (MARCKS) is a key molecule regulating mucin exocytosis, a process also involving cooperative interaction between protein kinase (PK) C and PKG. The epidermal growth factor (EGF) cascade and calcium activated chloride channels (CLCA) are key signalling molecules involved in development of goblet cell hyperplasia, with Bcl-2, an inhibitor of apoptosis, involved in maintenance of hyperplasia. Goblet cell hyperplasia and associated mucus hypersecretion is a pathophysiological feature of asthma and chronic obstructive pulmonary disease (COPD). Novel therapeutic strategies to prevent or reverse goblet cell hyperplasia include inhibitors of EGF receptor tyrosine kinase and CLCA, of which viable pharmaceutical molecules are now available for clinical trial in hypersecretory conditions of the airways.
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PMID:The airway goblet cell. 1246 41

Damage to the airway epithelium is one prominent feature of chronic asthma. Mucosal damage includes gap openings, partial denudation, and loss of ciliated cells. Apoptosis of the airway epithelium is increasingly recognized as a potential mechanism by which damage may occur. Corticosteroids (CSs) induce apoptosis in inflammatory cells, which in part explains their ability to suppress airway inflammation. However, CS therapy does not necessarily reverse epithelial damage. We examined whether CS therapy actually could induce airway epithelial apoptosis using culture models of primary airway epithelial cells and cell lines. The administration of CSs in low-micromolar concentrations induces apoptosis that involves the disruption of mitochondrial polarity, the activation of caspases, and the involvement of Bcl-2. Clear differences exist between CS-induced apoptosis in the cultured epithelium vs cultured hematopoietic cells in regard to time course and resistance to apoptosis. Our data suggest that the use of CSs, in concentrations that could be attained in vivo with the inhalation of potent preparations or with systemic administration, may be one factor in the airways remodeling and epithelial damage that is seen in many patients with chronic, persistent asthma.
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PMID:Corticosteroid-induced apoptosis of airway epithelium: a potential mechanism for chronic airway epithelial damage in asthma. 1247 99


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