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)

Using morphological and molecular approaches, we characterized cisplatin-induced cell necrosis and apoptosis in rat kidney. Male Sprague-Dawley rats ( n=5 per group) received a single intraperitoneal injection of either cisplatin (5 mg/kg) or saline, and were killed on day 5. Functionally, cisplatin-treated rats developed polyuric acute renal failure. Morphologically, kidneys of cisplatin-treated rats showed overt tubular necrosis associated with apoptosis in the corticomedullary junction. Cell necrosis was segment-specific and was distributed in radial fashion at the corticomedullary junction. The apoptosis was limited to discrete cells in apparently intact tubules in the vicinity of the necrosed tubules. The apoptotic changes were confirmed by TUNEL (TdT-mediated deoxyuridine triphosphate nick-end labeling) and staining for cleaved caspase-3. Analysis of outer medullary tissue for apoptosis-related molecules by RNase protection assay revealed a significant increase in the expression of pro-apoptotic mRNAs (caspases 1, 2, and 8, and Bax) in cisplatin-treated rats. On the other hand, the expression of mRNA for the anti-apoptotic Bcl-2 did not change, resulting in a decrease in relative ratio of Bcl-2/Bax, and thus favoring apoptosis. The above changes were paralleled by a marked increase in caspase-3 precursor, the executioner protease. Furthermore, these pro-apoptotic molecular changes were associated with a 3-fold increase in the activity of JNK1 in the outer medulla, but not in the cortex, of cisplatin-treated rat kidneys, localizing to the site of maximal apoptosis. Upregulation of JNK1 activity in the outer medulla was not accompanied by changes in the activities of ERK or p38 kinase. In conclusion, these data suggest that cisplatin-induced apoptotic cell death in native kidney may be mediated by cooperative activation of the JNK1 pathway and Bax in the outer medulla.
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PMID:Cellular and molecular studies on cisplatin-induced apoptotic cell death in rat kidney. 1455 73

Loss of cardiomyocytes by apoptosis is proposed to cause heart failure. Angiotensin II (ANG II), an important neurohormonal factor during heart failure, can induce cardiomyocyte apoptosis. Inasmuch as hexarelin has been reported to have protective effects in this process, we examined whether hexarelin can prevent cardiomyocytes from ANG II-induced cell death. Cultured cardiomyocytes from neonatal rats were stimulated with ANG II. Apoptosis was evaluated using fluorescence microscopy, TdT-mediated dUTP nick-end labeling (TUNEL) method, flow cytometry, DNA laddering, and analysis of cell viability by (3,4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). It was found that incubation with 0.1 micromol/l ANG II for 48 h increased cardiomyocyte apoptosis. Administration of 0.1 micromol/l hexarelin significantly decreased this ANG II-induced apoptosis and DNA fragmentation and increased myocyte viability. To further investigate the underlying mechanisms, caspase-3 activity assay and mRNA expression of Bax, Bcl-2, and growth hormone secretagogue receptor (GHS-R; the supposed hexarelin binding site) were examined. GHS-R mRNA was abundantly expressed in cardiomyocytes and was upregulated after administration of hexarelin. These results suggest that hexarelin abates cardiomyocytes from ANG II-induced apoptosis possibly via inhibiting the increased caspase-3 activity and Bax expression induced by ANG II and by increasing the expression of Bcl-2, which is depressed by ANG II. Whether the upregulated expression of GHS-R induced by hexarelin is associated with this antiapoptotic effect deserves further investigation.
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PMID:Hexarelin protects rat cardiomyocytes from angiotensin II-induced apoptosis in vitro. 1461 77

Cardiomyocyte (CM) apoptosis has been reported in a variety of cardiovascular diseases, including myocardial infarction, ischemia/reperfusion, end-stage heart failure, arrhythmogenic right ventricular dysplasia, and adriamycin-induced cardiomyopathy. The role of CM apoptosis in the development and progression of cardiac diseases merits further investigation. Cumulative evidence suggests that reactive oxygen species (ROS), which have been implicated in cardiac pathophysiology, can trigger myocyte apoptosis by up-regulating proapoptotic proteins, such as Bax and caspases, and the mitochondria-dependent pathway. These apoptotic proteins and pathways are inhibited by various antioxidants, as well as by overexpression of the antiapoptotic protein Bcl-2 by way of the antioxidant pathway. Detection of CM apoptosis with the terminal transferase-mediated DNA nick-end labeling assay alone has recently been questioned because of technical concerns regarding its sensitivity and specificity. Because CMs are mononuclear or binuclear, if only one nucleus or a certain percentage of fragmented nuclei is stained with TUNEL assay at the early stage of apoptotic cell death, it remains unknown whether this particular early apoptotic CM is still functionally active. The issue of TUNEL specificity further questions reports of high percentages of apoptotic CM nuclei (0.02%-35%) in the heart. Nevertheless, oxidative stress is a major apoptotic stimulus in many cardiovascular diseases and the process can be inhibited by antioxidants both in vitro and in vivo.
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PMID:Apoptosis and oxidants in the heart. 1464 32

Bcl-2 defines a new class of proto-oncogenes that block cell death without promoting cell proliferation. To elucidate the role of Bcl-2 in the development of glomerular lesions in human IgA nephropathy (IgAN), we applied immunohistochemistry coupled with in situ hybridization to detect the expression of Bcl-2 products and their association with Bax, p27(kip1), and p57(kip2) in modulating the apoptotic, proliferative, and sclerotic events in progressive glomerular injury. Glomerular cell apoptosis was examined by TdT-mediated dUTP-biotin nick-end labeling (TUNEL) staining. A total of 51 IgAN cases were categorized into four subgroups (A to D) according to the severity of their histopathological lesions. Creatinine levels, creatinine clearance, and magnitude of proteinuria based on 24-h urine collections at the time of diagnostic renal biopsy were available for the majority of subjects. Bcl-2 expression was observed predominantly in podocytes in IgAN. Podocyte expression of Bcl-2 was found to be upregulated in early-stage disease and downregulated in late-stage disease. Bcl-2 downregulation in progressive IgAN was associated with an increased Bax/Bcl-2 ratio in glomerular epithelial cells and correlated with the downregulation of high endogenous podocyte p27(kip1) and p57(kip2) expression. Bax/Bcl-2 ratios positively correlated with glomerular cell apoptosis and the degree of glomerulosclerosis, whereas p27(kip1) and p57(kip2) expression levels were inversely correlated with mesangial hypercellularity and glomerulosclerosis. Clinicopathologic correlations demonstrated that downregulation of Bcl-2 protein expression was associated with indices of poor renal prognosis in human IgAN. The results suggest that Bcl-2 expression by podocytes may exert modulatory effects on cellular processes that contribute to progressive glomerular injury and play an important role in determining renal outcome in human IgA nephropathy.
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PMID:Downregulation of Bcl-2 by podocytes is associated with progressive glomerular injury and clinical indices of poor renal prognosis in human IgA nephropathy. 1469 60

Apoptosis plays an important role in atherosclerosis. The factors regulating this process are not well defined. We examined the relation of apoptotic cells with the terminal complement complex C5b-9 in human atherosclerotic lesions. The extent of apoptosis was determined using TdT dUTP nick-end labeling (TUNEL) and immunohistochemistry of apoptosis regulators caspase-3, caspase-9, Bax, and Bcl-2. C5b-9 was localized by immunohistochemistry and immunoelectron microscopy. The apoptotic index was higher in fibrous plaques when compared with intimal fatty streaks and intimal thickenings. Bax expression was present in TUNEL+ apoptotic cells, and Bcl-2 was rarely present in the atherosclerotic wall. Active caspase 9 and caspase 3 deposits were present in the same areas, suggesting an involvement of the mitochondrial pathway. C5b-9 deposits colocalized with TUNEL+ cells, and the percent of double-positive cells was 2% in fatty streaks, 12% in intimal thickenings, and 35% in fibrous plaques. Colocalization of apoptotic cells with C5b-9 was also confirmed by immunoelectron microscopy. In conclusion, some apoptotic cells carry C5b-9 deposits, suggesting that complement might be activated by apoptotic cells and involved in the promotion of apoptosis, contributing to the progression of atherosclerotic lesions.
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PMID:C5b-9 terminal complement complex assembly on apoptotic cells in human arterial wall with atherosclerosis. 1473 64

The p38 branch of the mitogen-activated protein kinase (MAPK) signaling cascade has been implicated as a regulator of cardiomyocyte apoptosis in culture as well as in the adult heart. However, considerable disagreement persists as to the functional effects attributed to p38 signaling, given that both pro- and anti-apoptotic regulatory roles have been reported. To address this area of uncertainty in the literature, we investigated the cell death effects associated with p38 inactivation in both cultured neonatal cardiomyocytes and the adult heart. In vitro, adenoviral-mediated gene transfer of two different dominant-negative-encoding p38 vectors reduced apoptosis induced by 2-deoxyglucose treatment, whereas overexpression of wild-type p38alpha or an activated mitogen-activated protein kinase kinase (MKK)6 mutant each enhanced cell death. In vivo, transgenic mice expressing a dominant-negative MKK6 mutant or a dominant-negative p38alpha mutant were each significantly protected from ischemia-reperfusion injury, as assessed by infarct area measurements, DNA laddering, terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling, and functional assessment of ventricular performance. Similarly, transgenic mice overexpressing the p38-inactivating dual specificity phosphatase MAPK phosphatase-1 (MKP-1) were also partially protected, whereas MKP-1 gene-targeted mice showed greater injury after ischemia-reperfusion injury. Mechanistically, inhibition of p38 signaling promoted a dramatic up-regulation of Bcl-2 in the hearts of transgenic mice. In primary neonatal cardiomyocyte cultures, adenoviral-mediated gene transfer of a p38 inhibitory mutant up-regulated Bcl-2, whereas expression of an activated p38 mutant down-regulated Bcl-2 protein levels. Collectively, these results indicate that p38 functions as a pro-death signaling effector in both cultured myocytes as well as in the intact heart.
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PMID:Targeted inhibition of p38 mitogen-activated protein kinase antagonizes cardiac injury and cell death following ischemia-reperfusion in vivo. 1474 28

Gaucher disease is a lysosomal storage disorder resulting from an inborn deficiency of glucocerebrosidase. To investigate the genes responsible for the neuronal symptoms of Gaucher disease, gene expression profiles were analyzed in brains of the Gaucher disease mouse model using a cDNA microarray, and it was found that the bcl-2 gene is down-regulated. Immunoblotting and apoptosis assay were performed to study the relationship between the decreased expression of Bcl-2 and neuronal death on the brains of Gaucher mice fetuses at embryonic day 17.5 (E17.5) and E19.5. Decreased expression of Bcl-2 was observed in the brain stem and cerebellum but not in cortex by immunoblotting. In situ labeling of DNA fragmentation using terminal transferase-mediated dUTP nick-end-labeling (TUNEL) assay confirmed that apoptosis occurred in the brain stem and cerebellum. More apoptotic cells were detected in the brains of Gaucher mice fetuses at E19.5 than at E17.5. These results suggest that the accumulation of either glucocerebroside or glucosylsphingosine, as a result of glucocerebrosidase deficiency, affects gene expression and could be responsible for neuronal cell death.
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PMID:Down-regulation of Bcl-2 in the fetal brain of the Gaucher disease mouse model: a possible role in the neuronal loss. 1517 59

The ability of insulin-like growth factor II (IGF-II) to modulate apoptosis was studied in murine osteoblasts. At 72 h of culture, 0.01, 0.1, and 1.0 nM IGF-II produced a dose-dependent increase in apoptosis assayed by TdT-mediated dUTP-biotin nick end labeling (TUNEL) and confirmed with acridine orange-ethidium bromide staining. A maximal increase of 5.0-fold above control was found with 1 nM IGF-II. A time course of treatment with 0.1 nM IGF-II demonstrated a significant increase in apoptosis compared to vehicle-treated cells by 48 h. IGF-II-induced apoptosis could not be inhibited by a blocking antibody to the IGF-I receptor. Human osteoblast cultures demonstrated a similar dose-dependent increase in apoptosis with IGF-II. No significant effect of IGF-II was found on proliferation in murine osteoblast cultures. Western blot analysis demonstrated that IGF-II decreased Bcl-2 protein levels, but not Bax, resulting in a significant reduction in the Bcl-2/Bax ratio. To determine if overexpression of Bcl-2 could block IGF-II-induced apoptosis, osteoblasts were isolated from a transgenic mouse that overexpresses human Bcl-2 in bone through a construct utilizing the 2.3 kb promoter region of the Type I collagen gene linked to a 1.8 kb region of human Bcl-2 (Col2.3Bcl-2). At 72 h, IGF-II significantly increased apoptosis in a dose-dependent manner in osteoblast cultures from the control littermates. In osteoblasts from Col2.3Bcl-2 mice, no significant effect on apoptosis was found with 0.01, 0.1, or 1.0 nM IGF-II. Western blot analysis of Bcl-2 and Bax levels demonstrated a transient decrease in the Bcl-2/Bax ratio at 24 h with no decrease in the ratio at 48 or 72 h. Thus, IGF-II appears to promote osteoblast apoptosis, and overexpression of Bcl-2 is able to block IGF-II-induced apoptosis.
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PMID:Insulin-like growth factor II induces apoptosis in osteoblasts. 1533 97

To investigate the possible mechanisms of nitric oxide (NO)-induced apoptosis in leukemia cell line HL-60, HL-60 cells in vitro were incubated with sodium nitroprusside (SNP), the in situ cell apoptosis quantitatively was assayed by TdT-mediated dUTP nick end labeling (TUNEL), the cell cycle DNA and proteins expression of Bcl-2, Bax, mitochondrial membrane protein (APO2.7) were analyzed by flow cytometry. The results showed that SNP induced HL-60 cell apoptosis in a dosage- and time-dependent manner. After exposure to SNP at the concentration of 1.0 mmol/L for 48 hours, the percentage of apoptosis HL-60 was (42.2 +/- 3.5)% for subG1 and (52.5 +/- 7.6)% for TUNEL respectively, and they are significantly higher than those in control and potassium ferricyanide (PFC) groups as same concentration. During the apoptosis process, it showed a decrease of Bcl-2 protein and an increase of Bax protein and mitochondrial membrane protein in HL-60 cell, proteins of Bcl-2, Bax and mitochondrial membrane were expressed in a dosage- and time-dependent manner too. In conclusion, during the process of SNP induced apoptosis in HL-60 cell, the expression of mitochondrial membrane protein was increased, Bcl-2 and Bax proteins may be important regulators.
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PMID:[Change of Bcl-2, Bax proteins and mitochondrial membrane protein on nitric oxide induced apoptosis in HL-60 cells]. 1536 28

The influence of aging on skeletal myocyte apoptosis is not well understood. In this study we examined apoptosis and apoptotic regulatory factor responses to muscle atrophy induced via limb unloading following loading-induced hypertrophy. Muscle hypertrophy was induced by attaching a weight to one wing of young and aged Japanese quails for 14 days. Removing the weight for 7 or 14 days after the initial 14 days of loading induced muscle atrophy. The contralateral wing served as the intra-animal control. A time-released bromodeoxyuridine (BrdU) pellet was implanted subcutaneously with wing weighting to identify activated satellite cells/muscle precursor cells throughout the experimental period. Bcl-2 mRNA and protein levels decreased after 7 days of unloading, but they were unchanged after 14 days of unloading in young muscles. Bcl-2 protein level but not mRNA level decreased after 7 days of unloading in muscles of aged birds. Seven days of unloading increased the mRNA level of Bax in muscles from both young and aged birds. Fourteen days of unloading increased mRNA and protein levels of Bcl-2, decreased protein levels of Bax, and decreased nuclear apoptosis-inducing factor (AIF) protein level in muscles of aged birds. BrdU-positive nuclei were found in all unloaded muscles from both age groups, but the number of BrdU-positive nuclei relative to the total nuclei decreased after 14 days of unloading compared with 7 days of unloading. The TdT-mediated dUTP nick end labeling (TUNEL) index was higher after 7 days of unloading in both young and aged muscles and after 14 days of unloading in aged muscles. Immunofluorescent staining revealed that almost all of the TUNEL-positive nuclei were also BrdU immunopositive, suggesting that activated satellite cell nuclei (both fused and nonfused) underwent nuclear apoptosis during unloading. There were significant correlations among levels of Bcl-2, Bax, and AIF and TUNEL index. Our data are consistent with the hypothesis that apoptosis regulates, at least in part, unloading-induced muscle atrophy and loss of activated satellite cell nuclei in previously loaded muscles. Moreover, these data suggest that aging influences the apoptotic responses to prolonged unloading following hypertrophy in skeletal myocytes.
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PMID:Aging influences cellular and molecular responses of apoptosis to skeletal muscle unloading. 1548 26


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