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)

The majority of follicular lymphoma and Burkitt's lymphoma are associated with reciprocal translocations involving BCL2 and cMYC, respectively. Unusual reports of aggressive lymphoma presenting with both translocations have been described as well as rare cases with a third structural alteration usually involving BCL6. The patient described here presented with aggressive high-grade lymphocytic leukemia, FAB subtype L2 (ALL-L2), and three reciprocal translocations, t(14;18)(q32;q21), t(8;14)(q24.1;q32), and t(1;2) (q22-23;p13). Despite immature morphology the leukemic blasts had a mature B-cell phenotype; they were positive for surface immunoglobulin heavy chains and negative for CD34, TdT, and CD10. Most reported dual t(14;18)/t(8;14) cases have not shown sIg and were positive for CD10. Molecular genetic analyses showed the typical rearrangements of BCL2 and cMYC as well as the FCGR2B gene on chromosome 1q23. The occurrence of a third oncogene rearrangement in association with the dual BCL2, cMYC translocations in ALL patients is very rare. To our knowledge, this is the first case where the third hit involves the FCGR2B locus. This report reiterates the poor prognosis associated with activation of cMYC together with elevated Bcl-2 expression. These data also support recent evidence that dysregulation of FCGR2B may play a role in tumor progression.
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PMID:Case of acute lymphoblastic leukemia presenting with t(14;18)/BCL2, t(8;14)/cMYC, and t(1;2)/FCGR2B. 1450 97

An in vitro ischemia model was established and the effect of the metabolic inhibitors cycloheximide (CHX) and actinomycin D (ActD) on apoptosis in astrocytes under ischemia studied. CHX decreased by 75% the number of cells dying after 6 hr of ischemia compared with control cultures. TdT-mediated dUTP nick end labelling (TUNEL) staining of comparable cultures was reduced by 40%. ActD decreased cell death by 60% compared with controls. The number of TUNEL-positive cells was reduced by 38%. The nuclear shrinkage in TUNEL-positive astrocytes in control cultures did not occur in ActD-treated astrocytes, indicating that nuclear shrinkage and DNA fragmentation during apoptosis are two unrelated processes. Expression of bcl-2 (alpha and beta), bax, and Ice in astrocytes under similar ischemic conditions, as measured by quantitative reverse transcription-polymerase chain reaction, indicated that ischemia down-regulated bcl-2 (alpha and beta) and bax. Ice was initially down-regulated from 0 to 4 hr, before returning to control levels after 8 hr of ischemia. ActD decreased the expression of these genes. CHX reduced the expression of bcl-2 (alpha and beta) but increased bax and Ice expression. It is hypothesized that the balance of proapoptotic (Bad, Bax) and antiapoptotic (Bcl-2, Bcl-Xl) proteins determines apoptosis. The data suggest that the ratio of Bcl-2/Bad in astrocytes following ActD and CHX treatment does not decrease as much in untreated cells during ischemia. Our data indicate that it is the ratio of Bcl-2 family members that plays a critical role in determining ischemia-induced apoptosis. It is also important to note that ischemia-induced apoptosis involves the regulation of RNA and protein synthesis.
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PMID:Cycloheximide and actinomycin D delay death and affect bcl-2, bax, and Ice gene expression in astrocytes under in vitro ischemia. 1451 61

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

Fumaric acid esters (FAE) have been used for the systemic treatment of psoriasis in Germany for almost 50 years. Recently, it has been shown that dimethylfumarate (DMF) as the main ingredient of the marketed FAE mixture is a potent inhibitor of the nuclear transcription factor NF-kappaB. DMF was also shown to induce apoptosis in various cells. Because T cells play a crucial role in psoriasis pathogenesis, we asked whether DMF and its main metabolite methylhydrogenfumarate (MHF) were able to induce apoptosis in these cells. Purified human T cells were treated with DMF and MHF (1-20 microg/mL) and stimulated with interleukin 2, anti-CD3 antibodies or both for 48 h, and apoptosis was subsequently determined by the expression of Apo2.7 as well as by terminal deoxynucleotide transferase nick end labeling. The expression of antiapoptotic protein Bcl-2 was simultaneously determined. The results showed a dose-and-time dependent up-regulation of Apo2.7 expression and DNA fragmentation by DMF preferable in stimulated T cells. MHF and the solvent dimethyl sulfoxide were without effect. DMF, but not MHF, led to a concentration-dependent decrease of Bcl-2 expression in interleukin-2-stimulated T cells. The data provide evidence that the effect of FAE treatment of psoriasis may at least in part be due to induction of apoptosis in activated T cells.
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PMID:Dimethylfumarate is a potent inducer of apoptosis in human T cells. 1467 87

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 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

CGRP is a well-known neuropeptide that has various protective effects on cardiovascular system. Our previous studies have shown that CGRP inhibits vascular smooth muscle cell (VSMC) proliferation in vitro. The present study aimed to explore the role of the CGRP in neointimal formation after balloon injury in the rat aortic wall and the underlying mechanism. Gene transfer of CGRP was performed with the use of intramuscular electroporation in a balloon-injured rat aorta model. Apoptosis in VSMCs was determined by electrophoresis assessment of DNA fragmentation and terminal deoxynucleotide transferase-mediated dUTP nick-end labeling assay. Overexpression of the CGRP gene significantly inhibited the neointimal formation after balloon injury compared with the mock transfer, as assessed by the intima-to-media ratio 14 days after balloon injury (29.2 +/- 3.7% vs. 52.7 +/- 5.4%; n = 9-12, P < 0.05). In addition, CGRP gene expression increased the number of apoptotic cells in the neointima in vivo 14 days after balloon injury. Similarly, the addition of bioactive CGRP and the nitric oxide donor induced similar apoptosis in cultured VSMCs. The antagonist of the CGRP(1) receptor and inhibitors of cAMP-PKA and nitric oxide blocked CGRP-mediated apoptosis. Furthermore, CGRP gene transfer increased inducible nitric oxide synthase and p53 but decreased PCNA and Bcl-2 protein levels in balloon-injured rat aorta. Our data demonstrated that CGRP potently inhibited neointimal thickening in the rat aorta, at least in part through its distinct effects on apoptosis and proliferation of VSMCs both in vivo and in vitro. Therefore, delivery of the CGRP gene may have therapeutic implications in limiting vascular restenosis.
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PMID:Intramuscular gene transfer of CGRP inhibits neointimal hyperplasia after balloon injury in the rat abdominal aorta. 1537 Dec 65


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