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)

Oblimersen (Genasense is a Bcl-2 antisense compound that selectively targets Bcl-2 RNA for degradation by RNase H and thereby decreases Bcl-2 protein production. Bcl-2 protein plays a major role in preventing apoptosis and has been linked to chemotherapy resistance in melanoma. Preclinical studies with oblimersen in melanoma cell lines and xenograft models of melanoma have demonstrated downregulation of Bcl-2 protein, induction of apoptosis and enhanced tumor response when combined with chemotherapy. Results of a Phase I/II study have shown that reducing Bcl-2 with oblimersen coincident with the administration of dacarbazine may amplify apoptosis and improve therapeutic outcome. A subsequent Phase III trial showed that the addition of oblimersen to dacarbazine significantly improved multiple clinical outcomes relative to dacarbazine alone based on an intent-to-treat analysis of progression-free survival and response rate (overall, complete and durable), as well as overall survival in patients with normal lactate dehydrogenase. This article reviews the biochemistry, pharmacodynamics and pharmacokinetics, safety and efficacy data related to oblimersen in melanoma.
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PMID:Oblimersen in the treatment of metastatic melanoma. 1754 20

Inadequate oxygen availability at high altitude causes oxidative stress and generation of reactive oxygen species, which may lead to memory impairment. Hippocampus, which plays a key role in the learning and memory processes, is especially vulnerable to hypoxic damage. The present study was aimed at investigating the effect of acetyl-L-carnitine on spatial working and reference memory deficits along with oxidative and apoptotic damage, caused by hypobaric hypoxia in male Sprague Dawley rats. Rats were trained in Morris Water Maze for eight days after which they were submitted to chronic hypobaric hypoxia exposure at a simulated altitude of 6100 m for three days. Rats received daily acetyl-L-carnitine at a dosage of 75 mg/kg body weight orally during exposure. Subsequent to exposure, performance of the animals was tested in Morris Water Maze, which revealed working memory impairment that was significantly improved by acetyl-L-carnitine. However, there was no change in the reference memory after hypobaric hypoxia exposure. Following behavioral study animals were sacrificed and biomarkers of oxidative damage like free radical production, lactate dehydrogenase activity, lipid peroxidation, antioxidant status and expression of apoptotic [viz. caspase-3, Apoptosis activating factor (Apaf-1), bax, cytochrome c] and anti-apoptotic protein-Bcl-2 were studied in the hippocampus. There was a significant increase in oxidative stress along with increased expression of apoptotic proteins and NR1 subunit of glutamate receptor indicating occurrence of excitotoxicity in hypoxia exposed rats. These results suggested that supplementation with acetyl-L-carnitine improves spatial working memory deficits reduces oxidative stress and inhibits apoptotic cascade induced by hypoxia.
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PMID:Acetyl-L-carnitine ameliorates hypobaric hypoxic impairment and spatial memory deficits in rats. 1761 Aug 72

Oridonin, a diterpenoid isolated from the plant Rabdosia rubescens, induces human epidermoid carcinoma A431 cell death through apoptosis and tyrosine kinase pathway. To examine the pathway of oridonin-induced A431 cell death, morphologic observation, lactate dehydrogenase activity-based assay, DNA agarose gel electrophoresis and Western blot analysis were carried out. When A431 cells, which overexpress epidermal growth factor receptor (EGFR), were treated with oridonin, caspase-3 was activated followed by the degradation of caspase-3 substrates, inhibitor of caspase-activated DNase (ICAD) and poly(ADP-ribose) polymerase (PARP) in a time-dependent manner. Oridonin promoted the release of cytochrome c and the down-regulation of mitochondrial transmembrane potential (DeltaPsim). Oridonin up-regulated the expression ratio of mitochondrial proteins, Bax/Bcl-2. In addition, the total tyrosine kinase activity of A431 cellular proteins and the expression of EGFR were markedly reduced after oridonin treatment. Taken together, oridonin induced apoptosis in A431 cells via mitochondrial pathway, activation of caspase-3 and inhibition of tyrosine kinase activities.
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PMID:Oridonin induces human epidermoid carcinoma A431 cell apoptosis through tyrosine kinase and mitochondrial pathway. 1805 84

Intravascular lymphoma (IVL) is a rare type of extranodal lymphoma in which the lymphoma cells proliferate exclusively in lumina of small vessels. Here, we report a clinicopathological study of 13 cases IVL diagnosed at our institution between March 1999 and July 2007, and evaluated the clinical characteristics, usefulness of random skin biopsy and response to chemotherapy containing rituximab. Three of 13 patients were diagnosed at autopsy. The most common clinical features were unexplained fever, neurological deterioration, respiratory failure, and poor performance status. Thrombocytopenia, high serum lactate dehydrogenase and soluble interleukin2 receptor levels were the most common laboratory abnormalities. Adrenal tumor was detected in four cases and pituitary involvement was seen in all three autopsied cases and in two surviving patient by brain magnetic resonance imaging. Bone marrow invasion was seen in all 13 cases by bone marrow smear, and it was subtle in trephine biopsy. Immunohistochemical analyses revealed that CD5 was positive in one-third of the cases. Most of the cases were positive for MUM1/IRF, Bcl-2 and negative for CD10 and BCL-6 indicating the postgerminal center cell origin of this peculiar type of lymphoma. On random skin biopsy, the most recent seven patients were diagnosed promptly and chemotherapy containing rituximab was successfully administered. Patients with IVL exhibit the characteristic clinical and immunophenotypic features cited above and the use of random skin biopsy facilitates prompt diagnosis. Early commencement of chemotherapy containing rituximab appears promising for this peculiar lymphoma. As the recent seven patients were diagnosed by random skin biopsy over the past 13 months, the incidence of IVL is thought to be much higher than generally accepted.
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PMID:A clinicopathological study of 13 cases of intravascular lymphoma: experience in a single institution over a 9-yr period. 1808

Dopamine receptors exist in many tissues, including rat cardiac tissue. However, the physiological importance of dopamine receptors in the homeostatic regulation of cardiac function is unclear. In this study, a model of ischaemia/reperfusion was established by culturing primary neonatal rat cardiomyocytes in ischaemia-mimetic solution for 2 hr, followed by incubation in normal culture medium for 24 hr. Lactate dehydrogenase activity, superoxide dismutase activity and malondialdehyde content were determined colorimetrically with a spectrophotometer. Apoptotic cell death was assayed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling staining and flow cytometry, and morphological alterations were observed with transmission electron microscopy. The intracellular free calcium concentration ([Ca2+]i) was measured by confocal laser scanning microscopy. Finally, the expression of dopamine receptor 1 (DR1), caspase-3, -8 and -9, Fas, Fas ligand and Bcl-2 and the release of cytochrome c were analysed by Western blot. The results showed that DR1 expression was increased markedly during ischaemia/reperfusion. Treatment with 10 microM SKF-38393 (DR1 agonist) significantly increased lactate dehydrogenase activity, decreased superoxide dismutase activity and increased malondialdehyde content in the culture medium. The DR1 agonist promoted the release of cytochrome c, accumulation of [Ca2+]i, and apoptosis induced by ischaemia/reperfusion. Furthermore, SKF-38393 up-regulated the expression of caspase-3, -8 and -9, Fas and Fas ligand, and down-regulated Bcl-2 expression. In contrast, 10 microM SCH-23390 (DR1 antagonist) had no significant effects on the above indicators. In conclusion, DR1 activation is involved in the apoptosis of cultured neonatal rat cardiomyocytes in simulated ischaemia/reperfusion through the mitochondrial and death receptor pathways.
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PMID:Effect of dopamine receptor 1 on apoptosis of cultured neonatal rat cardiomyocytes in simulated ischaemia/reperfusion. 1829 76

Steroid hormones have been reported to activate various signal transducers that trigger a variety of cellular responses. Among these hormones, testosterone has been identified as an antioxidant that protects against cellular damage. Therefore, using mouse embryonic stem (ES) cells as a model system, this study evaluated the effects of dihydrotestosterone (DHT), a biologically active testosterone metabolite, on H2O2-induced apoptosis. H2O2 increased the release of lactate dehydrogenase (LDH) and DNA fragmentation but reduced the cell viability in a time-dependent manner (> or =8 h). Moreover, H2O2 decreased the level of DNA synthesis and the levels of the cell cycle regulatory proteins [cyclin D1, cyclin E, cyclin-dependent kinase (CDK) 2, and CDK 4]. These effects of H2O2 were inhibited by a pretreatment with DHT. However, a treatment with flutamide (androgen receptor inhibitor, 10(-3) M) abolished the protective effects of DHT. This result was supported by the presence of the androgen receptor in mouse ES cells. The activity of the antioxidant enzyme, catalase, was increased by the DHT treatment but not by a co-treatment with DHT and flutamide. Using CM-H(2)DCFDA (DCF-DA) for the detection of intracellular H2O2, DHT decreased the intracellular H2O2 levels but flutamide blocked this effect. H2O2 also increased the level of p38 MAPK, JNK/SAPK, and NF-kappaB phosphorylation, which were inhibited by the DHT pretreatment. Catalase inhibited the effect of H2O2 on MAPKs and NF-kappaB. However, the flutamide treatment abolished the inhibitory effects of DHT on the H2O2-induced increase in the levels of p38 MAPK, JNK/SAPK, and NF-kappaB phosphorylation. DHT inhibited the H2O2-induced increase in caspase-3 expression and decreased the level of Bcl-2 and the cellular inhibitor of apoptosis protein (cIAP)-2. These effects were abolished by the flutamide treatment. In conclusion, DHT prevents the H2O2-induced apoptotic cell death of mouse ES cells through the activation of catalase and the downregulation of p38 MAPK, JNK/SAPK, and NF-kappaB via the androgen receptor.
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PMID:Effect of dihydrotestosterone on hydrogen peroxide-induced apoptosis of mouse embryonic stem cells. 1833 Aug 93

Cellular and molecular pathways underlying hypoxic neurotoxicity and cell death are multifaceted and complex. Although many potentially neuroprotective agents have been investigated, the protection conferred is often inadequate, resulting in their insufficient clinical utility. In light of the above, we investigated the therapeutic potential and mechanism of action of acetyl-L-carnitine (ALCAR) in protecting hippocampal neurons from hypoxia-induced neurotoxicity and cellular death. Results showed decreased viability of hippocampal cells when exposed to hypoxia (3% O(2)) for 48 hr along with concomitant membrane depolarization, adenosine triphosphate depletion, DNA fragmentation, accentuated free radical production, and lactate dehydrogenase activity. Pretreatment with ALCAR significantly attenuated hypoxia-induced cytotoxicity in a dose-dependent manner and improved cellular glutathione levels and cytochrome c oxidase activity compared with normoxic controls. Supplementation of ALCAR also prevented apoptosis by down-regulating caspase-3 levels, cytochrome c release, and p-Bcl-2 expression. A decrease in nerve growth factor (NGF) was observed in hypoxic stress despite increased phosphorylation of ERK1/2 (extracellular signal-related kinase) and its downstream effector, Elk-1. Supplementation of ALCAR, on the other hand, up-regulated NGF and tyrosine kinase A expression along with concomitant increase in ERK1/2 phosphorylation, thus enhancing cell survival. ALCAR therefore provides neuroprotection by stabilizing mitochondrial membrane, restoring the cholinergic transmission, and more importantly, it stimulates NGF receptors, thus triggering cell survival pathway via ERK phosphorylation. Therefore, ALCAR may be useful as an effective therapeutic agent for hypoxic stress and associated neurodegenerative diseases.
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PMID:Hypoxia-induced deactivation of NGF-mediated ERK1/2 signaling in hippocampal cells: neuroprotection by acetyl-L-carnitine. 1850 Jul 55

Oridonin, a diterpenoid isolated from Rabdosia rubescences, has been reported to have antitumor effects. In this study, the growth-inhibitory activity of oridonin for L929 cells was exerted in a time-and dose-dependent manner. After treatment with oridonin for 24 h, L929 cells underwent both apoptosis and necrosis as measured by an lactate dehydrogenase (LDH) activity-based assay. A rapid generation of reactive oxygen species (ROS) was triggered by oridonin, and subsequently up-regulation of phospho-p53 (ser 15) expression and an increased expression ratio of Bax/Bcl-2 was observed. Furthermore, there was a significant fall in mitochondrial membrane potential (MMP) and increase in caspase-3 activity after exposure to oridonin for 24 h. Surprisingly, the pan-caspase inhibitor z-VAD-fmk and caspase3 inhibitor z-DEVD-fmk rendered L929 cells more sensitive to oridonin, rather than preventing oridonin-induced cell death. Oridonin and z-VAD-fmk co-treatment not only resulted in an even higher ROS production, but also made a more significant reduction in the MMP. Pretreatment of ROS scavenger N-acetylcysteine (NAC) led to a complete inhibition of oridonin-induced cell death, intracellular ROS generation, and MMP collapse. NAC treatment also reversed the potentiation of cell death by the pan-caspase inhibitor z-VAD-fmk. Taken together, these observations showed that oridonin-induced cell death in L929 cells involved intracellular ROS generation, activation of phospho-p53 (ser 15), and up-regulation of the Bax/Bcl-2 ratio; and the augmented cell death by z-VAD-fmk was dependent on an increased ROS production.
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PMID:Caspase inhibition augmented oridonin-induced cell death in murine fibrosarcoma l929 by enhancing reactive oxygen species generation. 1881 79

Excitotoxicity contributes to neuronal death and is involved in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease (AD). In the present study, cryptotanshinone, an active ingredient from a Chinese plant, Salvia miltiorrhiza, was investigated to assess its neuroprotective effects against glutamate-induced toxicity in primary culture of rat cortical neurons. Cryptotanshinone reversed glutamate-induced neuronal toxicity, which was characterized by decreased cell viability, increased lactate dehydrogenase release, neuronal DNA condensation, and the alteration of the expression of Bcl-2 family proteins. The neuroprotective effects of cryptotanshinone could be blocked by LY294002 and wortmannin, two inhibitors of PI3K. The importance of the PI3K pathway was further confirmed by the activation of Akt and anti-apoptotic Bcl-2 by cryptotanshinone in a PI3K-dependent manner. These results suggest that cryptotanshinone protects primary cortical neurons from glutamate-induced neurotoxicity through the activation of PI3K/Akt pathway. Such neuroprotective effects may be of interest in AD and other neurodegenerative diseases.
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PMID:Cryptotanshinone protects primary rat cortical neurons from glutamate-induced neurotoxicity via the activation of the phosphatidylinositol 3-kinase/Akt signaling pathway. 1893 23

Oxidative stress, followed by the apoptotic death of pancreatic beta cells, is considered to be one of causative agents in the evolution of the type 2 diabetic state; therefore, the protection of beta cells can comprise an efficacious strategy for preventing type 2 diabetes. In the present study, RIN-m5F cells (i.e. the rat insulinoma beta cell line) were stimulated with streptozotocin, resulting in a time- and concentration-dependent release of lactate dehydrogenase. There appeared to be significant apoptotic cell death after 2 h of treatment with streptozotocin at 10 mM, as demonstrated by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling staining and 2.6-fold activation of cellular caspase-3, an apoptotic enzyme. By contrast, some neuropeptides of the glucagon-secretin family and coenzyme Q(10), an endogenous mitochondrial antioxidant, could attenuate streptozotocin cytotoxicity, and especially pituitary adenylate cyclase-activating polypeptide (PACAP), at a concentration of 10(-7) M, exhibited 34% attenuation of lactate dehydrogenase release from streptozotocin-treated RIN-m5F cells. Quantitative RT-PCR experiments indicated the inhibitory effect of PACAP on streptozotocin-evoked up-regulation of pro-apoptotic factor (Noxa and Bax) and a 2.3-fold enhancement of Bcl-2 mRNA expression, a pro-survival protein, was also observed after addition of PACAP. The data obtained suggest the anti-apoptotic role of PACAP in streptozotocin-treated RIN-m5F cells through the regulation of pro-apoptotic and pro-survival factors.
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PMID:Pituitary adenylate cyclase-activating polypeptide attenuates streptozotocin-induced apoptotic death of RIN-m5F cells through regulation of Bcl-2 family protein mRNA expression. 1895 42


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