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)

Bcl-2 inhibits apoptosis induced by a variety of death stimuli but does not completely inhibit Fas-mediated apoptosis. We have previously shown that a HeLa-derived cell line lacking mitochondrial DNA (mtDNA) expresses Fas at a high level and apoptosis is easily induced using a low concentration of an anti-Fas antibody. In this study, overexpression of Bcl-2 in the mtDNA-less cells completely blocked Fas-mediated apoptosis, and this was not due to a depression of the enhanced Fas expression. These findings suggest that the Fas-mediated apoptotic pathway is directly linked to Bcl-2 protection in the cells with an accompanying mitochondrial dysfunction.
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PMID:Bcl-2 completely blocks Fas-mediated apoptosis in mtDNA-depleted HeLa cells. 929 22

A case of Hodgkin's disease (HD), lymphocyte depression (LD) type in an immunosuppressive patient is described. The patient was a 48-year-old male and his parents were born in the Kyushu area, which is an endemic area for adult T cell lymphoma/leukemia (ATL). He was seropositive for ATL virus (ATLV, also referred to as HTLV-I) and showed a marked immunosuppressive condition. He developed LD-HD and Pneumocystis carinii pneumonia, and died due to respiratory failure. The immunohistochemical and in situ hybridization analyses revealed that the Reed-Sternberg-like cells in the lymph node biopsy sample were positive for Ber-H2 (CD30), Leu-M1 (CD15), L-26 (CD20), Bcl-2, p53 and EBER, the viral genome of Epstein-Barr virus (EBV).
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PMID:Epstein-Barr virus-related Hodgkin's disease showing B cell lineage in an immunosuppressive patient seropositive for HTLV-I. 941 42

Squamous cell carcinoma (SSC) is the most frequent malignant tumor of the oral cavity. Aberration of programmed cell death is thought to participate in cancer. Using specific antibodies a study of the expression and subcellular distribution of Bcl-2, BAX, caspase-3 and cytochrome c in normal human keratinocytes and mouth carcinoma slowly (HN) and rapidly growing (KB) cells has been carried out. In carcinoma cells depressed expression of BAX, presence in the cytosol of procaspase-3 and absence in this fraction of cytochrome c have been found. PGE2 treatment prevented cell growth depression induced by pro-apoptotic serum starvation both in control and carcinoma cell cultures. It is also shown that PGE2 promoted both in keratinocytes and KB cells expression of Bcl-2, which was accompanied in the first case by increase in its mitochondrial level. These results indicate that in carcinoma cells there is an apparent down regulation of the apoptotic cascade as compared to normal keratinocytes. Thus the possibility that down regulation of apoptosis is associated with promotion of tumor development in the oral mucosa cells seems to be supported by these observations.
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PMID:Expression and subcellular distribution of Bcl-2 and BAX proteins in serum-starved human keratinocytes and mouth carcinoma epidermoid cultures. 1451 71

Both omega-6 and omega-3 long-chain polyunsaturated fatty acids (LCPUFAs) modulate TH1 and TH2 cell generation, their cytokine production, and cell proliferation and thus may serve as endogenous anti-inflammatory molecules. LCPUFAs suppress the production of tumor necrosis factor-alpha (TNF-alpha) (and so also of OX40, since it belongs to the family of TNFR) and the expression of Bcl-2, suggesting that these fatty acids have the ability to prevent/suppress autoimmune diseases. Human breast milk contains substantial amounts of both omega-3 and omega-6 fatty acids. This indicates that LCPUFAs present in human breast milk suppress the levels of OX40 and decrease the expression of Bcl-xL and Bcl-2 on exposure to self-antigens and thus, protects against the development of autoimmune diseases in later life. In view of this, I propose that supplementation of appropriate amounts of LCPUFAs during perinatal period protects against atopy, asthma, auto-immune diseases, type 1 and type 2 diabetes mellitus, hypertension, coronary heart disease, metabolic syndrome X, lymphomas, leukemias and other cancers, schizophrenia, depression and other adult diseases in which low-grade systemic inflammation plays a significant role. It is also likely that perinatal supplementation of LCPUFAs in adequate amounts modulates the expression of genes concerned with immune response, angiogenesis, central osmo/sodium and glucose sensors etc. This renders various tissues and organs including T cells and macrophages, endothelial cells, hypothalamic neurons, and various cardiovascular tissues to be able to counteract the pathological mechanisms that tend to induce various adult diseases by blunting the inflammatory responses in those who received adequate amounts of LCPUFAs during the perinatal period compared to those who did not.
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PMID:Perinatal supplementation of long-chain polyunsaturated fatty acids, immune response and adult diseases. 1511 76

Morphological and functional changes have been repeatedly reported in the brain organization of depressed patients. The main modifications demonstrated by structural magnetic resonance imaging (MRI) are a reduction in the gray matter volume within the prefrontal cortex, the hippocampus, and the striatum. The reduction in gray matter volume and the morphological atrophy are probably due to an excess of neural loss (apoptosis) and an altered regulation of the neurotrophic processes. Hence, a deficit in neurotrophic factor synthesis (brain-derived neurotrophic factor [BDNF], neurotrophin [NT]-3, NT-4/5, Bcl-2, etc.) may be responsible for increased apoptosis in the hippocampus and prefrontal cortex corresponding to the cognitive impairment described in depression. This hypothesis seems to be confirmed by the decreased expression of neurotrophic factors (e.g., BDNF mRNA) in animal models of depression. In parallel, the neural plasticity (functional aspects of synaptic connectivity and long-term potential activity [LTP]) is decreased. However, the most interesting data concern the possible reversibility of this dysregulation with antidepressant treatment. For example, communication between the hippocampus and the prefrontal cortex could be re-established, enabling in a way the cognitive processes to be "reset." From a clinical point of view, the consequences of such a phenomenon are manifold:
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PMID:Neuroplasticity: from MRI to depressive symptoms. 1555 Mar 49

Degeneration of nigrostriatal dopamine neurons and cholinergic cortical neurones are the main pathological features of Parkinson's disease (PD) and for the cognitive deficit in dementia of the Alzheimer' type (AD) and in dementia with Lewy bodies (DLB), respectively. Many PD and DLB subjects have dementia and depression resulting from possible degeneration of cholinergic and noradrenergic and serotonergic neurons. On the other hand, AD patients may also develop extrapyramidal features as well as depression. In both PD and AD there is, respectively, accumulation of iron within the melanin containing dopamine neurons of pars compacta and with in the plaques and tangle. It has been suggested that iron accumulation may contribute to the oxidative stress induced apoptosis reported in both diseases. This may result from increased glia hydrogen peroxide producing monoamine oxidase (MAO) activity that can generate of reactive hydroxyl radical formed from interaction of iron and hydrogen peroxide. We have therefore prepared a series of novel bifunctional drugs from the neuroprotective-antiapoptotic antiparkinson monoamine oxidase B inhibitor, rasagiline, by introducing a carbamate cholinesterase (ChE) inhibitory moiety into it. Ladostigil (TV-3326, N-propargyl-3R-aminoindan-5yl)-ethyl methylcarbamate), has both ChE and MAO-AB inhibitory activity, as potential treatment of AD and DLB or PD subjects with dementia Being a brain selective MAO-AB inhibitor it has limited potentiation of the pressor response to oral tyramine and exhibits antidepressant activity similar to classical non-selective MAO inhibitor antidepressants by increasing brain serotonin and noradrenaline. Ladostigil inhibits brain acetyl and butyrylcholinesterase in rats and antagonizes scopolamine-induced inhibition of spatial learning. Ladostigil like MAO-B inhibitor it prevents MPTP Parkinsonism in mice model and retains the in vitro and in vivo neuroprotective activity of rasagiline. Ladostigil, rasagiline and other propargylamines have been demonstrated to have neuroprotective activity in several in vitro and in vivo models, which have been shown be associated with propargylamines moiety, since propargylamines itself possess these properties. The mechanism of neuroprotective activity has been attributed to the ability of propargylamines-inducing the antiapoptotic family proteins Bcl-2 and Bcl-xl, while decreasing Bad and Bax and preventing opening of mitochondrial permeability transition pore. Iron accumulates in brain regions associated with neurodegenerative diseases of PD, AD, amyotrophic lateral sclerosis and Huntington disease. It is thought to be involved in Fenton chemistry oxidative stress observed in these diseases. The neuroprotective activity of propargylamines led us to develop several novel bifunctional iron chelator from our prototype brain permeable iron chelators, VK-28, possessing propargylamine moiety (HLA-20, M30 and M30A) to iron out iron from the brain. These compounds have been shown to have iron chelating and monoamine oxidase A and B selective brain inhibitory and neuroprotective-antiapoptotic actions.
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PMID:Bifunctional drug derivatives of MAO-B inhibitor rasagiline and iron chelator VK-28 as a more effective approach to treatment of brain ageing and ageing neurodegenerative diseases. 1562 Dec 13

The p53 binding protein 2 (53BP2) has been identified as the interacting protein to p53, Bcl-2, and p65 subunit of nuclear factor kappaB (NF-kappaB). The TP53BP2 gene encodes two splicing variants, 53BP2S and 53BP2L, previously known as apoptosis stimulating protein 2 of p53 (ASPP2). We found that these 53BP2 proteins are located predominantly in the cytoplasm and induce apoptosis as demonstrated by cleavage of poly ADP ribose polymerase (PARP) and annexin V staining. Furthermore, we demonstrate that 53BP2 is located in the mitochondria and induces apoptosis associated with depression of the mitochondrial trans-membrane potential (DeltaPsim) and activation of caspase-9. From these findings we conclude that 53BP2 induces apoptosis through the mitochondrial death pathway.
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PMID:53BP2 induces apoptosis through the mitochondrial death pathway. 1574 14

There is growing evidence that anxiety disorders are associated with impairments of cellular plasticity and resilience. Paralleling these advances in our understanding of the neurobiologic underpinnings of anxiety disorders is the growing appreciation of the diverse functions that mitochondria play in regulating integrated CNS function. The emerging data suggest that mitochondrial Ca2+ sequestration has a key role in modulating the tone of synaptic plasticity in a variety of neuroanatomical regions, including those implicated in the pathophysiology of anxiety disorders. Furthermore, activation of peripheral mitochondrial benzodiazepine receptors resulted in reduced anxiety in rats. One of the major modulators of mitochondrial function is Bcl-2 proteins imbedded in the inner mitochondrial membrane. Bcl-2 overexpression increases mitochondria Ca2+ uptake capacity and resistance to Ca2+-inhibition of respiration and upregulation of Bcl-2 increases maximal uptake capacity of mitochondria. We have, therefore, explored the significance of Bcl-2 in the association between mitochondrial function and affective disorders testing Bcl-2 heterozygote mice in models of affective and anxiety disorders. Mutant mice have reduced mitochondrial Bcl-2 levels, and although they have no gross behavioral abnormalities, they demonstrate a significant increase of anxiety-like behaviors. Bcl-2 heterozygote mice spent less time in the center of an open field, spent less time outside an enclosure in the "emergence test", were less likely to explore the transparent part of a black/white box or the open arms of an elevated plus maze compared with WT controls. Mutant mice did not differ from WT in measures of locomotion or in the forced swim test for depression-like behavior suggesting a specific effect on anxiety-like behaviors. Our study, therefore demonstrates that Bcl-2 may be a key factor in anxiety disorders and that its effects may possibly originate from its role in the mitochondria.
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PMID:Increased anxiety-like behaviors and mitochondrial dysfunction in mice with targeted mutation of the Bcl-2 gene: further support for the involvement of mitochondrial function in anxiety disorders. 1609 31

The p53 binding protein 2 (53BP2) has been identified independently as the interacting protein to p53, Bcl-2, and p65 subunit of nuclear factor kappaB (NF-kappaB). It was demonstrated that over-expression of 53BP2 (renamed as 53BP2S) induces apoptotic cell death. In this study we explored the effect of NF-kappaB activation elicited by a physiological NF-kappaB inducer, interleukin-1beta (IL-1beta), and anti-apoptotic Bcl-2 family proteins on the 53BP2S-mediated apoptosis. We found that both NF-kappaB activation and Bcl-2 family proteins could prevent the 53BP2S-mediated depression of mitochondrial transmembrane potential, activation of caspase-9, cleavage of poly ADP ribose polymerase (PARP), and cell death. These observations suggested that 53BP2S/Bbp and its directly or indirectly interacting proteins might play crucial roles in the regulation of apoptosis and contribute to carcinogenesis. It is also suggested that 53BP2S/Bbp induces apoptosis through the mitochondrial death pathway presumably by counteracting the actions of anti-apoptotic Bcl-2 family proteins. The regulatory network of the 53BP2S-mediated apoptosis cascade including its interacting proteins is discussed.
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PMID:Inhibition of the 53BP2S-mediated apoptosis by nuclear factor kappaB and Bcl-2 family proteins. 1609 44

Fluoxetine is a widely used antidepressant compound which inhibits the reuptake of serotonin in the central nervous system. Recent studies have shown that fluoxetine can promote neurogenesis and improve the survival rate of neurons. However, whether fluoxetine modulates the proliferation or neuroprotection effects of neural stem cells (NSCs) needs to be elucidated. In this study, we demonstrated that 20 microM fluoxetine can increase the cell proliferation of NSCs derived from the hippocampus of adult rats by MTT test. The up-regulated expression of Bcl-2, Bcl-xL and the cellular FLICE-inhibitory protein (c-FLIP) in fluoxetine-treated NSCs was detected by real-time RT-PCR. Our results further showed that fluoxetine protects the lipopolysaccharide-induced apoptosis in NSCs, in part, by activating the expression of c-FLIP. Moreover, c-FLIP induction by fluoxetine requires the activation of the c-FLIP promoter region spanning nucleotides -414 to -133, including CREB and SP1 sites. This effect appeared to involve the phosphatidylinositol-3-kinase-dependent pathway. Furthermore, fluoxetine treatment significantly inhibited the induction of proinflammatory factor IL-1beta, IL-6, and TNF-alpha in the culture medium of LPS-treated NSCs (p<0.01). The results of high performance liquid chromatography coupled to electrochemical detection further confirmed that fluoxentine increased the functional production of serotonin in NSCs. Together, these data demonstrate the specific activation of c-FLIP by fluoxetine and indicate the novel role of fluoxetine for neuroprotection in the treatment of depression.
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PMID:Fluoxetine up-regulates expression of cellular FLICE-inhibitory protein and inhibits LPS-induced apoptosis in hippocampus-derived neural stem cell. 1654 75


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