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)

There is growing concern over detrimental neurologic effects to human newborns caused by increased inspired oxygen concentrations. We hypothesize that hyperoxia (FiO(2)>0.95) results in increased high-affinity Ca(2+)-ATPase activity, Ca(2+)-influx, and proapoptotic protein expression in cortical neuronal nuclei of newborn piglets. Neuronal cerebral energy metabolism was documented by determining ATP and phosphocreatine levels. Neuronal nuclear conjugated dienes and fluorescent compounds were measured as indices of lipid peroxidation. High-affinity Ca(2+)-ATPase activity and ATP-dependent Ca(2+)-influx were determined to document neuronal nuclear membrane function. Hyperoxia resulted in increases in lipid peroxidation, high-affinity Ca(2+)-ATPase activity, ATP-dependent Ca(2+)-influx, and Bax/Bcl-2 ratio in the cortical neuronal nuclei of newborn piglets. We conclude that hyperoxia results in modification of neuronal nuclear membrane function leading to increased nuclear Ca(2+)-influx, and propose that hyperoxia-induced increases in intranuclear Ca(2+) activates the Ca(2+)/calmodulin-dependent protein kinase pathway, triggering increased CREB protein-mediated apoptotic protein expression in hyperoxic neurons.
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PMID:Effect of hyperoxia on cortical neuronal nuclear function and programmed cell death mechanisms. 1740 66

Neuronal death can take on many different forms, from well-defined apoptosis to caspase-independent processes. While members of the Bcl-2 family of intracellular proteins are known to be involved in classic apoptotic cascades, their role in necrosis has been less well defined. Here, we applied a cell-permeable form of the anti-apoptotic Bcl-2 family member Bcl-x(L) on glutamate-treated rat primary cerebellar granule neurons to test its effect on neuronal survival. Bcl-x(L) inhibited the late phase of cell death, when caspases are activated, but it did not inhibit the early, caspase-independent phase of cell death. These different phases of cell death following glutamate treatment have not been taken into account in many earlier reports either supporting or refuting an involvement of Bcl-2 family members in excitotoxic cell death. Our results suggest that under our experimental conditions, Bcl-x(L) inhibits caspase-dependent apoptosis, but not caspase-independent neuronal death.
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PMID:Bcl-xL protects cerebellar granule neurons against the late phase, but not against the early phase of glutamate-induced cell death. 1764 76

Neuronal cell loss is a critical feature of age-related neurodegenerative diseases such as Alzheimer's disease (AD). In the AD brain, a marked increase in pro-inflammatory cytokines and chemokines, including IL-8, has been documented. The objective of this study was to determine the effect of IL-8 on cell viability and expression of neurotoxic, apoptotic, and cell cycle proteins in cultured neurons. Incubation of cultured neurons with IL-8 for 24 h resulted in neuronal cell death. RT-PCR analysis of primary rat neuronal cultures treated with IL-8 for 24 h showed induction of genes for matrix metalloproteinases (MMP-2 and MMP-9), proinflammatory proteases with neurotoxic properties. Gelatin zymography demonstrated IL-8 induced MMP-2 and MMP-9 activity. Western blot analysis showed that IL-8 also increased levels of the pro-apoptotic protein Bim (Bcl-2-interacting mediator of cell death). In addition, message levels of the cell cycle protein cyclin D1, an early marker for G1/S transition and a protein implicated as a regulator of neuronal apoptosis, were elevated after IL-8 exposure. These results suggest that IL-8 could be an important mediator of neuronal death in AD both via its effects on release of neurotoxins such as MMPs as well as by induction of cell cycle and pro-apoptotic proteins.
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PMID:IL-8 induces expression of matrix metalloproteinases, cell cycle and pro-apoptotic proteins, and cell death in cultured neurons. 1785 Nov 81

Aluminum (Al), a known neurotoxin, has been implicated in Alzheimer's Disease (AD), Amyotrophic Lateral Sclerosis (ALS), Parkinsonism Dementia Complex, etc., and it causes extensive damage to the nervous system, including the impairment of learning and memory. However, to date, the mechanism of Al neurotoxicity has not been fully elucidated. Neuronal apoptosis has become a focus of interest, as it has been reported to play a key role in the impairment of learning and memory processes (Thompson, Science 267:1456, 1995). The Bcl-2 gene acts as an important effector for inhibiting apoptosis. In the present study we observe neuronal apoptosis in association with learning and memory impairment, as well as regional brain alterations in Bcl-2 expression in rats chronically exposed to Al. The chronic Al-intoxicated model was established by i.p. injection of AlCl3 in adult Sprague Dawley rats for 3 successive days, with one-day intervals, for 60 days. After exposure, the step-down test was performed to examine the behavioral reaction of the rats. Neuronal apoptosis and Bcl-2 protein expression in different regions of rat brain were then assessed by an immunohistochemical method. In the step-down test, the latency of Al-exposed rats was significantly lower than that of controls. Also, the number of performance errors in 5 minutes of exposure was significantly higher than that of controls. Neuronal apoptosis was extensive in the brain of Al-exposed groups, and the expressions of Bcl-2 protein in frontal cortex, cerebellum and hippocampus of Al-exposed rats was stronger. In conclusion, chronic Al-exposure in rats is associated with neuronal apoptosis in brain, and impaired learning and memory. Augmented Bcl-2 protein expression may be a stimulated compensatory mechanism.
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PMID:The relationship between Bcl-gene expression and learning and memory impairment in chronic aluminum-exposed rats. 1796 40

Here we discuss the probable role of autophagy in cerebral ischemia based on our own recent data and the literature. We examined the protein level of Beclin 1 (Bcl-2 interacting protein) and microtubule-associated protein 1 light chain 3 (LC3) which were previously found to promote autophagy. We found a dramatic elevation in Beclin 1 levels and LC3 in the penumbra of rats challenged by cerebral ischemia. We found also that a subpopulation of Beclin 1-upregulating cells is also expressing the active form of caspase-3, and that all Beclin 1 upregulating cells display dense staining of LC3. Neuronal cells that overexpress Beclin 1 may exhibit damaged DNA but without changes in nuclear morphology, which indicates that not all the Beclin 1-upregulating cells are predestined to die. We conclude that the cell death in the penumbra bears a resemblance not only to necrosis, apoptosis, or a compromise between the two, but exhibits also biochemical and morphological characteristics of autophagic cell death. The question that constantly arises, however, is whether autophagic activity in damaged cells is the cause of death or is actually an attempt to prevent it as a part of an endogenous neuroprotective response.
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PMID:Upregulation of Beclin 1 in the ischemic penumbra. 1807 95

Estrogens are considered neurotrophic for dopamine neurons. Parkinson's disease is more frequent in males than in females, and more prevalent in females with short reproductive life. Estrogens are neuroprotective against neurotoxic agents for dopamine neurons in vivo and in vitro. Here, we have investigated the role of estrogens in wild-type (WT) and parkin null mice (PK-/-). WT mice present sexual dimorphisms in neuroprotective mechanisms (Bcl-2/Bax, chaperones, and GSH), but some of these inter-sex differences disappear in PK-/-. Tyrosine hydroxylase (TH) protein and TH+ cells decreased earlier and more severely in female than in male PK-/- mice. Neuronal cultures from midbrain of WT and PK-/- mice were treated with estradiol from 10 min to 48 h. Short-term treatments activated the mitogen-activated protein kinase pathway of WT and PK-/- neurons and the phosphatidylinositol 3'-kinase/AKT/glycogen synthase kinase-3 pathway of WT but not of PK-/- cultures. Long-term treatments with estradiol increased the number of TH+ neurons, the TH expression, and the extension of neurites, and decreased the level of apoptosis, the expression of glial fibrillary acidic protein, and the number of microglial cells in WT but not in PK-/- cultures. The levels of estrogen receptor-alpha were elevated in midbrain cultures and in the striatum of adult PK-/- male mice, suggesting that suppression of parkin changes the estrogen receptor-alpha turnover. From our data, it appears that parkin participates in the cellular estrogen response which could be of interest in the management of parkin-related Parkinson's disease patients.
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PMID:Gender differences and estrogen effects in parkin null mice. 1864 94

Studies of neuronal dysfunction in the central nervous system (CNS) are frequently limited by the failure of primary neurons to propagate in vitro. Neuronal cell lines can be substituted for primary cells but they often misrepresent normal conditions. We hypothesized that a three-dimensional (3D) cell culture system would drive the phenotype of transformed neurons closer to that of untransformed cells, as has been demonstrated in non-neuronal cell lines. In our studies comparing 3D versus two-dimensional (2D) culture, neuronal SH-SY5Y (SY) cells underwent distinct morphological changes combined with a significant drop in their rate of cell division. Expression of the proto-oncogene N-myc and the RNA-binding protein HuD was decreased in 3D culture as compared to standard 2D conditions. We observed a decline in the anti-apoptotic protein Bcl-2 in 3D culture, coupled with increased expression of the pro-apoptotic proteins Bax and Bak. Moreover, thapsigargin (TG)-induced apoptosis was enhanced in the 3D cells. Microarray analysis demonstrated significantly differing mRNA levels for over 700 genes in the cells of the two culture types, and indicated that alterations in the G1/S cell-cycle progression contributed to the diminished doubling rate in the 3D-cultured SY cells. These results demonstrate that a 3D culture approach narrows the phenotypic gap between neuronal cell lines and primary neurons. The resulting cells may readily be used for in vitro research of neuronal pathogenesis.
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PMID:Closing the phenotypic gap between transformed neuronal cell lines in culture and untransformed neurons. 1867 2

Neurodegeneration is a characteristic feature of AIDS dementia complex and is commonly associated with neuronal death in the brains of both pediatric and adult patients. Neuronal death associated with AIDS dementia complex can be induced by the HIV-1 protein gp120, but the underlying signal transduction mechanism remains unclear, especially for HIV-1 subtypes commonly seen in China. We have now demonstrated that the human CC ligand 3-like protein 1 (CCL3L1), a member of the CC chemokine family, appears to protect neuronal cultures through its ability to attenuate gp120-induced neuronal death. We found that (i) both pCREB levels and Bcl-2 expression are up-regulated in neuronal culture following treatment with CCL3L1 plus gp120; (ii) CCL3L1 induces cell survival via phosphorylation of CREB by way of the PKA and CaMKI/CaMKIV cell signaling pathways; (iii) transcription of the cell survival gene bcl-2 is induced by pCREB; and (iv) CCL3L1 protects cultured neurons against CCR5-mediated excitotoxicity induced by gp120. Thus, the CCL3L1/bcl-2-regulated anti-apoptotic pathway significantly contributes to reduction of HIV-1/gp120-induced neuronal apoptosis, and therefore, CCL3L1 should be further investigated as a potential chemokine to protect against neuronal injury in gp120-related neuronal toxicity.
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PMID:CCL3L1 prevents gp120-induced neuron death via the CREB cell signaling pathway. 1910 Jul 22

Mitochondrial ATP-sensitive potassium channel opener, diazoxide, is shown to have protective effect on the heart and brain following ischemia-reperfusion-induced injury (IR/II). However, the detailed effect of diazoxide and its antagonist on neuronal death, mitochondrial changes, and apoptosis in cerebral IR/II has not fully studied. IR/II was induced in rats by the 4-vessel occlusion model. Neuronal cell death and mitochondrial changes in CA1-CA4 pyramidal cells of the hippocampus were studied by light and electron microscopy, respectively. Apoptosis was assessed by measuring the amount of protein expressed by Bax and Bcl-2 genes. In light microscopy studies, the number of total and normal cells were increased only following 18 mg/kg of diazoxide. Lower doses (2 and 6 mg/kg) failed to change the cell numbers. All three doses of glibenclamide (1, 5, and 25 mg/kg) decreased the number of total and normal cell populations. In electron microscopy studies, different doses of diazoxide and glibenclamide prevented and aggravated the IR-induced morphological changes, respectively. Western blot analysis showed that diazoxide and glibenclamide inhibited and enhanced Bax protein expression respectively. Regarding Bcl-2 expression, only diazoxide showed a significant enhancement of gene expression. In conclusion, the results show that diazoxide can exhibit neuroprotective effects against IR/II in hippocampal regions, possibly through the opening of mitochondrial ATP-sensitive K(+) channels.
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PMID:Neuroprotective effects of diazoxide and its antagonism by glibenclamide in pyramidal neurons of rat hippocampus subjected to ischemia-reperfusion-induced injury. 1992 61

Neuronal iron homeostasis disruption and oxidative stress are closely related to the pathogenesis of Parkinson's disease (PD). Adult iron-regulatory protein 2 knockout (Ireb2(-/-)) mice develop iron accumulation in white matter tracts and nuclei in different brain area and display severe neurodegeneration in Purkinje cells of the cerebrum. Mitochondrial ferritin (MtFt), a newly discovered ferritin, specifically expresses in high energy-consuming cells, including neurons of brain and spinal cord. Interestingly, the decreased expression of MtFt in cerebrum, but not in striatum, matches the differential neurodegeneration pattern in these Ireb2(-/-) mice. To explore its effect on neurodegeneration, the effects of MtFt expression on 6-hydrodopamine (6-OHDA)-induced neuronal damage was examined. The overexpression of MtFt led to a cytosolic iron deficiency in the neuronal cells and significantly prevented the alteration of iron redistribution induced by 6-OHDA. Importantly, MtFt strongly inhibited mitochondrial damage, decreased production of the reactive oxygen species and lipid peroxidation, and dramatically rescued apoptosis by regulating Bcl-2, Bax and caspase-3 pathways. In conclusion, this study demonstrates that MtFt plays an important role in preventing neuronal damage in an 6-OHDA-induced parkinsonian phenotype by maintaining iron homeostasis. Regulation of MtFt expression in neuronal cells may provide a new neuroprotective strategy for PD.
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PMID:Neuroprotective mechanism of mitochondrial ferritin on 6-hydroxydopamine-induced dopaminergic cell damage: implication for neuroprotection in Parkinson's disease. 2012 42


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