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Mitochondrial Transmembrane Potential (mitochondrial + transmembrane_potential)
Selected AbstractsIL-7 inhibits dexamethasone-induced apoptosis via Akt/PKB in mature, peripheral T cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 4 2003Hadassah Sade Abstract We have investigated the mechanism of IL-7-mediated inhibition of dexamethasone-induced apoptosis in T cells. Broad-spectrum caspase inhibitors block dexamethasone-triggered nuclear fragmentation, but not the loss of mitochondrial transmembrane potential or membrane integrity in CD3+ mature T cells isolated from adult mouse spleens. IL-7 blocked dexamethasone-induced apoptosis and the processing of caspase-3 and caspase-7. IL-7 also blocked dexamethasone-triggered dephosphorylation of the serine-threonine kinase Akt/PKB and its target, the Ser136 residue in Bad. The loss of anti-apoptotic proteins Bcl-xL and inhibitor of apoptosis protein-2 (IAP-2) was also blocked by IL-7. The protective effect was attenuated by pharmacological inhibitors of phosphatidylinositol-3 kinase (PI3K) with one exception: inhibition of PI3K did not abrogate Bcl-xL expression in the presence of IL-7. The anti-apoptotic role of Akt suggested by these experiments was tested by overexpression of constitutively active Akt, which blocked dexamethasone-induced apoptosis and elevated IAP-2 but not Bcl-xL levels in a mature T cell line. Thus, IL-7 regulates IAP-2 expression and inhibits dexamethasone-induced apoptosis by activating Akt via PI3K-dependent signaling, but regulates Bcl-xL expression via a PI3K-independent pathway in mature T cells. [source] The Bcl-2 family pro-apoptotic molecule, BNIP3 regulates activation-induced cell death of effector cytotoxic T lymphocytesIMMUNOLOGY, Issue 1 2003J. Wan Summary BNIP3 is a recently described pro-apoptotic member of the Bcl-2 family and in BNIP3 cDNA-transfected cell lines, cell death occurs via a caspase-independent pathway with opening of the mitochondrial permeability transition (PT) pore and rapid loss of mitochondrial transmembrane potential (,,m). However, its expression or function in physiologic cell types is not known. Our results using the T-cell receptor transgenic mice P14, specific for lymphocyte choreomeningitis virus (LCMV) glycoprotein, show that in contrast to the other Bcl-2 family pro-apoptotic molecules, BNIP3 is transcriptionally highly up-regulated in effector cytotoxic T lymphocytes (CTL). Because CTL have a propensity to undergo activation-induced cell death (AICD) upon restimulation, we tested for other features associated with BNIP3-induced cell death. AICD of CTL was caspase-independent as determined by measuring caspase activation during target cell killing as well as by lack of inhibition with caspase inhibitors. Moreover, similar to BNIP3-induced cell death, CTL apoptosis was associated with increased production of reactive oxygen species and decreased ,,m. Finally, retroviral transduction of BNIP3 antisense RNA diminished AICD in effector CTL. These results suggest that BNIP3 may play an important role in T-cell homeostasis by regulating effector CTL numbers. [source] Nerve growth factor blocks thapsigargin-induced apoptosis at the level of the mitochondrion viaregulation of BimJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 6a 2008E. Szegezdi Abstract This study examined how the neurotrophin, nerve growth factor (NGF), protects PC12 cells against endoplasmic reticulum (ER) stress-induced apoptosis. ER stress was induced using thapsigargin (TG) that inhibits the sarcoplasmic/ER Ca2+ -ATPase pump (SERCA) and depletes ER Ca2+ stores. NGF pre-treatment inhibited translocation of Bax to the mitochondria, loss of mitochondrial transmembrane potential, cytochrome c release, activation of caspases (,3, ,7 and ,9) and apoptosis induction by TG. Notably, TG also caused a marked induction of Bimel mRNA and protein, and knockdown of Bim with siRNA protected cells against TG-induced apoptosis. NGF delayed the induction and increased the phosphorylation of Bimel. NGF-mediated protection was dependent on phosphatidylinositol-3 kinase (PI3K) signalling since all above apoptotic events, including expression and phosphorylation status of Bimel protein, could be reverted by the PI3K inhibitor LY294002. In contrast, NGF had no effect on the TG-mediated induction of the unfolded protein response (increased expression of Grp78, GADD34, splicing of XBP1 mRNA) or ER stress-associated pro-apoptotic responses (induction of C/EBP homologous protein [CHOP], induction and processing of caspase-12). These data indicate that NGF-mediated protection against ER stress-induced apoptosis occurs at the level of the mitochondria by regulating induction and activation of Bim and mitochondrial translocation of Bax. [source] Vitamin E blocks early events induced by 1-methyl-4-phenylpyridinium (MPP+) in cerebellar granule cellsJOURNAL OF NEUROCHEMISTRY, Issue 2 2003Rosa A. González-Polo Abstract Exposure of cerebellar granule cells (CGCs) to 1-methyl-4-phenylpyridinium (MPP+) results in apoptotic cell death, which is markedly attenuated by co-treatment of CGCs with the radical scavenger vitamin E. Analysis of free radical production and mitochondrial transmembrane potential (,,m), using specific fluorescent probes, showed that MPP+ mediates early radical oxygen species (ROS) production without a loss of ,,m. Exposure to MPP+ also produces an early increase in Bad dephosphorylation and translocation of Bax to the mitochondria. These events are accompanied by cytochrome c release from mitochondria to cytosol, which is followed by caspase 3 activation. Exposure of the neurons to vitamin E maintains Bad phosphorylation and attenuates Bax translocation, inhibiting cytochrome c release and caspase activation. MPP+ -mediated cytochrome c release is also prevented by allopurinol, suggesting the participation of xanthine oxidase in the process. Our results indicate that free radicals play an active role in the MPP+ -induced early events that culminate with cell death. [source] Fluoxetine Induces Apoptosis in Ovarian Carcinoma Cell Line OVCAR-3 Through Reactive Oxygen Species-Dependent Activation of Nuclear Factor-,BBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 6 2010Chung Soo Lee FLX-induced mitochondrial membrane permeability change and formation of reactive oxygen species, leading to cell death. FLX-induced increase in mitochondrial Bax levels, decrease in cytosolic Bid and Bcl-2 levels, loss of the mitochondrial transmembrane potential, cytochrome c release, caspase-3 activation and up-regulation of p53. Oxidant scavengers and Bay 11-7085 [an inhibitor of nuclear factor kappaB (NF-,B) activation] prevented the FLX-induced cell death, increase in phosphorylated inhibitory ,B-, and NF-,B p65 levels, and binding of NF-,B p65 to DNA. Results from this study suggest that FLX may exhibit apoptotic effect against ovarian cancer cell lines by inducing the mitochondrial membrane permeability change, which leads to cytochrome c release and subsequent caspase-3 activation, through reactive oxygen species-dependent activation of NF-,B. [source] Functional studies of an HIV-1 encoded glutathione peroxidaseBIOFACTORS, Issue 1-4 2006Lijun Zhao Abstract In an alternate reading frame overlapping the viral envelope gene, HIV-1 has been shown to encoded a truncated glutathione peroxidase (GPx) module. Essential active site residues of the catalytic core regions of mammalian GPx sequences are conserved in the putative viral GPx (vGPx, encoded by the env-fs gene). Cells transfected with an HIV-1 env-fs construct show up to a 100% increase in GPx enzyme activity, and are protected against the loss of mitochondrial transmembrane potential and subsequent cell death induced by exogenous oxidants or mitochondrial reactive oxygen species. An intact vGPx gene was observed to be more common in HIV-1-infected long-term non-progressors, as compared to HIV-1 isolates from patients developing AIDS. An antioxidant/antiapoptotic protective role of the vGPx is also consistent with the observation that ,1 frameshifting induced by the HIV-1 env-fs sequence AAAAAGA (which contains a potential "hungry" arginine codon, AGA) increases during arginine deficiency, which has been associated with increased oxidative stress. Under arginine-limited conditions, nitric oxide synthase generates superoxide, which rapidly combines with NO to form peroxynitrite, which can cause activated T-cells to undergo apoptosis. Thus, biosynthesis of the HIV-1 GPx as an adaptive response to low arginine conditions might delay oxidant-induced apoptotic cell death, providing an enhanced opportunity for viral replication. [source] Geranylgeraniol, an Intermediate Product in Mevalonate Pathway, Induces Apoptotic Cell Death in Human Hepatoma Cells: Death Receptor-independent Activation of Caspase-8 with Down-regulation of Bcl-xL ExpressionCANCER SCIENCE, Issue 9 2001Yoshio Takeda Geranylgeraniol (GGOH), an intermediate of mevalonate metabolism, is known to induce apoptosis in various lines of cancer cells. The present study was undertaken to clarify the signaling pathways of apoptosis induced by GGOH in human hepatoma cells. HuH-7 human hepatoma cells were incubated in the absence or presence of GGOH. Activation of caspase-8/-9/-3 in HuH-7 cells was found after 8 h treatment with GGOH, at which tune DNA fragmentation and loss of mitochondrial transmembrane potential (,,m) occurred. HuH-7 cells do not express Bcl-2; however, down-regulation of Bcl-xL expression preceded activation of the caspase cascade in GGOH-treated HuH-7 cells, while Bax expression was not changed by GGOH treatment. Addition of caspase inhibitors restored the decreased cell viability of HuH-7 cells by GGOH, including ,,m, to the baseline level, which indicated that caspase triggers mitochondria-dependent apoptotic pathways in GGOH-treated HuH-7 cells. Similarly, GGOH-mediated apoptosis of HuH-7 cells was clearly prevented by coadministration of ursodeoxycholic acid (UDCA), which led to restoration of the level of Bcl-xL expression. Activation of caspase-8/-9/-3, as well as ,,m, by GGOH treatment was suppressed by addition of UDCA. Our results indicate that activation of the caspase cascade initiating from caspase-8, which could be accelerated by down-regulation of Bcl-xL expression, plays a key role in an apoptotic process induced by GGOH in human hepatoma cells. [source] Synthesis and Biological Evaluation of New Geiparvarin DerivativesCHEMMEDCHEM, Issue 5 2009Stefano Chimichi Prof. Abstract New geiparvarin derivatives modified at the alkenyloxy bridge, where the 3,-methyl group was replaced by a hydrogen atom, were synthesized and evaluated against a panel of human tumor cell lines in,vitro. Compounds (R)- 4 and (R)- 5 show greater inhibitory activity toward cell growth than the parent geiparvarin. New geiparvarin derivatives modified at the unsaturated alkenyloxy bridge, where a hydrogen atom replaces the 3,-methyl group, were synthesized and evaluated against a panel of human tumor cell lines in,vitro. These compounds demonstrated an increase in growth inhibitory activity relative to the parent compound, geiparvarin. The activity increased even further in the series of demethylated compounds, with the introduction of a methyl group at the 1,-position of the alkenyloxy chain. In contrast, a remarkable decrease in activity was observed with the introduction of a methyl group at the 2,-position. Interestingly, the new derivatives fully inhibited the growth of drug-resistant cell lines, suggesting that they are not subject to pump-mediated drug efflux. On the basis of their cytotoxic profiles, the most active compounds (R)- 4 and (R)- 5 were selected for further biological evaluation in comparison with the lead compound. The new derivatives strongly induce apoptosis in a promyelocytic leukemia cell line (HL-60) mediated by depolarization of mitochondrial transmembrane potential and mitochondrial production of reactive oxygen species (ROS). [source] | |||||||||||||