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- ItemSomente MetadadadosApoptosis induced by A beta 25-35 peptide is Ca2+-IP3 signaling-dependent in murine astrocytes(Wiley-Blackwell, 2014-08-01) Oseki, Karen Tubono [UNIFESP]; Monteforte, Priscila Totarelli [UNIFESP]; Pereira, Gustavo José da Silva [UNIFESP]; Hirata, Hanako [UNIFESP]; Ureshino, Rodrigo Portes [UNIFESP]; Bincoletto, Claudia [UNIFESP]; Hsu, Yi-Te; Smaili, Soraya Soubhi [UNIFESP]; Universidade Federal de São Paulo (UNIFESP); Med Univ S CarolinaAlthough the accumulation of the neurotoxic peptide beta-amyloid (A beta) in the central nervous system is a hallmark of Alzheimer's disease, whether A beta acts in astrocytes is unclear, and downstream functional consequences have yet to be defined. Here, we show that cytosolic Ca2+ dysregulation, induced by a neurotoxic fragment (A beta 25-35), caused apoptosis in a concentration-dependent manner, leading to cytoplasmic Ca2+ mobilization from extra-and intracellular sources, mainly from the endoplasmic reticulum (ER) via IP3 receptor activation. This mechanism was related to A beta-mediated apoptosis by the intrinsic pathway because the expression of pro-apoptotic Bax was accompanied by its translocation in cells transfected with GFP-Bax. A beta-mediated apoptosis was reduced by BAPTA-AM, a fast Ca2+ chelator, indicating that an increase in intracellular Ca2+ was involved in cell death. Interestingly, the Bax translocation was dependent on Ca2+ mobilization from IP3 receptors because pre-incubation with xestospongin C, a selective IP3 receptor inhibitor, abolished this response. Taken together, these results provide evidence that A beta dysregulation of Ca2+ homeostasis induces ER depletion of Ca2+ stores and leads to apoptosis; this mechanism plays a significant role in A beta apoptotic cell death and might be a new target for neurodegeneration treatments.
- ItemSomente MetadadadosBax affects intracellular Ca2+ stores and induces Ca2+ wave propagation(Nature Publishing Group, 2004-12-01) Carvalho, ACP; Sharpe, J.; Rosenstock, T. R.; Teles, AFV; Youle, R. J.; Smaili, Soraya Soubhi [UNIFESP]; Universidade Federal de São Paulo (UNIFESP); NINDS; Universidade de São Paulo (USP)In the present study, we evaluated proapoptotic protein Bax on mitochondria and Ca2+ homeostasis in primary cultured astrocytes. We found that recombinant Bax (rBax, 10 and 100 ng/ml) induces a loss in mitochondrial membrane potential (DeltaPsi(m)). This effect might be related to the inhibition of respiratory rates and a partial release of cytochrome c, which may change mitochondrial morphology. the loss of DeltaPsi(m) and a selective permeabilization of mitochondrial membranes contribute to the release of Ca2+ from the mitochondria. This was inhibited by cyclosporin A (5 muM) and Ruthenium Red (1 mug/ml), indicating the involvement of mitochondrial Ca2+ transport mechanisms. Bax-induced mitochondrial Ca2+ release evokes Ca2+ waves and wave propagation between cells. Our results show that Bax induces mitochondrial alteration that affects Ca2+ homeostasis and signaling. These changes show that Ca2+ signals might be correlated with the proapoptotic activities of Bax.
- ItemSomente MetadadadosBax translocation to mitochondria subsequent to a rapid loss of mitochondrial membrane potential(Nature Publishing Group, 2001-09-01) Smaili, Soraya Soubhi [UNIFESP]; Hsu, Y. T.; Sanders, K. M.; Russel, J. T.; Youle, R. J.; NINDS; Universidade Federal de São Paulo (UNIFESP); NICHHD; Med Univ S CarolinaBax, a pro-apoptotic member of the Bcl-2 family, is a cytosolic protein that inserts into mitochondrial membranes upon induction of cell death. Using the green fluorescent protein fused to Bax (GFP-Bax) to quantitate mitochondrial binding in living cells we have investigated the cause of Bax association with mitochondria and the time course relative to endogenous and induced changes in mitochondrial membrane potential (Delta Psi (m)). We have found that staurosporine (STS) induces a loss in Delta Psi (m) before GFP-Bax translocation can be measured. the onset of the Delta Psi (m) loss is followed by a rapid and complete collapse of Delta Psi (m) which is followed by Bax association with mitochondria. the mitochondria uncoupler FCCP, in the presence of the F-1-F-0 ATPase inhibitor oligomycin, can trigger Bax translocation to mitochondria suggesting that when ATP levels are maintained a collapse of Delta Psi (m) induces Bax translocation. Neither FCCP nor oligomycin alone alters Bax location. Bax association with mitochondria is also triggered by inhibitors of the electron transport chain, antimycin and rotenone, compounds that collapse Delta Psi (m) without inducing rapid ATP hydrolysis that typically occurs with uncouplers such as FCCP. Taken together, our results suggest that alterations in mitochondrial energization associated with apoptosis can initiate Bax docking to mitochondria.
- ItemSomente MetadadadosBcl-X-L inhibits Bax-induced alterations in mitochondrial respiration and calcium release(Elsevier B.V., 2008-09-12) Teles, Alessandra Vaz Fernandes Fiuza [UNIFESP]; Ureshino, Rodrigo Portes [UNIFESP]; Dorta, Daniel Junqueira [UNIFESP]; Lopes, Guiomar Silva [UNIFESP]; Hsu, Yi-Te; Smaili, Soraya Soubhi [UNIFESP]; Universidade Federal de São Paulo (UNIFESP); Med Univ S CarolinaApoptosis is a natural cell elimination process involved in a number of physiological and pathological events. This process can be regulated by members of the Bcl-2 family. Bax, a pro-apoptotic member of this family, accelerates cell death, while the pro-survival member, Bcl-X-L, can antagonize the pro-apoptotic function of Bax to promote cell survival. in the present study, we have evaluated the effect of Bcl-X-L on Bax-induced alterations in mitochondrial. respiration and calcium release. We found that in primary cultured astrocytes, recombinant Bcl-X-L is able to antagonize Bax-induced decrease in mitochondrial respiration and increase in mitochondrial. calcium release. in addition, we found that Bcl-X-L can lower the calcium store in the endoplasmic reticulum, thus limiting potential calcium flux induced by apoptosis. This regulation of calcium flux by Bcl-X-L may represent an important mechanism by which this protein promotes cell survival. (c) 2008 Elsevier Ireland Ltd. All rights reserved.
- ItemAcesso aberto (Open Access)Calcium and cell death signaling in neurodegeneration and aging(Academia Brasileira de Ciências, 2009-09-01) Smaili, Soraya Soubhi [UNIFESP]; Hirata, Hanako [UNIFESP]; Ureshino, Rodrigo Portes [UNIFESP]; Monteforte, Priscila T. [UNIFESP]; Morales, Ana P. [UNIFESP]; Muler, Mari Luminosa [UNIFESP]; Terashima, Juliana [UNIFESP]; Oseki, Karen Tubono [UNIFESP]; Rosenstock, Tatiana R. [UNIFESP]; Lopes, Guiomar Silva [UNIFESP]; Bincoletto, Claudia [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)Transient increase in cytosolic (Cac2+) and mitochondrial Ca2+ (Ca m2+) are essential elements in the control of many physiological processes. However, sustained increases in Ca c2+ and Ca m2+ may contribute to oxidative stress and cell death. Several events are related to the increase in Ca m2+, including regulation and activation of a number of Ca2+ dependent enzymes, such as phospholipases, proteases and nucleases. Mitochondria and endoplasmic reticulum (ER) play pivotal roles in the maintenance of intracellular Ca2+ homeostasis and regulation of cell death. Several lines of evidence have shown that, in the presence of some apoptotic stimuli, the activation of mitochondrial processes maylead to the release of cytochrome c followed by the activation of caspases, nuclear fragmentation and apoptotic cell death. The aim of this review was to show how changes in calcium signaling can be related to the apoptotic cell death induction. Calcium homeostasis was also shown to be an important mechanism involved in neurodegenerative and aging processes.
- ItemSomente MetadadadosEffects of 17 beta-estradiol replacement on the apoptotic effects caused by ovariectomy in the rat hippocampus(Elsevier B.V., 2010-05-22) Sales, Sayuri; Ureshino, Rodrigo Portes [UNIFESP]; Santos Pereira, Renato Tavares dos; Amaral Luna, Milene Schmidt; Oliveira, Marcelo Pires de [UNIFESP]; Yamanouye, Norma; Godinho, Rosely Oliveira [UNIFESP]; Smaili, Soraya Soubhi [UNIFESP]; Porto, Catarina Segreti [UNIFESP]; Francis Abdalla, Fernando Mauricio; Inst Butantan; Universidade Federal de São Paulo (UNIFESP)Aims: the aim of the present study was to investigate the effects of different periods of ovariectomy and 17 beta-estradiol replacement on apoptotic cell death and expression of members of the Bcl-2 family in the rat hippocampus.Main methods: Hippocampi were obtained from rats in proestrus, ovariectomized (15 days, 21 days and 36 days), ovariectomized for 15 days and then treated with 17 beta-estradiol for 7 or 21 days, and rats ovariectomized and immediately treated with 17 beta-estradiol for 21 days. the expression of Bcl-2 and Bax and the number of apoptotic cells were determined.Key findings: Ovariectomy decreased Bcl-2 expression and increased Bax expression and the number of apoptotic cells. Replacement with 17 beta-estradiol (21 days) throughout the post-ovariectomy period reduced the number of apoptotic cells to the control levels, and prevented the effects of ovariectomy on Bax expression, but only partially restored the Bcl-2 expression. After 15 days of ovariectomy. the replacement with 17 beta-estradiol for 21 days, but not for 7 days, restored the Bcl-2 and Bax expression and the percentage of apoptotic cells to the levels found in the proestrus control.Significance: the present results show that a physiological concentration of 17 beta-estradiol may help maintain long-term neuronal viability by regulating the expression of members of the Bcl-2 family. Even after a period of hormonal deprivation, treatment with 17 beta-estradiol is able to restore the expression of Bax and Bcl-2 to control levels, but the duration of the treatment is a key factor to obtain the desired effect. These data provide new understanding into the mechanisms contributing to the neuroprotective action of estrogen. (C) 2010 Elsevier Inc. All rights reserved.
- ItemSomente MetadadadosEndoplasmic Reticulum Calcium Release Engages Bax Translocation in Cortical Astrocytes(Springer, 2011-05-01) Morales, A. P.; Carvalho, A. C. P.; Monteforte, P. T.; Hirata, H.; Han, S. W. [UNIFESP]; Hsu, Y. -T.; Smaili, Soraya Soubhi [UNIFESP]; Universidade Federal de São Paulo (UNIFESP); Med Univ S CarolinaApoptosis is a highly complex form of cell death that can be triggered by alterations in Ca(2+) homeostasis. Members of the Bcl-2 family may regulate apoptosis and modulate Ca(2+) distribution within intracellular compartments. Bax, a proapoptotic member of the family, is constitutively expressed and soluble in the cytosol and, under apoptotic induction, translocates to mitochondrial membranes. However, it is not clear if the intracellular Ca(2+) stores and selective Ca(2+) releases can modulate or control Bax translocation. the aim of this study was to investigate the relation of intracellular Ca(2+) stores with Bax translocation in rat cortical astrocytes. Results show that the classical apoptotic inducer, staurosporine, caused high elevations of cytosolic Ca(2+) that precede Bax translocation. On the other hand, agents that mobilize Ca(2+) from endoplasmic reticulum such as noradrenaline or thapsigargin, induced Bax translocation, while mitochondrial Ca(2+) release evoked by carbonyl cyanide-p-(trifluoromethoxyphenyl) hydrazone was not able to cause Bax punctation. in addition, microinjection of inositol 1,4,5- trisphosphate induced Bax translocation. Taken together, our results show that in Bax overexpressing cortical astrocytes, endoplasmic reticulum-Ca(2+) release may induce Bax transactivation and specifically control apoptosis.
- ItemAcesso aberto (Open Access)Fludarabine induces apoptosis in chronic lymphocytic leukemia - the role of P53, Bcl-2, Bax, Mcl-1, and Bag-1 proteins(Associação Brasileira de Divulgação Científica, 2006-03-01) Faria, Jose Roberto de [UNIFESP]; Yamamoto, Mihoko [UNIFESP]; Faria, Rosa Malena Delbone de [UNIFESP]; Kerbauy, José [UNIFESP]; Oliveira, José Salvador Rodrigues de [UNIFESP]; Universidade Federal de Minas Gerais Hospital das Clínicas Serviço de Hematologia e Hemoterapia; Universidade Federal de São Paulo (UNIFESP)The expression of P53, Bcl-2, Bax, Bag-1, and Mcl-1 proteins in CD5/CD20-positive B-chronic lymphocytic leukemia (B-CLL) cells from 30 typical CLL patients was evaluated before and after 48 h of incubation with 10-6 M fludarabine using multiparametric flow cytometric analysis. Protein expression was correlated with annexin V expression, Rai modified clinical staging, lymphocyte doubling time, and previous treatment. Our main goal was to determine the predictive value of these proteins in CLL cells in terms of disease evolution. Bcl-2 expression decreased from a median fluorescence index (MFI) of 331.71 ± 42.2 to 245.81 ± 52.2 (P < 0.001) after fludarabine treatment, but there was no difference between viable cells (331.57 ± 44.6 MFI) and apoptotic cells (331.71 ± 42.2 MFI) before incubation (P = 0.859). Bax expression was higher in viable cells (156.24 ± 32.2 MFI) than in apoptotic cells (133.56 ± 35.7 MFI) before incubation, probably reflecting defective apoptosis in CLL (P = 0.001). Mcl-1 expression was increased in fludarabine-resistant cells and seemed to be a remarkable protein for the inhibition of the apoptotic process in CLL (from 233.59 ± 29.8 to 252.04 ± 35.5; P = 0.033). After fludarabine treatment, Bag-1 expression was increased in fludarabine-resistant cells (from 425.55 ± 39.3 to 447.49 ± 34.5 MFI, P = 0.012), and interestingly, this higher expression occurred in patients who had a short lymphocyte doubling time (P = 0.022). Therefore, we could assume that Bag-1 expression in such situation might identify CLL patients who will need treatment earlier.
- ItemRestritoImuno Expressão de proteínas regulatórias da apoptose, p53, Bcl-2 e Bax em Ulcerações Aftosas Recorrentes(Universidade Federal de São Paulo (UNIFESP), 2011-03-30) Rodrigues, Joao Flavio Nishihara Pinto [UNIFESP]; Ribeiro, Daniel Araki [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)Recurrent aphthous ulceration (RAU) is considered to be a chronic inflammatory disease of unknown pathogenesis. Apoptosis may represent an important event in the control of inflammation.The aim of this study was to investigate apoptosis process in RAU by means of immunohistochemistry. We studied the expression and location of proteins related with intrinsic pathway of apoptosis p53, bcl-2 and bax in ulcerated lesions clinically diagnosed as RAU (n = 12) and to compare it with that of oral clinically normal mucosa (7) and of other inflammatory chronic disease such as oral fibrous inflammatory hyperplasia (FIH; n = 18). Significant statistically differences (p<0.05) in p53 expression were noticed to RAU when compared to normal mucosa. Bcl-2 and bax did not show remarkable differences between groups. Taken together, the data suggest that RAU induces apoptosis as a result of p53 upregulation. This protein might be related with the aetiopathogenesis of the ulcerated oral lesions.