Melatonina: modulador de morte celular / Melatonin: cell death modulator

A apoptose ou morte programada é um fenômeno biológico essencial para o desenvolvimento e manutenção de uma população celular. Neste processo, as células senescentes ou indesejáveis são eliminadas após ativação de um programa de morte celular, que envolve a participação de moléculas pró-apoptóticas (Fas, FasL, Bax, Caspases 2, 3, 6, 7, 8 e 9). A ativação destas moléculas provoca típicas alterações morfológicas como a retração celular, perda de aderência à matriz extracelular e às células vizinhas, condensação da cromatina, fragmentação do DNA e formação de corpos apoptóticos. Moléculas antiapoptóticas (Bcl2, FLIP) bloqueiam o surgimento e a evolução destas alterações celulares e evitam a morte celular. É o equilíbrio entre moléculas pró e antiapoptóticas que assegura a homeostase tecidual. O descontrole da apoptose pode contribuir para o aparecimento de diversas doenças neoplásicas, autoimunes e neurodegenerativas. Diversos agentes indutores e inibidores de apoptose são reconhecidos como armas potenciais no combate a doenças relacionadas a distúrbios de proliferação e morte celular, dentre eles, destacam-se os hormônios. A melatonina tem sido relatada com importante ação antiápoptótica em diversos tecidos, modulando a expressão de agentes, reduzindo a entrada de cálcio na célula, bem como atenuando a produção de espécies reativas de oxigênio e de proteínas pró-apoptóticas, tal como, diminuição da Bax. O conhecimento de novos agentes capazes de atuar nas vias da apoptose é de grande valia para o desenvolvimento de futuras terapias no tratamento de diversas doenças. Assim, o objetivo dessa revisão é elucidar os principais aspectos da morte celular pela apoptose e o papel da melatonina neste processo.

Apoptosis or programmed death is a biological phenomenon, which is essential for the development and maintenance of a cell population. In this process, senescent or damaged cells are eliminated after activation of a cell death program involving participation of pro-apoptotic molecules (Fas, Fas-L, Bax, caspases 2, 3, 6, 7, 8 and 9). Molecule activation causes typical morphological changes, such as cell shrinkage, loss of adhesion to the extracellular matrix and neighboring cells, chromatin condensation, DNA fragmentation and formation of apoptotic bodies. Anti-apoptotic molecules (Bcl-2, FLIP) block the emergence and evolution of these cell changes and prevent cell death. The balance between molecules pro and anti-apoptotic ensures tissue homeostasis. When apoptosis is out of control, it contributes to the emergence of several neoplastic, autoimmune and neurodegenerative diseases. Several inducing and inhibitors of apoptosis agents are recognized as potential weapons in the fight against diseases related to proliferation and cell death disorders among which stand out hormones. Melatonin has been reported as important anti-apoptotic agent in various tissues by reducing cell calcium uptake, modulating expression of anti-oxidants and decreasing pro-apoptotic protein, such as Bax. The knowledge of new agents capable to act on the course pf apoptosis is important and of great value for developing further therapies against many diseases. Thus, the objective of this review was to elucidate the main aspects of cell death by apoptosis and the role of melatonin in this process.

Envelhecer e morrer / To age and to die

Após breve consideração sobre a origem da vida, os autores questionaram o porquê de se envelhecer e evoluir para o fim. A morte celular programada (apoptose) é discutida, com seu substrato bioquímico (proteases, família, BCL-2, mediadores-chaves na ativação das caspases, inibidores da apoptose). Expõem 18 teorias que procuram explicar o envelhecimento. Relatam, de forma objetiva, as conseqüências da ação do tempo sobre os diversos órgãos e sistemas. Concluem questionando a relação de causalidade entre as teorias expostas e os achados físicos observados no processo de envelhecimento.

After some consideration on the origin of life, the authors question the reason to age and to go to an end. The programmed cellular death (apoptosis) is discussed with its biochemical substratum (proteases, BCL-2 family, key-mediators in the activation of caspases, inhibitors of apoptosis). Eighteen theories that try to explain aging are presented. The consequences of the actin of time on the variios organs and systems will be objectivelly reported. The authors conclude by questioning the relation of causality between the theories displayed and the physical findings observed in the aging process.

Molecular correlates of syncytialization in muscle and placenta.

Syncytialization is one of the most fundamental processes in life. It is observed during development of muscle and osteoclast, and syncytiotrophoblast formation in placental villi. Syncytialization involves recognition, migration, adhesion and finally cell fusion between two interacting cells. It is an energy-dependent process which is essentially restricted to a small portion of interacting cellular membranes. Such regions of membranes may differ from other regions of cell surface in terms of physico-chemistry and expression of specific protein biomolecules resulting in restriction of this process to cells of specific competence. Despite the fact that membrane biologists have given significant quanta of efforts to understand the basic principle underlying this fundamental process of life, further large scale initiatives have to be undertaken to dissect the underlying molecular correlates central to this event.

Involvement of Sox-4 in the cytochrome c-dependent AIF-independent apoptotic pathway in HeLa cells induced by delta12-prostaglandin J2

delta12-Prostaglandin (PG) J2 is known to elicit an anti-neoplastic effects via apoptosis induction. Previous study showed delta12-PGJ2-induced apoptosis utilized caspase cascade through cytochrome c-dependent pathways in HeLa cells. In this study, the cellular mechanism of delta12-PGJ2- induced apoptosis in HeLa cells, specifically, the role of two mitochondrial factors; bcl-2 and apoptosis-inducing factor (AIF) was investigated. Bcl-2 attenuated delta12-PGJ2-induced caspase activation, loss of mitochondrial transmembrane potential (delta psi m), nuclear fragmentation, DNA laddering, and growth curve inhibition for approximately 24 h, but not for longer time. AIF was not released from mitochondria, even if the delta psi m was dissipated. One of the earliest events observed in delta12-PGJ2-induced apoptotic events was dissipation of delta psi m, the process known to be inhibited by bcl-2. Pre-treatment of z-VAD- fmk, the pan-caspase inhibitor, resulted in the attenuation of delta psi m depolarization in delta12-PGJ2- induced apoptosis. Up-regulation of Sox-4 protein by delta12-PGJ2 was observed in HeLa and bcl-2 overexpressing HeLa B4 cell lines. Bcl-2 overexpression did not attenuate the expression of Sox-4 and its expression coincided with other apoptotic events. These results suggest that delta12-PGJ2 induced Sox-4 expression may activate another upstream caspases excluding the caspase 9-caspase 3 cascade of mitochondrial pathway. These and previous findings together suggest that delta12-PGJ2-induced apoptosis in HeLa cells is caspase-dependent, AIF-independent events which may be affected by Sox-4 protein expression up-regulated by delta12-PGJ2.

-Melanocyte Stimulating Hormone (MSH) decreases cyclosporine A induced apoptosis in cultured human proximal tubular cells

The pathogenesis of chronic cyclosporine A (CsA) nephrotoxicity has not been elucidated, but apoptosis is thought to play an important role in CsA induced tubular atrophy. Recently Fas-Fas ligand system mediated apoptosis has been frequently reported in many epithelial cells as well as in T lymphocytes. We investigated the ability of CsA to induce apoptosis in cultured human proximal tubular epithelial cells and also the effect of -MSH on them. Fas, Fas ligand, and an intracellular adaptor protein, Fas-associating protein with death domain (FADD) expression, and poly-ADP ribose polymerase (PARP) cleavage were also studied. CsA induced apoptosis in cultured tubular epithelial cells demonstrated by increased number of TUNEL positive cells and it was accompanied by a significant increase in Fas mRNA and Fas ligand protein expressions. FADD and the cleavage product of PARP also increased, indicating the activation of caspase. In -MSH co-treated cells, apoptosis markedly decreased with downregulation of Fas, Fas ligand and FADD expressions and also the cleavage product of PARP. In conclusion, these data suggest that tubular cell apoptosis mediated by Fas system may play a role in tubular atrophy in chronic CsA nephrotoxicity and pretreatment of -MSH may have a some inhibitory effect on CsA induced tubular cell apoptosis.

Apoptosis: muerte celular programada: parte I / Apoptosis: programmed cell death: part I

Apoptosis o "muerte celular programada" es una función biológica normal que mantiene el número de células en tejidos adultos, desarrollo embriológico e involución (atresia), regulada y ejecutada por genes específicos. La apoptosis es responsable del balance en la proliferación celular y mantención del número constante de células en los tejidos y eliminación de células potencialmente peligrosas (infectadas por virus, con daño del ADN, o afectadas por tóxicos o hipoxia) incluyendo mutaciones que pueden conducir al desarrollo del cáncer. El programa de muetre celular es controlado por diferentes vías moleculares que convergen en un objetivo común: autodigestión de componentes intracelulares y fragmentación de la cromatina, llamados cuerpos apotósicos. Hasta el momento los agentes proapoptósicos más importabntes son cisteínoaspártico proteasas o "caspasas". El gen bcl 2 (proto-oncogen responsable del linfoma folicular humano) protege a las células de su autodestrucción. Varias proteínas sintetizadas por el Bcl 2 pueden prevenir la salida del citocromo c desde las mitocondrias, factor esencial para conducir a la apoptosis a su etapa final