Papel da titina na modulação da função cardíaca e suas implicações fisiopatológicas / The role of titin in the modulation of cardiac function and its pathophysiological implications / Papel de la Titina en la Modulación de la Función Cardíaca y sus Implicaciones Fisiopatológicas

A titina é uma proteína sarcomérica gigante que se estende desde a linha Z até a linha M. Em razão de sua localização, representa um importante sensor biomecânico com um papel fundamental na manutenção da integridade estrutural do sarcômero. A titina funciona como uma "mola bidirecional" que regula o comprimento sarcomérico e realiza ajustes adequados da tensão passiva sempre que o comprimento varia. Dessa forma, não só determina a rigidez ventricular e a função diastólica, como também influencia a função cardíaca sistólica, modulando o mecanismo de Frank-Starling. O miocárdio expressa duas isoformas dessa macromolécula: a N2B, mais rígida, e a isoforma N2BA, mais complacente. As alterações na expressão relativa das duas isoformas da titina ou alterações do seu estado de fosforilação têm sido implicadas na fisiopatologia de várias doenças como a insuficiência cardíaca diastólica, a cardiomiopatia dilatada, a cardiomiopatia isquêmica e a estenose aórtica. Neste artigo pretende-se descrever sumariamente a estrutura e localização da titina, a sua relação com diferentes cardiomiopatias, e compreender de que forma as alterações dessa macromolécula influenciam a fisiopatologia da insuficiência cardíaca diastólica, salientando o potencial terapêutico da manipulação dessa macromolécula.

Titin is a giant sarcomeric protein that extends from the Z-line to the M-line. Due to its location, it represents an important biomechanical sensor, which has a crucial role in the maintenance of the sarcomere structural integrity. Titin works as a "bidireactional spring" that regulates the sarcomeric length and performs adequate adjustments of passive tension whenever the length varies. Therefore, it determines not only ventricular rigidity and diastolic function, but also systolic cardiac function, modulating the Frank-Starling mechanism. The myocardium expresses two isoforms of this macromolecule: the N2B, more rigid and the isoform N2BA, more compliant. The alterations in the relative expression of the two titin isoforms or alterations in their state of phosphorylation have been implicated in the pathophysiology of several diseases, such as diastolic heart failure, dilated cardiomyopathy, ischemic cardiomyopathy and aortic stenosis. The aim of this study is to describe, in brief, the structure and location of titin, its association with different cardiomyopathies and understand how alterations in this macromolecule influence the pathophysiology of diastolic heart failure, emphasizing the therapeutic potential of the manipulation of this macromolecule.

La titina es una proteína sarcomérica gigante que se extiende desde la línea Z hasta la línea M. En razón de su ubicación, representa un importante sensor biomecánico con un papel fundamental en la manutención de la integridad estructural del sarcómero. La titina funciona como un "resorte bidireccional" que regula el largo sarcomérico y realiza ajustes adecuados de la tensión pasiva siempre que ese largo varía. De esa forma, no sólo determina la rigidez ventricular y la función diastólica, sino también influye en la función cardíaca sistólica, modulando el mecanismo de Frank-Starling. El miocardio expresa dos isoformas de esa macromolécula: la N2B, más rígida, y la isoforma N2BA, más complaciente. Las alteraciones en la expresión relativa de las dos isoformas de la titina o alteraciones de su estado de fosforilación han sido implicadas en la fisiopatología de varias enfermedades como la insuficiencia cardíaca diastólica, la cardiomiopatía dilatada, la cardiomiopatía isquémica y la estenosis aórtica. Este artículo pretende describir sumariamente la estructura y ubicación de la titina, su relación con diferentes cardiomiopatías, y comprender de qué forma las alteraciones de esa macromolécula influyen en la fisiopatología de la insuficiencia cardíaca diastólica, destacando el potencial terapéutico de la manipulación de esa macromolécula.

Molecular signaling in pathogenicity and host recognition in smut fungi taking Karnal bunt as a model system.

Karnal bunt of wheat, incited by a phytopathogen Tilletia indica (Syn. Neovossia indica) is a floret infecting disease. In the floral tissues fungus proliferates and produces massive amount of black spores. In smut fungi, belonging to order Ustilaginales, communication between cells is necessary to regulate growth, differentiation and monokaryotic to dikaryotic transition during pathogenic and sexual development. Neighbouring cells are able to communicate with each other by direct cell to cell contact through plasma membrane bound signaling molecules or through formation of gap junctions and alternatively through secretion of chemical signals if cells are some distance away. Current research efforts toward understanding of pathogenic and sexual development in phytopathogenic fungi, offer a number of opportunities. These include the analysis of molecular signal(s) for direct contribution of sexual interactions to ability of smut and bunt pathogens to cause disease. These efforts will provide not only to explore the mechanisms of pathogenesis, but also to enhance knowledge of basic cellular biology of an economically important group of fungi.

Induction of apoptosis in colon cancer cells by nonsteroidal anti-inflammatory drugs

Epidemiological studies have demonstrated that nonsteroidal anti-inflammatory drugs (NSAIDs) decrease the incidence of colon cancer. In addition, NSAIDs reduce the number and size of polyps in patients with familial adenomatous polyposis. The mechanisms of the anti-neoplastic effect of NSAIDs are still far from complete understanding, but one possible mechanism is the induction of apoptosis. Several lines of evidence suggest that NSAIDs-induced apoptosis in colon cancer cells are mediated through the cyclooxygenase (COX)-independent pathway. In this study we explored the mechanism of NSAIDs-induced apoptosis in the colon cancer cell line, HT-29. We confirmed that NSAIDs induce apoptosis in HT-29 cells irrespective of their COX-selectivity. Indomethacin enhanced the expression of p21waf-1 in HT-29 cells. However the expression of apoptosis-related genes such as Fas, bcl-2 and bax was not affected by indomethacin. Intra- and extra-cellular calcium chelators, protein tyrosine kinase (PTK) inhibitor, protein kinase A (PKA) inhibitor and protein kinase C (PKC) inhibitors did not influence indomethacin-induced apoptosis in HT-29 cells. We concluded that NSAIDs-induced apoptosis in colon cancer cells may be independent from signals transducted through [Ca++]i, PTK, PKA, PKC or the expression of apoptosis-related genes. In contrast, our results demonstrating the induction of p21waf-1 transcription by NSAIDs suggest the possible association of NSAIDs-induced apoptosis and cell-cycle control in colon cancer cells.