Mechanisms of cell death pathway activation following drug-induced inhibition of mitochondrial complex I

AbstractRespiratory complex I inhibition by drugs and other chemicals has been implicated as a frequent mode of mitochondria-mediated cell injury. However, the exact mechanisms leading to the activation of cell death pathways are incompletely understood. This study was designed to explore the relative contributions to cell injury of three distinct consequences of complex I inhibition, i.e., impairment of ATP biosynthesis, increased formation of superoxide and, hence, peroxynitrite, and inhibition of the mitochondrial protein deacetylase, Sirt3, due to imbalance of the NADH/NAD+ ratio. We used the antiviral drug efavirenz (EFV) to model drug-induced complex I inhibition. Exposure of cultured mouse hepatocytes to EFV resulted in a rapid onset of cell injury, featuring a no-effect level at 30µM EFV and submaximal effects at 50µM EFV. EFV caused a concentration-dependent decrease in cellular ATP levels. Furthermore, EFV resulted in increased formation of peroxynitrite and oxidation of mitochondrial protein thiols, including cyclophilin D (CypD). This was prevented by the superoxide scavenger, Fe-TCP, or the peroxynitrite decomposition catalyst, Fe-TMPyP. Both ferroporphyrins completely protected from EFV-induced cell injury, suggesting that peroxynitrite contributed to the cell injury. Finally, EFV increased the NADH/NAD+ ratio, inhibited Sirt3 activity, and led to hyperacetylated lysine residues, including those in CypD. However, hepatocytes isolated from Sirt3-null mice were protected against 40µM EFV as compared to their wild-type controls. In conclusion, these data are compatible with the concept that chemical inhibition of complex I activates multiple pathways leading to cell injury; among these, peroxynitrite formation may be the most critical

Abnormal systolic blood pressure response during exercise is related to subendocardial hypoperfusion detected by exercise 201Tl myocardial scintigraphy in patient with hypertrophic cardiomyopathy

Balcells, EugèniaPla general, d'alguns dels elements que formen la taula periòdica. Cadascun dels 112 elements és representat pel seu espectre de color. Es van produir diverses còpies de l'obra, aquesta està a la Biblioteca de la Facultat de Química

FKF1 conveys timing information for CONSTANS stabilization in photoperiodic flowering

Plants use day-length information to coordinate flowering time with the appropriate season to maximize reproduction. In Arabidopsis, the long-day specific expression of CONSTANS (CO) protein is crucial for flowering induction. Although light signaling regulates CO protein stability, the mechanism by which CO is stabilized in the long-day afternoon has remained elusive. Here we demonstrate that FLAVIN-BINDING, KELCH REPEAT, F-BOX 1 (FKF1) protein stabilizes CO protein in the afternoon in long days. FKF1 interacts with CO through its LOV domain, and blue light enhances this interaction. In addition, FKF1 simultaneously removes CYCLING DOF FACTOR 1 (CDF1) that represses CO and FLOWERING LOCUS T (FT) transcription. Together with CO transcriptional regulation, FKF1 protein controls robust FT mRNA induction through multiple feedforward mechanisms that accurately control flowering timing

Metabolizable protein supply according to the NRC (2001) for dairy cows grazing elephant grass.

Pastagens tropicais fertilizadas com nitrogênio podem ter alto teor de proteína bruta (PB) com alta degradabilidade ruminal. O fornecimento de concentrado com alto teor de PB para vacas mantidas nestas pastagens pode aumentar os custos sem efeitos positivos no desempenho. Objetivou-se avaliar os efeitos do suprimento de proteína metabolizável acima das recomendações do NRC (2001) para vacas em pastejo. Quatorze piquetes de capim elefante (Pennisetum purpureum Schum. cv. Napier) com 0,2 ha cada, foram usados em sistema de pastejo rotacionado. Três concentrados (6,3 kg MS-1 vaca-1 dia-1) foram avaliados. O concentrado controle com 17% PB na MS (17% PB) foi ajustado em proteína metabolizável de acordo com o NRC (2001). Os outros dois concentrados foram formulados inclusão extra de farelo de soja para conterem 21,2 (CP) e 25% (CP) de PB na MS. Foram usadas 12 vacas holandesas multíparas com 150 dias em lactação e produção de leite de 19,5 kg dia-1, arranjadas em QL 3 × 3 com quatro replicatas. A massa de forragem disponível era de 11.270 kg MS dia-1 com 34% de folhas verdes e 12% de PB. A produção de leite, produção de leite corrigida para 3,5%, teores de gordura, proteína, lactose e sólidos totais não foram afetados (P > 0,05) pelos tratamentos. O nitrogênio uréico do leite e o nitrogênio uréico do plasma aumentaram linearmente (P 0,05) o ganho de peso, condição corporal, tempo de pastejo, tempo de ruminação, tempo em ócio, temperatura retal e a freqüência respiratória dos animais. O teor de PB no concentrado para suprir proteína metabolizável de acordo com o NRC (2001), é adequado para vacas em terço médio de lactação, mantidas em pastagens tropicais

Composição morfológica e bromatológica de pastagens de Pennisetum pirpureum submetidas a diferentes intervalos entre pastejos.

As composições bromatológica e morfológica são duas características qualitativas das plantas forrageiras de grande importância para o desempenho de bovinos em pastejo. Desse modo, o objetivo do ensaio experimental foi avaliar os efeitos de dois diferentes intervalos entre pastejos sobre a composição bromatológica e morfológica de pastagens de capim Elefante, pastejada por vacas lactantes. Os tratamentos testados foram: intervalo entre pastejos variável, determinado pela entrada dos animais na área a ser pastejada, quando o dossel atingisse 95% de interceptação de luz e intervalo entre pastejos fixo em 27 dias. O delineamento experimental foi o inteiramente casualizado com medidas repetidas no tempo (4 sub-periodos). Foram observados maiores (P<0,05) teores de extrato etéreo, fibra em detergente neutro e fibra em detergente ácido para o intervalo entre pastejos fixo em 27 dias. O intervalo entre pastejos variável proporcionou maior (P<0,05) teor de matéria mineral na forragem. Não foram observados efeitos dos tratamentos sobre os teores de matéria seca, proteína bruta e lignina. Houve maior massa de material senescido (P<0,05) e tendência (P~0,08) de maior massa de colmos para o intervalo entre pastejo fixo de 27 dias no pré e pós-pastejo. Houve também tendência (P=O,10) de maior massa de folhas para o intervalo entre pastejo variável no resíduo pós-pastejo. O intervalo entre pastejo variável melhorou os aspectos bromatológicos e morfológicos do capim Elefante

Características produtivas e qualitativas de pastagens de Pennisetum purpureum submetidas a diferentes intervalos entre pastejos.

O intervalo entre pastejos pode exercer forte influência nos aspectos produtivos e qualitativos das plantas forrageiras tropicais, com reflexos na produção dos animais mantidos em pastagens. Assim, o objetivo do ensaio experimental foi comparar os efeitos de dois diferentes intervalos entre pastejos sobre algumas caracteristicas produtivas e qualitativas do dossel de capim Elefante pastejado por vacas em lactação. Os tratamentos foram: intervalo entre pastejos variável, determinado pela entrada dos animais na área a ser pastejada, quando o dossel atingisse 95% de interceptação de luz e intervalo entre pastejos fixados em 27 dias. O delineamento experimental foi o inteiramente casualizado com medidas repetidas no tempo. A frequência de desfolha, a altura do dossel no pré e pós-pastejo,. a interceptação de luz pelo dossel e o índice de área foliar, foram maiores (PO,O5) dos tratamentos sobre a massa de forragem em pré e pós-pastejo. O intervalo entre pastejos fixado em 27 dias, durante a época das águas, proporcionou forragem de pior qualidade

Diferentes teores de proteína metabolizável em rações com cana-de-açúcar para vacas em lactação.

O presente trabalho teve como objetivo avaliar o efeito de diferentes teores de proteína metabolizável (PM) na ração de vacas lactantes alimentadas com cana-de-açúcar

An explanatory model of temperature influence on flowering through whole-plant accumulation of FLOWERING LOCUS T in Arabidopsis thaliana

We assessed mechanistic temperature influence on flowering by incorporating temperature-responsive flowering mechanisms across developmental age into an existing model. Temperature influences the leaf production rate as well as expression of FLOWERING LOCUS T (FT), a photoperiodic flowering regulator that is expressed in leaves. The Arabidopsis Framework Model incorporated temperature influence on leaf growth but ignored the consequences of leaf growth on and direct temperature influence of FT expression. We measured FT production in differently aged leaves and modified the model, adding mechanistic temperature influence on FT transcription, and causing whole-plant FT to accumulate with leaf growth. Our simulations suggest that in long days, the developmental stage (leaf number) at which the reproductive transition occurs is influenced by day length and temperature through FT, while temperature influences the rate of leaf production and the time (in days) the transition occurs. Further, we demonstrate that FT is mainly produced in the first 10 leaves in the Columbia (Col-0) accession, and that FT accumulation alone cannot explain flowering in conditions in which flowering is delayed. Our simulations supported our hypotheses that: (i) temperature regulation of FT, accumulated with leaf growth, is a component of thermal time, and (ii) incorporating mechanistic temperature regulation of FT can improve model predictions when temperatures change over time

An explanatory model of temperature influence on flowering through whole-plant accumulation of FLOWERING LOCUS T in Arabidopsis thaliana

We assessed mechanistic temperature influence on flowering by incorporating temperature-responsive flowering mechanisms across developmental age into an existing model. Temperature influences the leaf production rate as well as expression of FLOWERING LOCUS T (FT), a photoperiodic flowering regulator that is expressed in leaves. The Arabidopsis Framework Model incorporated temperature influence on leaf growth but ignored the consequences of leaf growth on and direct temperature influence of FT expression. We measured FT production in differently aged leaves and modified the model, adding mechanistic temperature influence on FT transcription, and causing whole-plant FT to accumulate with leaf growth. Our simulations suggest that in long days, the developmental stage (leaf number) at which the reproductive transition occurs is influenced by day length and temperature through FT, while temperature influences the rate of leaf production and the time (in days) the transition occurs. Further, we demonstrate that FT is mainly produced in the first 10 leaves in the Columbia (Col-0) accession, and that FT accumulation alone cannot explain flowering in conditions in which flowering is delayed. Our simulations supported our hypotheses that: (i) temperature regulation of FT, accumulated with leaf growth, is a component of thermal time, and (ii) incorporating mechanistic temperature regulation of FT can improve model predictions when temperatures change over time