Protease Activated Receptor-2 Contributes to Heart Failure

Heart failure is a major clinical problem worldwide. Previous studies have demonstrated an important role for G protein-coupled receptors, including protease-activated receptors (PARs), in the pathology of heart hypertrophy and failure. Activation of PAR-2 on cardiomyocytes has been shown to induce hypertrophic growth in vitro. PAR-2 also contributes to myocardial infarction and heart remodeling after ischemia/reperfusion injury. In this study, we found that PAR-2 induced hypertrophic growth of cultured rat neonatal cardiomyocytes in a MEK1/2 and p38 dependent manner. In addition, PAR-2 activation on mouse cardiomyocytes increased expression of the pro-fibrotic chemokine MCP-1. Furthermore, cardiomyocyte-specific overexpression of PAR-2 in mice induced heart hypertrophy, cardiac fibrosis, inflammation and heart failure. Finally, in a mouse model of myocardial infarction induced by permanent ligation of the left anterior descending coronary artery, PAR-2 deficiency attenuated heart remodeling and improved heart function independently of its contribution to the size of the initial infarct. Taken together, our data indicate that PAR-2 signaling contributes to the pathogenesis of hypertrophy and heart failure.     

Osmoregulation in symbiosis-independent mutants of Bdellovibrio bacteriovorus.

Bdellovibrios capable of axenic growth grow in a cell-free medium at a rate considerably lower than that attainable in a two-membered culture with Escherichia coli. The axenic growth rate may be improved either by adjustment of the osmosity of the medium or by the addition of low concentrations of spermine.     

Metabolic reduction of chromium,as related to its carcinogenic properties

At variance with Cr(III), Cr(VI) compounds easily cross cell membranes and exert genotoxic effects. No metabolic oxidation of Cr(III) could be detected, whereas Cr(VI) reduction was observed in the presence of body fluids and subcellular fractions of various tissues from several animal species. The differential efficiency of this process may account for the selection of target tissues in Cr(VI) carcinogenesis. For instance, reduction by saliva and gastric juice may explain a lack of carcinogenicity by the oral route; reduction inside erythrocytes may explain a lack of carcinogenicity at a distance from administration sites; reduction by the epithelial-lining fluid of terminal airways and by alveolar macrophages may be consistent with the occurrence of thresholds in lung carcinogenesis. Liver preparations displayed the top efficiency in reducing Cr(VI), whereas skeletal muscle, i.e., a typical target in experimental Cr(VI) carcinogenesis, had no detectable activity. Bronchial tree and peripheral lung parenchyma preparations from almost 100 individuals reduced Cr(VI) to a variable extent. The efficiency of lung parenchyma and of isolated alveolar macrophages was enhanced in cigarette smokers. In rats, Cr(VI) reduction by lung preparations was significantly stimulated by the repeated i.t. instillation of Cr(VI) itself. Among the electron donors (chiefly GSH) and enzymatic mechanisms responsible for the intracellular Cr(VI) reduction, such as cytochrome P-450 reductase, glutathione redactase, and aldehyde oxidase, an important role can be ascribed to cytosolic DT diaphorase activity, usually catalyzing a 2-electron reduction.     

Prevention by N-acetylcysteine of benzo[a]pyrene clastogenicity and DNA adducts in rats

The daily i.t. administration of benzo[a]pyrene (BP) to Sprague-Dawley rats, for 3 consecutive days, did not cause any toxicity or clastogenicity in bone marrow cells, as evaluated by monitoring the ratio of polychromatic to normochromatic erythrocytes and the frequency of micronucleated polychromatic erythrocytes. However, BP produced a considerable enhancement of binucleated and micronucleated pulmonary alveolar macrophages, as well as a significant increase in polymorphonucleates recovered by bronchoalveolar lavage. These effects were prevented by administering the thiol N-acetylcysteine (NAC) by gavage 5 h before each BP instillation. In addition, the i.t. treatment with BP resulted in the formation of BP diolepoxide (BPDE)-DNA adducts in lungs and liver, as assessed by synchronous fluorescence spectrophotometry, with fluorescence peaks of similar magnitude in the 2 tissues. Pretreatment with NAC by gavage completely prevented BPDE adducts to liver DNA and significantly decreased those to lung DNA.     

Sequence and structural organization of the human gene encoding ciliary neurotrophic factor.

Ciliary neurotrophic factor (CNTF) is a potent polypeptide hormone whose actions appear to be restricted to the nervous system where it promotes survival, neurotransmitter synthesis and neurite outgrowth in certain neuronal populations. We have cloned the gene encoding human CNTF (hCNTF) and have characterized its structure and organization. The hCNTF gene appears to be a unique-copy gene with a simple genetic organization, since only a single intron interrupts the coding domain. The hCNTF gene is located on chromosome 11, as determined using human-hamster somatic cell hybrids. The CNTF protein is highly conserved in evolution. The amino acid (aa) sequences of rat and rabbit CNTF translated from cDNAs display approx. 85% homology with the deduced aa sequence encoding hCNTF.     

Stoichiometric and catalytic hydrogenation of the [Co2(CO)6(μ2-η2-alkyne)] complexes

The [Co₂(CO)₆(RC₂R′)] complexes (R, R′ = H, Me, Et, Prⁿ) react with molecular hydrogen under mild conditions of temperature and pressure, at low but appreciable rates. The effect of the steric hindrance of the substituents and the strength of the metalcarbon bonds are discussed. The kinetic data measured for [Co₂(CO)₆(HC₂H)], suggest that both H₂-coordination and CO-dissociation are involved in the rate-determining step of the overall hydrogenation process.The catalytic activity of [Co₂(CO)₆(HC₂H)] in the homogeneous hydrogenation of acetylene is described. At low substrate/catalyst ratio the initial hydrogenation rate is equal, within experimental error, to that found for the stoichiometric reaction; on increasing the acetylene concentration, cyclotrimerization to benzene becomes the dominant process. Interestingly C₄ hydrocarbons (mainly butadiene and 1-butene) are produced in measurable yield (?8%). The formation of these products is interpreted as the result of the hydrogenation of the elusive [Co₂(CO)₅(HC₂H)₂] complex, an unstable intermediate in the cyclotrimerization chain.     

Calcium-Dependent Transglutaminase of Rat Sympathetic Ganglion in Development and After Nerve Injury

The activity of transglutaminase (TG) was examined in the rat superior cervical ganglion (SCG) during development and after postganglionic nerve crush. During postnatal development the enzyme activity is increased by sevenfold in parallel to protein content of the ganglion and reaches adult levels by day 35 after birth. The endogenous activity (enzyme activity assayed in the absence of the exogenous substrate) during development is transiently elevated with a peak at day 21 postnatal. In the adult ganglion the enzyme specific activity is evenly distributed in all subcellular compartments, but most of it is contained in the cytosol. Within the first hour after axotomy TG activity is rapidly and transiently elevated. The peak value, 80% above control levels, is attained by 30 min postoperative. At this time the activity is increased in all subcellular fractions, but the endogenous activity is selectively increased in the fraction containing nuclei. The enhanced TG activity after axotomy can be prevented by topical treatments with verapamil, an inhibitor of voltage-dependent calcium fluxes across excitable membranes, or with the calcium chelator EGTA. The results show that intracellular TG activity is present in the SCG and that it increases with postnatal growth of the ganglion. After axotomy the enzyme activity is rapidly and transiently increased in the ganglion and this elevation critically depends on calcium fluxes.