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.     

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.     

Structure of the human neutrophil elastase gene

The gene for human neutrophil elastase (NE), a powerful serine protease carried by blood neutrophils and capable of destroying most connective tissue proteins, was cloned from a genomic DNA library of a normal individual. The NE gene consists of 5 exons and 4 introns included in a single copy 4-kilobase segment of chromosome 11 at q14. The coding exons of the NE gene predict a primary translation product of 267 residues including a 29-residue N-terminal precursor peptide and a 20-residue C-terminal precursor peptide. Analysis of the N-terminal peptide sequence suggests it contains a 27-residue "pre" signal peptide followed by a "proN" dipeptide, similar to that of other blood cell lysosomal proteases. The sequences for the mature 218-residue NE protein are included in exons II-V. The 5'-flanking region of the gene includes typical TATA, CAAT, and GC sequences within 61 base pairs (bp) of the cap site. The sequence 1.5 kilobases 5' to exon I contains several interesting repetitive sequences including six tandem repeats of unique 52- or 53-bp sequences. The 5'-flanking region also contains a 19-bp segment with 90% homology to a segment of the 5'-flanking region of the human myeloperoxidase (MPO) gene, a gene also expressed in bone marrow precursor cells and a protein stored in the same neutrophil granules as NE. In addition, like the MPO gene, the NE 5'-flanking region has several regions with greater than or equal to 75% homology to sequences 5' to c-myc, but there is no overlap between the NE-c-myc and MPO-c-myc homologous sequences.     

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.     

Temperature control of germination and its possible role in the survival of a non-dormant population of Avena fatua

Germination of freshly harvested seeds of a non-dormant (ND) line (Stonehouse 319) of wild oats ( Avena fatua L.) was inhibited by incubation of the seeds at relatively high temperatures of 25 and 30°C. The germination inhibition in these seeds appeared to be a case of thermo-inhibition which was the direct effect of hightemperature treatment (HIT), since it did not persist after transferring the seeds to an optimum germination temperature of 20°C. Even a prolonged HTT of 30°C for over 5 weeks did not prevent germination of about 80% of the seeds transferred to 20°C. However, in a significant proportion of the seeds, thermo-dormancy was induced by 10 days of HTT at 30°C if the seeds were then incubated at sub-optimal temperatures of 5 to 15°C. This thermo-dormancy would appear to be 'restrictive' in form, since its expression was restricted to very specific conditions. Relatively low inclubation temperaturs of 5 and 10°C markedly slowed germination whether HTT was applied or not. The results suggest that thermo-inhibition and thermo-dormancy, induced during seasonal temperature fluctuations, may provide a survival mechanism for seeds of such ND lines as Stonehouse 319.