Synthesis, in vitro, and in vivo antibacterial activity of nocathiacin I thiol-Michael adducts

The synthesis and antibacterial activity of a series of nocathiacin I derivatives (4-20) containing polar water solubilizing groups is described. Thiol-Michael adducts containing acidic polar groups have reduced antibacterial activity whereas those with basic polar groups have retained very good antibacterial activity.     

Inhibition of B(a)P induced strand breaks in presence of curcumin

Incidence of cancer at different sites may be related to oxidative damage to host genome by genotoxicants. These oxidative actions may be modified by phytochemicals present in foods. The non-nutritive dietary constituents which possess antimutagenic property appear to be promising chemopreventive agents. This study reports the protective effect of curcumin on B(a)P induced DNA damage in human peripheral blood lymphocyte cells. The study group consisted of 10 male smokers, 10 non-smokers and 10 non-smoking females aged between 25 and 45. The DNA damage was assessed using comet assay. In all the groups curcumin showed a dose-dependent inhibitory effect. The effect appeared to be sex dependent. There was no correlation between DNA damage and GST-Mu levels and levels of micronutrients namely Vitamins A, E and beta carotene. The results of this study are in line with our earlier observations on turmeric/curcumin as a potential chemopreventer.     

Global patterns in human mitochondrial DNA and Y-chromosome variation caused by spatial instability of the local cultural processes

Because of the widespread phenomenon of patrilocality, it is hypothesized that Y-chromosome variants tend to be more localized geographically than those of mitochondrial DNA (mtDNA). Empirical evidence confirmatory to this hypothesis was subsequently provided among certain patrilocal and matrilocal groups of Thailand, which conforms to the isolation by distance mode of gene diffusion. However, we expect intuitively that the patterns of genetic variability may not be consistent with the above hypothesis among populations with different social norms governing the institution of marriage, particularly among those that adhere to strict endogamy rules. We test the universality of this hypothesis by analyzing Y-chromosome and mtDNA data in three different sets of Indian populations that follow endogamy rules to varying degrees. Our analysis of the Indian patrilocal and the matrilocal groups is not confirmatory to the sex-specific variation observed among the tribes of Thailand. Our results indicate spatial instability of the impact of different cultural processes on the genetic variability, resulting in the lack of universality of the hypothesized pattern of greater Y-chromosome variation when compared to that of mtDNA among the patrilocal populations.     

Protective effect of CardiPro against doxorubicin-induced cardiotoxicity in mice

The effect of CardiPro, a polyherbal formulation, with an antioxidant property, has been studied on doxorubicin (DXR)-induced cardiotoxicity in mice. CardiPro (150 mg/kg b.w., twice daily was administered orally for 7 weeks along with four equal injections (each containing 4.0 mg/kg b.w., DXR) intraperitoneally, once weekly (cumulative dose 16 mg/kg). After a 3-week post DXR treatment period, cardiotoxicity was assessed by noting mortality, volume of ascites, liver congestion, changes in heart weight, myocardial lipid peroxidation, antioxidant enzymes and histology of heart. DXR-treated animals showed higher mortality (50%) and more ascites. Myocardial SOD and glutathione peroxidase activity were decreased and lipid peroxidation was increased. Histology of heart of DXR-treated animals showed loss of myofibrils and focal cytoplasmic vacuolization. CardiPro significantly protected the mice from DXR-induced cardiotoxic effects as evidenced by lower mortality (25%), less ascites, myocardial lipid peroxidation, normalization of antioxidant enzymes and minimal damage to the heart histologically. Our data confirm the earlier reports that DXR cardiotoxicity is associated with the free radical-induced tissue damage. Administration of CardiPro, with an antioxidant property, protected the DXR-induced cardiotoxicity in mice.     

Eugenol--the active principle from cloves inhibits 5-lipoxygenase activity and leukotriene-C4 in human PMNL cells

Polymorphonuclear leukocytes (PMNL) play an important role in the modulation of inflammatory conditions in humans. PMNL cells recruited at the site of inflammation, release inflammatory mediators such as leukotrienes, proteolytic enzymes and reactive oxygen species. Among these, leukotrienes are implicated in pathophysiology of allergic and inflammatory disorders like asthma, allergic rhinitis, arthritis, inflammatory bowel disease and psoriasis. 5-lipoxygenase (5-LO) is the key enzyme in biosynthetic pathway of leukotrienes. Our earlier studies showed that spice phenolic active principles significantly inhibit 5-LO enzyme in human PMNLs. In this study we have further characterized the inhibitory mechanism of eugenol, the active principle of spice-clove on 5-LO enzyme and also its effect on leukotriene C((4)) (LTC(4)). Substrate dependent enzyme kinetics showed that the inhibitory effect of eugenol on 5-LO was of a non-competitive nature. Further, eugenol was found to significantly inhibit the formation of LTC(4) in calcium ionophore A23187 and arachidonic acid (AA) stimulated PMNL cells. These data clearly suggest that eugenol inhibits 5-LO by non-competitive mechanism and also inhibits formation of LTC(4) in human PMNL cells and thus may have beneficial role in modulating 5-LO pathway in human PMNL cells.     

Photosynthesis, productivity, and yield of maize are not affected by open-air elevation of CO2 concentration in the absence of drought

While increasing temperatures and altered soil moisture arising from climate change in the next 50 years are projected to decrease yield of food crops, elevated CO2 concentration ([CO2]) is predicted to enhance yield and offset these detrimental factors. However, C4 photosynthesis is usually saturated at current [CO2] and theoretically should not be stimulated under elevated [CO2]. Nevertheless, some controlled environment studies have reported direct stimulation of C4 photosynthesis and productivity, as well as physiological acclimation, under elevated [CO2]. To test if these effects occur in the open air and within the Corn Belt, maize (Zea mays) was grown in ambient [CO2] (376 micromol mol(-1)) and elevated [CO2] (550 micromol mol(-1)) using Free-Air Concentration Enrichment technology. The 2004 season had ideal growing conditions in which the crop did not experience water stress. In the absence of water stress, growth at elevated [CO2] did not stimulate photosynthesis, biomass, or yield. Nor was there any CO2 effect on the activity of key photosynthetic enzymes, or metabolic markers of carbon and nitrogen status. Stomatal conductance was lower (-34%) and soil moisture was higher (up to 31%), consistent with reduced crop water use. The results provide unique field evidence that photosynthesis and production of maize may be unaffected by rising [CO2] in the absence of drought. This suggests that rising [CO2] may not provide the full dividend to North American maize production anticipated in projections of future global food supply.     

High-throughput comparison of gene fitness among related bacteria

ABSTRACT: BACKGROUND: The contribution of a gene to the fitness of a bacterium can be assayed by whether and to what degree the bacterium tolerates transposon insertions in that gene. We use this fact to compare the fitness of syntenic homologous genes among related Salmonella strains to reveal differences not apparent at the gene sequence level. RESULTS: A transposon Tn5 derivative was used to construct mutants in Salmonella Typhimurium ATCC14028 (STM1) and Salmonella Typhi Ty2 (STY1), which were then grown in rich media. The locations of 234,152 and 53,556 integration sites, respectively, were mapped by sequencing. These data were compared to similar data available for a different Ty2 strain (STY2) and essential genes identified in E. coli K-12 (ECO). Of 277 genes considered essential in ECO, all had syntenic homologs in STM1, STY1, and STY2, and all but nine genes were either devoid of Tn insertions or had very few. For three of these nine genes, part of the annotated gene lacked Tn integrations (yejM, ftsN and murB). At least one of the other six genes, trpS, had a potentially functionally redundant gene encoded elsewhere in Salmonella but not in ECO. An additional 165 genes were almost entirely devoid of transposon integrations in all three Salmonella strains examined, including many genes associated with protein and DNA synthesis. Four of these genes (STM14_1498.L, STM14_2872, STM14_3360.RJ, and STM14_5442) are not found in E. coli. Notable differences in the extent of gene selection were also observed among the three different Salmonella isolates. Mutations in hns, for example, were selected against in STM1 but not in the two STY strains, which have a defect in rpoS rendering hns nonessential. CONCLUSIONS: Comparisons among transposon integration profiles from different members of a species and among related species, all grown in similar conditions, identify differences in gene fitness among syntenic homologous genes. Further differences in fitness profiles among shared genes can be expected in other selective environments, with potential relevance for comparative systems biology.     

PIASy-mediated Tip60 sumoylation regulates p53-induced autophagy

Posttranslational modifications of p53 integrate diverse stress signals and regulate its activity, but their combinatorial contribution to overall p53 function is not clear. We investigated the roles of lysine (K) acetylation and sumoylation on p53 and their relation to apoptosis and autophagy. Here we describe the collaborative role of the SUMO E3 ligase PIASy and the lysine acetyltransferase Tip60 in p53-mediated autophagy. PIASy binding to p53 and PIASy-activated Tip60 lead to K386 sumoylation and K120 acetylation of p53, respectively. Even though these two modifications are not dependent on each other, together they act as a “binary death signal” to promote cytoplasmic accumulation of p53 and execution of PUMA-independent autophagy. PIASy-induced Tip60 sumoylation augments p53 K120 acetylation and apoptosis. In addition to p14^ARF inactivation, impairment in this intricate signaling may explain why p53 mutations are not found in nearly 50% of malignancies.