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41.
Sudhakar Reddy Ganta Senthil Perumal Sundar Ram Reddy Pagadala Ørjan Samuelsen James Spencer R.F. Pratt John D. Buynak 《Bioorganic & medicinal chemistry letters》2009,19(6):1618-1622
A series of cephalosporin-derived reverse hydroxamates and oximes were prepared and evaluated as inhibitors of representative metallo- and serine-β-lactamases. The reverse hydroxamates showed submicromolar inhibition of the GIM-1 metallo-β-lactamase. With respect to interactions with the classes A, C, and D serine β-lactamases, as judged by their correspondingly low Km values, the reverse hydroxamates were recognized in a manner similar to the non-hydroxylated N–H amide side chains of the natural substrates of these enzymes. This indicates that, with respect to recognition in the active site of the serine β-lactamases, the OC–NR–OH functionality can function as a structural isostere of the OC–NR–H group, with the N–O–H group presumably replacing the amide N–H group as a hydrogen bond donor to the appropriate backbone carbonyl oxygen of the protein. The reverse hydroxamates, however, displayed kcat values up to three orders of magnitude lower than the natural substrates, thus indicating substantial slowing of the hydrolytic action of these serine β-lactamases. Although the degree of inactivation is not yet enough to be clinically useful, these initial results are promising. The substitution of the amide N–H bond by N–OH may represent a useful strategy for the inhibition of other serine hydrolases. 相似文献
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Hassan Shabbeer Yellur Rajashree Subramani Pooventhan Adiga Poornima Gokhale Manoj Iyer Manasa S. Mayya Shreemathi S. 《PloS one》2015,10(4)
Good quality medical research generally requires not only an expertise in the chosen medical field of interest but also a sound knowledge of statistical methodology. The number of medical research articles which have been published in Indian medical journals has increased quite substantially in the past decade. The aim of this study was to collate all evidence on study design quality and statistical analyses used in selected leading Indian medical journals. Ten (10) leading Indian medical journals were selected based on impact factors and all original research articles published in 2003 (N = 588) and 2013 (N = 774) were categorized and reviewed. A validated checklist on study design, statistical analyses, results presentation, and interpretation was used for review and evaluation of the articles. Main outcomes considered in the present study were – study design types and their frequencies, error/defects proportion in study design, statistical analyses, and implementation of CONSORT checklist in RCT (randomized clinical trials). From 2003 to 2013: The proportion of erroneous statistical analyses did not decrease (χ2=0.592, Φ=0.027, p=0.4418), 25% (80/320) in 2003 compared to 22.6% (111/490) in 2013. Compared with 2003, significant improvement was seen in 2013; the proportion of papers using statistical tests increased significantly (χ2=26.96, Φ=0.16, p<0.0001) from 42.5% (250/588) to 56.7 % (439/774). The overall proportion of errors in study design decreased significantly (χ2=16.783, Φ=0.12 p<0.0001), 41.3% (243/588) compared to 30.6% (237/774). In 2013, randomized clinical trials designs has remained very low (7.3%, 43/588) with majority showing some errors (41 papers, 95.3%). Majority of the published studies were retrospective in nature both in 2003 [79.1% (465/588)] and in 2013 [78.2% (605/774)]. Major decreases in error proportions were observed in both results presentation (χ2=24.477, Φ=0.17, p<0.0001), 82.2% (263/320) compared to 66.3% (325/490) and interpretation (χ2=25.616, Φ=0.173, p<0.0001), 32.5% (104/320) compared to 17.1% (84/490), though some serious ones were still present. Indian medical research seems to have made no major progress regarding using correct statistical analyses, but error/defects in study designs have decreased significantly. Randomized clinical trials are quite rarely published and have high proportion of methodological problems. 相似文献
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Sathish Prasad Poorna Manasa Sailaja Buddhi Preethi Tirunagari Zareena Begum Sivaraman Rajan Sisinthy Shivaji 《Current microbiology》2014,68(2):233-238
The diversity and abundance of culturable bacteria in Kongsfjorden water (15 stations) and sediments (12 stations) were studied. Viable numbers ranged between 105–106 CFU l?1 in water and 102–104 CFU g?1 in the sediments. A total of 291 and 43 bacterial isolates were retrieved from the water (KJF) and sediments (FS), respectively. Based on 16S rRNA gene sequence similarities, the KJF and FS isolates were grouped into 49 and 23 phylotypes, respectively. The KJF and FS phylotypes represented three phyla namely, Actinobacteria, Bacteroidetes, and Proteobacteria. At the genus level, Flavobacterium and Shewanella and at the species level, Pseudoaltermonas arctica and Colwellia psychrerythraea were dominant in the water and sediments, respectively. Most phylotypes were psychrotolerant with upper growth temperature limit of 25–37 °C and tolerated 0.3–2.5 M NaCl and pH values of 5.0–11.0. Majority of the phylotypes produced one or more of the extracellular hydrolytic enzymes amylase, lipase, caseinase, urease, gelatinase, and DNase at 4 and 18 °C, while none were chitinolytic. Few of the FS phylotypes exhibited extracellular activity only at 4 or 18 °C. Nine FS and 21 KJF isolates were pigmented. The predominant cellular fatty acids were unsaturated, branched, and modified fatty acids, which are unique to cold-adapted bacteria. 相似文献
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Nataraj Sekhar Pagadala Manish Arha P. S. Reddy Ranadheer Kumar V. L. Sirisha S. Prashant K. Janardhan Reddy Bashir Khan S. K. Rawal P. B. Kavi Kishor 《Journal of molecular modeling》2009,15(2):203-221
Caffeoyl coenzyme A O-methyltransferase (CCoAOMT) is an important enzyme that participates in lignin biosynthesis especially in the formation of
cell wall ferulic esters of plants. It plays a pivotal role in the methylation of the 3-hydroxyl group of caffeoyl CoA. Two
cDNA clones that code CCoAOMT were isolated earlier from subabul and in the present study; 3D models of CCoAOMT1 and CCoAOMT2
enzymes were built using the MODELLER7v7 software to find out the substrate binding sites. These two proteins differed only
in two amino acids and may have little or no functional redundancy. Refined models of the proteins were obtained after energy
minimization and molecular dynamics in a solvated water layer. The models were further assessed by PROCHECK, WHATCHECK, Verify_3D
and ERRAT programs and the results indicated that these models are reliable for further active site and docking analysis.
The refined models showed that the two proteins have 9 and 10 α-helices, 6 and 7 β-sheets respectively. The models were used
for docking the substrates CoA, SAM, SAH, caffeoyl CoA, feruloyl CoA, 5-hydroxy feruloyl CoA and sinapyl CoA which showed
that CoA and caffeoyl CoA are binding with high affinity with the enzymes in the presence and absence of SAM. It appears therefore
that caffeoyl CoA is the substrate for both the isoenzymes. The results also indicated that CoA and caffeoyl CoA are binding
with higher affinity to CCoAOMT2 than CCoAOMT1. Therefore, CCoAOMT2 conformation is thought to be the active form that exists
in subabul. Docking studies indicated that conserved active site residues Met58, Thr60, Val63, Glu82, Gly84, Ser90, Asp160,
Asp162, Thr169, Asn191 and Arg203 in CCoAOMT1 and CCoAOMT2 enzymes create the positive charge to balance the negatively charged
caffeoyl CoA and play an important role in maintaining a functional conformation and are directly involved in donor-substrate
binding. 相似文献
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Sharda Kumari Susheel N. Chaurasia Manasa K. Nayak Ram L. Mallick Debabrata Dash 《The Journal of biological chemistry》2015,290(19):12290-12299
Sirtuins are evolutionarily conserved NAD+-dependent acetyl-lysine deacetylases that belong to class III type histone deacetylases. In humans, seven sirtuin isoforms (Sirt1 to Sirt7) have been identified. Sirtinol, a cell-permeable lactone ring derived from naphthol, is a dual Sirt1/Sirt2 inhibitor of low potency, whereas EX-527 is a potent and selective Sirt1 inhibitor. Here we demonstrate that Sirt1, Sirt2, and Sirt3 are expressed in enucleate platelets. Both sirtinol and EX-527 induced apoptosis-like changes in platelets, as revealed by enhanced annexin V binding, reactive oxygen species production, and drop in mitochondrial transmembrane potential. These changes were associated with increased phagocytic clearance of the platelets by macrophages. Expression of acetylated p53 and the conformationally active form of Bax were found to be significantly higher in both sirtinol- and EX-527-treated platelets, implicating the p53-Bax axis in apoptosis induced by sirtuin inhibitors. Administration of either sirtinol or EX-527 in mice led to a reduction in both platelet count and the number of reticulated platelets. Our results, for the first time, implicate sirtuins as a central player in the determination of platelet aging. Because sirtuin inhibitors are being evaluated for their antitumor activity, this study refocuses attention on the potential side effect of sirtuin inhibition in delimiting platelet life span and management of thrombosis. 相似文献
47.
Fealy CE Haus JM Solomon TP Pagadala M Flask CA McCullough AJ Kirwan JP 《Journal of applied physiology (Bethesda, Md. : 1985)》2012,113(1):1-6
Increased hepatocyte apoptosis is a hallmark of nonalcoholic fatty liver disease (NAFLD) and contributes to the profibrogenic state responsible for the progression to nonalcoholic steatohepatitis (NASH). Strategies aimed at reducing apoptosis may result in better outcomes for individuals with NAFLD. We therefore examined the effect of a short-term exercise program on markers of apoptosis-plasma cytokeratin 18 (CK18) fragments, alanine aminotransferase (ALT), aspartate aminotransferase (AST), soluble Fas (sFas), and sFas ligand (sFasL)-in 13 obese individuals with NAFLD [body mass index 35.2 ± 1.2 kg/m(2), >5% intrahepatic lipid (IHL) assessed by (1)H-MR spectroscopy]. Exercise consisted of treadmill walking for 60 min/day on 7 consecutive days at ~85% of maximal heart rate. Additionally, subjects underwent an oral glucose tolerance test and a maximal oxygen consumption (Vo(2max)) test before and after the exercise intervention. The Matsuda index was used to assess insulin sensitivity. We observed significant decreases in CK18 fragments (558.4 ± 106.8 vs. 323.4 ± 72.5 U/l, P < 0.01) and ALT (30.2 ± 5.1 vs. 24.3 ± 4.8 U/l, P < 0.05), and an increase in whole body fat oxidation (49.3 ± 6.1 vs. 69.4 ± 7.1 mg/min, P < 0.05), while decreases in circulating sFasL approached statistical significance (66.5 ± 6.0 vs. 63.0 ± 5.7 pg/ml, P = 0.06), as did the relationship between percent change in circulating CK18 fragments and ALT (r = 0.55, P = 0.05). We also observed a significant correlation between changes in fat oxidation and circulating sFasL (rho = -0.65, P < 0.05). There was no change in IHL following the intervention (18.2 ± 2.5 vs. 17.5 ± 2.1%, NS). We conclude that short-term exercise reduces a circulatory marker of hepatocyte apoptosis in obese individuals with NAFLD and propose that changes in the proapoptotic environment may be mediated through improved insulin sensitivity and increased oxidative capacity. 相似文献
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Raman Sukirtha Kandula Manasa Priyanka Jacob Joe Antony Soundararajan Kamalakkannan Ramar Thangam Palani Gunasekaran Muthukalingan Krishnan Shanmugam Achiraman 《Process Biochemistry》2012,47(2):273-279
This communication explains the biosynthesis of stable silver nanoparticles (AgNPs) from Melia azedarach and its cytotoxicity against in vitro HeLa cells and in vivo Dalton's ascites lymphoma (DAL) mice model. The AgNPs synthesis was determined by UV–visible spectrum and it was further characterized by scanning electron microscopy (SEM), dynamic light scattering (DLS) and X-ray diffraction (XRD) analysis. Zeta potential analysis revealed stable AgNPs at ?24.9 mV. UV visible spectrum indicated an absorption peak at 436 nm which reflects its specific Surface Plasmon Resonance (SPR). Biosynthesized AgNPs were predominantly cubical and spherical with an average particle size of 78 nm approximately as observed through SEM and DLS analysis, respectively. Cytotoxicity of biosynthesized AgNPs against in vitro Human epithelial carcinoma cell line (HeLa) showed a dose–response activity. Lethal dose (LD50) value was found to be 300 μg/mL of AgNPs against HeLa cell line. Cytotoxicity against normal continuous cell line human breast lactating, donor 100 (HBL 100) was found only in increased concentration of both AgNPs and 5-FU. In addition, in vivo DAL mice model showed significant increase in life span, induction of apoptosis was evidenced by acridine orange and ethidium bromide (AO and EB) staining. 相似文献