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101.
Sajiv K. Nair Jean J. Matthews Stephan J. Cripps Hengmiao Cheng Jacqui E. Hoffman Christopher Smith Stanley Kupchinsky Michael Siu Wendy D. Taylor Yong Wang Theodore O. Johnson Klaus R. Dress Martin P. Edwards Sue Zhou Natilie A. Hosea Amy LaPaglia Ping Kang Arturo Castro Deepak Dalvie 《Bioorganic & medicinal chemistry letters》2013,23(8):2344-2348
N-(Pyridin-2-yl) arylsulfonamides 1 and 2 (PF-915275) were identified as potent inhibitors of 11β-hydroxysteroid dehydrogenase type 1. A screen for bioactivation revealed that these compounds formed glutathione conjugates. This communication presents the results of a risk benefit analysis carried out to progress 2 (PF-915275) to a clinical study and the strategies used to eliminate reactive metabolites in this series of inhibitors. Based on the proposed mechanism of bioactivation and structure–activity relationships, design efforts led to N-(pyridin-2-yl) arylsulfonamides such as 18 and 20 that maintained potent 11β-hydroxysteroid dehydrogenase type 1 activity, showed exquisite pharmacokinetic profiles, and were negative in the reactive metabolite assay. 相似文献
102.
Vinay Nair Monalisa Dutta Sowmya S Manian Ramya Kumari S Valadi K Jayaraman 《Bioinformation》2013,9(9):481-484
Penicillin-Binding Proteins are peptidases that play an important role in cell-wall biogenesis in bacteria and thus maintaining
bacterial infections. A wide class of β-lactam drugs are known to act on these proteins and inhibit bacterial infections by disrupting
the cell-wall biogenesis pathway. Penicillin-Binding proteins have recently gained importance with the increase in the number of
multi-drug resistant bacteria. In this work, we have collected a dataset of over 700 Penicillin-Binding and non-Penicillin Binding
Proteins and extracted various sequence-related features. We then created models to classify the proteins into Penicillin-Binding
and non-binding using supervised machine learning algorithms such as Support Vector Machines and Random Forest. We obtain a
good classification performance for both the models using both the methods. 相似文献
103.
Machender R. Kandadi Yinan Hua Meijun Zhu Subat Turdi Peter W. Nathanielsz Stephen P. Ford Sreejayan Nair Jun Ren 《The Journal of nutritional biochemistry》2013,24(11):1982-1990
Maternal overnutrition is associated with predisposition of offspring to cardiovascular disease in later life. Since maternal overnutrition may promote fetal and placental inflammatory responses, we hypothesized that maternal overnutrition/obesity increases expression of fetal cardiac proinflammatory mediators and alter cardiac morphometry. Multiparous ewes were fed either 150% of National Research Council (NRC) nutrient recommendations (overfed) or 100% of NRC requirement (control) from 60 days prior to mating to gestation Day 75 (D75), when ewes were euthanized. An additional cohort of overfed and control ewes were necropsied on D135. Cardiac morphometry, histology, mRNA and protein expression of toll-like receptor 4, iNOS, IL-1a, IL-1b, IL-6, IL-18, CD-14, CD-68, M-CSF and protein levels of phosphorylated I-κB and nuclear factor κB (NF-κB) were examined. Immunohistochemistry was performed to assess neutrophil and monocyte infiltration. Crown rump length, left and right ventricular free wall weights as well as left and right ventricular wall thickness were significantly increased in D75 fetuses of overfed mothers. Hematoxylin and eosin staining revealed irregular myofiber orientation and increased interstitial space in fetal ventricular tissues born to overfed mothers. Oil red O staining exhibited marked lipid droplet accumulation in the overfed fetuses. Overfeeding significantly enhanced TLR4, IL-1a, IL-1b IL-6 expression, promoted phosphorylation of IκB, decreased cytoplasmic NF-κB levels and increased neutrophil and monocyte infiltration. Collectively, these data suggest that maternal overfeeding prior to and throughout gestation leads to inflammation in the fetal heart and alters fetal cardiac morphometry. 相似文献
104.
Luiz Fernando Mendes Leonardo Zambotti-Villela Pio Colepicolo Eliane Marinho-Soriano Cassius Vinicius Stevani Nair Sumie Yokoya 《Journal of applied phycology》2013,25(6):1939-1947
Macroalgae of the genus Gracilaria have considerable economic importance as raw material for agar production and belong to an important group of organisms that are tolerant of high concentrations of metal. The median inhibitory concentration (IC50) values obtained by measuring the ratio of fresh mass variation (i.e., daily growth rates) of the red macroalga Gracilaria domingensis during a 48-h aquatic toxicity assay are reported here. The alga was exposed to 14 different metal cations as well as the molybdate anion in synthetic seawater. The actual concentrations of these ionic species (at IC50 values) and the proportion of free ions (aqueous complexes) were determined by inductively coupled plasma atomic emission spectroscopy and the Environmental Protection Agency-recommended software, MINTEQA2, respectively. Based on the free IC50 values (IC50 F), the ions were ranked in terms of toxicity: Cd2+???Cu2+???Pb2+???Zn2+???Ni2+?>?Co2+?>?La3+???Mn2+?>?Ca2+?~?Li+???MoO4 2????Sr2+?>?Mg2+???K+?>?Na+. As a member of the first trophic level in the marine food chain, G. domingensis is an appropriate target organism both for the development of toxicological assays and as a bioindicator of marine degradation. 相似文献
105.
Xiao L. Moore Danielle Michell Sabrina Lee Michael R. Skilton Rajesh Nair John B. Dixon Anthony M. Dart Jaye Chin-Dusting 《PloS one》2013,8(1)
Carotid intima-media-thickness (cIMT) and carotid distensibility (distensibility), structural and functional properties of carotid arteries respectively, are early markers, as well as strong predictors of cardiovascular disease (CVD). The characteristic of these two parameters in individuals with BMI>40.0 kg/m2 (Class III obesity), however, are largely unknown. The present study was designed to document cIMT and distensibility in this population and to relate these to other factors with established association with CVD in obesity. The study included 96 subjects (65 with BMI>40.0 kg/m2 and 31, age- and gender-matched, with BMI of 18.5 to 30.0 kg/m2). cIMT and distensibility were measured by non-invasive high resolution ultrasonography, circulatory CD133+/KDR+ angiogenic cells and endothelial microparticles (EMP) by flow cytometry, and plasma levels of adipokines, growth factors and cytokines by Luminex immunoassay kits. The study results demonstrated increased cIMT (0.62±0.11 mm vs. 0.54±0.08 mm, P = 0.0002) and reduced distensibility (22.52±10.79 10−3kpa−1
vs. 29.91±12.37 10−3kpa−1, P<0.05) in individuals with BMI>40.0 kg/m2. Both cIMT and distensibility were significantly associated with traditional CVD risk factors, adiposity/adipokines and inflammatory markers but had no association with circulating angiogenic cells. We also demonstrated, for the first time, elevated plasma EMP levels in individuals with BMI>40.0 kg/m2. In conclusion, cIMT is increased and distensibility reduced in Class III obesity with the changes predominantly related to conventional CVD risk factors present in this condition, demonstrating that both cIMT and distensibility remain as CVD markers in Class III obesity. 相似文献
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108.
Small molecule rescue of mutant forms of human carbonic anhydrase II (HCA II) occurs by participation of exogenous donors/acceptors in the proton transfer pathway between the zinc-bound water and solution. To examine more thoroughly the energetics of this activation, we have constructed a mutant, H64W HCA II, which we have shown is activated by 4-methylimidazole (4-MI) by a mechanism involving the binding of 4-MI to the side chain of Trp-64 approximately 8 A from the zinc. A series of experiments are consistent with the activation of H64W HCA II by the interaction of imidazole and pyridine derivatives as exogenous proton donors with the indole ring of Trp-64; these experiments include pH profiles and H/D solvent isotope effects consistent with proton transfer, observation of approximately fourfold greater activation with the mutant containing Trp-64 compared with Gly-64, and the observation by x-ray crystallography of the binding of 4-MI associated with the indole side chain of Trp-64 in W5A-H64W HCA II. Proton donors bound at the less flexible side chain of Trp-64 in W5A-H64W HCA II do not show activation, but such donors bound at the more flexible Trp-64 of H64W HCA II do show activation, supporting suggestions that conformational mobility of the binding site is associated with more efficient proton transfer. Evaluation using Marcus theory showed that the activation of H64W HCA II by these proton donors was reflected in the work functions w(r) and w(p) rather than in the intrinsic Marcus barrier itself, consistent with the role of solvent reorganization in catalysis. 相似文献
109.
110.
Melanocyte–keratinocyte interaction induces calcium signalling and melanin transfer to keratinocytes
Preeti G. Joshi Nirmala Nair Gulnaz Begum Nanda B. Joshi Vilas P. Sinkar Shilpa Vora 《Pigment cell & melanoma research》2007,20(5):380-384
Physical contact between melanocytes and keratinocytes is a prerequisite for melanosome transfer to occur, but cellular signals induced during or after contact are not fully understood. Herein, it is shown that interactions between melanocyte and keratinocyte plasma membranes induced a transient intracellular calcium signal in keratinocytes that was required for pigment transfer. This intracellular calcium signal occurred due to release of calcium from intracellular stores. Pigment transfer observed in melanocyte–keratinocyte co‐cultures was inhibited when intracellular calcium in keratinocytes was chelated. We propose that a ‘ligand‐receptor’ type interaction exists between melanocytes and keratinocytes that triggers intracellular calcium signalling in keratinocytes and mediates melanin transfer. 相似文献