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221.
Abhay?Kumar Jaswandi?Ujwal?Dandekar Paike?Jayadeva?BhatEmail author 《Journal of biosciences》2017,42(4):585-601
Tumour cells distinguish from normal cells by fermenting glucose to lactate in presence of sufficient oxygen and functional mitochondria (Warburg effect). Crabtree effect was invoked to explain the biochemical basis of Warburg effect by suggesting that excess glucose suppresses mitochondrial respiration. It is known that the Warburg effect and Crabtree effect are displayed by Saccharomyces cerevisiae, during growth on abundant glucose. Beyond this similarity, it was also demonstrated that expression of human pro-apoptotic proteins in S. cerevisiae such as Bax and p53 caused apoptosis. Here, we demonstrate that p53 expression in S. cerevisiae (Crabtree-positive yeast) causes increase in ROS levels and apoptosis when cells are growing on non-fermentable carbon sources but not on fermentable carbon sources, a feature similar to tumour cells. In contrast, in Kluyveromyces lactis (Crabtree-negative yeast) p53 causes increase in ROS levels and apoptosis regardless of the carbon source. Interestingly, the increased ROS levels and apoptosis are correlated to increased oxygen uptake in both S. cerevisiae and K. lactis. Based on these results, we suggest that at least in yeast, fermentation per se does not prevent the escape from apoptosis. Rather, the Crabtree effect plays a crucial role in determining whether the cells should undergo apoptosis or not. 相似文献
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Oxidation of glycerophospholipids results in the formation of large variety of oxidized phospholipid products that differs significantly in their chemical compositions and molecular structures. Biological activities of these oxidized products also differ considerably. Here we report the comparisons of the physicochemical properties of non-oxidized phospholipid particle containing two closely related tOx-PLs: 1-palmitoyl-2-(5-keto-6-octendioyl)-sn-glycero-3-phosphocholine (KOdiA-PC) and 1-palmitoyl-2-(9-keto-10-dodecendioyl)-sn-glycero-3-phosphocholine (KDdiA-PC). DMPC (1,2-dimyristoyl-sn-glycero-3-phosphocholine) was used as a model membrane non-oxidized phospholipid. Physicochemical properties of the lipid particles were characterized by using fluorescence spectroscopy, native polyacrylamide gel and agarose gel electrophoresis. Our result shows that the presence of closely related tOx-PLs, which differ only in the chemical composition of the oxidized fatty acyl chains at the sn-2 position, exerts considerably different effect on the physicochemical properties of non-oxidized phospholipid particles containing them. 相似文献
225.
Nagarajan Muthukaman Sanjay Deshmukh Shital Tondlekar Macchindra Tambe Dnyandeo Pisal Neelam Sarode Siddharth Mhatre Samitabh Chakraborti Daisy Shah Vikram M. Bhosale Abhay Kulkarni Mahamad Yunnus A. Mahat Satyawan B. Jadhav Girish S. Gudi Neelima Khairatkar-Joshi Laxmikant A. Gharat 《Bioorganic & medicinal chemistry letters》2018,28(23-24):3766-3773
Endogenous nitrosothiols (SNOs) including S-nitrosoglutathione (GSNO) serve as reservoir for bioavailable nitric oxide (NO) and mediate NO-based signaling, inflammatory status and smooth muscle function in the lung. GSNOR inhibition increases pulmonary GSNO and induces bronchodilation while reducing inflammation in lung diseases. In this letter, design, synthesis and structure–activity relationships (SAR) of novel imidazole-biaryl-tetrazole based GSNOR inhibitors are described. Many potent inhibitors (30, 39, 41, 42, 44, 45 and 58) were identified with low nanomolar activity (IC50s: <15?nM) along with adequate metabolic stability. Lead compounds 30 and 58 exhibited good exposure and oral bioavailability in mouse pharmacokinetic (PK) study. Compound 30 was selected for further profiling and revealed comparable mouse and rat GSNOR potency, high selectivity against alcohol dehydrogenase (ADH) and carbonyl reductase (CBR1) family of enzymes, low efflux ratio and permeability in PAMPA, a high permeability in CALU-3 assay, significantly low hERG activity and minimal off-target activity. Further, an in vivo efficacy of compound 30 is disclosed in cigarette smoke (CS) induced mouse model for COPD. 相似文献
226.
Microsomal cytochrome P450 family 1 enzymes has great importance in the bioactivation of mutagens. P450 catalyzed reactions
involve a wide range of substrates, and this versatality is reflected in a structural diversity, evident in the active sites
of available P450 structures. This structure offers a template to study further structure-function relationships of alternative
substrates and other cytochrome P450 family 1 members. In this paper, we document a homology model of CYP P450 1A1 from Homo
sapiens, developed on the basis of template crystal structure of human microsomal P450 1a2 in complex with inhibitor (PDB
Id: 2HI4). Homology modeling is performed at the programs, both in the commercial and public realms. We tried to explore CYP1A1
as a potential target for anticancer chemotherapy. To gain an insight into the binding of ligands with enzyme, protein-ligand
complex was developed by including information about the known ligand as spatial restraints and optimizing the mutual interactions
between the ligand and the binding site. Active site characterization and the study for involvement of specific aminoacids
in binding with ligand, facilitates structure based inhibitor design. This study should prove useful in the design and development
of potential novel anticancer agents.
Figure The refined structure of homology model of CYP1A1 相似文献
227.
Groundwater is the main source of drinking water in both rural and urban areas of the Pratapgarh district in the eastern Uttar Pradesh. Fifty-five groundwater samples were collected from 17 blocks of the Pratapgarh district and analyzed for fluoride (F?) and other water quality parameters (pH, EC, TDS, turbidity, Cl?, HCO3?, SO42?, NO3?, Ca2+, Mg2+, Na+, K+, silica and total hardness) to assess its suitability for drinking uses. The fluoride concentration in the analyzed groundwater of the Pratapgarh district varied between 0.41 and 3.99 mg/L. Fluoride concentration in about 78% of the groundwater samples exceeded the acceptable level of 1.0 mg/L, while in 70% samples it exceeded the maximum permissible limit of 1.5 mg/L. A geographic information system (GIS) tool was used to study the spatial variation of fluoride concentrations in the groundwater of the Pratapgarh district. Fluoride is positively correlated with pH (0.36) and HCO3? (0.22) and negatively with Ca2+ (?0.23) and Mg2+ (?0.08), suggesting dissolution of fluoride-bearing minerals with the precipitation of Ca/Mg carbonate in the alkaline environment. The maximum exposure dose to fluoride for adults in the study area was found to be 6.8 times higher than the minimum risk level (MRL) of 0.05 mg kg?1 day?1 estimated by the Agency for Toxic Substances and Disease Registry (ATSDR). 相似文献
228.
Aarti Desai Veer Singh Marwah Akshay Yadav Vineet Jha Kishor Dhaygude Ujwala Bangar Vivek Kulkarni Abhay Jere 《PloS one》2013,8(4)
Next Generation Sequencing (NGS) is a disruptive technology that has found widespread acceptance in the life sciences research community. The high throughput and low cost of sequencing has encouraged researchers to undertake ambitious genomic projects, especially in de novo genome sequencing. Currently, NGS systems generate sequence data as short reads and de novo genome assembly using these short reads is computationally very intensive. Due to lower cost of sequencing and higher throughput, NGS systems now provide the ability to sequence genomes at high depth. However, currently no report is available highlighting the impact of high sequence depth on genome assembly using real data sets and multiple assembly algorithms. Recently, some studies have evaluated the impact of sequence coverage, error rate and average read length on genome assembly using multiple assembly algorithms, however, these evaluations were performed using simulated datasets. One limitation of using simulated datasets is that variables such as error rates, read length and coverage which are known to impact genome assembly are carefully controlled. Hence, this study was undertaken to identify the minimum depth of sequencing required for de novo assembly for different sized genomes using graph based assembly algorithms and real datasets. Illumina reads for E.coli (4.6 MB) S.kudriavzevii (11.18 MB) and C.elegans (100 MB) were assembled using SOAPdenovo, Velvet, ABySS, Meraculous and IDBA-UD. Our analysis shows that 50X is the optimum read depth for assembling these genomes using all assemblers except Meraculous which requires 100X read depth. Moreover, our analysis shows that de novo assembly from 50X read data requires only 6–40 GB RAM depending on the genome size and assembly algorithm used. We believe that this information can be extremely valuable for researchers in designing experiments and multiplexing which will enable optimum utilization of sequencing as well as analysis resources. 相似文献
229.
Chung KW Ferrell RE Ellis D Barmada M Moritz M Finegold DN Jaffe R Vats A 《American journal of human genetics》2003,73(2):420-429
Hypertensive nephropathy (HN) and focal segmental glomerulosclerosis (FSGS) are significant causes of end-stage renal disease (ESRD), but no genes or loci have been associated with this phenotype among African Americans, a group at high risk. We performed a genomewide linkage scan with approximately 400 microsatellite markers on 23 individuals of a large four-generation African American family with 18 affected individuals (7 with ESRD), in which the 13-year-old proband (also with ESRD) presented with hypertension and proteinuria (2-4 g/day) and underwent a kidney biopsy that revealed FSGS-like lesions with arteriolar thickening. A genomewide scan revealed LOD scores of >2.5 for markers on chromosomes 3 and 9, and fine mapping was performed on 5 additional members (total 28 members) that showed a maximum multipoint LOD score of 5.4 in the 9q31-q32 region, under an autosomal dominant model with 99% penetrance. This 8-cM (6-Mb) region is flanked by markers D9S172 and D9S105, and further candidate gene sequencing studies excluded the coding regions of three genes (ACTL7A, ACTL7B, and CTNNAL1). To our knowledge, this is the first report of a locus, denoted as "HNP1," for the HN/FSGS phenotype in a large African American family with dominantly inherited nephropathy characterized by ESRD, hypertension, and some features of FSGS. 相似文献
230.
Flores-García Y Rosales-Encina JL Satoskar AR Talamás-Rohana P 《International journal of biological sciences》2011,7(8):1093-1100
During the acute phase of infection, T. cruzi replicates extensively and releases immunomodulatory molecules that delay parasite-specific responses mediated by effector T cells. This mechanism of evasion allows the parasite to spread in the host. Parasite molecules that regulate the host immune response during Chagas'disease have not been fully identified. GPI-anchored mucins, glycoinositolphospholipids, and glycoproteins comprise some of the most abundant T. cruzi surface molecules. IL-10 IFN-γ-secreting CD4+ T cells are activated during chronic infections and are responsible for prolonged persistence of parasite and for host protection against severe inflammatory responses. In this work we evaluated the role of rMBP::SSP4 protein of T. cruzi, a recombinant protein derived from a GPI anchored antigen, SSP4, as an immunomodulator molecule, finding that it was able to induce high concentrations of IL-10 and IFN-γ both in vivo and in vitro; during this last condition, both cytokines were produced by IL-10-IFN-γ-secreting CD4+ T cells. 相似文献