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31.
32.
Persaud SJ Muller D Belin VD Papadimitriou A Huang GC Amiel SA Jones PM 《Archives of physiology and biochemistry》2007,113(3):104-109
Arachidonic acid (AA) is generated in pancreatic beta-cells through the activation of Ca2+-dependent cytosolic phospholipase A2 (cPLA2) and the consequent hydrolysis of membrane phospholipids in the sn-2 position of the glycerophospholipid backbone. AA acts as a second messenger in beta-cells to elevate cytosolic Ca2+ levels and stimulate insulin secretion, but it is not clear whether these are direct effects of AA or are dependent on its metabolism by cyclooxygenase (COX) and/or lipoxygenase (LOX) enzymes. In addition, much of the published data in this area have been generated using insulin-secreting cell lines or rodent islets, with very little information on AA generation and metabolism in human islets of Langerhans. This short review examines cPLA2, COX and LOX expression and function in insulin- secreting cell lines and rodent and human islets. 相似文献
33.
Zvonok N Yaddanapudi S Williams J Dai S Dong K Rejtar T Karger BL Makriyannis A 《Journal of proteome research》2007,6(6):2068-2079
The CB1 and CB2 cannabinoid receptors belong to the GPCR superfamily and are associated with a variety of physiological and pathophysiological processes. Both receptors, with several lead compounds at different phases of development, are potentially useful targets for drug discovery. For this reason, fully elucidating the structural features of these membrane-associated proteins would be extremely valuable in designing more selective, novel therapeutic drug molecules. As a first step toward obtaining information on the structural features of the drug-receptor complex, we describe the full mass spectrometric (MS) analysis of the recombinant human cannabinoid CB2 receptor. This first complete proteomic characterization of a GPCR protein beyond rhodopsin was accomplished by a combination of several LC/MS approaches involving nanocapillary liquid chromatography, coupled with either a quadrupole-linear ion trap or linear ion trap-FTICR mass spectrometer. The CB2 receptor, with incorporated N-terminal FLAG and C-terminal HIS6 epitope tags, was functionally expressed in baculovirus cells and purified using a single step of anti-FLAG M2 affinity chromatography. To overcome the difficulties involved with in-gel digestion, due to the highly hydrophobic nature of this membrane-associated protein, we conducted in-solution trypsin and chymotrypsin digestions of purified and desalted samples in the presence of a low concentration of CYMAL5. This was followed by nanoLC peptide separation and analysis using a nanospray ESI source operated in the positive mode. The results can be reported confidently, based on the overlapping sequence data obtained using the highly mass accurate LTQ-FT and the 4000 Q-Trap mass spectrometers. Both instruments gave very similar patterns of identified peptides, with full coverage of all transmembrane helices, resulting in the complete characterization of the cannabinoid CB2 receptor. Mass spectrometric identification of all amino acid residues in the cannabinoid CB2 receptor is a key step toward the "Ligand Based Structural Biology" approach developed in our laboratory for characterizing ligand binding sites in GPCRs using a variety of covalent cannabinergic ligands. 相似文献
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35.
Pattengale ND Aberer AJ Swenson KM Stamatakis A Moret BM 《IEEE/ACM transactions on computational biology and bioinformatics / IEEE, ACM》2011,8(4):902-911
Many of the steps in phylogenetic reconstruction can be confounded by “rogue” taxa—taxa that cannot be placed with assurance anywhere within the tree, indeed, whose location within the tree varies with almost any choice of algorithm or parameters. Phylogenetic consensus methods, in particular, are known to suffer from this problem. In this paper, we provide a novel framework to define and identify rogue taxa. In this framework, we formulate a bicriterion optimization problem, the relative information criterion, that models the net increase in useful information present in the consensus tree when certain taxa are removed from the input data. We also provide an effective greedy heuristic to identify a subset of rogue taxa and use this heuristic in a series of experiments, with both pathological examples from the literature and a collection of large biological data sets. As the presence of rogue taxa in a set of bootstrap replicates can lead to deceivingly poor support values, we propose a procedure to recompute support values in light of the rogue taxa identified by our algorithm; applying this procedure to our biological data sets caused a large number of edges to move from “unsupported” to “supported” status, indicating that many existing phylogenies should be recomputed and reevaluated to reduce any inaccuracies introduced by rogue taxa. We also discuss the implementation issues encountered while integrating our algorithm into RAxML v7.2.7, particularly those dealing with scaling up the analyses. This integration enables practitioners to benefit from our algorithm in the analysis of very large data sets (up to 2,500 taxa and 10,000 trees, although we present the results of even larger analyses). 相似文献
36.
Rose AJ Díaz MB Reimann A Klement J Walcher T Krones-Herzig A Strobel O Werner J Peters A Kleyman A Tuckermann JP Vegiopoulos A Herzig S 《Cell metabolism》2011,14(1):123-130
Systemic bile acid (BA) homeostasis is a critical determinant of dietary fat digestion, enterohepatic function, and postprandial thermogenesis. However, major checkpoints for the dynamics and the molecular regulation of BA homeostasis remain unknown. Here we show that hypothalamic-pituitary-adrenal (HPA) axis impairment in humans and liver-specific deficiency of the glucocorticoid receptor (GR) in mice disrupts the normal changes in systemic BA distribution during the fasted-to-fed transition. Fasted mice with hepatocyte-specific GR knockdown had smaller gallbladder BA content and were more susceptible to developing cholesterol gallstones when fed a cholesterol-rich diet. Hepatic GR deficiency impaired liver BA uptake/transport via lower expression of the major hepatocyte basolateral BA transporter, Na(+)-taurocholate transport protein (Ntcp/Slc10a1), which affected dietary fat absorption and brown adipose tissue activation. Our results demonstrate a role of the HPA axis in the endocrine regulation of BA homeostasis through the liver GR control of enterohepatic BA recycling. 相似文献
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38.
Georgakilas A 《World journal of biological chemistry》2011,2(7):173-176
Humans are daily exposed to background radiation and various sources of oxidative stress. My research has focused in the last 12 years on the effects of ionizing radiation on DNA, which is considered as the key target of radiation in the cell. Ionizing radiation and endogenous cellular oxidative stress can also induce closely spaced oxidatively induced DNA lesions called "clusters" of DNA damage or locally multiply damage sites, as first introduced by John Ward. I am now interested in the repair mechanisms of clustered DNA damage, which is considered as the most difficult for the cell to repair. A main part of my research is devoted to evaluating the role of clustered DNA damage in the promotion of carcinogenesis in vitro and in vivo . Currently in my laboratory, there are two main ongoing projects. (1) Study of the role of BRCA1 and DNA-dependent protein kinase catalytic subunit repair proteins in the processing of clustered DNA damage in human cancer cells. For this project, we use several tumor cell lines, such as breast cancer cell lines MCF-7 and HCC1937 (BRCA1 deficient) and human glioblastoma cells MO59J/K; and (2) Possible use of DNA damage clusters as novel cancer biomarkers for prognostic and therapeutic applications related to modulation of oxidative stress. In this project human tumor and mice tissues are being used. 相似文献
39.
Fotinopoulou A Tsachaki M Vlavaki M Poulopoulos A Rostagno A Frangione B Ghiso J Efthimiopoulos S 《The Journal of biological chemistry》2005,280(35):30768-30772
Transmembrane proteins BRI2 and amyloid precursor protein (APP) co-localize with amyloid beta (Abeta) lesions in sporadic Alzheimer disease and mutations in both precursor proteins are linked to early-onset familial cases of cerebral amyloidosis associated with dementia and/or cerebral hemorrhage. A specific interaction between BRI2 and APP was unveiled by immunoprecipitation experiments using transfected and non-transfected cells. The use of deletion mutants further revealed that stretches 648-719 of APP751 and 46-106 of BRI2, both inclusive of the full transmembrane domains, are sufficient for the interaction. Removal of most of the APP and BRI2 extracellular domains without affecting the interaction implies that both proteins interact when are expressed on the same cell membrane (cis) rather than on adjacent cells (trans). The presence of BRI2 had a modulatory effect on APP processing, specifically increasing the levels of cellular APP as well as beta-secretase-generated COOH-terminal fragments while decreasing the levels of alpha-secretase-generated COOH-terminal fragments as well as the secretion of total APP and Abeta peptides. Determining the precise molecular pathways affected by the specific binding between APP and BRI2 could result in the identification of common therapeutic targets for these sporadic and familial neurodegenerative disorders. 相似文献
40.
Kalemi T Efthimiadis G Zioutas D Lambropoulos A Mitakidou A Giannakoulas G Vassilikos V Karvounis H Kotsis A Parharidis G Louridas G 《Biochemical genetics》2005,43(11-12):637-642
Hypertrophic cardiomyopathy (HCM) is a genetically transmitted cardiac disease characterized by unexplained myocardial hypertrophy and diverse clinical spectrum. Currently, more than 250 HCM-related mutations in 10 genes encoding contractile sarcomeric proteins have been identified. Phospholamban (PLN) is a modest modulator of intracellular Ca2+ homeostasis and may be a candidate gene responsible for cardiomyopathy. In this study 53 consecutive patients with HCM, coming from Northern Greece, were screened for mutations of PLN gene. The patients were evaluated by clinical history, physical examination, electrocardiogram and echocardiography. All PCR products were analyzed for mutation by both restriction analysis and sequencing. The systematic mutation screening did not reveal any mutation in exons 1 and 2 or in the promoter region of phospholamban gene. Additionally, no polymorphisms were detected in all patients. Therefore, PLN gene mutations were not found to be associated with HCM in a Northern Greece population. 相似文献