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31.
Caterina Mele Mathieu Lemaire Paraskevas Iatropoulos Rossella Piras Elena Bresin Serena Bettoni David Bick Daniel Helbling Regan Veith Elisabetta Valoti Roberta Donadelli Luisa Murer Maria Neunh?userer Matteo Breno Véronique Frémeaux-Bacchi Richard Lifton Giuseppe Remuzzi Marina Noris 《Clinical journal of the American Society of Nephrology》2015,10(6):1011-1019
Background and objectives
Genetic and acquired abnormalities causing dysregulation of the complement alternative pathway contribute to atypical hemolytic uremic syndrome (aHUS), a rare disorder characterized by thrombocytopenia, nonimmune microangiopathic hemolytic anemia, and acute kidney failure. However, in a substantial proportion of patients the disease-associated alterations are still unknown.Design, setting, participants, & measurements
Whole-exome and whole-genome sequencing were performed in two unrelated families with infantile recessive aHUS. Sequencing of cDNA from affected individuals was used to test for the presence of aberrant mRNA species. Expression of mutant diacylglycerol kinase epsilon (DGKE) protein was evaluated with western blotting.Results
Whole-exome sequencing analysis with conventional variant filtering parameters did not reveal any obvious candidate mutation in the first family. The report of aHUS-associated mutations in DGKE, encoding DGKE, led to re-examination of the noncoding DGKE variants obtained from next-generation sequencing, allowing identification of a novel intronic DGKE mutation (c.888+40A>G) that segregated with disease. Sequencing of cDNA from affected individuals revealed aberrant forms of DGKE mRNA predicted to cause profound abnormalities in the protein catalytic site. By whole-genome sequencing, the same mutation was found in compound heterozygosity with a second nonsense DGKE mutation in all affected siblings of another unrelated family. Homozygous and compound heterozygous patients presented similar clinical features, including aHUS presentation in the first year of life, multiple relapsing episodes, and proteinuria, which are prototypical of DGKE-associated aHUS.Conclusions
This is the first report of a mutation located beyond the exon-intron boundaries in aHUS. Intronic mutations such as these are underreported because conventional filtering parameters used to process next-generation sequencing data routinely exclude these regions from downstream analyses in both research and clinical settings. The results suggest that analysis of noncoding regions of aHUS-associated genes coupled with mRNA sequencing might provide a tool to explain genetically unsolved aHUS cases. 相似文献32.
The effects of propranolol or phentolamine on the metabolism of phospholipids, diacylglycerol, and triacylglycerol were studied in the bovine retina in vitro. Lipid labeling was followed during short-term incubation of intact bovine retinas with [U-14C]glycerol and [1-14C]palmitic acid. Each of these precursors was recovered in the appropriate lipid moiety. Most of the [14C]glycerol appeared progressively in triacylglycerol (TG) through the sequence from phosphatidic acid (PA) to diacylglycerol (DG). Labeled palmitate appeared in much lower quantities than labeled glycerol in all glycerolipids except phosphatidylcholine (PC). Propranolol and phentolamine greatly enhanced the [14'C]glycerol specific activities of PA, phosphatidylinositol (PI), and phosphatidylserine (PS), whereas labeling in other glycerolipids was much lower than in controls. The labeling in TG with both precursors was found to be less than 50% of the control values; however, a late increase in DG labeling was observed. The effects of these drugs on broken cell preparations were also described, although lipid synthesis from labeled glycerol in these preparations was only 9% that of intact retinas. It appeared that an amphiphilic cationic structure was necessary to produce these drug effects; propranolol glycol, the hydrophobic moiety of propranolol, did not elicit the same effects. It is suggested that, among other changes, the drugs inhibited phosphatidate phosphohydrolase and redirected the flux predominantly toward PI. Support for the proposed multiple lipid effects elicited by these drugs was provided by the dual changes found in the labeling of DG. 相似文献
33.
34.
Protein kinase C isoforms as specific targets for modulation of vascular smooth muscle function in hypertension 总被引:8,自引:0,他引:8
Vascular contraction is an important determinant of the peripheral vascular resistance and blood pressure. The mechanisms underlying vascular smooth muscle (VSM) contraction and the pathological changes that occur in hypertension have been the subject of numerous studies and interpretations. Activation of VSM by vasoconstrictor stimuli at the cell surface causes an increase in [Ca(2+)](i), Ca(2+)-dependent activation of myosin light chain (MLC) kinase, MLC phosphorylation, actin-myosin interaction and VSM contraction. Additional signaling pathways involving Rho-kinase and protein kinase C (PKC) may increase the myofilament force sensitivity to [Ca(2+)](i) and MLC phosphorylation, and thereby maintain vascular contraction. PKC is a particularly intriguing protein kinase as it comprises a family of Ca(2+)-dependent and Ca(2+)-independent isoforms, which have different tissue and subcellular distribution, and undergo differential translocation during cell activation. PKC translocation to the cell surface may trigger a cascade of protein kinases, such as mitogen-activated protein kinase (MAPK) and MAPK kinase (MEK) that ultimately interact with the contractile myofilaments and cause VSM contraction. Also, PKC translocation to the nucleus may promote VSM growth and proliferation. Increased PKC expression and activity have been identified in several forms of hypertension. The subcellular location of PKC may determine the state of VSM activity, and may be useful in the diagnosis/prognosis of hypertension. Vascular PKC isoforms may represent specific targets for modulation of VSM hyperactivity, and isoform-specific PKC inhibitors may be useful in treatment of Ca(2+) antagonist-resistant forms of hypertension. 相似文献
35.
Azaspiracid-4 inhibits Ca2+ entry by stored operated channels in human T lymphocytes 总被引:1,自引:0,他引:1
Alfonso A Román Y Vieytes MR Ofuji K Satake M Yasumoto T Botana LM 《Biochemical pharmacology》2005,69(11):1627-1636
Azaspiracids (AZs) are a new group of phycotoxins discovered in the Ireland coast that includes the isolated analogues: AZ-1, AZ-2, AZ-3, AZ-4 and AZ-5 and the recently described AZ-6-11. Azaspiracid toxic episodes show gastrointestinal illness, but neurotoxic symptoms are also observed in mouse bioassay. Despite their great importance in human health, so far its mechanism of action is largely unknown. In this report, we present the first data about the effect of AZ-4 on cytosolic calcium concentration [Ca2+]i in freshly human lymphocytes. Cytosolic Ca2+ variations were determined by fluorescence digital imaging microscopy using Fura2 acetoxymethyl ester (Fura2-AM). AZ-4 did not modify cytosolic Ca2+ in resting cells. However, the toxin dose-dependent inhibited the increase in cytosolic Ca2+ levels induced by thapsigargin (Tg). AZ-4 decreased Ca2+-influx induced by Tg but did not affect the Ca2+-release from internal stores induced by this drug. The effects of AZ-4 on Ca2+-influx induced by Tg were reversible and not regulated by adenosine 3',5'-cyclic monophosphate (cAMP) pathway. When AZ-4 was added before, after or together with nickel, an unspecific blocker of Ca2+ channels, the effects were indistinguishable and additive. AZ-4 also inhibited maitotoxin (MTX)-stimulated Ca2+-influx by 5-10%. Thus, AZ-4 appeared to be a novel inhibitor of plasma membrane Ca2+ channels, affecting at least to store operated channels, showing an effect clearly different from other azaspiracid analogues. 相似文献
36.
Activation of the Ca(2+)-activated nonselective cation channel by diacylglycerol analogues in rat cardiomyocytes 总被引:2,自引:0,他引:2
Guinamard R Chatelier A Lenfant J Bois P 《Journal of cardiovascular electrophysiology》2004,15(3):342-348
INTRODUCTION: Cardiac hypertrophy is associated with changes in electrophysiologic properties due to ionic channel modifications and increases in protein kinase C (PKC) activity and diacylglycerol (DAG) content. These changes may contribute to an increased propensity for arrhythmia. Similar electrophysiologic modifications have been reported in adult rat cardiomyocytes undergoing dedifferentiation in primary culture. METHODS AND RESULTS: Single-channel measurements on such cells identified the appearance of a Ca(2+)-activated nonselective cation channel (NSC(Ca)) during the dedifferentiation process. The current study investigated the sensitivity of this channel to PKC and DAG analogues. In the cell-attached configuration, channel conductance was 20.2 pS under physiologic conditions. Perfusion with the DAG analogue 1-oleoyl-2-acetyl-sn-glycerol (OAG, 0.1 mM) or the PKC activator phorbol 12-myristate 13-acetate (PMA, 0.5 microM) increased the channel normalized open probability (nPo), whereas in the presence of the PKC inhibitor calphostin C (1 microM), only OAG retained this effect. In the inside-out configuration, perfusion of both DAG analogues OAG (0.1 mM) and 1-stearoyl-2-arachidonoyl-sn-glycerol (SAG, 10 microM) on the inside of the membrane increased nPo. These results indicate that DAG regulates the NSC(Ca) channel via both the PKC pathway and by a direct interaction. CONCLUSION: DAG content, PKC activity, and channel expression increased during hypertrophy. This indicates that the NSC(Ca) channel exhibits high activity in this condition and, therefore, is a candidate for the genesis of arrhythmias in ventricular cardiomyocytes. In addition, regulation of the channel by DAG and PKC contributes to current understanding of the physiologic role of this channel, which shares properties with the cloned TRPM4b channel. 相似文献
37.
Protein kinase C (PKC) is a family of serine/threonine kinases comprised of 10 isoforms. Although commercial antibodies are available for all 10 isoforms, the specificity of these antibodies has been questioned. We have identified immunoblot conditions in which commercially purchased PKC antibodies are specific for their respective isoform. We then used these conditions to determine that PKC isoforms alpha, betaI, betaII, delta, epsilon, gamma, lambda, theta, and zeta are present in rat primary cultured cerebellar granule cells (CGCs) 6-14 days in vitro (DIV). This PKC profile is identical to that observed in cerebellar homogenates taken from 6-, 14- and 21-day-old rats. Western blot analysis indicated that the classical and the atypical PKC isoforms were more prevalent in the cytosolic subcellular fraction compared to the particulate fraction under basal conditions. Immunoreactivity for the novel isoforms tended to be higher in the particulate fraction under basal conditions. Phorbol 12-myristate 13-acetate (PMA) treatment resulted in translocated immunoreactivity from the cytosolic to the particulate fraction for all of the classical and novel PKC isoforms, but not for the atypical isoforms. However, the degree of translocation as well as the speed of translocation varied among the isoforms. The stability of the individual isoforms after PMA-induced activation also varied among the isoforms. Differences in these parameters were dependent upon culture batches and PKC isoform groups. We have identified experimental conditions in which reproducible results can be obtained with primary cultured CGCs in the study of PKC. We discuss possible solutions for problems encountered when utilizing primary cultured neurons to study PKC-mediated signal transduction. 相似文献
38.
Anna Fernandez Núria Matias Raquel Fucho Vicente Ribas Claudia Von Montfort Natalia Nuño Anna Baulies Laura Martinez Núria Tarrats Montserrat Mari Anna Colell Albert Morales Laurent Dubuquoy Philippe Mathurin Ramón Bataller Joan Caballeria Montserrat Elena Jesus Balsinde Neil Kaplowitz Carmen Garcia-Ruiz Jose C. Fernandez-Checa 《Journal of hepatology》2013
39.
Tiziana Bisogno Anu Mahadevan Roberto Coccurello Jae Won Chang Marco Allarà Yugang Chen Giacomo Giacovazzo Aron Lichtman Benjamin Cravatt Anna Moles Vincenzo Di Marzo 《British journal of pharmacology》2013,169(4):784-793
Background and Purpose
The development of potent and selective inhibitors of the biosynthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG) via DAG lipases (DAGL) α and β is just starting to be considered as a novel and promising source of pharmaceuticals for the treatment of disorders that might benefit from a reduction in endocannabinoid tone, such as hyperphagia in obese subjects.Experimental Approach
Three new fluorophosphonate compounds O-7458, O-7459 and O-7460 were synthesized and characterized in various enzymatic assays. The effects of O-7460 on high-fat diet intake were tested in mice.Key Results
Of the new compounds, O-7460 exhibited the highest potency (IC50 = 690 nM) against the human recombinant DAGLα, and selectivity (IC50 > 10 μM) towards COS-7 cell and human monoacylglycerol lipase (MAGL), and rat brain fatty acid amide hydrolase. Competitive activity-based protein profiling confirmed that O-7460 inhibits mouse brain MAGL only at concentrations ≥10 μM, and showed that this compound has only one major ‘off-target’, that is, the serine hydrolase KIAA1363. O-7460 did not exhibit measurable affinity for human recombinant CB1 or CB2 cannabinoid receptors (Ki > 10 μM). In mouse neuroblastoma N18TG2 cells stimulated with ionomycin, O-7460 (10 μM) reduced 2-AG levels. When administered to mice, O-7460 dose-dependently (0–12 mg·kg−1, i.p.) inhibited the intake of a high-fat diet over a 14 h observation period, and, subsequently, slightly but significantly reduced body weight.Conclusions and Implications
O-7460 might be considered a useful pharmacological tool to investigate further the role played by 2-AG both in vitro and in vivo under physiological as well as pathological conditions.Linked Articles
This article is part of a themed section on Cannabinoids. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.169.issue-4 & http://dx.doi.org/10.1111/bph.2012.167.issue-8 相似文献40.
DGAT1 promoter polymorphism associated with alterations in body mass index,high density lipoprotein levels and blood pressure in Turkish women 总被引:3,自引:0,他引:3
Ludwig EH Mahley RW Palaoglu E Ozbayrakçi S Balestra ME Borecki IB Innerarity TL Farese RV 《Clinical genetics》2002,62(1):68-73
Triglyceride synthesis is catalyzed by acyl CoA:diacylglycerol acyltransferases (DGAT), microsomal enzymes that use diacylglycerol and fatty acyl CoAs as substrates. Because DGAT1 expression is up-regulated during adipocyte differentiation and DGAT1 deficiency is associated with leanness in mice, we hypothesized that alterations in DGAT1 expression may affect human body weight. We identified five polymorphisms in the human DGAT1 promoter and 5' non-coding sequence in a random Turkish population. Functional analysis of one common variant, C79T, revealed reduced promoter activity for the 79T allele in cultured cell lines. In 476 Turkish women, the 79T allele was associated with lower body mass index (BMI) (p = 0.004), conferring an odds ratio of 2.0 (95% CI = 1.30-3.07, p = 0.0001) for BMI = 20. Interestingly, after controlling for the influence of BMI, the 79T allele was also associated with higher plasma HDL cholesterol levels (p = 0.0006) and lower diastolic blood pressure (p = 0.019) in these women. No association was found in Turkish men (n = 846). Our findings suggest that genetic variation at the DGAT1 locus may influence BMI and other metabolic parameters associated with cardiovascular risk in selected human populations. 相似文献