29 research outputs found

    Regulation of Macrophage‐Derived Fibroblast Growth Factor Release by Arachidonate Metabolites

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    The macrophage is a source of many mediators with direct and indirect fibrogenic potential. In this study, release of macrophage‐derived fibroblast growth factor (MDGF) activity by murine peritoneal macrophages is examined with regard to its regulation by arachidonate metabolites. Upon stimulation with 10 μg/ml lipopolysaccharide (LPS), resident peritoneal macrophages from CBA/J mice released MDGF activity into media rapidly, reaching maximal levels in approximately 1 h. Lysates of these stimulated cells also revealed significantly increased cell‐associated MDGF activity, composing 45% of the total assayable activity. This activity, as assayed by radioactive thymidine incorporation by primary cultures of rat lung fibroblasts, was separable from interleukin‐1 (IL‐1) activity by reverse phase high performance liquid chromatography (HPLC). Furthermore, purified murine IL‐1 had no MDGF activity in this assay system. This stimulated MDGF release was enhanced by the cylooxygenase inhibitors indomethacin, Ibuprofen, and aspirin at micromolar concentrations, but inhibited in a dose‐dependent manner by prostaglandin E2 (PGE2). On the other hand, nordihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor was inhibitory at 0.1 and 0.4 μM but not at 2.5 μM. Zymosan‐stimulated macrophages also markedly increased MDGF release, albeit with a different time course which was characterized by a delay of approximately 7 h before peak levels were attained. Such stimulation, which is known to cause increased lipoxygenase activity, was also inhibited by 0.5 μM NDGA. In contrast, the lipoxygenase pathway products leukotrienes B4 (LTB4) and C4 (LTC4) stimulated MDGF release in a dose‐dependent (10‐10‐10‐8 M) manner, with LTC4 being more potent on a per unit dose basis. Stimulation by LTC4 was inhibited by the putative leukotriene receptor antagonist, FPL55712, while LTD4 and LTE4 did not stimulate MDGF release, thus suggesting the mediation of this effect by specific LTC4 receptors. These data suggest also that products of the cyclooxygenase and lipoxygenase pathways are potentially important both as exogenous (ie, derived from cells other than the macrophage itself) and auto‐ or self‐regulators of macrophage MDGF release. This, in turn, implies that cyclooxygenase products are antifibrogenic and important in maintaining or returning to the quiescent or normal state, whereas the lipoxygenase products are profibrogenic and important in induction of fibrosis or wound‐healing and tissue repair. Any alteration in the balance between these two pathways may result in either a desirable or a harmful outcome.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141690/1/jlb0106.pd

    Omeprazole ameliorates aspirin-induced gastroduodenal injury

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    Aspirin and nonsteroidal antiinflammatory drugs (NSAIDs) damage the gastroduodenal epithelium by two mechanisms: direct toxic effects and effects related to the depletion of endogenous prostaglandins. The prostaglandin-depleted mucosa has increased suceptibility to luminal aggressive factors, yet the role of acid in the pathogenesis of the NSAID ulcer is controversial. In humans, standard doses of H 2 -receptor antagonists prevent only duodenal injury and provide no protection for the gastric mucosa. It is not known whether more potent suppression of acid can prevent NSAID damage. Twenty healthy volunteers were randomized to a double-blind, placebo-controlled, crossover study to determine if omeprazole, 40 mg/day prevents gastroduodenal injury due to two weeks of aspirin administration (650 mg four times a day). The severity of mucosal injury was quantitated by endoscopy and stratified by a scale from 0 (normal) to 4 (ulcer). Fourteen of the 20 subjects had less gastric injury during cotherapy with omeprazole. All six with no difference received aspirin plus omeprazole in the first treatment period. Omeprazole significantly decreased aspirin-induced gastric mucosal injury ( P <0.001, Wilcoxon signed-rank test). Omeprazole protected 85% of subjects from extensive gastric erosions (often associated with evidence of intraluminal bleeding) or ulceration, whereas 70% of the subjects developed aspirin-induced grades 3 and 4 gastric injury on placebo ( P <0.01 by X 2 ). No subject taking omeprazole developed duodenal injury of any grade, while 50% taking placebo developed erosions and 15% had ulcer ( P <0.001). Medication side effects were mild in the majority of subjects. Heartburn occurred in seven subjects on aspirin and placebo vs one on aspirin and omeprazole ( P <0.01). Salicylate levels were 7.39±4.72 mg/dl (535±340 µmol/liter) in the placebo group and 6.95±4.3 mg/dl (503±311 µmol/liter) in the omeprazole group. We conclude that omeprazole, 40 mg/day eliminates duodenal injury and markedly ameliorates gastric injury due to administration of aspirin 2600 mg/day. Omeprazole prophylaxis of NSAID injury deserves further study.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44420/1/10620_2005_Article_BF02090067.pd

    Genome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes

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    Type 2 diabetes (T2D) is a very common disease in humans. Here we conduct a meta-analysis of genome-wide association studies (GWAS) with ~16 million genetic variants in 62,892 T2D cases and 596,424 controls of European ancestry. We identify 139 common and 4 rare variants associated with T2D, 42 of which (39 common and 3 rare variants) are independent of the known variants. Integration of the gene expression data from blood (n = 14,115 and 2765) with the GWAS results identifies 33 putative functional genes for T2D, 3 of which were targeted by approved drugs. A further integration of DNA methylation (n = 1980) and epigenomic annotation data highlight 3 genes (CAMK1D, TP53INP1, and ATP5G1) with plausible regulatory mechanisms, whereby a genetic variant exerts an effect on T2D through epigenetic regulation of gene expression. Our study uncovers additional loci, proposes putative genetic regulatory mechanisms for T2D, and provides evidence of purifying selection for T2D-associated variants

    Genome-Wide Association Study and Functional Characterization Identifies Candidate Genes for Insulin-Stimulated Glucose Uptake

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    Distinct tissue-specific mechanisms mediate insulin action in fasting and postprandial states. Previous genetic studies have largely focused on insulin resistance in the fasting state, where hepatic insulin action dominates. Here we studied genetic variants influencing insulin levels measured 2 h after a glucose challenge in \u3e55,000 participants from three ancestry groups. We identified ten new loci (P \u3c 5 × 10-8) not previously associated with postchallenge insulin resistance, eight of which were shown to share their genetic architecture with type 2 diabetes in colocalization analyses. We investigated candidate genes at a subset of associated loci in cultured cells and identified nine candidate genes newly implicated in the expression or trafficking of GLUT4, the key glucose transporter in postprandial glucose uptake in muscle and fat. By focusing on postprandial insulin resistance, we highlighted the mechanisms of action at type 2 diabetes loci that are not adequately captured by studies of fasting glycemic traits

    The genetic architecture of the human cerebral cortex

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    The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

    Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

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    Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts
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