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Sökning: WFRF:(Hansen Torben) > Linköpings universitet

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1.
  • Kurilshikov, Alexander, et al. (författare)
  • Large-scale association analyses identify host factors influencing human gut microbiome composition
  • 2021
  • Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 53:2, s. 156-165
  • Tidskriftsartikel (refereegranskat)abstract
    • To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P < 5 x 10(-8)) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 x 10(-20)), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 x 10(-10) < P < 5 x 10(-8)) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome might have causal effects in ulcerative colitis and rheumatoid arthritis.
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2.
  • Efsen, Eva, et al. (författare)
  • Ramiprilate Inhibits Functional Matrix Metalloproteinase Activity in Crohns Disease Fistulas
  • 2011
  • Ingår i: Basic & Clinical Pharmacology & Toxicology. - : WILEY-BLACKWELL, COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA. - 1742-7835 .- 1742-7843. ; 109:3, s. 208-216
  • Tidskriftsartikel (refereegranskat)abstract
    • Increased expression of matrix metalloproteinase (MMP)-2, -3 and -9 has been demonstrated in Crohns disease fistulas, but it is unknown whether these enzymes are biologically active and represent a therapeutic target. Therefore, we investigated the proteolytic activity of MMPs in fistula tissue and examined the effect of inhibitors, including clinically available drugs that beside their main action also suppress MMPs. Fistula specimens were obtained by surgical excision from 22 patients with Crohns disease and from 10 patients with fistulas resulting from other causes. Colonic endoscopic biopsies from six controls were also included. Total functional MMP activity was measured by a high-pressure liquid chromatography (HPLC)-based, fluorogenic MMP-substrate cleavage assay, and the specific activity of MMP-2, -3 and -9 by the MMP Biotrak Activity Assay. The MMP inhibitors comprised ethylene-diamine-tetraacetic acid (EDTA), the synthetic broad-spectrum inhibitor, GM6001, the angiotensin-converting enzyme (ACE) inhibitor, ramiprilate, and the tetracycline, doxycycline. In Crohns disease fistulas, about 50% of the total protease activity was attributable to MMP activity. The average total MMP activity was significantly higher (about 3.5-times) in Crohns fistulas (471 FU/mu g protein, range 49-2661) compared with non-Crohns fistulas [134 FU/mu g protein, range 0-495, (p andlt; 0.05)] and normal colon [153 FU/mu g protein, range 77-243, (p andlt; 0.01)]. MMP-3 activity was increased in Crohns fistulas (1.4 ng/ml, range 0-9.83) compared with non-Crohns fistulas, [0.32 ng/ml, range 0-2.66, (p andlt; 0.02)]. The same applied to MMP-9 activity [0.64 ng/ml, range 0-5.66 and 0.17 ng/ml, range 0-1.1, respectively (p andlt; 0.04)]. Ramiprilate significantly decreased the average total MMP activity level by 42% and suppressed the specific MMP-3 activity by 72%, which is comparable to the effect of GM6001 (87%). Moreover, MMP-9 activity was completely blunted by ramiprilate. Doxycycline had no effect on MMP activity. Increased functional MMP activity, notably MMP-3 and -9, is present in Crohns fistulas and may be inhibited by ramiprilate, a widely available ACE inhibitor.
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