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| 1 | Arachidyl amido cholanoic acid improves liver glucose and lipid homeostasis in nonalcoholic steatohepatitis via AMPK and mTOR regulation显示文摘BACKGROUND Arachidyl amido cholanoic acid(Aramchol)is a potent downregulator of hepatic stearoyl-CoA desaturase 1(SCD1)protein expression that reduces liver triglycerides and fibrosis in animal models of steatohepatitis.In a phase IIb clinical trial in patients with nonalcoholic steatohepatitis(NASH),52 wk of treatment with Aramchol reduced blood levels of glycated hemoglobin A1c,an indicator of glycemic control.AIM To assess lipid and glucose metabolism in mouse hepatocytes and in a NASH mouse model[induced with a 0.1%methionine and choline deficient diet(0.1MCD)]after treatment with Aramchol.METHODS Isolated primary mouse hepatocytes were incubated with 20μmol/L Aramchol or vehicle for 48 h.Subsequently,analyses were performed including Western blot,proteomics by mass spectrometry,and fluxomic analysis with 13C-uniformly labeled glucose.For the in vivo part of the study,male C57BL/6J mice were randomly fed a control or 0.1MCD for 4 wk and received 1 or 5 mg/kg/d Aramchol or vehicle by intragastric gavage for the last 2 wk.Liver metabolomics were assessed using ultra-high-performance liquid chromatography-time of flight-MS for the determination of glucose metabolism-related metabolites.RESULTS Combination of proteomics and Western blot analyses showed increased AMPK activity while the activity of nutrient sensor mTORC1 was decreased by Aramchol in hepatocytes.This translated into changes in the content of their downstream targets including proteins involved in fatty acid(FA)synthesis and oxidation[PACCα/β(S79),SCD1,CPT1A/B,HADHA,and HADHB],oxidative phosphorylation(NDUFA9,NDUFB11,NDUFS1,NDUFV1,ETFDH,and UQCRC2),tricarboxylic acid(TCA)cycle(MDH2,SUCLA2,and SUCLG2),and ribosome(P-p70S6K[T389]and P-S6[S235/S236]).Flux experiments with 13Cuniformely labeled glucose showed that TCA cycle cataplerosis was reduced by Aramchol in hepatocytes,as indicated by the increase in the number of rounds that malate remained in the TCA cycle.Finally,liver metabolomic analysis showed that glucose homeostasis was improved by Aramchol in 0.1MCD fed mice in a dose-dependent manner,showing normalization of glucose,G6P,F6P,UDP-glucose,and Rbl5P/Xyl5P.CONCLUSION Aramchol exerts its effect on glucose and lipid metabolism in NASH through activation of AMPK and inhibition of mTORC1,which in turn activate FAβ-oxidation and oxidative phosphorylation. | David Fernández-Ramos Fernando Lopitz-Otsoa Laura Delacruz-Villar Jon Bilbao Martina Pagano Laura Mosca Maider Bizkarguenaga Marina Serrano-Macia Mikel Azkargorta Marta Iruarrizaga-Lejarreta Jesús Sot Darya Tsvirkun Sebastiaan Martijn van Liempd Felix M Goni Cristina Alonso María Luz Martínez-Chantar Felix Elortza Liat Hayardeny Shelly C Lu JoséM Mato | 2020 | World Journal of Gastroenterology2020，26，34： | 5 |
| 2 | Cryopreservation of human embryos and its contribution to in vitro fertilization success rates显示文摘 | Kai MW Sebastiaan M Sjoerd R | 2014 | Fertil Steril2014，102，： | 1 |
| 3 | Narcolepsy: clinical features new pathophysiologic insights, and future perspectives]显示文摘 | Sebastiaan O Emmanuel M | 2001 | J Clin Neurophysiol2001，18，： | 1 |
| 4 | Narcolepsy:clinical features new patho2 physiologic insights, and future perspectives显示文摘 | Sebastiaan O Emmanuel M | 2001 | JClin Nduroohvsiol2001，18，2： | 1 |
| 5 | Narcolepsy:clinical features new pathophysiologic insights, and future perspectives 显示文摘 | Sebastiaan O Emmanuel M | 2001 | Clin Neurophysiol2001，18，： | 1 |
| 6 | Biological control of thrips and whiteflies by a shared predator: Two pests are better than one显示文摘 | Messelink G J Roos van M Sebastiaan E F | 2008 | Biological Control2008，44，： | 1 |
| 7 | Internet enabled coordination in the supply chain显示文摘 | Sebastiaan J Garcia D Douglas M | 2003 | Industrial Marketing Management2003，32，3： | 1 |
| 8 | Unspecified live kidney donation by urological patients显示文摘BACKGROUND Individuals with benign kidney disorders undergoing nephrectomy have three possibilities:Autotransplantation,with a certain risk of complications,but without a clear benefit;discarding the kidney;or living kidney donation.AIM To investigate whether patients with benign kidney disorders and a medical indication for nephrectomy are suitable as unspecified live kidney donors.METHODS We searched all clinical data from 1994-2019 for unspecified donors and their transplant recipients(n=160).Nine of these 160 donors had pre-existing kidney disorders necessitating nephrectomy and had decided to donate their kidney anonymously after discussing the possibility of kidney donation.We studied the clinical course of these nine donating patients and their transplant recipients.RESULTS Seven of nine donating patients indicated unbearable loin pain as the main complaint,one donating patient refused ureterocutaneostomy and one had two aneurysms of the renal artery.Postoperatively,seven donating patients described absence of pain and one a significant reduction after the nephrectomy.The average 1-year creatinine level in the donating patients was 88μmol/L and after a median of 6.9 years the average creatinine level was 86.6μmol/L.In the transplant recipients,one major complication occurred which led to death and in one transplant recipient graft function failed to normalize at first but has been stable for nine years now.Currently,all transplant recipients are off dialysis.CONCLUSION Our data show that patients undergoing nephrectomy as part of treatment in selected kidney disorders can function as live kidney donors. | Sebastiaan Ceuppens Hendrikus J A N Kimenai Karel W J Klop Willij C Zuidema Michiel G H Betjes Willem Weimar Jan N M IJzermans Frank J M F Dor Robert C Minnee | 2020 | World Journal of Transplantation2020，10，8： | 0 |
| 9 | Hemolysis results in impaired intestinal microcirculation and intestinal epithelial cell injury显示文摘AIM:To study the effect of circulating cell-free oxy-hemoglobin(FHb) on intestinal microcirculation and intestinal epithelial injury in a rat model. METHODS:To induce elevated intravascular circulating FHb,male Sprague-Dawley rats received water or FHb infusion.Microcirculatory changes in jejunum,ileum and colon were evaluated using fluorescent microspheres.Intestinal injury was quantified as plasmatic release of ileal lipid binding protein(iLBP) and verified by histological analysis of the ileum. RESULTS:Water and FHb infusions resulted,when compared with saline infusion,in reduced intestinal microcirculation(after 30 min P<0.05,or better;after 60 min FHb infusion P<0.05 for jejunum and colon) .Circulating FHb levels correlated significantly with release of iLBP(Spearman r=0.72,P=0.0011) .Epithelial cell injury of the villi was histologically observed after water and FHb infusions. CONCLUSION:This study shows that circulating FHb leads to a reduction in intestinal microcirculatory blood flow with marked injury to intestinal epithelial cells. These data support the hypothesis that circulating FHb contributes to the development of intestinal injury. | Sebastiaan J Hanssen Tim Lubbers Caroline M Hodin Frits W Prinzen Wim A Buurman Michael J Jacobs | 2011 | World Journal of Gastroenterology2011，17，2： | 0 |
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