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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 | Lymphocyte subsets in alcoholic liver disease显示文摘AIM:To compare lymphocyte subsets between healthy controls and alcoholics with liver disease.METHODS:The patient cohort for this study included individuals who were suspected to have alcoholic liver disease(ALD) and who had undergone liver biopsy(for disease grading and staging,doubts about diagnosis,or concurrent liver disease;n = 56).Normal controls included patients who were admitted for elective cholecystectomy due to non-complicated gallstones(n = 27).Formalin-fixed,paraffin-embedded liver biopsy specimens were sectioned and stained with hematoxylin and eosin and Perls' Prussian blue.The non-alcoholic steatohepatitis score was used to assess markers of ALD.Lymphocyte population subsets were determined by flow cytometry.T lymphocytes were identified(CD3+),and then further subdivided into CD4+ or CD8+ populations.B lymphocytes(CD19+) and natural killer(NK) cell numbers were also measured.In addition to assessing lymphocyte subpopulation differences between ALD patients and controls,we also compared subsets of alcoholic patients without cirrhosis or abstinent cirrhotic patients to normal controls.RESULTS:The patient cohort primarily consisted of older men.Active alcoholism was present in 66.1%.Reported average daily alcohol intake was 164.9 g and the average lifetime cumulative intake was 2211.6 kg.Cirrhosis was present in 39.3% of the patients and 66.1% had significant fibrosis(perisinusoidal and portal/periportal fibrosis,bridging fibrosis,or cirrhosis) in their liver samples.The average Mayo end-stage liver disease score was 7.6.No hereditary hemochromatosis genotypes were found.ALD patients(n = 56) presented with significant lymphopenia(1.5 × 109/L ± 0.5 × 109/L vs 2.1 × 109/L ± 0.5 × 109/L,P < 0.0001),due to a decrease in all lymphocyte subpopulations,except for NK lymphocytes:CD3+(1013.0 ± 406.2/mm3 vs 1523.0 ± 364.6/mm3,P < 0.0001),CD4+(713.5 ± 284.7/mm3 vs 992.4 ± 274.7/mm3,P < 0.0001),CD8+(262.3 ± 140.4/mm3 vs 478.9 ± 164.6/mm3,P < 0.0001),and CD19+(120.6 ± 76.1/mm3 vs 264.6 ± 88.0/mm3,P < 0.0001).CD8+ lymphocytes suffered the greatest reduction,as evidenced by an increase in the CD4+/CD8+ ratio(3.1 ± 1.3 vs 2.3 ± 0.9,P = 0.013).This ratio was associated with the stage of fibrosis on liver biopsy(rs = 0.342,P = 0.01) and with Child-Pugh score(rs = 0.482,P = 0.02).The number of CD8+ lymphocytes also had a positive association with serum ferritin levels(rs = 0.345,P = 0.009).Considering only patients with active alcoholism but not cirrhosis(n = 27),we found similar reductions in total lymphocyte counts(1.8 × 109/L ± 0.3 × 109/L vs 2.1 × 109/L ± 0.5 × 109/L,P = 0.018),and in populations of CD3+(1164.7 ± 376.6/mm3 vs 1523.0 ± 364.6/mm3,P = 0.001),CD4+(759.8 ± 265.0/mm3 vs 992.4 ± 274.7/mm3,P = 0.003),CD8+(330.9 ± 156.3/mm3 vs 478.9 ± 164.6/mm3,P = 0.002),and CD19+(108.8 ± 64.2/mm3 vs 264.6 ± 88.0/mm3,P < 0.0001).In these patients,the CD4+/CD8+ ratio and the number of NK lymphocytes was not significantly different,compared to controls.Comparing patients with liver cirrhosis but without active alcohol consumption(n = 11),we also found significant lymphopenia(1.3 × 109/L ± 0.6 × 109/L vs 2.1 × 109/L ± 0.5 × 109/L,P < 0.0001) and decreases in populations of CD3+(945.5 ± 547.4/mm3 vs 1523.0 ± 364.6/mm3,P = 0.003),CD4+(745.2 ± 389.0/mm3 vs 992.4 ± 274.7/mm3,P = 0.032),CD8+(233.9 ± 120.0/mm3 vs 478.9 ± 164.6/mm3,P < 0.0001),and CD19+(150.8 ± 76.1/mm3 vs 264.6 ± 88.0/mm3,P = 0.001).The NK lymphocyte count was not significantly different,but,in this group,there was a significant increase in the CD4+/CD8+ ratio(3.5 ± 1.3 vs 2.3 ± 0.9,P = 0.01).CONCLUSION:All patient subsets presented with decreased lymphocyte counts,but only patients with advanced fibrosis presented with a significant increase in the CD4+/CD8+ ratio. | Luís Costa Matos Paulo Batista Nuno Monteiro Joo Ribeiro Maria A Cipriano Pedro Henriques Fernando Giro Armando Carvalho | 2013 | World Journal of Hepatology2013，5，2： | 4 |
| 3 | Antiherpetic activity of a sulfated polysaccharide from Agaricus brasiliensis mycelia显示文摘 | Francielle Tramontini Gomes de Sousa Cardozo Carla Maísa Camelini Alessandra Mascarello Márcio José Rossi Ricardo José Nunes Célia Regina Monte Barardi Margarida Matos de Mendon?a Cláudia Maria Oliveira Sim?es | 2011 | Antiviral Research2011，，1： | 2 |
| 4 | Validation of an immunoperoxidase monolayer assay for total anti-Vac- cinia virus antibody titration 显示文摘 | Gerber P F Matos A C Guedes M I | 2012 | J Vet Diagn Invest2012，24，2： | 1 |
| 5 | Characterization and prediction of biomass pyrolysis products显示文摘 | NEVES D THUNMAN H MATOS A | 2011 | Progress in Energy and Combustion Science2011，37，5： | 1 |
| 6 | Bioplastic production usingwood mill effluents as feedstock 显示文摘 | Ben M Mato T Lopez A | 2011 | Water Science andTechnology2011，63，6： | 1 |
| 7 | Effect of drought stress on lipid metabolism in the leaves of Arabidopsis thaliana( Ecotype Columbia) 显示文摘 | Gigon A Matos A-R Laffray D | 2004 | Annals of Botany2004，94，： | 1 |
| 8 | Enthalpies of combustion, vapour pressures, and enthalpies of sublimation of 8- hydroxyquinoline, 5-nitro-8-hydroxyquinoline, and 2-methyl-8-hydroxyquinoline显示文摘 | Ribeiro Da Silva M A V Monte M J S Matos M A R | 1989 | Chem Thermodyn1989，，21： | 1 |
| 9 | Removal of inorganic charged micro-pollutants in an ion-exchange membrane bioreactor 显示文摘 | Velizarov S Matos C Reis M A M | 2005 | Desalination2005，178，13： | 1 |
| 10 | Dehydration studies of rare earth p-toluenesulfonate hydrates by TG/DTG and DSC 显示文摘 | Santos A V Matos J R | 2002 | Al- loyscomp2002，344，12： | 1 |
| 11 | Competitive adsorption of zinc,cadmium,copper and lead in three highly weathered Brazilian soils显示文摘 | Fontes M P F Matos A F Costa L M | 2000 | Commun Soil Sci Plant Anal2000，31，： | 1 |
| 12 | Survey of Mycobacterium avium subspecies paratuberculosis in road-killed wild carnivores in Portugal显示文摘 | Matos A C Figueira L Martins M H | 2014 | J Zoo Wildl Med2014，45，4： | 1 |
| 13 | Prophylactie anastomotic drainage for colorectal surgery 显示文摘 | Jesus E Karliczek A Matos D | 2004 | Cochrane Database Syst Rev2004，18，00： | 1 |
| 14 | Influence of limestone addition on the behavior of NO and N20 dur- ing fluidised bed coal combustion 显示文摘 | Tarelho L A C Matos M A A Pereira F J M A | 2006 | Fuel2006，85，7： | 1 |
| 15 | Diagenesis and reservoir quality evolution of fluvial sandstones during progressive burial and uplift : evi- dence from the Upper Jurassic Boipeba Member, Recrncavo basin, Northeastern Brazil显示文摘 | Salem A M Morad S Mato L F | 2000 | AAPG Bulletin2000，84，7： | 1 |
| 16 | Ultrasound -assisted treatment of pahn oil samples for the determination of copper and lead by stripping chronopotenfiometry显示文摘 | Cypriano J C Matos M A C Mates R C | 2008 | Microchem J2008，90，： | 1 |
| 17 | Ecophysiological responses of Empetrum nigrum to heavy metal pollution 显示文摘 | Matos A T Uhlig C Hansen E | 2001 | Environmental Pollution2001，112，： | 1 |
| 18 | Activated carbon supported Ni-Ca:Influence of reaction parameters on activity and stability of catalyst on methane reformation显示文摘 | D?az K Garc?a V Matos J | 2007 | Fuel2007，86，9： | 1 |
| 19 | Keratin8, 10, 13, and 17 are useful markers in the diagnosis of human cervix carcinomas显示文摘 | Carla C Matos A Landim B | 2004 | Hum Pathol2004，35，5： | 1 |
| 20 | Loss allocation in distribution net- works with embedded generation显示文摘 | Costa P M Matos M A | 2004 | IEEE Trans on Power Systems2004，19，1： | 1 |
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