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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 | Beta-blocker therapy in elderly patients with renal dysfunction and heart failure显示文摘OBJECTIVE To assess the role of beta-blockers(BB)in patients with chronic kidney disease(CKD)aged≥75 years.METHODS AND RESULTS From January 2008 to July 2014,we included 390 consecutive patients≥75 years of age with ejection fraction≤35%and glomerular filtration rate(GFR)≤60 m L/min per 1.73 m^2.We analyzed the relationship between treatment with BB and mortality or cardiovascular events.The mean age of our population was 82.6±4.1 years.Mean ejection fraction was 27.9%±6.5%.GFR was 60-45 m L/min per 1.73 m^2 in 50.3%of patients,45-30 m L/min per 1.73 m^2 in 37.4%,and<30 m L/min per 1.73 m^2 in 12.3%.At the conclusion of follow-up,67.4%of patients were receiving BB.The median follow-up was28.04(IR:19.41-36.67)months.During the study period,211 patients(54.1%)died and 257(65.9%)had a major cardiovascular event(death or hospitalization for heart failure).BB use was significantly associated with a reduced risk of death(HR=0.51,95%CI:0.35-0.74;P<0.001).Patients receiving BB consistently showed a reduced risk of death across the different stages of CKD:stage IIIa(GFR=30-45 m L/min per 1.73 m^2;HR=0.47,95%CI:0.26-0.86,P<0.0001),stage IIIb(GFR 30-45 m L/min per 1.73 m^2;HR=0.55,95%CI:0.26-1.06,P=0.007),and stages IV and V(GFR<30 m L/min per 1.73 m~2;HR=0.29,95%CI:0.11-0.76;P=0.047).CONCLUSIONS The use of BB in elderly patients with HFr EF and renal impairment was associated with a better prognosis.Use of BB should be encouraged when possible. | Juan Martínez-Milla Marcelino Cortés García Julia Anna Palfy Mikel Taibo Urquía Marta López Castillo Ana Devesa Arbiol Ana Lucía Rivero Monteagudo María Luisa Martín Mariscal Inés Jiménez-Varas Sem Briongos Figuero Juan Antonio Franco-Pelaéz JoséTuñón | 2021 | Journal of Geriatric Cardiology2021，18，1： | 3 |
| 3 | Relationships between sensory descriptors, consumer acceptability and volatile flavor compounds of American dry-cured ham显示文摘 | PHAM A J SCHILLING M W MIKEL W B | 2008 | Meat Science2008，80，3： | 1 |
| 4 | Stationary solutions to a quasi-newtonian flow with virous heating显示文摘 | Baranger J Mikelic A | 1995 | M3 AS:Math Model Meth Appl Sci1995，5，6： | 1 |
| 5 | Use of molecular markers to differentiate between commercial strains of the button mushroom A-garicus bisporus显示文摘 | Ramirez L Victor M Mikel A | 2001 | FEMS Microbiology Letters2001，198，1： | 1 |
| 6 | Alternative wnt signaling is ini- tiated by distinctreceptors显示文摘 | van Amerongen R Mikels A Nusse R | 2008 | Science Signaling2008，35，1： | 1 |
| 7 | Rigid punch problem with friction显示文摘 | Klarbring A Mikelic A Shillor M | 1991 | Int J of Engng Sci1991，29，6： | 1 |
| 8 | Chick pulmonary Wnt5a directs airway and vascular tubulogenesis 显示文摘 | Loscertales M Mikels A J Hu J K | 2008 | Development2008，135，7： | 1 |
| 9 | Rot2 receptor requires tyro-sine kinase activity to mediate WntSA signaling 显示文摘 | Mikels A Minami Y Nusse R | 2009 | J Biol Chem2009，284，30： | 1 |
| 10 | Maintenance and selfrenewal of longterm reconstituting hematopoietic stem cells supported by amniotic fluid显示文摘 | Barria E Mikels A Haas M | 2004 | Stem cells Dev2004，13，5： | 1 |
| 11 | Chick pulmonary Wnt5a directs airway and vascular tubulogenesis 显示文摘 | Loscertales M Mikels A J Hu JK | 2008 | Development2008，135，7： | 1 |
| 12 | Characteristics and purification of an oxygen insensitive azoreductase from Caulobacter subvibrioides strain C7-D 显示文摘 | Mazumder R Logan J R Mikell A T Jr | 1999 | J Indust Microbiol Biotechnol1999，23，6： | 1 |
| 13 | Stationary solutions to a quasi-Newtonian flow with viscous heating显示文摘 | Baranger J Mikelic A | 1995 | Math Models Methods Appl Sci1995，5，： | 1 |
| 14 | Asset Pricing and Systematic Liquidity Risk: An Empirical Investigation of the Spanish Stock Market显示文摘 | Miguel A Martinez Belen Nieto Gonzalo Rubio Mikel Tapia | 2005 | International Review of Economics and Finance2005，，14： | 1 |
| 15 | Alternative Wnt Signaling Is Initiated by Distinct Receptors 显示文摘 | van Amerongen R Mikels A Nusse R | 2008 | Sci Signal2008，1，35： | 1 |
| 16 | Alternative wnt signaling is initiated by distinct receptors 显示文摘 | VAN AMERONGEN R MIKELS A NUSSE R | 2008 | Sci Signal2008，1，35： | 1 |
| 17 | Purified Wnt5a protein aetivates or inhibits β-Catenin-TCF signal transduetion depending on receptor eontext显示文摘 | MIKELS A J NUSSE R | 2006 | PLoS Biol2006，4，4： | 1 |
| 18 | Purified Wnt5a protein activates or in- hibits beta- catenin- TCF signaling depending on receptor context 显示文摘 | Mikels A J Nusse R | 2006 | PLoS Biol2006，4，4： | 1 |
| 19 | Autologous preparations rich in growth factors promote proliferation and induce VEGF and HGF production by human tendon ceils in cuhure显示文摘 | Eduardo A Isabel A Mikel S | 2005 | J Orth Res2005，23，2： | 1 |
| 20 | On the interface boundary condition of Beavers, Joseph, and Saffman 显示文摘 | Jager W Mikelic A | 2000 | SIAMJApplMath2000，60，14： | 1 |
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