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Biomarkers and subtypes of deranged lipid metabolism in nonalcoholic fatty liver disease

World Journal of Gastroenterology 2019年第24期25卷 3009-3020页

作者： josé m mato Cristina Alonso mazen Noureddin Shelly C Lu CIC bioGUNE Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd)Technology Park of BizkaiaDerio 48160BizkaiaSpain OWL metabolomics Technology Park of BizkaiaDerio 48160BizkaiaSpain Division of Digestive and Liver Diseases Comprehensive Transplant CenterCedars-Sinai Medical CenterLos AngelesCA 90048United States

Nonalcoholic fatty liver disease(NAFLD)is a heterogeneous and complex disease that is imprecisely diagnosed by liver *** covers a spectrum that ranges from simple steatosis,nonalcoholic steatohepatitis(NASH)with varying degrees of fibrosis,to cirrhosis,which is a major risk factor for hepatocellular *** and eating habit changes during the last century have made NAFLD the most common liver disease linked to obesity,type 2 diabetes mellitus and dyslipidemia,with a global prevalence of 25%.NAFLD arises when the uptake of fatty acids(FA)and triglycerides(TG)from circulation and de novo lipogenesis saturate the rate of FAβ-oxidation and verylow density lipoprotein(VLDL)-TG *** lipid metabolism is also associated with NAFLD progression from steatosis to NASH,and therefore,alterations in liver and serum lipidomic signatures are good indicators of the disease’s development and *** review focuses on the importance of the classification of NAFLD patients into different subtypes,corresponding to the main alteration(s)in the major pathways that regulate FA homeostasis leading,in each case,to the initiation and progression of *** concept also supports the targeted intervention as a key approach to maximize therapeutic efficacy and opens the door to the development of precise NASH treatments.

关键词： S-adenosylmethionine methionine adenosyltransferase Lipid metabolism multiomics Lipidomics Nonalcoholic steatohepatitis One-carbon metabolism Very low-density lipoproteins Steatosis Precision medicine

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Early treatment efficacy of S-adenosylmethionine in patients with intrahepatic cholestasis: A systematic review

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World Journal of Hepatology 2020年第2期12卷 46-63页

作者： mazen Noureddin Suntje Sander-Struckmeier josém mato Division of Digestive and Liver Diseases Comprehensive Transplant CenterCedars-Sinai Medical CenterLos AngelesCA 90048United State Gastroenterology/Hepatology Abbott Laboratories GmbHHannover 30173Germany CIC bioGUNE Basque Research and Technology Alliance(BRTA)CIBERehdDerio 48160BizkaiaSpain

BACKGROUND S-adenosylmethionine(Adomet)is a metabolically pleiotropic molecule used to treat intrahepatic cholestasis(IHC)and chronic liver *** the efficacy of Adomet has been demonstrated previously,it has not been systematically investigated within the early weeks of *** To systematically review the early treatment efficacy of Adomet in adult patients with *** Studies reporting the efficacy of intravenous,intramuscular,or oral forms of Adomet within 8 wk of treatment initiation were considered;three randomized and six non-randomized studies were eligible for inclusion(PROSPERO registration number CRD42018090936).Of the three randomized studies,two were double-blind and placebo-controlled,and one was comparator-controlled with unclear blinding and a relatively high risk of *** serum levels of alanine aminotransferase(ALT),aspartate aminotransferase(AST),alkaline phosphatase(ALP),and gamma-glutamyl transferase(γGT)following Adomet treatment vs placebo,comparator,or baseline were summarized to determine differences in liver *** in patient-reported clinical symptoms of cholestasis were also *** Both placebo-controlled randomized studies reported significant reductions in serum ALT levels with Adomet vs placebo within 2 *** of these also reported significant ALP reductions,and the other reported significant AST andγGT reductions within 2 *** comparator-controlled randomized study,which had a number of notable limitations,reported significant reductions in serum ALT and AST levels with Adomet vs potassium magnesium aspartate within 4 wk,but not within2 *** of the non-randomized studies(4/4)that investigated ALT,AST,ALP and/orγGT reported significant reductions in at least two of these parameters within 2 *** the five studies that evaluated fatigue,reductions were observed within 2 wk in one randomized and two nonrandomized *** remaining two non-randomized studies reported improvements in fa

关键词： S-adenosylmethionine Intrahepatic cholestasis Chronic liver disease Liver enzymes Symptoms of cholestasis

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methionine adenosyltransferases in liver cancer

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World Journal of Gastroenterology 2019年第31期25卷 4300-4319页

作者： Ben murray Lucia Barbier-Torres Wei Fan josém mato Shelly C Lu Division of Digestive and Liver diseases Department of MedicineCedars-Sinai Medical CenterLos AngelesCA 90048United States CIC bioGUNE Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas(Ciberehd)TechnologyPark of BizkaiaDerio 48160BizkaiaSpain

methionine adenosyltransferases(mATs)are essential enzymes for life as they produce S-adenosylmethionine(SAme),the biological methyl donor required for a plethora of reactions within the *** systems express two genes,mAT1A and mAT2A,which encode for mATα1 and mATα2,the catalytic subunits of the mAT isoenzymes,respectively.A third gene mAT2B,encodes a regulatory subunit known as mATβwhich controls the activity of mATα***1A,which is mainly expressed in hepatocytes,maintains the differentiated state of these cells,whilst mAT2A and mAT2B are expressed in extrahepatic tissues as well as non-parenchymal cells of the liver(e.g.,hepatic stellate and Kupffer cells).The biosynthesis of SAme is impaired in patients with chronic liver disease and liver cancer due to decreased expression and inactivation of mATα1.A switch from mAT1A to mAT2A/mAT2B occurs in multiple liver diseases and during liver growth and dedifferentiation,but this change in the expression pattern of mATs results in reduced hepatic SAme *** of study have utilized the mat1a-knockout(KO)mouse that spontaneously develops non-alcoholic steatohepatitis(NASH)and hepatocellular carcinoma(HCC)to elucidate a variety of mechanisms by which mAT proteins dysregulation contributes to liver *** increasing volume of work indicates that mATs have SAme-independent functions,distinct interactomes and multiple subcellular *** we aim to provide an overview of mAT biology including genes,isoenzymes and their regulation to provide the context for understanding consequences of their *** will highlight recent breakthroughs in the field and underscore the importance of mAT’s in liver tumorigenesis as well as their potential as targets for cancer therapy.

关键词： methionine adenosyltransferases S-adenosylmethionine Liver cancer Hepatocellular carcinoma Cholangiocarcinoma Biomarkers Therapeutic targets

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Arachidyl amido cholanoic acid improves liver glucose and lipid homeostasis in nonalcoholic steatohepatitis via AmPK and mTOR regulation

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World Journal of Gastroenterology 2020年第34期26卷 5101-5117页

作者： 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 Precision medicine and metabolism Laboratory Centro de Investigación Cooperativa en Biociencias(CIC bioGUNE)Derio 48160BizkaiaSpain CIBERehd-Centro de Investigación Biomédica en Red de enfermedades hepáticas y digestivas Madrid 28029Spain Department of Precision medicine University of Campania"Luigi Vanvitelli"Naples 80138Italy Liver Disease Laboratory Centro de Investigación Cooperativa en Biociencias(CIC bioGUNE)Derio 48160Spain Proteomics Platform Centro de Investigación Cooperativa en Biociencias(CIC bioGUNE)Derio 48160Spain OWL metabolomics Derio 48160Spain Instituto Biofisika(UPV/EHU CSIC)Leioa 48940SpainDepartamento de Bioquímica y Biología MolecularUniversidad del País VascoLeioa 48940Spain Pre-clinical and Chemistry Manufacturing and ControlsGalmed PharmaceuticalsTel Aviv 6578317Israel metabolomics Platform Centro de Investigación Cooperativa en Biociencias(CIC bioGUNE)Derio 48160Spain Division of Digestive and Liver Diseases Cedars-Sinai Medical CenterLos AngelesCA 90048United States

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 *** 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 *** 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 *** Isolated primary mouse hepatocytes were incubated with 20μmol/L Aramchol or vehicle for 48 ***,analyses were performed including Western blot,proteomics by mass spectrometry,and fluxomic analysis with 13C-uniformly labeled *** 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 *** metabolomics were assessed using ultra-high-performance liquid chromatography-time of flight-mS for the determination of glucose metabolism-related *** Combination of proteomics and Western blot analyses showed increased AmPK activity while the activity of nutrient sensor mTORC1 was decreased by Aramchol in *** 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 ***,liver metabolomic analysis showed

关键词： Nonalcoholic fatty liver disease Steatohepatitis methionine and choline deficient diet Tricarboxylic acid cycle Hemoglobin A1c Stearoyl-CoA desaturase 1

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mitochondria–cGAS–STING axis is a potential therapeutic target for senescence-dependent inflammaging-associated neurodegeneration

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Neural Regeneration Research 2025年第3期20卷 805-807页

作者： josém.Izquierdo Centro de Biología molecular Severo Ochoa(CBm) Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid(CSIC-UAM)MadridSpain

The word “senescence” comes from the Latin senescens, meaning “to begin to age”, and is characterized by a long-lasting but reversible block in proliferation, resulting from stress-induced cell cycle arrest of pre... 详细信息

关键词： Latin potential lasting

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Ferroelectricity Induced by Oxygen Vacancies in Rhombohedral ZrO_(2) Thin Films

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Energy & Environmental materials 2024年第1期7卷 229-237页

作者： Veniero Lenzi josé P.B.Silva Břetislav Šmíd Vladimir matoín Cosmin m.Istrate Corneliu Ghica Judith L.macmanus-Driscoll Luís marques Physics Center of minho and Porto Universities(CF-Um-UP) University of MinhoCampus de Gualtar 4710-057Braga Portugal Laboratory of Physics for materials and Emergent Technologies LapMETUniversity of Minho4710-057Braga Portugal Department of Surface and Plasma Science Faculty of Mathematics and PhysicsCharles UniversityV Holešovičkách 218000Prague 8 Czech Republic National Institute of materials Physics 105 bis Atomistilor 077125Magurele Romania Department of materials Science and metallurgy 27 Charles Babbage Rd.Cambridge CB3 OFSUK

Rhombohedral phase Hf_(x)Zr_(1.x)O_(2)(HZO,x from 0 to 1)films are promising for achieving robust ferroelectric polarization without the need for an initial wake-up pre-cycling,as is normally the case for the more commonly studied orthorhombic ***,a large spontaneous polarization observed in rhombohedral films is not fully understood,and there are also large discrepancies between experimental and theoretical *** this work,in rhombohedral ZrO_(2)thin films,we show that oxygen vacancies are not only a key factor for stabilizing the phase,but they are also a source of ferroelectric polarization in the *** is shown experimentally through the investigation of the structural properties,chemical composition and the ferroelectric properties of the films before and after an annealing at moderate temperature(400℃)in an oxygen environment to reduce the V_(o)concentration *** experimental work is supported by density functional theory(DFT)calculations which show that the rhombohedral phase is the most stable one in highly oxygen defective ZrO_(2)*** DFT calculations also show that V_(o)contribute to the ferroelectric *** findings reveal the importance of V_(o)for stabilizing rhombohedral ZrO_(2)thin films with superior ferroelectric properties.

关键词： charged defects ferroelectric polarization rhombohedral phase stability zirconia

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Induced and heavy aggregation operators with distance measures

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Journal of Systems Engineering and Electronics 2010年第3期21卷 431-439页

作者： josé m.merigó montserrat Casanovas Department of Business Administration University of Barcelona

This paper introduces a new aggregation model by using induced and heavy aggregation operators in distances measures such as the Hamming *** is called the induced heavy ordered weighted averaging（OWA） distance（IHOWAD） *** paper studies some of its main properties and a wide range of particular cases such as the induced heavy OWA（IHOWA） operator,the induced OWA distance（IOWAD） operator and the heavy OWA distance（HOWAD） *** approach is generalized by using generalized and quasi-arithmetic means obtaining the induced generalized IHOWAD（IGHOWAD） operator and the Quasi-IHOWAD *** application of the new approach in a decision making problem regarding the selection of strategies is developed.

关键词： distance measures aggregation operators decision making OWA operator.

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How to select a journal for your research

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World Journal of Gastroenterology 2023年第21期29卷 3379-3384页

作者： josém Ramia Department of Surgery Hospital General Universitario Dr.BalmisAlicante 03010Spain

Publication in a peer-reviewed journal is the goal of any research *** of the most important(and possibly the least understood)aspects of the publication process is the choice of a suitable journal that is likely to a... 详细信息

关键词： Research Journal Altmetrics Publication

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Differential response of injured and healthy retinas to syngeneic and allogeneic transplantation of a clonal cell line of immortalized olfactory ensheathing glia:a double-edged sword

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Neural Regeneration Research 2025年第8期20卷 2395-2407页

作者： maría Norte-muñoz maría Portela-Lomba Paloma Sobrado-Calvo Diana Simón Johnny Di Pierdomenico Alejandro Gallego-Ortega mar Pérez josémCabrera-maqueda Javier Sierra manuel Vidal-Sanz maría Teresa moreno-Flores marta Agudo-Barriuso Grupo de Investigación Oftalmología Experimental Departamento de OftalmologíaOptometríaOtorrinolaringología y Anatomía PatológicaFacultad de MedicinaUniversidad de MurciaInstituto Murciano de Investigación Biosanitaria(IMIB)Campus de Ciencias de la SaludMurciaSpain Experimental Sciences Faculty Universidad Francisco de VitoriaPozuelo de AlarcónMadridSpain Anatomy Histology and Neuroscience DepartmentMedicine FacultyUniversidad Autónoma de MadridMadridSpain Center of Neuroimmunology Service of NeurologyLaboratory of Advanced Imaging in Neuroimmunological DiseasesHospital Clínic of BarcelonaInstitut d’Investigacions Biomèdiques August Pi i Sunyer(IDIBAPS)and Universitat de BarcelonaBarcelonaSpain medicine Faculty Universidad Francisco de VitoriaPozuelo de AlarcónMadridSpain

Olfactory ensheathing glia promote axonal regeneration in the mammalian central nervous system,including retinal ganglion cell axonal growth through the injured optic ***,it is unknown whether olfactory ensheathing glia also have neuroprotective *** ensheathing glia express brain-derived neurotrophic factor,one of the best neuroprotectants for axotomized retinal ganglion ***,we aimed to investigate the neuroprotective capacity of olfactory ensheating glia after optic nerve *** ensheathing glia cells from an established rat immortalized clonal cell line,TEG3,were intravitreally injected in intact and axotomized retinas in syngeneic and allogeneic mode with or without microglial inhibition or immunosuppressive *** and gene expression analyses were *** bulb-derived primary olfactory ensheathing glia and TEG3 express major histocompatibility complex classⅡ*** and syngenically transplanted TEG3 cells survived in the vitreous for up to 21 days,forming an *** axotomized retinas,only the allogeneic TEG3 transplant rescued retinal ganglion cells at 7 days but not at 21 *** these retinas,microglial anatomical activation was higher than after optic nerve crush *** intact retinas,both transplants activated microglial cells and caused retinal ganglion cell death at 21 days,a loss that was higher after allotransplantation,triggered by pyroptosis and partially rescued by microglial inhibition or ***,neuroprotection of axotomized retinal ganglion cells did not improve with these *** different neuroprotective properties,different toxic effects,and different responses to microglial inhibitory treatments of olfactory ensheathing glia in the retina depending on the type of transplant highlight the importance of thorough preclinical studies to explore these variables.

关键词： cell therapy immune recognition major histocompatibility complex class II(mHCII) neuroprotection olfactory ensheathing glia retinal ganglion cells

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Vitamin D-dependent microbiota-enhancing tumor immunotherapy

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Cellular & molecular Immunology 2024年第10期21卷 1083-1086页

作者： josé m.Izquierdo Centro de Biología molecular Severo Ochoa Consejo Superior de Investigaciones CientíficasUniversidad Autónoma de Madrid(CSIC/UAM)C/Nicolás Cabrera 128049MadridSpain

The antitumor immune response plays a crucial role in successful cancer *** a recent article in Science,Giampazolias et al.[1]reported a vitamin D(VitD)-mediated antitumor mechanism in murine intestinal epithelial cells(IECs)associated with a specific microbiota signature(Bacteroides fragilis)that enhances the antitumor immune *** strong positive association between VitD-dependent microbiota and the antitumor immune response provides a proof-of-concept for supplementing immunotherapy regimens with VitD to strengthen antitumor immunity and improve immunotherapysuccess.

关键词： immunotherapy immunity vitamin

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