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Mechanisms of Hepatic Cholestatic Drug Injury

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Journal of Clinical and Translational Hepatology 2019年第1期7卷 86-92页

作者： Tea Omanovic Kolaric Vjera Nincevic Robert smolic martina smolic George Y Wu Department of Pharmacology Faculty of Medicine OsijekOsijekCroatia Department of Pharmacology Faculty of Dental Medicine and HealthOsijekCroatia Department of Medicine Division of Gastroenterology-HepatologyUniversity of Connecticut Health CenterFarmingtonCTUSA

Drug-induced cholestasis represents a form of drug-induced liver disease that can lead to severe impairment of liver *** drugs have been shown to cause cholestasis and consequently bile duct ***,there is still lack of therapeutic tools that can prevent progression to advanced stages of liver *** review focuses on the various pathological mechanisms by which drugs expresstheir hepatotoxic effects,as well as consequences of increased bile acid and toxin accumulation in the hepatocytes.

关键词： Drug-induced liver injury Bile acids Cholestasis

An Update on Efficacy and Safety of Emerging Hepatic Antifibrotic Agents

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Journal of Clinical and Translational Hepatology 2021年第1期9卷 60-70页

作者： Vinka Rupcic Rubin Kristina Bojanic martina smolic Jurica Rubin Ashraf Tabll Robert smolic Department of Gynaecology and Obstetrics Osijek University Hospital CentreFaculty of MedicineJosip Juraj Strossmayer University of OsijekOsijekCroatia Department of Biophysics and Radiology Faculty of Dental Medicine and Health OsijekJ.J.Strossmayer University of OsijekOsijekCroatia Department of Biophysics and Radiology Faculty of Medicine OsijekJ.J.Strossmayer University of OsijekOsijekCroatia Department of Radiology Health Center OsijekOsijekCroatia Department of Pharmacology and Biochemistry Faculty of Dental Medicine and Health OsijekJ.J.Strossmayer University of OsijekOsijekCroatia Department of Pharmacology Faculty of Medicine OsijekJ.J.Strossmayer University of OsijekOsijekCroatia Department of Medicine Division of Gastroenterology/HepatologyUniversity Hospital OsijekOsijekCroatia Microbial Biotechnology Department Genetic Engineering and Biotechnology Research DivisionNational Research CentreDokkiEgypt Department of immunology Egypt Center for Research and RegenerativeMedicine(ECRRM)CairoEgypt Department of Pathophysiology Physiology and ImmunologyFaculty of Dental Medicine and Health OsijekJ.J.Strossmayer University of OsijekOsijekCroatia Department of Pathophysiology Faculty of Medicine OsijekJ.J.Strossmayer University of OsijekOsijekCroatia

Liver fibrosis represents a response to chronic liver *** dysfunction-associated fatty liver disease and metabolic dysfunction-associated steatohepatitis are the most common chronic liver diseases,both with increasing ***,there is a great impetus for development of agents targeting these *** data on possible treatment options for liver fibrosis are emerging in the ***,despite extensive research and much effort in the field,approved agents for liver fibrosis are still *** this critical review,we have summarized the main data about specific treatment options for liver fibrosis gained from ongoing clinical trials,with an emphasis on efficacy and safety of these agents.

关键词： Liver fibrosis MAFLD MASH Clinical trials Antifibrotic agents Efficacy Safety

Inhibition of hepatitis C virus replication by single-stranded RNA structural mimics

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World Journal of Gastroenterology 2010年第17期16卷 2100-2108页

作者： Robert smolic martina smolic John H Andorfer Catherine H Wu Robert M Smith George Y Wu Department of Medicine Division of Gastroenterology-HepatologyUniversity of Connecticut Health Center263 Farmington Ave.FarmingtonCT 06030-1845United States

AIM: To examine the effect of hepatitis C virus (HCV) structural mimics of regulatory regions of the genome on HCV ***: HCV RNA structural mimics were constructed and tested in a HCV genotype 1b aBB7 replicon,and a Japanese fulminant hepatitis-1 (JFH-1) HCV genotype 2a infection *** sequences were computer-predicted to adopt stem-loop structures identical to the corresponding elements in full-length viral ***7.5 cells bearing the BB7 replicon or infected with JFH-1 virus were transfected with expression vectors generating HCV mimics and *** HCV RNA and protein levels were quantified by real-time polymerase chain reaction and Western blotting,*** evaluate possible antisense effects,complementary RNAs spanning a mimic were ***: In the BB7 genotype 1b replicon system,mimics of the polymerase (NS-5B),X and BA regions inhibited replication by more than 90%,50%,and 60%,*** the JFH-1 genotype 2 infection system,mimics that were only 74% and 46% identical in sequence relative to the corresponding region in JFH-1 inhibited HCV replication by 91.5% and 91.2%,respectively,as effectively as a mimic with complete identity to HCV genotype *** inhibitory effects were confirmed by NS3 protein *** RNA molecules spanning the 74% identical mimic had no significant ***: HCV RNA structural mimics can inhibit HCV RNA replication in replicon and infectious HCV systems and do so independent of close sequence identity with the target.

关键词： Hepatitis C virus Japanese fulminant hepatitis virus Complementarity RNA sequence Hybridization

Anabolic androgenic steroid-induced liver injury:An update

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World Journal of Gastroenterology 2022年第26期28卷 3071-3080页

作者： Ana Petrovic Sonja Vukadin Renata Sikora Kristina Bojanic Robert smolic Davor Plavec George Y Wu martina smolic Department of Pharmacology and Biochemistry Faculty of Dental Medicine and Health OsijekJ.J.Strossmayer University of OsijekOsijek 31000Croatia Department of Pharmacology Faculty of Medicine OsijekJ.J.Strossmayer University of OsijekOsijek 31000Croatia Department of Dental Medicine Faculty of Dental Medicine and Health OsijekJ.J.Strossmayer University of OsijekOsijek 31000Croatia Department of Dental Medicine Health Center Osijek-Baranja CountyOsijek 31000Croatia Department of Otorhinolaryngology Neurosurgery and RadiologyFaculty of Dental Medicine and Health OsijekJ.J.Strossmayer University of OsijekOsijek 31000Croatia Department of Biophysics and Radiology Faculty of Medicine OsijekJ.J.Strossmayer University of OsijekOsijek 31000Croatia Department of Radiology Health Center Osijek-Baranja CountyOsijek 31000Croatia Research Department Srebrnjak Children's HospitalZagreb 10000Croatia Department of Medicine Division of Gastrenterology/HepatologyUniversity of Connecticut Health CenterFarmingtonCT 06030United States

Anabolic androgenic steroids(AASs)are a group of molecules including endogenous testosterone and synthetic derivatives that have both androgenic and anabolic *** properties make them therapeutically beneficial in medical conditions such as ***,they are commonly bought illegally and misused for their anabolic,skeletal muscle building,and performanceenhancing *** and long-term use of AASs affects all organs,leading to cardiovascular,neurological,endocrine,gastrointestinal,renal,and hematologic *** is one of the major concerns regarding AASs treatment and *** and its derivatives have been most often shown to induce a specific form of cholestasis,peliosis hepatis,and hepatic benign and malignant *** is currently believed that mechanisms of pathogenesis of these disorders include disturbance of antioxidative factors,upregulation of bile acid synthesis,and induction of hepatocyte *** toxicity cases are treated with supportive measures and liver function normalizes with discontinuation of ***,some long-term consequences are ***-induced liver injury should be taken in consideration in patients with liver disorders,especially with the increasing unintentional ingestion of supplements containing *** this paper,we review the most current knowledge about AAS-associated adverse effects on the liver,and their clinical presentations,prevalence,and pathophysiological mechanisms.

关键词： Androgens Steroids Cholestasis Fibrosis Liver Chemical and drug induced liver injury

Effect of COVID-19 on management of type 1 diabetes:Pushing the boundaries of telemedical healthcare

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World Journal of Diabetes 2021年第6期12卷 780-785页

作者： Ines Bilic Curcic Maja Cigrovski Berkovic Tomislav Kizivat Silvija Canecki Varzic Robert smolic martina smolic Department of Endocrinology University Hospital OsijekOsijek 31000Croatia Department of Pharmacology Faculty of Medicine OsijekOsijek 31000Croatia Department of Endocrinology DiabetesMetabolism and Clinical PharmacologyUniversity Hospital DubravaZagreb 10000Croatia Department of Kinesiological Anthropology and Methodology Faculty of KinesiologyUniversity of ZagrebZagreb 10000Croatia Clinical Institute of Nuclear Medicine and Radiation Protection University Hospital OsijekOsijek 31000Croatia Department of Nuclear Medicine and Oncology Faculty of Medicine OsijekOsijek 31000Croatia Department of Internal Medicine Family Medicineand HistoryFaculty of Medicine OsijekOsijek 31000Croatia Department of Pathophysiology Faculty of Medicine OsijekOsijek 31000Croatia Department of Pathophysiology Physiology and ImmunologyFaculty of Dental Medicine and HealthOsijek 31000Croatia Department of Pharmacology and Biochemistry Faculty of Dental Medicine and HealthOsijek 31000Croatia

The new coronavirus disease 2019(COVID-19)pandemic posed a great burden on health care systems worldwide and is an enormous and real obstacle in providing needed health care to patients with chronic diseases such as *** to COVID-19,there have been great advances in technology used for management of type 1 diabetes,primarily insulin pumps,sensors,integrated and closed loop systems,ambulatory glucose profile software,and smart phone apps providing necessary essentials for telemedicine implementation right at the beginning of the COVID-19 *** results of these remote interventions are reassuring in terms of glycemic management and hemoglobin A1c ***,data on long-term outcomes and cost reductions are missing as well as proper technical infrastructure and government health policy support.

关键词： Diabetes management Telemedicine COVID-19 Diabetes type 1

Noninvasive Fibrosis Assessment in Chronic Hepatitis C Infection: An Update

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Journal of Clinical and Translational Hepatology 2023年第5期11卷 1228-1238页

作者： Kristina Bojanic Mirta Sudaric Bogojevic Sonja Vukadin Renata Sikora Gordana Ivanac Nikola Raguz Lucic martina smolic Ashraf ATabll George YWu Robert smolic Faculty of Dental Medicine and Health Osijek Josip Juraj Strossmayer University of OsijekOsijekCroatia Faculty of Medicine Osijek Josip Juraj Strossmayer University of OsijekOsijekCroatia Health Center Osijek-Baranja County OsijekCroatia Department of Biology Josip Juraj Strossmayer University of OsijekOsijekCroatia University Hospital Dubrava ZagrebCroatia School of Medicine University of ZagrebZagrebCroatia Microbial Biotechnology Department Biotechnology Research InstituteNational Research CenterGizaEgypt Egypt Center for Research and Regenerative Medicine(ECRRM) CairoEgypt University of Connecticut Health Center FarmingtonCTUSA

Liver biopsy is historically the gold standard for liver fibrosis assessment of chronic hepatitis C ***,with the introduction and validation of noninvasive tests(NITs)to evaluate advanced fibrosis,and the direct-acting antiviral agents for treatment of chronic hepatitis C virus(HCV),the role of NITs have become even more *** is now need for longitudinal monitoring and elucidation of cutoff values for prediction of liver-related complication after sustained virological *** aim of this report is to provide a critical overview of the various NITs available for the assessment of liver fibrosis in HCV patients.

关键词： Hepatitis C virus Fibrosis Noninvasive serum fibrosis markers Transient elastography Shear wave elastography Magnetic resonance elastography Steatohepatitis

Hypothyroidism and Nonalcoholic Fatty Liver Disease:Pathophysiological Associations andTherapeutic Implications

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Journal of Clinical and Translational Hepatology 2020年第3期8卷 347-353页

作者： Tomislav Kizivat Ivana Maric Dunja Mudri Ines Bilic Curcic Dragan Primorac martina smolic University of Osijek Faculty of MedicineOsijekCroatia University Hospital Osijek OsijekCroatia St Catherine Specialty Hospital Zagreb&ZabokCroatia University of Split School of Medicine SplitCroatia Eberly College of Science State CollegePenn State UniversityPAUSA The Henry C Lee College of Criminal Justice&Forensic Sciences University of New HavenWest HavenCTUSA University of Rijeka School of Medicine RijekaCroatia University of Osijek Faculty of Dental Medicine&Health OsijekCroatia

Nonalcoholic fatty liver disease(NAFLD)is a complex clinical entity which can be secondary to many other diseases including hypothyroidism,characterized by lowering of thyroid hormones and increased thyroid stimulating hormone(TSH).A lot of emerging data published recently advocates the hypothesis that hypothyroid induced NAFLD could be a separate clinical entity,even suggesting possible treatment options for NAFLD involving substitution therapy for hypothyroidism along with lifestyle *** addition,a whole new field of research is focused on thyromimetics in NAFLD/NASH treatment,currently in phase 3 clinical *** this critical review we summarized epidemiological and pathophysiological evidence linking these two clinical entities and described specific treatment options with the accent on promising new agents in NAFLD treatment,specifically thyroid hormone receptor(THR)agonist and its metabolites.

关键词： NAFLD MAFLD Hypothyroidism Metabolic syndrome Thyromimetics

Obesity Paradox in Chronic Liver Diseases:Product of Bias or a Real Thing?

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Journal of Clinical and Translational Hepatology 2019年第3期7卷 275-279页

作者： Ines Bilic Curcic Maja Cigrovski Berkovic Lucija Kuna Hrvoje Roguljic Robert smolic Silvija Canecki Varzic Lucija Virovic Jukic martina smolic Department of Pharmacology Faculty of MedicineJ.J.Strossmayer University of OsijekOsijekCroatia Department of Diabetes Endocrinology and Metabolism DisordersOsijek University Hospital CentreFaculty of MedicineJosip Juraj Strossmayer University of OsijekOsijekCroatia Department for Endocrinology Diabetes and Metabolism University Hospital Center"Sestre Milosrdnice"ZagrebCroatia Department of Pharmacology and Biochemistry Faculty of Dental Medicine and HealthJ.J.Strossmayer University of OsijekOsijekCroatia Department for Cardiovascular Disease Osijek University HospitalOsijekCroatia Department of Gastroenterology and Hepatology Osijek University Hospital CentreFaculty of MedicineJosip Juraj Strossmayer University of OsijekOsijekCroatia Department of Pathophysiology Faculty of MedicineJosip Juraj Strossmayer University of OsijekOsijekCroatia Department of Internal Medicine Faculty of MedicineJosip Juraj Strossmayer University of OsijekOsijekCroatia Department of Gastroenterology and Hepatology Sisters of Mercy University HospitalUniversity of Zagreb School of MedicineZagrebCroatia Department of Pharmacology J.J.Stross-mayer University of Osijek Faculty of Medicine OsijekJ.Huttlera 4Osijek 31000Croatia

In recent years,evidence supporting the theory of obesity paradox has increased,showing that obese/overweight people with prevalent chronic diseases experience lower mortality compared with patients of normal *** far,evidence is most comprehensive in cardiovascular and chronic renal diseases;however,published studies are prone to many biases,enabling us to reach a definite *** data in chronic liver disease is scarce and *** is traditionally associated with nonalcoholic fatty liver disease and steatosis in viral hepatitis and as such one would not expect the obesity paradox to be a real possibility in liver ***,there seem to be new data indicating the opposite-the obesity paradox exists in severe and end-stage liver cirrhosis,which could be attributed to a better lean mass in patients with higher body mass index,meaning that sarcopenia,as one of the most important prognostic factors of survival,is less likely to be ***,the problem of various methodological problems addressing the association between body weight and mortality,which is present both in liver disease and other chronic diseases,are preventing us from attaining an unanimous ***,we should be aware that the obesity paradox might be true,especially in severe and end-stage *** suggests focusing our efforts toward preserving or building up fat-free mass and decreasing infiammatory activity responsible for catabolism and sarcopenia,and implying that the underlaying cause should be treated.

关键词： Obesity paradox Chronic liver disease NAFLD NASH Cirrhosis

Targeting the Wnt Signaling Pathway in Liver Fibrosis for Drug Options:An Update

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Journal of Clinical and Translational Hepatology 2021年第6期9卷 960-971页

作者： Kristina Duspara Kristina Bojanic Josipa Ivanusic Pejic Lucija Kuna Tea Omanovic Kolaric Vjera Nincevic Robert smolic Aleksandar Vcev Marija Glasnovic Ines Bilic Curcic martina smolic Department of Pharmacology and Biochemistry Faculty of Dental Medicine and Health OsijekJ.J.Strossmayer University of OsijekOsijekCroatia Department of Pharmacology Faculty of Medicine OsijekJ.J.Strossmayer University of OsijekOsijekCroatia Department of Biophysics and Radiology Faculty of Dental Medicine and Health OsijekJ.J.Strossmayer University of OsijekOsijekCroatia Department of Biophysics and Radiology Faculty of Medicine OsijekJ.J.Strossmayer University of OsijekOsijekCroatia Department of Radiology Health Center OsijekOsijekCroatia Department of Medi-cine Division of Gastroenterology/HepatologyUniversity Hospital OsijekOsijekCroatia Department of Pathophysiology Physiology and ImmunologyFaculty of Dental Medicine and Health OsijekJ.J.Strossmayer University of OsijekOsijekCroatia Department of Pathophysiology Faculty of Medicine OsijekJ.J.Strossmayer University of OsijekOsijekCroatia Department of Medicine Family Medicine and History of MedicineFaculty of Medicine OsijekJ.J.Strossmayer University of OsijekOsijekCroatia Department of Medicine Division of EndocrinologyUniversity Hospital OsijekOsijekCroatia

morbidity and mortality for healthcare systems *** imparts an enormous economic burden to societies,making continuous research and informational updates about its pathogenesis and treatment *** review′s focus is on the current knowledge about the Wnt signaling path-way,serving as an important pathway in liver fibrosis development and activation of hepatic stellate cells(HSCs).Two types of Wnt pathways are distinguished,namely the ß-catenin-dependent canonical and non-canonical Ca^(2+) or planar cell polarity(PCP)-dependent *** dynamic balance of physiologically healthy liver and hepatocytes is disturbed by repeated liver *** of theß-catenin Wnt pathway prevents the regeneration of hepatocytes by the replacement of extracellular matrix(ECM),leading to the appearance of scar tissue and the formation of regenerated nodular hepatocytes,lacking the original function of healthy ***,liver function is reduced due to the severely advanced *** inhibition ofß-catenin inhibits inflammatory processes(since chemokines and pro-inflammatory cytokines are produced during Wnt activation),reduces growth of activated HSCs and reduces collagen synthesis and angiogenesis,thereby reducing the progression of liver fibrosis in *** the canonical Wnt pathway is usually inactive in a physiologically healthy liver,it shows activity during cell regeneration or renewal and in certain pathophysiological conditions,such as liver diseases and *** blocking of some of the basic components of the Wnt path-way is a therapeutic *** include the frizzled transmembrane receptor(Fz)receptors using the secreted frizzled-related protein family(sFRP),Fz-coreceptors low-density LRP 5/6 through dickkopf-related protein 1(DKK1)or niclosamide,glycogen kinase-3 beta(GSK-3β)using SB-216763,cyclic-AMP response element-binding protein(CBP)using PRI-724 and ICG-001,the lymphoid enhancer binding factor(LEF)/T cell-spec

关键词： Liver fibrosis Wnt signaling pathway Hepatic stellate cell Therapeutic solutions