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Molecular mechanisms of insulin resistance in chronic hepatitis C

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World Journal of Gastroenterology 2009年第35期15卷 4356-4364页

作者： Mark W Douglas jacob george Storr Liver Unit Westmead Millennium InstituteUniversity of Sydney at Westmead Hospita

It is now widely recognized that chronic hepatitis C (CHC)is associated with insulin resistance(IR)and type 2 diabetes,so can be considered a metabolic *** is most strongly associated with hepatitis C virus(HCV)genotype 1,in contrast to hepatic steatosis, which is associated with genotype 3 *** from the well-described complications of diabetes,IR in CHC predicts faster progression to fibrosis and cirrhosis that may culminate in liver failure and hepatocellular *** recently,it has been recognized that IR in CHC predicts a poor response to antiviral therapy. The molecular mechanisms for the association between IR and HCV infection are not well *** review will elaborate on the clinical associations between CHC and IR and summarize current knowledge regarding the molecular mechanisms that potentially mediate HCV-associated IR.

关键词： Hepatitis C virus Insulin resistance Treatment response Interferon

Circulating CD14＋ monocytes in patients with aortic stenosis

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Journal of Geriatric Cardiology 2016年第1期13卷 81-87页

作者： Sara Shimoni Valery Meledin Iris Bar jacob Fabricant Gera Gandelman jacob george Heart Institute Kaplan Medical Center Rehovot Israel

BackgroundCalcific aortic stenosis （AS） is an active process sharing similarities with atherosclerosis and chronic inflammation. The pathophysiology of AS is notable for three cardinal components： inflammation, fibrosis and calcification. Monocytes play a role in each of these processes. The role of circulating monocytes in AS is not clear. The aim of the present study was to study an association between cir-culating apoptotic and non apoptotic CD14＋ monocytes and AS *** assessed the number of CD14＋ monocytes and apoptotic monocytes in 54 patients with significant AS （aortic valve area 0.74 ± 0.27 cm2） and compared them to 33 patients with similar risk factors and no valvular disease. The level of CD14＋ monocytes and apoptotic monocytes was assessed by flow *** was no difference in the risk factor profile and known coronary or peripheral vascular diseases between patients with AS and ***-tients with AS exhibited increased numbers of CD14＋ monocytes as compared to controls （9.9% ± 4.9%vs. 7.7% ± 3.9%,P= 0.03）. CD14＋ monocyte number was related to age and the presence and severity of AS. In patients with AS, both CD14＋ monocytes and apoptotic mono-cytes were inversely related to aortic valve *** with significant AS have increased number of circulating CD14＋ monocytes and there is an inverse correlation between monocyte count and aortic valve area. These findings may suggest that inflammation is operative not only in early valve injury phase, but also at later developed stages such as calcification when AS is severe.

关键词： Aortic stenosis Inflammation Monocytes

Macrophages in metabolic associated fatty liver disease

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World Journal of Gastroenterology 2020年第16期26卷 1861-1878页

作者： Jawaher Alharthi Olivier Latchoumanin jacob george Mohammed Eslam Storr Liver Centre Westmead Institute for Medical ResearchWestmead Hospital and University of SydneySydney 2145NSWAustralia

Metabolic associated fatty liver disease(MAFLD),formerly named non-alcoholic fatty liver disease is the most common liver disorder in many *** inflammatory subtype termed steatohepatitis is a driver of disease progression to cirrhosis,hepatocellular carcinoma,liver transplantation,and death,but also to extrahepatic complications including cardiovascular disease,diabetes and chronic kidney *** plasticity of macrophages in response to various environmental cues and the fact that they can orchestrate cross talk between different cellular players during disease development and progression render them an ideal target for drug *** report reviews recent advances in our understanding of macrophage biology during the entire spectrum of MAFLD including steatosis,inflammation,fibrosis,and hepatocellular carcinoma,as well as for the extra-hepatic manifestations of *** discuss the underlying molecular mechanisms of macrophage activation and polarization as well as cross talk with other cell types such as hepatocytes,hepatic stellate cells,and adipose *** conclude with a discussion on the potential translational implications and challenges for macrophage based therapeutics for MAFLD.

关键词： Metabolic associated fatty liver disease Macrophages Inflammation Fibrosis Hepatic stellate cells

Determining the role for uric acid in non-alcoholic steatohepatitis development and the utility of urate metabolites in diagnosis:An opinion review

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World Journal of Gastroenterology 2020年第15期26卷 1683-1690页

作者： Paul Brennan Kathleen Clare jacob george John F Dillon Department of Molecular and Clinical Medicine University of DundeeNinewells Hospital and Medical SchoolDundee DD19SYUnited Kingdom Department of Neurology Queen Elizabeth HospitalGlasgow G514TFUnited Kingdom

There has long been a recognised association between non-alcoholic fatty liver disease(NAFLD)and the composite aspects of the metabolic *** of this association highlighted the supposed co-existence of elevated uric acid levels in those with *** is interest in exploitation of this as a putative diagnostic and prognostic biomarker in *** the increased economic and health burden associated with the NAFLD epidemic,improved methods of population-based,minimally-invasive methods and biomarkers are clearly highly sought and *** this opinion review we review the proposed role of uric acid in the pathogenesis of NAFLD and its potential utilisation in the diagnosis and monitoring of the disease process.

关键词： Non-alcoholic fatty liver disease Non-alcoholic steatohepatitis Uric acid Urate Non-invasive fibrosis markers Fatty liver index

Interaction of IFNL3 with insulin resistance,steatosis and lipid metabolism in chronic hepatitis C virus infection

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World Journal of Gastroenterology 2013年第41期19卷 7055-7061页

作者： Mohammed Eslam David R Booth jacob george Golo Ahlenstiel Storr Liver Unit Westmead Millennium Institute and Westmead HospitalUniversity of SydneySydneyNSW 2145Australia Institute for Immunology and Allergy Research Westmead Millennium InstituteUniversity of SydneySydneyNSW 2145Australia

Metabolic changes are inextricably linked to chronic hepatitis C(CHC).Recently polymorphisms in the IFNL3(IL28B)region have been shown to be strongly associated with spontaneous and treatment induced recovery from hepatitis C virus(HCV)***,circumstantial evidence suggests a link between IFNL3single nucleotide polymorphisms and lipid metabolism,steatosis and insulin resistance in *** emerging picture suggests that the responder genotypes of IFNL3polymorphisms are associated with a higher serum lipid profile,and less frequent steatosis and insulin *** review analyzes the current data regarding this interaction and its meaning for HCV pathogenesis and disease progression.

关键词： IFNL3 Chronic hepatitis C Insulin resistance Lipids

Dendritic cells in hepatitis C virus infection:Key players in the IFNL3-genotype response

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World Journal of Gastroenterology 2014年第47期20卷 17830-17838页

作者： Kate S O'Connor jacob george David Booth Golo Ahlenstiel Institute for Immunology and Allergy Research Westmead Millennium InstituteUniversity of SydneySydneyNSW 2145Australia Storr Liver Unit Westmead Millennium Institute and Westmead HospitalUniversity of SydneySydneyNSW 2145Australia

Recently,single nucleotide polymorphisms,in the vicinity of the interferon lambda 3(IFNL3)gene have been identified as the strongest predictor of spontaneous and treatment induced clearance of hepatitis C virus(HCV)*** then,increasing evidence has implicated the innate immune response in mediating the IFNL3 genotype *** cells(DCs)are key to the host immune response in HCV infection and their vital role in the IFNL3 genotype effect is *** have identified subclasses of DCs,particularly myeloid DC2s and potentially plasmacytoid DCs as the major producers of IFNL3 in the setting of HCV *** the complexities of dendritic cell biology and the conflicting current available data,this review aims to summarize what is currently known regarding the role of dendritic cells in HCV infection and to placeit into context of what is know about lambda interferons and dendritic cells in general.

关键词： Hepatitis C virus Interferon lambda 3 Dendritic cells Plasmacytoid dendritic cells Myeloid dendritic cells Innate immunity

Metabolic(dysfunction)associated fatty liver disease:more evidence and a bright future

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Hepatobiliary Surgery and Nutrition 2021年第6期10卷 849-852页

作者： Ting-Yao Wang jacob george Ming-Hua Zheng Department of Nephrology The First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina Storr Liver Centre Westmead Institute for Medical ResearchWestmead Hospital and University of SydneySydneyAustralia NAFLD Research Center Department of HepatologyThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina Institute of Hepatology Wenzhou Medical UniversityWenzhouChina Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province WenzhouChina

Recently,metabolic(dysfunction)associated fatty liver disease(MAFLD)has been proposed as a name to replace non-alcoholic fatty liver disease(NAFLD)(1).Controversy over the name is in full swing and evidence-based debate will determine the ***-based medicine is predicated on rigorous scientific data,clinical experience and patient *** how does MAFLD stack up?We briefly summarize the existing evidence and find that MAFLD does hold up to its promise as an advance in the terminology for the disease we all treat.

关键词： NAFLD replace terminology

Preventive treatment of alveolar pulmonary edema of cardiogenic origin

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Journal of Geriatric Cardiology 2012年第4期9卷 321-327页

作者： Gideon Charach Michael Shochat Alexander Rabinovich Oded Ayzenberg jacob george Lior Charach Pavel Rabinovich Department of Internal Medicine 'C' Tel Aviv Sourasky Medical Center 6 Weizman Street Tel Aviv 64239 Israel Department of Cardiology Hillel Yaffe Medical Center Hadera P.O. Box 169 Hadera 38100 Israel Department of Geriatrics Tel Aviv Sourasky Medical Center 6 Weizman Street Tel Aviv 64239 Israel Department of Cardiology Kaplan Medical Center Pasternak Street P.O. Box 1 Rehovot 76100 Israel

Objective To evaluate the efficacy of preventive treatment (PT) on alveolar pulmonary edema (APE) of cardiogenic origin using a monitor based on principles of internal thoracic impedance (ITI) *** We conducted blinded clinical trials on patients with ST-elevation myocardial infarction (STEMI) and monitored whether the condition would progress to APE. ITI was measured noninvasively by the Edema Guard Monitor (EGM, model RS-207) every 30 min. The measurement threshold for the diagnosis of APE was fixed at > 12% decrease in ITI from baseline as described in our methodology. The patients were divided into one group that received standard treatment after the appearance of clinical signs of APE without considering the prediction of APE by EGM devise (Group 1), and another group of asymptomatic patients in whom development of APE was predicted by using only EGM measurements (Group 2). The latter participants’PT consisted of furosemide, intravenous nitroglycerine and supplemental oxygen. Results One-hundred and fifty patients with acute STEMI were enrolled into this study. Group 1 included 100 patients (53% males, age 64.1 ±12.6 years). Treatment was started after the clinical appearance of overt signs of APE. Group 2 included 50 patients (54% males, age 65.2 ±11.9 years) who received PT based on EGMmeasurements. Group 2 had significantly fewer cases of APE (n = 4, 8%) than Group 1 (n = 100, 100%) (P > 0.001). While APE was lethal in six (6%) Group 1 patients, PT resulted in prompt resolution of APE in all four (8%) Group 2 patients. Conclusion ITI is a usefulmodality for early diagnosis and PT of pulmonary edema of cardiogenic origin.

关键词： Cardiogenic pulmonary edema Early prediction Internal thoracic impedance Monitoring cardiac patients Preventive treatment

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World Journal of Gastroenterology 2020年第22期26卷 2931-2947页

作者： Tea L Laursen Thomas D Sandahl Konstantin Kazankov jacob george Henning Gronbæk Department of Hepatology and Gastroenterology Aarhus University HospitalAarhus N DK-8200Denmark Storr Liver Centre Westmead Institute for Medical ResearchWestmead HospitalSydney NSW 2145Australia University of Sydney Sydney NSW 2145Australia

More than five years ago,the treatment of hepatitis C virus infection was revolutionized with the introduction of all-oral direct-acting antiviral(DAA)*** proved highly efficient in curing patients with chronic hepatitis C(CHC),including patients with *** new DAA treatments were alleged to induce significant improvements in clinical outcome and prognosis,but the exact cause of the expected benefit was ***,little was known about how the underlying liver disease would be affected during and after viral *** this review,we describe and discuss the liver-related effects of the new treatments in regards to both pathophysiological aspects,such as macrophage activation,and the time-dependent effects of therapy,with specific emphasis on inflammation,structural liver changes,and liver function,as these factors are all related to morbidity and mortality in CHC *** seems clear that antiviral therapy,especially the achievement of a sustained virologic response has several beneficial effects on liver-related parameters in CHC patients with advanced liver fibrosis or *** seems to be a timedependent effect of DAA therapy with viral clearance and the resolution of liver inflammation followed by more discrete changes in structural liver *** improvements lead to favorable effects on liver function,followed by an improvement in cognitive dysfunction and portal ***,the data provide knowledge on the several beneficial effects of DAA therapy on liverrelated parameters in CHC patients suggesting short-and long-term improvements in the underlying disease with the promise of an improved longterm prognosis.

关键词： Chronic hepatitis C Antiviral treatment Inflammation Liver fibrosis Liver cirrhosis Metabolic liver function Galactose elimination capacity Urea synthesis capacity Portal hypertension Hepatic encephalopathy