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Genetic factors that affect nonalcoholic fatty liver disease: A systematic clinical review

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World Journal of Gastroenterology 2016年第29期22卷 6742-6756页

作者： Tyler J Severson Siddesh Besur herbert l bonkovsky Department of Gastroenterology and Hepatology Wake Forest University NC Baptist Medical Center Abdominal Transplant Program Aurora St Luke’s Medical Center

AIM: To investigate roles of genetic polymorphisms in non-alcoholic fatty liver disease (NAFlD) onset, severity, and outcome through systematic literature ***: The authors conducted both systematic and specific searches of PubMed through December 2015 with special emphasis on more recent data (from 2012 onward) while still drawing from more historical data for background. We identified several specific genetic polymorphisms that have been most researched and, at this time, appear to have the greatest clinical significance on NAFlD and similar hepatic diseases. These were further investigated to assess their specific effects on disease onset and progression and the mechanisms by which these effects ***: We focus particularly on genetic polymorphisms of the following genes: PNPlA3, particularly the p. I148M variant, TM6SF2, particularly the p. E167K variant, and on variants in FTO, lIPA, IFNλ4, and iron metabolism, specifically focusing on HFE, and HMOX-1. We discuss the effect of these genetic variations and their resultant protein variants on the onset of fatty liver disease and its severity, including the effect on likelihood of progression to cirrhosis and hepatocellular carcinoma. While our principal focus is on NAFlD, we also discuss briefly effects of some of the variants on development and severity of other hepatic diseases, including hepatitis C and alcoholic liver disease. These results are briefly discussed in terms of clinical application and future potential for personalized ***: Polymorphisms and genetic factors of several genes contribute to NAFlD and its end results. These genes hold keys to future improvements in diagnosis and management.

关键词： Genetic polymorphisms Non-alcoholic fatty liver disease Non-alcoholic steatohepatitis PNPlA3 TM6SF2 FTO Cirrhosis Iron metabolism

Chinese Medicine for Treatment of Chronic Hepatitis B

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Chinese Journal of Integrative Medicine 2012年第4期18卷 253-255页

作者： Guqi WANG lingyi ZHANG herbert l.bonkovsky Carolinas Medical Center CharlotteNC28203 USA

Contemporary Western medicines approved by the U.S. Food and Drug Administration （FDA） for the treatment of chronic hepatitis B （CHB）, although available in China, have high costs, or major side effects and limited effectiveness. Research efforts have focused on looking for natural products as alternative medicines with low cost and good safety for CHB treatment. Chinese medicine （CM） has ancient, time-honored theories about methods of diagnosis and treatment for liver diseases. In recent decades, a large number of clinical trials and pre-clinical studies, which were performed in China and other countries, indicated that CM has potential benefit in several aspects of the treatment of CHB, e.g., anti-inflammatory, anticancer, antioxidant, immunomodulating, antifibrosis, and antiviral. However, there are many concerns regarding the study design and the quality of clinical trials. Further larger, stringently designed, double-blind, placebo control, randomized clinical trials and long-term follow-up are needed to provide conclusive evidence of their efficacy and safety. Components of CM deserve further study in pre-clinical models of HBV infection and in clinical trials world-wide.

关键词： chronic hepatitis B natural products Chinese medicine Western medicine clinical trial

Hepatitis B and liver transplantation: Molecular and clinical features that influence recurrence and outcome

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World Journal of Gastroenterology 2014年第39期20卷 14142-14155页

作者： Tahereh Ghaziani Hossein Sendi Saeid Shahraz Philippe Zamor herbert l bonkovsky Department of Medicine School Beth Israel Deaconess Medical Center and Harvard Medical Liver Transplantation Institute Boston MA 02115 United States Departments of Medicine and Research Carolinas HealthCare System Charlotte NC 28203 United States Heller School of Social Policy and Management Brandeis University Waltham MA 02454 United States Department of Medicine Carolinas HealthCare System Charlotte NC 28204 United States The liver-Biliary-Pancreatic Center Department of Medicine Carolinas HealthCare System Charlotte NC 28204 United States

Hepatitis B virus (HBV) continues to be a major cause of morbidity and mortality worldwide. It is estimated that about 350 million people throughout the world are chronically infected with HBV. Some of these people will develop hepatic cirrhosis with decompensation and/or hepatocellular carcinoma. For such patients, liver transplantation may be the only hope for cure or real improvement in quality and quantity of life. Formerly, due to rapidity of recurrence of HBV infection after liver transplantation, usually rapidly progressive, liver transplantation was considered to be contraindicated. This changed dramatically following the demonstration that hepatitis B immune globulin (HBIG), could prevent recurrent HBV infection. HBIG has been the standard of care for the past two decades or so. Recently, with the advent of highly active inhibitors of the ribose nucleic acid polymerase of HBV (entecavir, tenofovir), there has been growing evidence that HBIG needs to be given for shorter lengths of time; indeed, it may no longer be necessary at all. In this review, we describe genetic variants of HBV and past, present, and future prophylaxis of HBV infection during and after liver transplantation. We have reviewed the extant medical literature on the subject of infection with the HBV, placing particular emphasis upon the prevention and treatment of recurrent HBV during and after liver transplantation. For the review, we searched PubMed for all papers on the subject of “hepatitis B virus AND liver transplantation”. We describe some of the more clinically relevant and important genetic variations in the HBV. We also describe current practices at our medical centers, provide a summary and analysis of comparative costs for alternative strategies for prevention of recurrent HBV, and pose important still unanswered questions that are in need of answers during the next decade or two. We conclude that it is now rational and cost-effective to decrease and, perhaps, ce

关键词： Cirrhosis End-stage liver disease Entecavir Genetic variants Hepatocellular carcinoma Hepatitis B Interferon alpha lamivudine liver transplantation Tenofovir

DNA methylation patterns in alcoholics and family controls

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World Journal of Gastrointestinal Oncology 2012年第6期4卷 138-144页

作者： Manish Thapar Jonathan Covault Victor Hesselbrock herbert l bonkovsky Department of Medicine The University of Connecticut Health Center Farmington CT 06030 United States The liver-Biliary-Pancreatic Center The University of Connecticut Health Center Farmington CT 06030 United States Department of Psychiatry The University of Connecticut Health Center Farmington CT 06030 United States The Alcohol Research Center The University of Connecticut Health Center Farmington CT 06030 United States The liver-Biliary-Pancreatic Center Carolinas Medical Center Suite 201 Cannon Research Center 1542 Garden Terrace Charlotte NC 28203 United States

AIM: To assess whether DNA methylation patterns in chronic alcoholics are different from non-alcoholic sibling controls. METHODS: We examined the methylation patterns in DNA samples from 25 chronic alcoholics and 22 matched siblings as controls (one per family). DNA was extracted from peripheral blood and analyzed for differences in the methylation patterns after bisulfite-conversion. We used the Illumina GoldenGate Methylation Cancer Panel I (Illumina, San Diego, CA), which probes the methylation profile at 1505 CpG sites from 807 cancer related genes. We excluded the 84 X-chromosome CpG sites and 134 autosomal CpG sites that failed to show a within sample reliability score of at least 95% for all samples, leaving 1287 autosomal CpG sites (associated with 743 autosomal genes) with reliable signals for all samples. A methylation score was calculated as the average methylation for the 1287 CpG sites examined. Differences were assessed by a two-sample t-test. We also examined the average sib pair differences in methylation scores at each of the 1287 sites. All analyses were performed using SPSS, version 9.0, P lTS: Methylation levels at the 1287 CpG sites averaged 28.2% for both alcoholics and controls. The mean difference in methylation scores between alcoholic and non-alcoholic sibs by CpG site was ll inter-individual variances; and only 5 CpG sites had an average sib difference > 5%. Subgroup analysis showed that methylation scores were significantly lower for the alcoholic-dependent subjects who smoked compared to their non-smoking unaffected siblings. Specifically, among smokers who are alcoholic, global methylation indices were significantly lower than in non-alcoholic sib controls, whereas among non-smoking alcoholics, the global indices were significantly higher (P = 0.008). CONClUSION: Although we observed no effect of alcoholism alone on DNA methylation, there is a decrease in alcoholics who smoke, suggesti

关键词： DNA methylation Alcohol Epigenetics Cancer Carcinogenesis Smoking Cigarettes Tobacco

Iron increases HMOX1 and decreases hepatitis C viral expression in HCV-expressing cells

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World Journal of Gastroenterology 2009年第36期15卷 4499-4510页

作者： Wei-Hong Hou lisa Rossi Ying Shan Jian-Yu Zheng Richard W lambrecht herbert l bonkovsky The Cannon Research Center and the liver Digestive Disease and Metabolism Laboratory Carolinas Medical Center Charlotte NC 28203 United States The University of North Carolina Charlotte NC 28223 United States Richard W lambrecht Department of Medicin e University of Connecticut Health Center Farmington CT 06030 United States Department of Molecular Microbial & Structural Biology University of Connecticut Health Center Farmington CT 06030 United States The Cannon Research Center and the liver Digestive Disease and Metabolism Laboratory Carolinas Medical Center Charlotte NC 28203 United States The University of North Carolina Charlotte 28223 United States The University of North Carolina Chapel Hill NC 27514 United States Departments of Medicine and Molecular Microbial & Structural Biology University of Connecticut Health Center Farmington CT 06030 United States Department of Medicine of the University of Massachusetts Medical School Worcester MA 01655 United States

AIM： To investigate effects of iron on oxidative stress, heme oxygenase-1 （HMOX1） and hepatitis C viral （HCV） expression in human hepatoma ceils stably expressing HCV proteins. METHODS： Effects of iron on oxidative stress, HMOX1, and HCV expression were assessed in CON1 cells. Measurements included mRNA by quantitative reverse transcription-polymerase chain reaction, and protein levels by Western blots. RESUlTS： Iron, in the form of ferric nitrilotriacetate,increased oxidative stress and upegulated HMOX1 gene expression. Iron did not affect mRNA or protein levels of Bach1, a repressor of HMOXl. Silencing the up-regulation of HMOXl nuclear factor-erythroid 2-related factor 2 （Nrf2） by Nrf2-siRNA decreased FeNTA-mediated up-regulation of HMOXl mRNA levels. These iron effects were completely blocked by deferoxamine （DFO）. Iron also significantly decreased levels of HCV core mRNA and protein by 80%-90%, nonstructural 5A mRNA by 90% and protein by about 50% in the Con1 full length HCV replicon cells, whereas DFO increased them. CONClUSION： Excess iron up-regulates HMOXl and down-regulates HCV gene expression in hepatoma cells. This probably mitigates liver injury caused by combined iron overload and HCV infection.

关键词： Deferoxamine Core protein of hepatitis Cvirus Hepatitis C Iron Heme oxygenase-1 Nuclearfactor-erythroid 2-related factor 2 Bachl Oxidativestress Nonstructural 5A protein of hepatitis C virus

legalon-SIl downregulates HCV core and NS5A in human hepatocytes expressing full-length HCV

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World Journal of Gastroenterology 2011年第13期17卷 1694-1700页

作者： Marjan Mehrab-Mohseni Hossein Sendi Nury Steuerwald Sriparna Ghosh laura W Schrum herbert l bonkovsky The liver-Biliary-Pancreatic Center Cannon Research Center Carolinas Medical Center Charlotte NC 28203 United States Department of Biology University of North Carolina at Charlotte Charlotte NC 28223 United States Department of Medicine University of North Carolina at Chapel Hill Chapel Hill NC United States

AIM: To determine the effect of legalon-SIl (lS) on hepatitis C virus (HCV) core and NS5A expression and on heme oxygenase-1 (HMOX-1) and its transcriptional regulators in human hepatoma cells expressing full length HCV genotype 1b. METHODS: CON1 cells were treated with 50 μmol/l or 200 μmol/l lS. Cells were harvested after 2, 6 and 24 h. HCV RNA and protein levels were determined by quantitative real-time polymerase chain reaction and Western blotting, respectively. RESUlTS: HCV RNA (core and NS5A regions) wasdecreased after 6 h with lS 200 μmol/l (P l/l lS decreased HCV RNA levels [core region (by 55% and 88%, respectively) and NS5A region (by 62% and 87%, respectively) after 24 h compared with vehicle (dimethyl sulphoxide) control (P larly HCV core and NS5A protein were decreased (by 85%, P ly) by lS 200 μmol/l. Bach1 and HMOX-1 RNA were also downregulated by lS treatment (P le Nrf2 protein was increased (P lUSION: Our results demonstrate that treatment with lS downregulates HCV core and NS5A expression in CON1 cells which express full length HCV genotype 1b, and suggests that lS may prove to be a valuable alternative or adjunctive therapy for the treatment of HCV infection.

关键词： Hepatitis Hepatitis C virus Silymarin Silybin Genotype Huh7.5 CON1

Non-coding RNAs in hepatitis C-induced hepatocellular carcinoma:Dysregulation and implications for early detection,diagnosis and therapy

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World Journal of Gastroenterology 2013年第44期19卷 7836-7845页

作者： Weihong Hou herbert l bonkovsky the liver Digestive and Metabolic Disorders Laboratory and the Liver-Biliary-Pancreatic Center Cannon Research Center Carolinas Medical CenterCharlotte NC 28203 United States

Hepatitis C virus(HCV)infection is one of main causes of hepatocellular carcinoma(HCC)and the prevalence of HCV-associated HCC is on the rise *** is particularly important and helpful to identify potential markers for screening and early diagnosis of HCC among high-risk individuals with chronic hepatitis C,and to identify target molecules for the prevention and treatment of *** noncoding RNAs,mainly microRNAs(miRNAs),and long non-coding RNAs(lncRNAs)with size greater than 200nucleotides,are likely to play important roles in a variety of biological processes,including development and progression of *** the most part their underlying mechanisms of action remain largely *** recent years,with the advance of high-resolution of microarray and application of next generation sequencing techniques,a significant number of non-coding RNAs(ncRNAs)associated with HCC,particularly caused by HCV infection,have been found to be differentially expressed and to be involved in pathogenesis of HCVassociated *** this review,we focus on recent studies of ncRNAs,especially miRNAs and lncRNAs related to HCV-induced *** summarize those ncRNAs aberrantly expressed in HCV-associated HCC and highlight the potential uses of ncRNAs in early detection,diagnosis and therapy of HCV-associated *** also discuss the limitations of recent studies,and suggest future directions for research in the ***,lncRNAs and their target genes may represent new candidate molecules for the prevention,diagnosis and treatment of HCC in patients with HCV *** of the potential uses of miRNAs and lncRNAs as diagnostic tools or therapies are still in their infancy.

关键词： MicroRNA long non-coding RNAs Non-coding RNAs Hepatitis C virus Hepatocellular carcinoma

Heme status affects human hepatic messenger RNA and microRNA expression

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World Journal of Gastroenterology 2013年第10期19卷 1593-1601页

作者： herbert l bonkovsky Weihong Hou Nury Steuerwald Qing Tian Ting li Judy Parsons Alicia Hamilton Sunil Hwang laura Schrum the liver Digestive and Metabolic Disorders LaboratoryCannon Research CenterCarolinas Medical Center1542 Garden TerraceCharlotteNC 28203United States the Molecular Core laboratory Cannon Research CenterCarolinas Medical CenterCharlotteNC 28203United States

AIM:To assess effects of heme on messenger RNA(mRNA) and microRNA(miRNA) profiles of liver cells derived from ***:We exposed human hepatoma cell line Huh-7 cells to excess iron protoporphyrin(heme)(10 μmol/l) or induced heme deficiency by addition of 4,6-dioxoheptanoic acid(500 μmol/l),a potent inhibitor of aminolevulinic acid dehydratase,for 6 h or 24 *** harvested total RNA from the cells and performed both mRNA and miRNA array analyses,with use of Affymetrix chips,reagents,and instruments(human genome U133 plus 2.0 and miRNA 2.0 arrays).We assessed changes and their significance and interrelationships with Target Scan,Pathway Studios,and Ingenuity ***:Changes in mRNA levels were most numerous and striking at 6 h after heme treatment but were similar and still numerous at 24 *** 6 h of heme exposure,the increase in heme oxygenase 1 gene expression was 60-fold by mRNA and 88-fold by quantitative reverse transcription-polymerase chain *** found striking changes,especially up-regulation by heme of nuclear erythroid-2 related factor-mediated oxidative stress responses,protein ubiquitination,glucocorticoid signaling,P53 signaling,and changes in RNAs that regulate intermediary *** mRNAs were down-regulated by heme,and the fold decreases were less exuberant than were the *** decreases after 24 h of heme exposure were patatin-like phospholipase domain-containing protein 3(-6.5-fold),neuronal PAS domain protein 2(-1.93-fold),and protoporphyrinogen oxidase(-1.7-fold).CONClUSION:Heme excess exhibits several toxic effects on liver and kidney,which deserve study in humans and in animal models of the human porphyrias or other disorders.

关键词： Delta-aminolevulinic acid synthase Heme Heat shock proteins Hepatotoxicity Messenger RNA MicroRNA

Comparison of direct fecal smear microscopy,culture,and polymerase chain reaction for the detection of Blastocystis *** human stool samples

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Asian Pacific Journal of Tropical Medicine 2013年第10期6卷 780-784页

作者： herbert J Santos Windell l Rivera Institute of Biology College of ScienceUniversity of the Philippines Molecular Protozoology laboratory Natural Sciences Research InstituteUniversity of the Philippines

Objective:To compare the sensitivity and specificity of direct fecal smear microscopy,culture,and polymerase chain reaction in the detection of Blastocystis *** human ***:Human stool samples were collected from a community in San Isidro,Rodriguez,Rizal,*** samples were subjected to direct fecal smear microscopy,culture and polymerase chain reaction to detect the presence of Blastocystis ***:Of the 110 stool samples collected,28(25%)were detected positive for the presence of Blastocystis *** two or more *** method detected the highest number of Blastocystis-positive stool samples(n=36),followed by PCR of DNA extracted from culture(n=26),PCR of DNA extracted from stool(n=10),and direct fecal smear(n=9).Compared to culture,the sensitivity of the other detection methods were 66.7%for PCR from culture and 19.4%for both PCR from stool and direct fecal *** of the methods was high,with PCR from culture and direct fecal smear having97.3%,while PCR from stool at 95.9%.Conclusions:In this study,in vitro culture is the best method for detecting Blastocystis *** human stool samples.

关键词： Blastocystis sp. Direct fecal smear Culture Polymerase chain reaction(PCR) Human stool Sensitivity Specificity