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| 1 | Treatment options for alcoholic and non-alcoholic fatty liver disease: A review显示文摘Alcoholic liver disease(ALD)and non-alcoholic fatty liver disease(NAFLD)are serious health problems worldwide.These two diseases have similar pathological spectra,ranging from simple steatosis to hepatitis to cirrhosis and hepatocellular carcinoma.Although most people with excessive alcohol or calorie intake display abnormal fat accumulation in the liver(simple steatosis),a small percentage develops progressive liver disease.Despite extensive research on understanding the pathophysiology of both these diseases there are still no targeted therapies available.The treatment for ALD remains as it was 50 years ago:abstinence,nutritional support and corticosteroids(or pentoxifylline as an alternative if steroids are contraindicated).As for NAFLD,the treatment modality is mainly directed toward weight loss and co-morbidity management.Therefore,new pathophysiology directed therapies are urgently needed.However,the involvement of several inter-related pathways in the pathogenesis of these diseases suggests that a single therapeutic agent is unlikely to be an effective treatment strategy.Hence,a combination therapy towards multiple targets would eventually be required.In this review,we delineate the treatment options in ALD and NAFLD,including various new targeted therapies that are currently under investigation.We hope that soon we will be having an effective multi-therapeutic regimen for each disease. | Sukhpreet Singh Natalia A Osna Kusum K Kharbanda | 2017 | World Journal of Gastroenterology2017，23，36： | 45 |
| 2 | Human immunodeficiency virus and hepatotropic viruses comorbidities as the inducers of liver injury progression显示文摘Hepatotropic viruses induced hepatitis progresses much faster and causes more liver-related health problems in people co-infected with human immunodeficiency virus(HIV). Although treatment with antiretroviral therapy has extended the life expectancy of people with HIV, liver disease induced by hepatitis B virus(HBV) and hepatitis C virus(HCV) causes significant numbers of non-acquired immune deficiency syndrome(AIDS)-related deaths in coinfected patients. In recent years, new insights into the mechanisms of accelerated fibrosis and liver disease progression in HIV/HCV and HIV/HBV co-infections have been reported. In this paper, we review recent studies examining the natural history and pathogenesis of liver disease in HIV-HCV/HBV co-infection in the era of direct acting antivirals(DAA) and antiretroviral therapy(ART). We also review the novel therapeutics for management of HIV/HCV and HIV/HBV coinfected individuals. | Murali Ganesan Larisa Y Poluektova Kusum K Kharbanda Natalia A Osna | 2019 | World Journal of Gastroenterology2019，25，4： | 12 |
| 3 | Implication of altered proteasome function in alcoholic liverinjury显示文摘The proteasome is a major protein-degrading enzyme, which catalyzes degradation of oxidized and aged proteins, signal transduction factors and cleaves peptides for antigen presentation. Proteasome exists in the equilibrium of 26S and 20S particles. Proteasome function is altered by ethanol metabolism, depending on oxidative stress levels: low oxidative stress induces proteasome activity, while high oxidative stress reduces it. The proposed mechanisms for modulation of proteasome activity are related to oxidative modification of proteasomal proteins with primary and secondary products derived from ethanol oxidation. Decreased proteolysis by the proteasome results in the accumulation of insoluble protein aggregates, which cannot be degraded by proteasome and which further inhibit proteasome function. Mallory bodies, a common signature of alcoholic liver diseases, are formed by liver cells, when proteasome is unable to remove cytokeratins. Proteasome inhibition by ethanol also promotes the accumulation of pro-apoptotic factors in mitochondria of ethanol-metabolizing liver cells that are normally degraded by proteasome. In addition, decreased proteasome function also induces accumulation of the negative regulators of cytokine signaling (I-kB and SOCS), thereby blocking cytokine signal transduction. Finally, ethanol-elicited blockade of interferon type 1 and 2 signaling and decreased proteasome function impairs generation of peptides for MHC class Ⅰ-restricted antigen presentation. | Natalia A Osna Terrence M Donohue Jr | 2007 | World Journal of Gastroenterology2007，13，37： | 10 |
| 4 | Liver as a target of human immunodeficiency virus infection显示文摘Liver injury is a characteristic feature of human immunodeficiency virus(HIV) infection, which is the second most common cause of mortality in HIV-infected patients. Now it is recognized that liver plays a key role in HIV infection pathogenesis. Antiretroviral therapy(ART), which suppresses HIV infection in permissive immune cells, is less effective in hepatocytes, thereby making these cells a silent reservoir of HIV infection. In addition to direct hepatotoxic effects of HIV, certain ART treatment modalities provide hepatotoxic effects. The exact mechanisms of HIV-triggered chronic hepatitis progression are not elucidated, but the liver is adversely affected by HIV-infection and liver cells are prominently involved in HIV-elicited injury. These effects are potentiated by second hits like alcohol. Here, we will focus on the incidence of HIV, clinical evidence of HIVrelated liver damage, interactions between HIV and liver cells and the role of alcohol and co-infection with hepatotropic viruses in liver inflammation and fibrosis progression. | Murali Ganesan Larisa Y Poluektova Kusum K Kharbanda Natalia A Osna | 2018 | World Journal of Gastroenterology2018，24，42： | 5 |
| 5 | Involvement of autophagy in alcoholic liver injury and hepatitis C pathogenesis显示文摘This review describes the principal pathways of macroautophagy (i.e. autophagy), microautophagy and chaperone-mediated autophagy as they are currently known to occur in mammalian cells. Because of its crucial role as an accessory digestive organ, the liver has a particularly robust autophagic activity that is sensitive to changes in plasma and dietary components. Ethanol consumption causes major changes in hepatic protein and lipid metabolism and both are regulated by autophagy, which is significantly affected by hepatic ethanol metabolism. Ethanol exposure enhances autophagosome formation in liver cells, but suppresses lysosome function. Excessive ethanol consumption synergizes with hepatitis C virus (HCV) to exacerbate liver injury, as alcohol-consuming HCV patients frequently have a longer course of infection and more severe manifestations of chronic hepatitis than abstinent HCV patients. Alcohol-elicited exacerbation of HCV infection pathogenesis is related to modulation by ethanol metabolism of HCV replication. Additionally, as part of this mechanism, autophagic proteins have been shown to regulate viral (HCV) replication and their intracel-lular accumulation. Because ethanol induces autophagosome expression, enhanced levels of autophagic proteins may enhance HCV infectivity in liver cells of alcoholics and heavy drinkers. | Natalia A Osna Paul G Thomes Terrence M Donohue | 2011 | World Journal of Gastroenterology2011，17，20： | 5 |
| 6 | Role of alcohol in pathogenesis of hepatitis B virus infection显示文摘Hepatitis B virus(HBV)and alcohol abuse often contribute to the development of end-stage liver disease.Alcohol abuse not only causes rapid progression of liver disease in HBV infected patients but also allows HBV to persist chronically.Importantly,the mechanism by which alcohol promotes the progression of HBVassociated liver disease are not completely understood.Potential mechanisms include a suppressed immune response,oxidative stress,endoplasmic reticulum and Golgi apparatus stresses,and increased HBV replication.Certainly,more research is necessary to gain a better understanding of these mechanisms such that treatment(s)to prevent rapid liver disease progression in alcohol-abusing HBV patients could be developed.In this review,we discuss the aforementioned factors for the higher risk of liver diseases in alcohol-induced HBV pathogenies and suggest the areas for future studies in this field. | Murali Ganesan Allison Eikenberry Larisa Y Poluektova Kusum K Kharbanda Natalia A Osna | 2020 | World Journal of Gastroenterology2020，26，9： | 5 |
| 7 | Hepatitis C virus and ethanol alter antigen presentation in liver cells显示文摘Alcoholic patients have a high incidence of hepatitis C virus (HCV) infection. Alcohol consumption enhances the severity of the HCV disease course and worsens the outcome of chronic hepatitis C. The accumulation of virally infected cells in the liver is related to the HCV-induced inability of the immune system to recognize infected cells and to develop the immune responses. This review covers the effects of HCV proteins and ethanol on major histocompatibility complex (MHC) class-restricted antigen presentation. Here, we discuss the liver which functions as an immune privilege organ; factors, which affect cleavage and loading of antigenic peptides onto MHC class and class in hepatocytes and dendritic cells, and the modulating effects of ethanol and HCV on antigen presentation by liver cells. Altered antigen presentation in the liver limits the ability of the immune system to clear HCV and infected cells and contributes to disease progression. HCV by itself affects dendritic cell function, switching their cytokine prof ile to the suppressive phenotype of interleukin-10 (IL-10) and transforming growth factor beta (TGFβ) predominance, preventing cell maturation and allostimulation capacity.The synergistic action of ethanol with HCV results in the suppression of MHC class-restricted antigen proteins reduce proteasome function and interferon signaling, thereby suppressing the generation of peptides for MHC class-restricted antigen presentation.Collectively, ethanol exposure further impairs antigen presentation in HCV-infected liver cells, which may provide a partial explanation for exacerbations and the poor outcome of HCV infection in alcoholics. | Natalia A Osna | 2009 | World Journal of Gastroenterology2009，15，10： | 4 |
| 8 | Alcohol Consumption Decreases Rat Hepatic Creatine Biosynthesis Via Altered Guanidinoacetate Methyltransferase Activity显示文摘 | Kusum K. Kharbanda Sandra L. Todero Jordan C. Moats Ryan M. Harris Natalia A. Osna Paul G. Thomes Dean J. Tuma | 2014 | Alcohol Clin Exp Res2014，，3： | 2 |
| 9 | Prolonged feeding with guanidinoacetate, a methyl group consumer, exacerbates ethanol-induced liver injury显示文摘AIM To investigate the hypothesis that exposure to guanidinoacetate(GAA, a potent methyl-group consumer) either alone or combined with ethanol intake for a prolonged period of time would cause more advanced liver pathology thus identifying methylation defects as the initiator and stimulator for progressive liver damage.METHODS Adult male Wistar rats were fed the control or ethanolLieber De Carli diet in the absence or presence of GAA supplementation. At the end of 6 wk of the feeding regimen, various biochemical and histological analyses were conducted. RESULTS Contrary to our expectations, we observed that GAA treatment alone resulted in a histologically normal liver without evidence of hepatosteatosis despite persistence of some abnormal biochemical parameters. This protection could result from the generation of creatine from the ingested GAA. Ethanol treatment for 6 wk exhibited changes in liver methionine metabolism and persistence of histological and biochemical defects as reported before. Further, when the rats were fed the GAA-supplemented ethanol diet, similar histological and biochemical changes as observed after 2 wk of combined treatment, including inflammation, macroand micro-vesicular steatosis and a marked decrease in the methylation index were noted. In addition, rats on the combined treatment exhibited increased liver toxicity and even early fibrotic changes in a subset of animals in this group. The worsening liver pathology could be related to the profound reduction in the hepatic methylation index, an increased accumulation of GAA and the inability of creatine generated to exert its hepato-protective effects in the setting of ethanol.CONCLUSION To conclude, prolonged exposure to a methyl consumer superimposed on chronic ethanol consumption causes persistent and pronounced liver damage. | Natalia A Osna Dan Feng Murali Ganesan Priya F Maillacheruvu David J Orlicky Samuel W French Dean J Tuma Kusum K Kharbanda | 2016 | World Journal of Gastroenterology2016，22，38： | 2 |
| 10 | Interferon gamma en- hances proteasome activity in recombinant Hep G2 cells that ex- press cytoehrome P450 2E1 :modulation by ethanol显示文摘 | Osna NA Clemens DL Jr Donohue TM | 2003 | Bioehem Pharmaeol2003，66，5： | 1 |
| 11 | Ethanol-induced oxidative stress suppresses generation of peptides for antigen presentation by hepatoma eells显示文摘 | Osna NA White RL Todero S etal | 2007 | Hepatology2007，45，1： | 1 |
| 12 | Ethanol metabolism al- ters major histocompatibility complex class I-restricted antigen presentation in liver cells显示文摘 | Osna NA White RL Thiele GM | 2009 | Hepatology2009，49，4： | 1 |
| 13 | Chronic hepatitis C: T-helper 1/T-helper 2 imbalance could cause virus persistence in peripheral blood显示文摘 | Osna N Silonova G Vilgert N Hagina E Kuse V Giedraitis V | 1997 | Scand J Clin Lab Invest1997，57，8： | 1 |
| 14 | Proteasome Activation by Hepatitis C Core Protein Is Reversed by Ethanol-Induced Oxidative Stress显示文摘 | Natalia A. Osna Ronda L. White Viatcheslav M. Krutik Ting Wang Steven A. Weinman Terrence M. Donohue | 2008 | Gastroenterology2008，，7： | 1 |
| 15 | CYP2El-eatalyzed alcohol metabolism: role of oxidant generation in interferon signaling, antigen presentation and autophagy 显示文摘 | Osna NA Jr Donohue TM | 2013 | Subeell Bioehem2013，67，： | 1 |
| 16 | Impaired methylation as a novel mechanism for proteasome suppression in liver cells显示文摘 | Natalia A. Osna Ronda L. White Terrence M. Donohue Michael R. Beard Dean J. Tuma Kusum K. Kharbanda | 2009 | Biochemical and Biophysical Research Communications2009，，2： | 1 |
| 17 | Betaine Treatment Attenuates Chronic Ethanol-Induced Hepatic Steatosis and Alterations to the Mitochondrial Respiratory Chain Proteome显示文摘 | Kusum K. Kharbanda Sandra L. Todero Adrienne L. King Natalia A. Osna Benita L. McVicker Dean J. Tuma James L. Wisecarver Shannon M. Bailey Laura Schrum | 2011 | International Journal of Hepatology2011，，： | 1 |
| 18 | Interferon gamma enhances proteasome activity in recombinant Hep G2 cells that express cytochrome P4502E1:modulation by ethanol显示文摘 | Osna N A Donohue TM Jr | 2003 | Biochem Pharmacol2003，66，5： | 1 |
| 19 | Obeticholic acid attenuates human immunodeficiency virus/alcohol metabolism-induced pro-fibrotic activation in liver cells显示文摘BACKGROUND The morbidity and mortality of human immunodeficiency virus(HIV)-infection is often associated with liver disease,which progresses slowly into severe liver dysfunction.There are multiple insults which exacerbate HIV-related liver injury,including HIV-associated dysregulation of lipid metabolism and fat turnover,coinfections with hepatotropic viruses and alcohol abuse.As we reported before,exposure of hepatocytes to HIV and alcohol metabolites causes high oxidative stress,impairs proteasomal and lysosomal functions leading to accumulation of HIV in these cells,which end-ups with apoptotic cell death and finally promotes development of liver fibrosis.AIM To study whether obeticholic acid(OCA)prevents HIV/ethanol metabolisminduced hepatotoxicity and subsequent activation of hepatic stellate cells(HSC)by HIV+apoptotic hepatocyte engulfment.METHODS Huh7.5-CYP(RLW)cells were exposed to HIV and acetaldehyde-generating system(AGS)in the presence or absence of OCA.In the cells,we measured the expression of HIV-related markers:HIVgagRNA-by real-time polymerase chain reaction(PCR),p24-by western blot,HIV DNA-by semi-nested PCR,integrated HIV DNA-by ddPCR.Lysosomal and proteasomal activities were measured using fluorometrically-labeled substrates.For hepatocyte apoptosis,cleaved caspase 3 and cleaved PARP were visualized by western blot and cytokeratin 18-by M30 ELISA-in supernatants.Apoptotic bodies were generated from untreated and HIV-treated RLW cells exposed to UV light.Pro-fibrotic activation of HSC was characterized by Col1A1 and transforming growth factor-βmRNAs,while inflammasome activation-by NLRP3,caspase 1,interleukin(IL)-6,IL-1βmRNA levels.RESULTS In RLW cells,OCA treatment attenuated HIV-AGS-induced accumulation of HIVgagRNA,HIV DNA and p24.OCA suppressed reactive oxygen species production and restored chymotrypsin-like proteasome activity as well as cathepsin B lysosome activity.OCA also decreased HIV-AGS-triggered apoptosis in RLW cells.Exposure of HIV-containing apoptotic hepatocytes to HSC prevented activation of inflammasome and induced pro-fibrotic activation in these cells.CONCLUSION We conclude that by suppressing oxidative stress and restoring proteasomal and lysosomal functions impaired by HIV and ethanol metabolism,OCA decreases accumulation of HIV in hepatocytes,leading to down-regulation of apoptosis in these cells.In addition,OCA reverses pro-fibrotic and inflammasome-related activation of HSC triggered by engulfment of HIV-containing apoptotic hepatocytes,potentially contributing to suppression of liver fibrosis development. | Moses New-Aaron Murali Ganesan Raghubendra Singh Dagur Kusum K Kharbanda Larisa Y Poluektova Natalia A Osna | 2020 | World Journal of Hepatology2020，12，11： | 1 |
| 20 | Impact of Altered Methylation in Cytokine Signaling and Proteasome Function in Alcohol and Viral‐Mediated Diseases显示文摘 | Kusum K. Kharbanda Fawzia Bardag‐Gorce Shirish Barve Patricia E. Molina Natalia A. Osna | 2012 | Alcohol Clin Exp Res2012，，1： | 1 |
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