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In vitro and in vivo models of acute alcohol exposure

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World Journal of Gastroenterology 2009年第10期15卷 1168-1177页

作者： Angela Dolganiuc gyongyi szabo Department of Medicine University of Massachusetts Medical School 364 Plantation Street Worcester MA 01605-2324 United States

Alcohol abuse is a global problem due to the financial burden on society and the healthcare system. While the harmful health effects of chronic alcohol abuse are well established, more recent data suggest that acute alcohol consumption also affects human wellbeing. Thus, there is a need for research models in order to fully understand the effect of acute alcohol abuse on different body systems and organs. The present manuscript summarizes the interdisciplinary advantages and disadvantages of currently available human and non-human models of acute alcohol abuse, and identifi es their suitability for biomedical research.

关键词：急性酒精中毒体内模型卫生保健系统体外酒精滥用全球性问题财政负担酒精消费

Mechanisms of alcohol-mediated hepatotoxicity in human-immunodeficiency-virus-infected patients

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World Journal of Gastroenterology 2011年第20期17卷 2500-2506页

作者： gyongyi szabo Samir Zakhari Department of Medicine LRB-208 University of Massachusetts Medical School National Institute on Alcohol Abuse and Al coholism National Institutes of Health

Clinical observations have demonstrated that excessive chronic alcohol use negatively affects human immuno- deficiency virus (HIV) infection and contributes to the liver manifestations of the disease, even in HIV mono- infection. HIV/hepatitis C virus (HCV) co-infection is as- sociated with increased progression of HVC liver disease compared to HCV infection alone, and both of these are negatively affected by alcohol use. Recent data suggest that alcohol use and HIV infection have common targets that contribute to progression of liver disease. Both HIV infection and chronic alcohol use are associated with increased gut permeability and elevated plasma levels of lipopolysaccharide; a central activator of inflammatory responses. Both alcoholic liver disease and HIV infec tionresult in non-specific activation of innate immunity, proinflammatory cytokine cascade upregulation, as well as impaired antigen presenting cell and dendritic cell functions. Finally, alcohol, HIV and antiretroviral therapyaffect hepatocyte functions, which contributes to liver damage. The common targets of alcohol and HIV infection in liver disease are discussed in this minireview.

关键词：艾滋病毒感染肝脏疾病酒精性毒性机制人类免疫缺陷病毒丙型肝炎病毒介导患者

Emerging role of microRNAs in liver diseases

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World Journal of Gastroenterology 2009年第45期15卷 5633-5640页

作者： Shashi Bala Miguel Marcos gyongyi szabo Department of Medicine University of Massachusetts Medical School WorcesterMA 01605 United States

MicroRNAs are a class of small non-coding RNAs that are found in plants, animals, and some viruses. They modulate the gene function at the post-transcriptional level and act as a fine tuner of various processes, such as development, proliferation, cell signaling, and apopto-sis. They are associated with different types and stages of cancer. Recent studies have shown the involvement of microRNAs in liver diseases caused by various factors, such as Hepatitis C, Hepatitis B, metabolic disorders, and by drug abuse. This review highlights the role of microRNAs in liver diseases and their potential use as therapeutic molecules.

关键词： microRNA 肝脏疾病 MicroRNA 细胞信号转导转录后水平核糖核酸动物体内细胞凋亡

Lipopolysaccharide induces and activates the Nalp3 inflammasome in the liver

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World Journal of Gastroenterology 2011年第43期17卷 4772-4778页

作者： Michal Ganz Timea Csak Bharath Nath gyongyi szabo Department of Medicine University of Massachusetts Medical School

AIM:To examine the activation of the Nalp3 inflammasome and its downstream targets following lipopolysaccharide(LPS) -induced stimulation in the liver. METHODS:Six-to-eight-week-old C57BL/6 chow fed mice were injected intraperitoneally with 0.5μg/g bodyweight LPS and sacrificed 2,4,6,18 or 24 h later. LPS-induced liver damage was confirmed by a biochemical assay to detect alanine aminotransferase(ALT) *** determine if LPS stimulation in the liver led to activation of the inflammasome,real-time quantitative polymerase chain reaction was used to evaluate the mRNA expression of components of the Nalp3 ***-linked immunosorbent assays were used to determine the protein expression levels of several downstream targets of the Nalp3 inflammasome,including caspase-1 and two cytokine targets of caspase-1,interleukin(IL) -1βand IL-18. RESULTS:We found that LPS injection resulted in liver damage as indicated by elevated ALT *** was associated with a significant increase in both mRNA and protein levels of the proinflammatory cy-tokine tumor necrosis factor(TNF) -αin the liver,as well as increased levels of TNFs in *** showed that LPS stimulation led to upregulation of mRNA levels in the liver for all the receptor components of the inflammasome,including Nalp3,Nalp1,pannexin-1 and the adaptor molecule apoptosis-associated specklike,caspase recruitment domain-domain containing *** also found increased levels of mRNA and protein for caspase-1,a downstream target of the *** addition,LPS challenge led to increased levels of both mRNA and protein in the liver for two cytokine targets of caspase-1,IL-1βand IL-18. Interestingly,substantial baseline expression of pre-IL1βand pre-IL-18 was found in the *** and caspase-1 activation was indicated by the significant increase in the active forms of IL-1βand IL-18 after LPS stimulation. CONCLUSION:Our results show that the Nalp3 inflammasome is upregulated and activated in the

关键词：脂多糖肝脏激活诱导 mRNA表达 IL-18 酶联免疫吸附试验聚合酶链反应

IL-1α in acetaminophen toxicity: a sterile danger signal

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Cellular & Molecular Immunology 2018年第3期15卷 284-285页

作者： Arvin Iracheta-Vellve gyongyi szabo Department of Medicine University of Massachusetts Medical SchoolWorcester01605MAUSA

Much controversy surrounds the pathogenesis of acetaminophen-induced ***(APAP)is a well-studied xenobiotic that in high doses results in a deadly,yet preventable,form of liver *** its effects are sudden and often irreversible,its mechanism is far from *** fact,at first glance,recent studies seem to refute each *** field has been grappling with seemingly contradictory results driven mainly by often-generalized assumptions and different experimental systems.

关键词： doses sterile pathogenesis

Plasma microRNA profiles distinguish lethal injury in acetaminophen toxicity: A research study

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World Journal of Gastroenterology 2012年第22期18卷 2798-2804页

作者： Jeanine Ward Shashi Bala Jan Petrasek gyongyi szabo Department of Emergency Medicine University of Massachusetts Medical School 55 Lake Avenue North Worcester MA 01655 United States Division of Gastroenterology Department of Medicine University of Massachusetts Medical School 364 Plantation Street Worcester MA 01655 United States

AIM: To investigate plasma microRNA (miRNA) profiles indicative of hepatotoxicity in the setting of lethal acetaminophen (APAP) toxicity in mice. METHODS: Using plasma from APAP poisoned mice, either lethally (500 mg/kg) or sublethally (150 mg/kg) dosed, we screened commercially available murine microRNA libraries (SABiosciences, Qiagen Sciences, MD) to evaluate for unique miRNA profiles between these two dosing parameters. RESULTS: We distinguished numerous, unique plasma miRNAs both up- and downregulated in lethally compared to sublethally dosed mice. Of note, many of the greatest up- and downregulated miRNAs, namely 574-5p, 466g, 466f-3p, 375, 29c, and 148a, have been shown to be associated with asthma in prior studies. Interestingly, a relationship between APAP and asthma has been previously well described in the literature, with an as yet unknown mechanism of pathology. There was a statistically significant increase in alanine aminotransferase levels in the lethal compared to sublethal APAP dosing groups at the 12 h time point (P < 0.001). There was 90% mortality in the lethally compared to sublethally dosed mice at the 48 h time point (P = 0.011). CONCLUSION: We identified unique plasma miRNAs both up- and downregulated in APAP poisoning which are correlated to asthma development.

关键词： microRNA 对乙酰氨基酚血浆毒性亚致死剂量 miRNA 型材谷丙转氨酶

Immunopathobiology and therapeutic targets related to cytokines in liver diseases

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Cellular & Molecular Immunology 2021年第1期18卷 18-37页

作者： Yong He Seonghwan Hwang Yeni Ait Ahmed Dechun Feng Na Li Marcelle Ribeiro Fouad Lafdil Tatiana Kisseleva gyongyi szabo Bin Gao Laboratory of Liver Diseases National Institute on Alcohol Abuse and AlcoholismNational Institutes of HealthBethesdaMD 20892USA Universite Paris-Est UMR-S955UPECF-94000 CreteilFrance Department of Medicine and Department of Surgery School of MedicineUniversity of CaliforniaSan DiegoCA 92093USA Department of Medicine Beth Israel Deaconess Medical Center and Harvard Medical SchoolBostonMAUSA INSERM U955F-94000 CreteilFrance Institut Universitaire de France(IUF) Paris F-75231 Cedex 05France

Chronic liver injury with any etiology can progress to fibrosis and the end-stage diseases cirrhosis and hepatocellular *** progression of liver disease is controlled by a variety of factors,including liver injury,inflammatory cells,inflammatory mediators,cytokines,and the gut *** the current review,we discuss recent data on a large number of cytokines that play important roles in regulating liver injury,inflammation,fibrosis,and regeneration,with a focus on interferons and T helper(Th)1,Th2,Th9,Th17,interleukin(IL)-1 family,IL-6 family,and IL-20 family *** can also produce certain cytokines(such as IL-7,IL-11;and IL-33),and the functions of these cytokines in the liver are briefly *** cytokines have great therapeutic potential,and some are currently being tested as therapeutic targets in clinical trials for the treatment of liver diseases,which are also described.

关键词： T helper ALD NAFLD Fibrosis Inflammation

Proton pump inhibitors increase the severity of hepatic encephalopathy in cirrhotic patients

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World Journal of Hepatology 2019年第6期11卷 522-530页

作者： Matthew Fasullo Prashanth Rau Dong-Qi Liu Erik Holzwanger Jomol P Mathew Yurima Guilarte-Walker gyongyi szabo Department of Medicine University of Massachusetts Medical SchoolWorcesterMA 01605United States Department of Population and Quantitative Health Sciences University of Massachusetts Medical SchoolWorcesterMA 01605United States Department of Data Sciences and Technology Information TechnologyUniversity of Massachusetts Medical SchoolWorcesterMA 01605United States

BACKGROUND Liver cirrhosis is the late stage of hepatic fibrosis and is characterized by portal hypertension that can clinically lead to decompensation in the form of ascites,esophageal/gastric varices or *** most common sequelae associated with liver cirrhosis are neurologic and neuropsychiatric impairments labeled as hepatic encephalopathy(HE).Well established triggers for HE include infection,gastrointestinal bleeding,constipation,and *** to the gut microbiome is one of the leading ammonia producers in the body,and therefore may make patients more susceptible to *** To investigate the relationship between the use of proton pump inhibitors(PPIs)and HE in patients with *** This is a single center,retrospective *** were included in the study with an admitting diagnosis of *** degree of HE was determined from subjective and objective portions of hospital admission notes using the West Haven *** primary outcome of the study was to evaluate the grade of HE in PPI users versus non-users at admission to the hospital and throughout their hospital *** outcomes included rate of infection,gastrointestinal bleeding within the last 12 mo,mean ammonia level,and model for end-stage liver disease scores at *** The HE grade at admission using the West Haven Criteria was 2.3 in the PPI group compared to 1.7 in the PPI nonuser group(P=0.001).The average length of hospital stay in PPI group was 8.3 d compared to 6.5 d in PPI nonusers(P=0.046).Twenty-seven(31.8%)patients in the PPI user group required an Intensive Care Unit admission during their hospital course compared to 6 in the PPI nonuser group(16.7%)(P=0.138).Finally,10(11.8%)patients in the PPI group expired during their hospital stay compared to 1 in the PPI nonuser group(2.8%)(P=0.220).CONCLUSION Chronic PPI use in cirrhotic patients is associated with significantly higher average West Haven Criteria for HE compared to pa

关键词： Cirrhosis Hepatic encephalopathy Proton pump inhibitors Hepatology Proton pump inhibitor

Distinct toll-like receptor expression in monocytes and T cells in chronic HCV infection

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World Journal of Gastroenterology 2006年第8期12卷 1198-1204页

作者： Angela Dolganiuc Catherine Garcia Karen Kodys gyongyi szabo Department of Medicine University of Massachusetts Medical School364 Plantation StreetWorcesterMA 01605-2324United States

瞄准：丙肝病毒经常建立长期的感染。最近的研究建议病毒、细菌的感染在与控制相比的感染 HCV 的病人是更普通的。病原体被像使用费的受体(TLR ) 认出塑造适应、天生的有免疫力的回答。方法：在这研究，估计感染 HCV 的主人的能力认识... 详细信息

瞄准：丙肝病毒经常建立长期的感染。最近的研究建议病毒、细菌的感染在与控制相比的感染 HCV 的病人是更普通的。病原体被像使用费的受体(TLR ) 认出塑造适应、天生的有免疫力的回答。方法：在这研究，估计感染 HCV 的主人的能力认识到入侵病原体，我们调查了像使用费的受体表示在天生(单核白血球) 并且适应(T 房间) 由即时 PCR 的有免疫力的房间。结果：我们决定 RNA 为 TLR 铺平 2， 6。7， 8， 9 和 10 个 mRNA 层次起来与控制相比在感染 HCV 的病人在单核白血球和 T 房间调整了。TLR4 在 T 淋巴细胞在仅仅上面被调整，当 TLR5 有选择地在感染 HCV 的病人的单核白血球被增加时。MD-2， TLR4 合作受体，当 CD14 和 MyD88 仅仅在单核白血球被增加时，在病人的单核白血球和 T 房间被增加。结论：我们的数据在多半在感染 HCV 的个人联系到病原体和有免疫力的防卫的天生的识别的 TLR 表示上披露新奇详情。

关键词：基因表达单核细胞慢性疾病丙型肝炎