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Kang J, Park SH, Khanam M, Park SB, Shin S, Seo W. Impact of binge drinking on alcoholic liver disease. Arch Pharm Res 2025; 48:212-223. [PMID: 40035998 DOI: 10.1007/s12272-025-01537-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 02/13/2025] [Indexed: 03/06/2025]
Abstract
Numerous studies have examined the pathophysiological changes induced by chronic alcohol (ethanol) consumption and the underlying mechanisms, while much less attention has been devoted to understanding the health impacts of binge drinking. Binge drinking is defined as the excessive consumption of alcohol within a single drinking episode, and is the typical consumption pattern among young people in Western countries. While most young binge drinkers are not clinically alcohol dependent, binge drinking has emerged as a significant social and public health concern. The circulating alcohol consumed during binge episodes permeates cellular membranes throughout the body, exerting profound effects on multiple organs, and signaling pathways. Regular binge drinking eventually induces hepatic steatosis (fatty liver), initiates acute inflammation, and accelerates neutrophil infiltration, de novo lipogenesis, adipocyte death/lipolysis, and the production of nonoxidative alcohol metabolites, processes that synergize to damage liver tissue and impair liver function. Metabolic abnormalities such as diabetes and obesity can also exacerbate the progression of alcohol-related liver disease among binge drinkers. Several animal models have been developed to evaluate the pathophysiological changes resulting from binge drinking; however, the pathogenesis of binge drinking is not fully understood due to differences in alcohol metabolism between animal models and humans. Thus, given the high prevalence and severe health implications of binge drinking, there is an urgent need for comprehensive experimental and clinical investigations to unravel the associated pathophysiological changes. This review summarizes recent research findings on the impact of binge drinking, specifically focusing on its contributions to alcoholic liver injury.
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Affiliation(s)
- Jisoo Kang
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Republic of Korea
| | - Seol Hee Park
- Department of Companion Animal Health, Hanyang Women's University, Seoul, 04763, Republic of Korea
| | - Mushira Khanam
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Republic of Korea
| | - Seo Bhin Park
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Republic of Korea
| | - Sumin Shin
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Republic of Korea
| | - Wonhyo Seo
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Republic of Korea.
- Graduate Program in Innovative Biomaterials Convergence, Ewha Womans University, Seoul, 03760, Republic of Korea.
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2
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Liu M, Zhou M, Ren X, Xie Y. Establishment and application of murine models of alcoholic liver disease: A narrative review. ALCOHOL, CLINICAL & EXPERIMENTAL RESEARCH 2025; 49:271-284. [PMID: 39715699 DOI: 10.1111/acer.15520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Accepted: 11/29/2024] [Indexed: 12/25/2024]
Abstract
In recent years, there have been significant advances in pathological research on alcoholic liver disease (ALD), with suitable animal models making a significant contribution. However, the currently established animal ALD models still have some significant drawbacks, especially the inability to induce the entire human ALD lineage, which may be related to physiological differences between animals and humans. This review comprehensively summarized the most widely used experimental models of ALD, including voluntary drinking, Lieber-DeCarli, Meadows-Cook, Tsukamoto-French, NIAAA, and the "second hit" model. "Second hit" refers to an additional factor that damages the liver. There are various "second hit" models that fall into two main categories: particular diets and drugs. These models can either simulate human drinking patterns more accurately or produce varying degrees of ALD without significantly increasing animal mortality. We introduced the established method of the original models, discussed the advantages and disadvantages of the existing models from the aspects of operability and practicality, and provided existing improvement methods, hoping to provide a reference for future researchers.
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Affiliation(s)
- Mengsi Liu
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
| | - Mingying Zhou
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
| | - Xueyi Ren
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
| | - Yandi Xie
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
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Zhao Z, Ma X, Li M, Chen G, Qi L, Song S, Li Z, Yan C. Alcoholic Extracts from the Ganoderma Lucidum Fermentation Product Alleviated Ethanol-Induced Liver Injury, Gut Leakiness, and Gut Dysbiosis in Mice. PLANT FOODS FOR HUMAN NUTRITION (DORDRECHT, NETHERLANDS) 2024; 80:2. [PMID: 39636452 DOI: 10.1007/s11130-024-01271-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 11/26/2024] [Indexed: 12/07/2024]
Abstract
The hepatoprotective effect of the alcoholic extracts of Ganoderma lucidum fermentation products (GFE) was investigated. C57BL/6 mice were pretreated with GFE for 7 days and then subjected to the chronic-binge ethanol feeding model. GFE pretreatment significantly reduced the ethanol-induced elevated serum levels of aspartate aminotransferase (AST) and alanine transaminase (ALT), hepatic steatosis, and increased triglyceride content. GFE pretreatment also altered hepatic alcohol metabolism, suppressed oxidative stress by decreasing the expression of Cyp2e1, and increasing the level of GSH. Lipidmoic analysis revealed that GFE pretreatment effectively increased ratio of phosphatidylcholines /phosphatidylethanolamine (PC/PE) in the liver. Furthermore, mice pretreated with GFE demonstrated decreased hepatic inflammation and plasma lipopolysaccharide (LPS) levels. Additionally, the mRNA expression of gut tight junction proteins such as ZO-1, Occludin and Claudin-1, along with antimicrobial peptide (e.g., Reg3β and Reg3γ) were up-regulated by GFE pretreatment. 16s rRNA sequencing revealed that GFE increased Bacteroidales, Parabacteroides, and Dubosiella, which were associated with hepatic steatosis, inflammation and intestinal barrier function parameters. These results demonstrate that GFE can prevent ethanol-induced liver injury and inflammation, gut leakiness and restore gut microbiota dysbiosis.
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Affiliation(s)
- Zhikun Zhao
- Liaoning Key Laboratory of Food Nutrition and Health, Collaborative Innovation Center of Seafood Deep Processing, National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian, 116034, China
| | - Xiaoxiao Ma
- Liaoning Key Laboratory of Food Nutrition and Health, Collaborative Innovation Center of Seafood Deep Processing, National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian, 116034, China
| | - Mingyan Li
- Zhejiang Key Laboratory of Biological Breeding and Exploitation of Edible and Medicinal Mushrooms, Zhejiang Shouxiangu Institute of Rare Medicine Plant, Wuyi, 321200, Zhejiang, China
| | - Guangyuan Chen
- Liaoning Key Laboratory of Food Nutrition and Health, Collaborative Innovation Center of Seafood Deep Processing, National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian, 116034, China
| | - Libo Qi
- Liaoning Key Laboratory of Food Nutrition and Health, Collaborative Innovation Center of Seafood Deep Processing, National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian, 116034, China
| | - Shuang Song
- Liaoning Key Laboratory of Food Nutrition and Health, Collaborative Innovation Center of Seafood Deep Processing, National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian, 116034, China
| | - Zhenhao Li
- Zhejiang Key Laboratory of Biological Breeding and Exploitation of Edible and Medicinal Mushrooms, Zhejiang Shouxiangu Institute of Rare Medicine Plant, Wuyi, 321200, Zhejiang, China.
| | - Chunhong Yan
- Liaoning Key Laboratory of Food Nutrition and Health, Collaborative Innovation Center of Seafood Deep Processing, National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian, 116034, China.
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4
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Fu Y, Maccioni L, Wang XW, Greten TF, Gao B. Alcohol-associated liver cancer. Hepatology 2024; 80:1462-1479. [PMID: 38607725 DOI: 10.1097/hep.0000000000000890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 03/28/2024] [Indexed: 04/14/2024]
Abstract
Heavy alcohol intake induces a wide spectrum of liver diseases ranging from steatosis, steatohepatitis, cirrhosis, and HCC. Although alcohol consumption is a well-known risk factor for the development, morbidity, and mortality of HCC globally, alcohol-associated hepatocellular carcinoma (A-HCC) is poorly characterized compared to viral hepatitis-associated HCC. Most A-HCCs develop after alcohol-associated cirrhosis (AC), but the direct carcinogenesis from ethanol and its metabolites to A-HCC remains obscure. The differences between A-HCC and HCCs caused by other etiologies have not been well investigated in terms of clinical prognosis, genetic or epigenetic landscape, molecular mechanisms, and heterogeneity. Moreover, there is a huge gap between basic research and clinical practice due to the lack of preclinical models of A-HCC. In the current review, we discuss the pathogenesis, heterogeneity, preclinical approaches, epigenetic, and genetic profiles of A-HCC, and discuss the current insights into and the prospects for future research on A-HCC. The potential effect of alcohol on cholangiocarcinoma and liver metastasis is also discussed.
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Affiliation(s)
- Yaojie Fu
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Luca Maccioni
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Xin Wei Wang
- Liver Carcinogenesis Section, Laboratory of Human Carcinogenesis, National Cancer Institute, NIH, Bethesda, Maryland, USA
- Liver Cancer Program, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA
| | - Tim F Greten
- Liver Cancer Program, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA
- Gastrointestinal Malignancies Section, Thoracic and Gastrointestinal Malignancies Branch, National Cancer Institute, NIH, Bethesda, Maryland, USA
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
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Aguirre-Maldonado I, Herrera-López EE, López-Zenteno F, Ramírez-Nava JC, López-Hernández NA, Arellanes-Robledo J, Del Pozo-Yauner L, García-Román R, Montero H, Alexander-Aguilera A, Noyola-Díaz JM, Camacho J, Pérez-Carreón JI. Intriguing hepatoprotective effects of sucrose on hepatocellular carcinoma pathogenesis. Sci Rep 2024; 14:23689. [PMID: 39390131 PMCID: PMC11467258 DOI: 10.1038/s41598-024-74991-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Accepted: 10/01/2024] [Indexed: 10/12/2024] Open
Abstract
Chronic liver disease is closely linked to dietary intake factors, such as high consumption of simple carbohydrates including sucrose. In this study, the influence of sucrose on the development of hepatocellular carcinoma (HCC), the most common primary liver malignancy, was explored. Using the hepatocarcinogen diethylnitrosamine (DEN) to induce HCC in the rat, we co-administered sucrose with DEN. The co-administration significantly modified body, liver and pancreas weight, as well as, serum fatty acids and triglycerides. DEN caused liver structural alteration, fibrosis, and tumor formation; surprisingly, co-administration with sucrose restored hepatic lipids, improved liver architecture, and reduced fibrosis and tumor development. Sucrose intake negatively regulated tumor markers and cell proliferation, and reduced the expression of genes associated with lipid metabolism and oxidative stress response. These findings highlight a hepatoprotective effect of sucrose during DEN-induced hepatocarcinogenesis, underlining an intriguing role of high sucrose consumption during HCC development and providing new insights as well as possible pathways of cellular protection under sucrose intake on hepatocarcinogenesis.
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Affiliation(s)
- Isaac Aguirre-Maldonado
- Laboratorio de Enfermedades Hepáticas, Instituto Nacional de Medicina Genómica, Periférico Sur No. 4809, Col. Arenal Tepepan, Alcaldía Tlalpan, 14610, Ciudad de México, Mexico
- Departamento de Farmacología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Av. Instituto Politécnico Nacional 2508, 07360, Ciudad de México, Mexico
| | - Ema Elvira Herrera-López
- Laboratorio de Enfermedades Hepáticas, Instituto Nacional de Medicina Genómica, Periférico Sur No. 4809, Col. Arenal Tepepan, Alcaldía Tlalpan, 14610, Ciudad de México, Mexico
| | - Fernando López-Zenteno
- Instituto de Investigación en Ciencias de la Salud de la SEMAR, Ciudad de México, Mexico
| | | | - Norma Arely López-Hernández
- Laboratorio de Enfermedades Hepáticas, Instituto Nacional de Medicina Genómica, Periférico Sur No. 4809, Col. Arenal Tepepan, Alcaldía Tlalpan, 14610, Ciudad de México, Mexico
| | - Jaime Arellanes-Robledo
- Laboratorio de Enfermedades Hepáticas, Instituto Nacional de Medicina Genómica, Periférico Sur No. 4809, Col. Arenal Tepepan, Alcaldía Tlalpan, 14610, Ciudad de México, Mexico
- Dirección Adjunta de Investigación Humanística y Científica, Consejo Nacional de Humanidades Ciencias y Tecnologías, Ciudad de México, Mexico
| | - Luis Del Pozo-Yauner
- Department of Pathology, College of Medicine, University of South Alabama, Alabama, USA
| | - Rebeca García-Román
- Instituto de Salud Pública, Universidad Veracruzana, Xalapa, Veracruz, Mexico
| | - Hilda Montero
- Instituto de Salud Pública, Universidad Veracruzana, Xalapa, Veracruz, Mexico
| | | | - Juana Martha Noyola-Díaz
- Departamento de Farmacología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Av. Instituto Politécnico Nacional 2508, 07360, Ciudad de México, Mexico
| | - Javier Camacho
- Departamento de Farmacología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Av. Instituto Politécnico Nacional 2508, 07360, Ciudad de México, Mexico
| | - Julio Isael Pérez-Carreón
- Laboratorio de Enfermedades Hepáticas, Instituto Nacional de Medicina Genómica, Periférico Sur No. 4809, Col. Arenal Tepepan, Alcaldía Tlalpan, 14610, Ciudad de México, Mexico.
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Yoladı FB, Burmaoğlu E, Palabıyık ŞS. Experimental In Vivo Toxicity Models for Alcohol Toxicity. Eurasian J Med 2023; 55:82-90. [PMID: 39109811 PMCID: PMC11075036 DOI: 10.5152/eurasianjmed.2023.23345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Accepted: 12/26/2023] [Indexed: 08/11/2024] Open
Abstract
Alcohol consumption poses a significant risk for the development of chronic illnesses, one of the leading causes of "preventable" disease and death worldwide. Harmful consumption of alcohol is thought to result in approximately 2.5-3 million deaths each year, the majority of which are caused by alcohol-related liver diseases. Hepatocellular carcinoma, cirrhosis, fibrosis, steatosis, and steatohepatitis are among the liver illnesses caused by alcohol. The mechanisms behind human diseases are often mimicked and understood through the use of animal models. Rodents are the ideal animals to study alcohol-related liver diseases. In these experimental models using rodents, the ethanol ratio, method of administration, and diet to be applied vary. Within the scope of this review, it is aimed at providing information about the experimental models used today for alcohol toxicity and the advantages and disadvantages of these models.
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Affiliation(s)
- Fatma Betül Yoladı
- Department of Pharmaceutical Toxicology, Atatürk University Faculty of Pharmacy, Erzurum, Turkey
- Department of Pharmaceutical Toxicology, Hacettepe University Faculty of Pharmacy, Ankara, Turkey
| | | | - Şaziye Sezin Palabıyık
- Department of Pharmaceutical Toxicology, Atatürk University Faculty of Pharmacy, Erzurum, Turkey
- Clinical Research, Development and Design Application and Research Center, Atatürk University, Erzurum, Turkey
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7
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Lin CY, Omoscharka E, Liu Y, Cheng K. Establishment of a Rat Model of Alcoholic Liver Fibrosis with Simulated Human Drinking Patterns and Low-Dose Chemical Stimulation. Biomolecules 2023; 13:1293. [PMID: 37759693 PMCID: PMC10526499 DOI: 10.3390/biom13091293] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 08/16/2023] [Accepted: 08/21/2023] [Indexed: 09/29/2023] Open
Abstract
Although alcohol is a well-known causal factor associated with liver diseases, challenges remain in inducing liver fibrosis in experimental rodent models. These challenges include rodents' natural aversion to high concentrations of alcohol, rapid alcohol metabolism, the need for a prolonged duration of alcohol administration, and technical difficulties. Therefore, it is crucial to establish an experimental model that can replicate the features of alcoholic liver fibrosis. The objective of this study was to develop a feasible rat model of alcoholic liver fibrosis that emulates human drinking patterns and combines low-dose chemicals within a relatively short time frame. We successfully developed an 8-week rat model of alcoholic liver fibrosis that mimics chronic and heavy drinking patterns. Rats were fed with a control liquid diet, an alcohol liquid diet, or alcohol liquid diet combined with multiple binges via oral gavage. To accelerate the progression of alcoholic liver fibrosis, we introduced low-dose carbon tetrachloride (CCl4) through intraperitoneal injection. This model allows researchers to efficiently evaluate potential therapeutics in preclinical studies of alcoholic liver fibrosis within a reasonable time frame.
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Affiliation(s)
- Chien-Yu Lin
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO 64108, USA
| | - Evanthia Omoscharka
- Department of Pathology, University Health/Truman Medical Center, School of Medicine, University of Missouri-Kansas City, 2301 Holmes Street, Kansas City, MO 64108, USA
| | - Yanli Liu
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO 64108, USA
| | - Kun Cheng
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO 64108, USA
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8
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Li J, Wang X, Ren M, He S, Zhao Y. Advances in experimental animal models of hepatocellular carcinoma. Cancer Med 2023; 12:15261-15276. [PMID: 37248746 PMCID: PMC10417182 DOI: 10.1002/cam4.6163] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 05/08/2023] [Accepted: 05/17/2023] [Indexed: 05/31/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a common malignant tumor with insidious early symptoms, easy metastasis, postoperative recurrence, poor drug efficacy, and a high drug resistance rate when surgery is missed, leading to a low 5-year survival rate. Research on the pathogenesis and drugs is particularly important for clinical treatment. Animal models are crucial for basic research, which is conducive to studying pathogenesis and drug screening more conveniently and effectively. An appropriate animal model can better reflect disease occurrence and development, and the process of anti-tumor immune response in the human body. This review summarizes the classification, characteristics, and advances in experimental animal models of HCC to provide a reference for researchers on model selection.
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Affiliation(s)
- Jing Li
- Department of GastroenterologyThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anPeople's Republic of China
| | - Xin Wang
- Department of GastroenterologyThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anPeople's Republic of China
| | - Mudan Ren
- Department of GastroenterologyThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anPeople's Republic of China
| | - Shuixiang He
- Department of GastroenterologyThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anPeople's Republic of China
| | - Yan Zhao
- Department of GastroenterologyThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anPeople's Republic of China
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Sarkar S, Das AK, Bhattacharya S, Gachhui R, Sil PC. Isorhamnetin exerts anti-tumor activity in DEN + CCl 4-induced HCC mice. Med Oncol 2023; 40:188. [PMID: 37226027 DOI: 10.1007/s12032-023-02050-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Accepted: 05/06/2023] [Indexed: 05/26/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the most prevalent type of liver cancer and the main cause of cancer death globally. The use of medicinal herbs as chemotherapeutic agents in cancer treatment is receiving attention as they possess no or minimum side effects. Isorhamnetin (IRN), a flavonoid, has been under attention for its anti-inflammatory and anti-proliferative properties in a number of cancers, including colorectal, skin, and lung cancers. However, the in vivo mechanism of isorhamnetin to suppress liver cancer has yet to be explored. METHODS AND RESULT HCC was induced by N-diethylnitrosamine (DEN) and carbon tetrachloride (CCL4) in Swiss albino mice. Isorhamnetin (100 mg/kg body weight) was given to examine its anti-tumor properties in HCC mice model. Histological analysis and liver function assays were performed to assess changes in liver anatomy. Probable molecular pathways were explored using immunoblot, qPCR, ELISA, and immunohistochemistry techniques. Isorhamnetin inhibited various pro-inflammatory cytokines to suppress cancer-inducing inflammation. Additionally, it regulated Akt and MAPKs to suppress Nrf2 signaling. Isorhamnetin activated PPAR-γ and autophagy while suppressing cell cycle progression in DEN + CCl4-administered mice. Additionally, isorhamnetin regulated various signaling pathways to suppress cell proliferation, metabolism, and epithelial-mesenchymal transition in HCC. CONCLUSION Regulating diverse cellular signaling pathways makes isorhamnetin a better anti-cancer chemotherapeutic candidate in HCC. Importantly, the anti-TNF-α properties of isorhamnetin could prove it a valuable therapeutic agent in sorafenib-resistant HCC patients. Additionally, anti-TGF-β properties of isorhamnetin could be utilized to reduce the EMT-inducing side effects of doxorubicin.
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Affiliation(s)
- Sayanta Sarkar
- Department of Life Sciences & Biotechnology, Jadavpur University, 188, Raja SC Mullick Road, Kolkata, 700032, India
| | - Abhishek Kumar Das
- Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata, West Bengal, 700054, India
| | - Semantee Bhattacharya
- Indian Association for the Cultivation of Science, 2A & 2B, Raja Subodh Chandra Mallick Rd, Jadavpur, Kolkata, West Bengal, 700032, India
| | - Ratan Gachhui
- Department of Life Sciences & Biotechnology, Jadavpur University, 188, Raja SC Mullick Road, Kolkata, 700032, India
| | - Parames C Sil
- Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata, West Bengal, 700054, India.
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10
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Aydemir Celep N, Gedikli S. Protective Effect of Silymarin on Liver in Experimental in the Sepsis Model of Rats. Acta Histochem Cytochem 2023; 56:9-19. [PMID: 36890848 PMCID: PMC9986308 DOI: 10.1267/ahc.22-00059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 01/16/2023] [Indexed: 03/03/2023] Open
Abstract
This study, it was investigated whether silymarin has a protective effect by performing histological, immunohistochemical, and biochemical evaluations on the liver damage induced by cecal ligation perforation (CLP). CLP model was established and silymarin was treated at a dose of 50 mg/kg, 100 mg/kg, and 200 mg/kg, by oral one hour before the CLP. As an effect of the histological evaluations of the liver tissues, venous congestion, inflammation, and necrosis in the hepatocytes were observed in the CLP group. A situation close to the control group was observed in the Silymarin (SM)100 and SM200 groups. As a result of the immunohistochemical evaluations, inducible nitric oxide synthase (iNOS), cytokeratine (CK)18, Tumor necrosis factor-alpha (TNF-α), and interleukine (IL)-6 immunoreactivities were intense in the CLP group. In the biochemical analysis, Alkaline Phosphatase (ALP), Aspartate Aminotransferase (AST), and Alanine Aminotransferase (ALT) levels were significantly increased in the CLP group, while a significant decrease was observed in the treatment groups. TNFα, IL-1β, and IL-6 concentrations were in parallel with histopathological evaluations. In the biochemical analysis, Malondialdehyte (MDA) level increased significantly in the CLP group, but there was a significant decrease in the SM100 and SM200 groups. Glutathione (GSH), Superoxide Dismutase (SOD), Catalase (CAT), and Glutathione Peroxidase (GSH-Px) activities were relatively low in the CLP group. According to these data, it was concluded that using silymarin reduces the existing liver damage in sepsis.
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Affiliation(s)
- Nevra Aydemir Celep
- Department of Histology and Embriology, Faculty of Veterinary Medicine, Atatürk University, Erzurum, Turkey
| | - Semin Gedikli
- Department of Histology and Embriology, Faculty of Veterinary Medicine, Atatürk University, Erzurum, Turkey
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11
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Tu T, Alba MM, Datta AA, Hong H, Hua B, Jia Y, Khan J, Nguyen P, Niu X, Pammidimukkala P, Slarve I, Tang Q, Xu C, Zhou Y, Stiles BL. Hepatic macrophage mediated immune response in liver steatosis driven carcinogenesis. Front Oncol 2022; 12:958696. [PMID: 36276076 PMCID: PMC9581256 DOI: 10.3389/fonc.2022.958696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 08/17/2022] [Indexed: 12/02/2022] Open
Abstract
Obesity confers an independent risk for carcinogenesis. Classically viewed as a genetic disease, owing to the discovery of tumor suppressors and oncogenes, genetic events alone are not sufficient to explain the progression and development of cancers. Tumor development is often associated with metabolic and immunological changes. In particular, obesity is found to significantly increase the mortality rate of liver cancer. As its role is not defined, a fundamental question is whether and how metabolic changes drive the development of cancer. In this review, we will dissect the current literature demonstrating that liver lipid dysfunction is a critical component driving the progression of cancer. We will discuss the involvement of inflammation in lipid dysfunction driven liver cancer development with a focus on the involvement of liver macrophages. We will first discuss the association of steatosis with liver cancer. This will be followed with a literature summary demonstrating the importance of inflammation and particularly macrophages in the progression of liver steatosis and highlighting the evidence that macrophages and macrophage produced inflammatory mediators are critical for liver cancer development. We will then discuss the specific inflammatory mediators and their roles in steatosis driven liver cancer development. Finally, we will summarize the molecular pattern (PAMP and DAMP) as well as lipid particle signals that are involved in the activation, infiltration and reprogramming of liver macrophages. We will also discuss some of the therapies that may interfere with lipid metabolism and also affect liver cancer development.
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Affiliation(s)
- Taojian Tu
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Mario M. Alba
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Aditi A. Datta
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Handan Hong
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Brittney Hua
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Yunyi Jia
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Jared Khan
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Phillip Nguyen
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Xiatoeng Niu
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Pranav Pammidimukkala
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Ielyzaveta Slarve
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Qi Tang
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Chenxi Xu
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Yiren Zhou
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Bangyan L. Stiles
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- *Correspondence: Bangyan L. Stiles,
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12
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Zhu L, Li HD, Xu JJ, Li JJ, Cheng M, Meng XM, Huang C, Li J. Advancements in the Alcohol-Associated Liver Disease Model. Biomolecules 2022; 12:biom12081035. [PMID: 36008929 PMCID: PMC9406170 DOI: 10.3390/biom12081035] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 07/22/2022] [Accepted: 07/25/2022] [Indexed: 02/06/2023] Open
Abstract
Alcohol-associated liver disease (ALD) is an intricate disease that results in a broad spectrum of liver damage. The presentation of ALD can include simple steatosis, steatohepatitis, liver fibrosis, cirrhosis, and even hepatocellular carcinoma (HCC). Effective prevention and treatment strategies are urgently required for ALD patients. In previous decades, numerous rodent models were established to investigate the mechanisms of alcohol-associated liver disease and explore therapeutic targets. This review provides a summary of the latest developments in rodent models, including those that involve EtOH administration, which will help us to understand the characteristics and causes of ALD at different stages. In addition, we discuss the pathogenesis of ALD and summarize the existing in vitro models. We analyse the pros and cons of these models and their translational relevance and summarize the insights that have been gained regarding the mechanisms of alcoholic liver injury.
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Affiliation(s)
| | | | | | | | | | - Xiao-Ming Meng
- Correspondence: (X.-M.M.); (C.H.); (J.L.); Tel.: +86-551-65161001 (J.L.); Fax: +86-551-65161001 (J.L.)
| | - Cheng Huang
- Correspondence: (X.-M.M.); (C.H.); (J.L.); Tel.: +86-551-65161001 (J.L.); Fax: +86-551-65161001 (J.L.)
| | - Jun Li
- Correspondence: (X.-M.M.); (C.H.); (J.L.); Tel.: +86-551-65161001 (J.L.); Fax: +86-551-65161001 (J.L.)
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13
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Yassin NYS, AbouZid SF, El-Kalaawy AM, Ali TM, Almehmadi MM, Ahmed OM. Silybum marianum total extract, silymarin and silibinin abate hepatocarcinogenesis and hepatocellular carcinoma growth via modulation of the HGF/c-Met, Wnt/β-catenin, and PI3K/Akt/mTOR signaling pathways. Biomed Pharmacother 2022; 145:112409. [PMID: 34781148 DOI: 10.1016/j.biopha.2021.112409] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 10/30/2021] [Accepted: 11/03/2021] [Indexed: 12/19/2022] Open
Abstract
Hepatocellular carcinoma (HCC) has been identified as one of the most deadly malignancies with limited therapeutic efficacy worldwide. However, understanding the molecular mechanisms of crosstalk between signaling pathways in HCC and predicting cancer cell responses to targeted therapeutic interventions remain to be challenge. Thus, in this study, we aimed to evaluate the anticancerous efficacy of Silybum marianum total extract (STE), silymarin (Sm), and silibinin (Sb) against experimentally-induced HCC in rats. In vitro investigations were also performed and the anticancer effects against HCC cell lines (HepG2 and Huh7) were confirmed. Wistar rats were given diethylnitrosamine (DEN)/2-acetylaminofluorene (AAF)/carbon tetrachloride (CCl4) and were orally treated with STE (200 mg/kg body weight (bw)), Sm (150 mg/kg bw), and Sb (5 mg/kg bw) every other day from the 1st or 16th week to the 25th week of DEN/AAF/CCl4 injection. Treatment with STE, Sm, and Sb inhibited the growth of cancerous lesions in DEN/AAF/CCl4-treated rats. This inhibition was associated with inhibition of Ki-67 expression and repression of HGF/cMet, Wnt/β-catenin, and PI3K/Akt/mTOR signaling pathways. STE, Sm, and Sb improved liver function biomarkers and tumor markers (AFP, CEA, and CA19.9) and increased total protein and albumin levels in serum. STE, Sm, and Sb treatment was also noted to reduce the hepatic production of lipid peroxides, increase hepatic glutathione content, and induce the activities of hepatic antioxidant enzymes in DEN/AAF/CCl4-treated rats. These results indicate that STE, Sm, and Sb exert anti-HCC effects through multiple pathways, including suppression of Ki-67 expression and HGF/cMet, Wnt/β-catenin, and PI3K/Akt/mTOR pathways and enhancement of antioxidant defense mechanisms.
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Affiliation(s)
- Nour Y S Yassin
- Physiology Division, Department of Zoology, Faculty of Science, Beni-Suef University, P.O. Box 62521, Beni-Suef, Egypt
| | - Sameh F AbouZid
- Department of Pharmacognosy, Faculty of Pharmacy, Heliopolis University for Sustainable Development, 3 Cairo-Belbeis Desert Road, P.O. Box 3020 El Salam, 11785 Cairo, Egypt
| | - Asmaa M El-Kalaawy
- Department of Pharmacology, Faculty of Medicine, Beni-Suef University, Beni-Suef, Egypt
| | - Tarek M Ali
- Department of Physiology, College of Medicine, Taif University, P. O. Box 11099, Taif 21944, Saudi Arabia
| | - Mazen M Almehmadi
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, P. O. Box 11099, Taif 21944, Saudi Arabia
| | - Osama M Ahmed
- Physiology Division, Department of Zoology, Faculty of Science, Beni-Suef University, P.O. Box 62521, Beni-Suef, Egypt.
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14
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Zelber-Sagi S, Noureddin M, Shibolet O. Lifestyle and Hepatocellular Carcinoma What Is the Evidence and Prevention Recommendations. Cancers (Basel) 2021; 14:cancers14010103. [PMID: 35008267 PMCID: PMC8750465 DOI: 10.3390/cancers14010103] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/20/2021] [Accepted: 12/22/2021] [Indexed: 12/13/2022] Open
Abstract
Simple Summary The increasing public health burden of Hepatocellular carcinoma (HCC) emphasizes the importance of defining important modifiable risk factors. In the following review, we will discuss the evidence for the relation of major lifestyle risk factors, mostly from large population-based studies. Generally, it is has been shown that healthy lifestyle habits, including minimizing obesity, eating a healthy diet, avoidance of smoking and alcohol, and increasing physical activity, have the potential to prevent HCC. Dietary composition is important beyond obesity. Consumption of n-3 polyunsaturated fatty acids, as well as fish and poultry, vegetables and fiber, are inversely associated with HCC, while red meat, saturated fat, cholesterol and sugar are related to increased risk. Data from multiple studies clearly show a beneficial effect for physical activity in reducing the risk of HCC. Smoking and alcohol can lead to liver fibrosis and liver cancer and jointly lead to an even greater risk. Abstract The increasing burden of hepatocellular carcinoma (HCC) emphasizes the unmet need for primary prevention. Lifestyle measures appear to be important modifiable risk factors for HCC regardless of its etiology. Lifestyle patterns, as a whole and each component separately, are related to HCC risk. Dietary composition is important beyond obesity. Consumption of n-3 polyunsaturated fatty acids, as well as fish and poultry, are inversely associated with HCC, while red meat, saturated fat, and cholesterol are related to increased risk. Sugar consumption is associated with HCC risk, while fiber and vegetable intake is protective. Data from multiple studies clearly show a beneficial effect for physical activity in reducing the risk of HCC. However, the duration, mode and intensity of physical activity needed are yet to be determined. There is evidence that smoking can lead to liver fibrosis and liver cancer and has a synergistic effect with alcohol drinking. On the other hand, an excessive amount of alcohol by itself has been associated with increased risk of HCC directly (carcinogenic effect) or indirectly (liver fibrosis and cirrhosis progression. Large-scale intervention studies testing the effect of comprehensive lifestyle interventions on HCC prevention among diverse cohorts of liver disease patients are greatly warranted.
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Affiliation(s)
- Shira Zelber-Sagi
- School of Public Health, Faculty of Social Welfare and Health Sciences, University of Haifa, Haifa 3498838, Israel
- Department of Gastroenterology & Hepatology, Tel Aviv Medical Center, Tel Aviv 6423906, Israel;
- Correspondence: ; Tel.: +972-54-4634440; Fax: +972-3-5446086
| | - Mazen Noureddin
- Karsh Division of Gastroenterology and Hepatology, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA;
| | - Oren Shibolet
- Department of Gastroenterology & Hepatology, Tel Aviv Medical Center, Tel Aviv 6423906, Israel;
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6697801, Israel
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15
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Chun HJ, Shim YJ, Kwon YH. Cholic acid supplementation accelerates the progression of nonalcoholic fatty liver disease to the procarcinogenic state in mice fed a high-fat and high-cholesterol diet. J Nutr Biochem 2021; 100:108869. [PMID: 34563665 DOI: 10.1016/j.jnutbio.2021.108869] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 02/22/2021] [Accepted: 09/01/2021] [Indexed: 12/24/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the major causes of hepatocellular carcinoma (HCC). Although the intracellular cholesterol accumulation has been demonstrated to regulate the gene expression responsible for steatohepatitis, the role played by cholesterol in the development of NAFLD-associated HCC has not been fully elucidated. In this study, using microarray analysis, we investigated the molecular mechanisms governing cholesterol-mediated progression of NAFLD. To ensure hepatic cholesterol accumulation, either a high-fat and high-cholesterol (HFHC) diet or a high-fat and high-cholesterol with cholic acid (HFHCCA) diet was fed to diethylnitrosamine (DEN)-injected C57BL/6J mice for 10 weeks. While an HFHC diet increased hepatic triglyceride levels, an HFHCCA diet induced hepatic cholesterol accumulation by reducing bile acid biosynthesis in DEN-injected mice. Livers from both HFHC and HFHCCA groups exhibited increases in steatosis and necrosis; however, histological features of HCC were not observed in any of the experimental groups. Hepatic gene expression profile of the HFHCCA group was different from those of other groups. Functional analysis showed that cholic acid supplementation upregulated differentially expressed genes (DEGs) associated with inflammation, proliferation, apoptosis, chemical drug response, and cancer signaling pathway. Downregulated DEGs were associated with steroid metabolism, mitochondrial function, and oxidative phosphorylation pathway. Furthermore, hepatic cholesterol accumulation lowered the expression of DEGs associated with energy and macronutrient metabolism, especially amino acid metabolism. In this study, the results of a global gene expression profile demonstrated that feeding the HFHCCA diet to DEN-injected mice accelerated the carcinogenic progression of NAFLD, implicating the critical role played by hepatic accumulation of cholesterol.
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Affiliation(s)
- Hee Jeong Chun
- Department of Food and Nutrition, Seoul National University, Seoul, Korea
| | - Yeon Joo Shim
- Department of Food and Nutrition, Seoul National University, Seoul, Korea
| | - Young Hye Kwon
- Department of Food and Nutrition, Seoul National University, Seoul, Korea; Research Institute of Human Ecology, Seoul National University, Seoul, Korea.
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16
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Liu SX, Du YC, Zeng T. A mini-review of the rodent models for alcoholic liver disease: shortcomings, application, and future prospects. Toxicol Res (Camb) 2021; 10:523-530. [PMID: 34141166 DOI: 10.1093/toxres/tfab042] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 04/12/2021] [Accepted: 04/15/2021] [Indexed: 12/19/2022] Open
Abstract
Rodents are the most common models in studies of alcoholic liver disease (ALD). Although several rodents ALD models have been established and multiple mechanisms have been elucidated based on them, these models have some non-negligible shortcomings, specifically only inducing early stage (mainly steatosis, slight to moderate steatohepatitis) but not the whole spectrum of human ALD. The resistance of rodents to advanced ALD has been suggested to be due to the physiological differences between rodents and human beings. Previous studies have reported significant interstrain differences in the susceptibility to ethanol-induced liver injury and in the manifestation of ALD (such as different alteration of lipid profiles). Therefore, it would be interesting to characterize the manifestation of ethanol-induced liver damage in various rodents, which may provide a recommendation to investigators of ALD. Furthermore, more severe ALD models need to be established for the study of serious ALD forms, which may be achieved by using genetic modified rodents.
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Affiliation(s)
- Shi-Xuan Liu
- Institute of Toxicology, School of Public Health, Cheeloo College of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan, Shandong, 250012, China
| | - Yan-Chao Du
- Jinan Institute for Product Quality Inspection, 1311 Longao Bei Road, Jinan, Shandong, 250102, China
| | - Tao Zeng
- Institute of Toxicology, School of Public Health, Cheeloo College of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan, Shandong, 250012, China
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17
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Shi J, Song S, Li S, Zhang K, Lan Y, Li Y. TNF-α/NF-κB signaling epigenetically represses PSD4 transcription to promote alcohol-related hepatocellular carcinoma progression. Cancer Med 2021; 10:3346-3357. [PMID: 33932127 PMCID: PMC8124102 DOI: 10.1002/cam4.3832] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Revised: 12/08/2020] [Accepted: 12/11/2020] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND Chronic alcohol consumption is more frequently associated with advanced, aggressive hepatocellular carcinoma (HCC) tumors. Alcohol adversely impacts ER/Golgi membrane trafficking and Golgi protein N-glycosylation in hepatocytes; these effects have been attributed (in part) to dysregulated adenosine diphosphate-ribosylation factor (ARF) GTPase signaling. Here, we investigated the role of the ARF GTPase guanine exchange factor PSD4 in HCC progression. METHODS R-based bioinformatics analysis was performed on publicly available array data. Modulating gene expression was accomplished via lentiviral vectors. Gene expression was analyzed using quantitative real-time PCR and immunoblotting. PSD4 promoter methylation was assessed using quantitative methylation-specific PCR. Phospho-p65(S276)/DNMT1 binding to the PSD4 promoter was analyzed via chromatin immunoprecipitation. We constructed ethanol/DEN-induced and DEN only-induced transgenic murine models of HCC. RESULTS We identified PSD4 as a hypermethylated, suppressed gene in alcohol-related HCC tumors; however, PSD4 was not dysregulated in all-cause HCC tumors. Certain HCC cell lines also displayed varying degrees of PSD4 downregulation. PSD4 overexpression or knockdown decreased and increased cell migration and invasiveness, respectively. Mechanistically, PSD4 transcription was repressed by TNF-α-induced phospho-p65(S276)'s recruitment of DNA methyltransferase 1 (DNMT1), resulting in PSD4 promoter methylation. PSD4 inhibited pro-EMT CDC42 activity, resulting in downregulation of E-cadherin and upregulation of N-cadherin and vimentin. Hepatocyte-specific PSD4 overexpression reduced ethanol/DEN-induced HCC tumor progression and EMT marker expression in vivo. CONCLUSIONS PSD4 is a hypermethylated, suppressed gene in alcohol-related HCC tumors that negatively modulated pro-EMT CDC42 activity. Furthermore, we present a novel phospho-NF-κB p65(S276)/DNMT1-mediated promoter methylation mechanism by which TNF-α/NF-κB signaling represses PSD4 transcription in HCC cells.
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Affiliation(s)
- Jia'ning Shi
- Department of Infectious Disease, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Shupeng Song
- Department of Infectious Disease, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Shuangxing Li
- Department of Infectious Disease, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Kaili Zhang
- Department of Infectious Disease, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Yinghua Lan
- Department of Infectious Disease, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Yongguo Li
- Department of Infectious Disease, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
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18
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Wang Y, Li X, Chen Q, Jiao F, Shi C, Pei M, Wang L, Gong Z. Histone Deacetylase 6 Regulates the Activation of M1 Macrophages by the Glycolytic Pathway During Acute Liver Failure. J Inflamm Res 2021; 14:1473-1485. [PMID: 33883923 PMCID: PMC8055295 DOI: 10.2147/jir.s302391] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Accepted: 03/18/2021] [Indexed: 12/19/2022] Open
Abstract
Background The glycolysis pathway of M1 macrophages is a key factor affecting the inflammatory response. The aim of this article is to investigate the role of histone deacetylase 6 (HDAC6) in the M1 macrophage glycolysis pathway during acute liver failure (ALF). Methodology Targeted metabolomics for quantitative analysis of energy metabolites technology was used to detect the characteristics of energy metabolism for 8 ALF patients and 8 normal volunteers. The ALF mice model was intervened with HDAC6 inhibitor ACY-1215. iTRAQ/TMT quantitative proteomics was used to detect protein expression in livers in different mice groups. The liver function, energy metabolites, M1 macrophages, cytokines, and pathological structure, DDX3X, NLRP3 and DNMT1 in liver tissue were detected. The changes of the above molecules were verified in cell groups. Results ALF patients and mice have significant energy metabolism disorders, accompanied by activation of M1 macrophages. After the intervention of ACY-1215, the activated M1 macrophages and cytokines levels in the mouse liver were reduced. The levels of IDH1, MDH1, and ATP were significantly increased. The expression of DDX3X increased, while the expression of NLRP3 and DNMT1 decreased. ACY-1215 could reduce the model cell apoptosis level and inflammatory response, and improve energy metabolism. It could also promote the expression of DDX3X, and inhibit the expression of NLRP3 and DNMT1. Conclusion ACY-1215 could inhibit the activation of M1 macrophages by improving the glycolytic pathway through regulating DNMT1 and DDX3X/NLRP3 signals to alleviate ALF.
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Affiliation(s)
- Yao Wang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China
| | - Xun Li
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China
| | - Qian Chen
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China
| | - Fangzhou Jiao
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China
| | - Chunxia Shi
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China
| | - Maohua Pei
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China
| | - Luwen Wang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China
| | - Zuojiong Gong
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China
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19
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Komeil IA, El-Refaie WM, Gowayed MA, El-Ganainy SO, El Achy SN, Huttunen KM, Abdallah OY. Oral genistein-loaded phytosomes with enhanced hepatic uptake, residence and improved therapeutic efficacy against hepatocellular carcinoma. Int J Pharm 2021; 601:120564. [PMID: 33812970 DOI: 10.1016/j.ijpharm.2021.120564] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 03/06/2021] [Accepted: 03/29/2021] [Indexed: 12/27/2022]
Abstract
Genistein (Gen) is one of the most potent soy isoflavones used for hepatocellular carcinoma (HCC) treatment. Low aqueous solubility and first-pass metabolism are the main obstacles resulting in low Gen oral bioavailability. The current study aims to introduce phytosomes as an approach to improve Gen solubility, protect it from metabolism by complexation with phospholipids (PL), and get used to PL in Gen lymphatic delivery. Different forms of PL namely: Lipiod® S100, Phosal® 53 MCT, and Phosal®75 SA were used in phytosomes preparation GP, GPM, and GPL respectively. The effect of formulation components on Gen absorption, metabolism, and liver accumulation was evaluated following oral administration to rats. Cytotoxicity and cellular uptake studies were applied on HepG2 cells and in-vivo anti-tumor studies were applied to the DEN-mice model. Results revealed that GP and GPL remarkably accumulated Gen aglycone in hepatic cells and minimized the metabolic effect on Gen. They significantly increased the intracellular accumulation of Gen in its complex form in HepG2 cells. Their cytotoxicity is time-dependent according to the complex stability. The enhanced in-vivo anti-tumor effect was observed for GP and GPL compared to Gen suspension on DEN-induced HCC in mice. In conclusion, Gen-phytosomes can represent a promising approach for liver cancer treatment.
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Affiliation(s)
- Ibrahim A Komeil
- Department of Pharmaceutics, Faculty of Pharmacy, Pharos University in Alexandria, Alexandria, Egypt
| | - Wessam M El-Refaie
- Department of Pharmaceutics, Faculty of Pharmacy, Pharos University in Alexandria, Alexandria, Egypt.
| | - Mennatallah A Gowayed
- Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Pharos University in Alexandria, Alexandria, Egypt
| | - Samar O El-Ganainy
- Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Pharos University in Alexandria, Alexandria, Egypt
| | - Samar N El Achy
- Department of Pathology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Kristiina M Huttunen
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1C, Kuopio, Finland
| | - Ossama Y Abdallah
- Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
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20
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Tang J, Yan Z, Feng Q, Yu L, Wang H. The Roles of Neutrophils in the Pathogenesis of Liver Diseases. Front Immunol 2021; 12:625472. [PMID: 33763069 PMCID: PMC7982672 DOI: 10.3389/fimmu.2021.625472] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 01/25/2021] [Indexed: 01/30/2023] Open
Abstract
Neutrophils are the largest population of circulating leukocytes and the first responder against invading pathogens or other danger signals. Sophisticated machineries help them play critical roles in immunity and inflammation, including phagocytosis, superoxide production, cytokine and chemokine production, degranulation, and formation of neutrophil extracellular traps (NETs). After maturation and release from the bone marrow, neutrophils migrate to inflamed tissues in response to many stimuli. Increasing evidences indicate that neutrophils are critically involved in the pathogenesis of liver diseases, including liver cancer, thus making them promising target for the treatment of liver diseases. Here, we would like to provide the latest finding about the role of neutrophils in liver diseases and discuss the potentiality of neutrophils as target for liver diseases.
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Affiliation(s)
- Jiaojiao Tang
- Division of Life Sciences and Medicine, Cancer Research Center, The First Affiliated Hospital of University of Science and Technology of China, Hefei, China
- International Cooperation Laboratory on Signal Transduction, Ministry of Education Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepato-Biliary Tumor Biology, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Zijun Yan
- International Cooperation Laboratory on Signal Transduction, Ministry of Education Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepato-Biliary Tumor Biology, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
- Graduate Management Unit, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Qiyu Feng
- Division of Life Sciences and Medicine, Cancer Research Center, The First Affiliated Hospital of University of Science and Technology of China, Hefei, China
- International Cooperation Laboratory on Signal Transduction, Ministry of Education Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepato-Biliary Tumor Biology, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
- National Center for Liver Cancer, Shanghai, China
| | - Lexing Yu
- Division of Life Sciences and Medicine, Cancer Research Center, The First Affiliated Hospital of University of Science and Technology of China, Hefei, China
- International Cooperation Laboratory on Signal Transduction, Ministry of Education Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepato-Biliary Tumor Biology, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
- National Center for Liver Cancer, Shanghai, China
| | - Hongyang Wang
- Division of Life Sciences and Medicine, Cancer Research Center, The First Affiliated Hospital of University of Science and Technology of China, Hefei, China
- International Cooperation Laboratory on Signal Transduction, Ministry of Education Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepato-Biliary Tumor Biology, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
- National Center for Liver Cancer, Shanghai, China
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21
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Okada F, Izutsu R, Goto K, Osaki M. Inflammation-Related Carcinogenesis: Lessons from Animal Models to Clinical Aspects. Cancers (Basel) 2021; 13:cancers13040921. [PMID: 33671768 PMCID: PMC7926701 DOI: 10.3390/cancers13040921] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 02/11/2021] [Accepted: 02/12/2021] [Indexed: 12/13/2022] Open
Abstract
Simple Summary In multicellular organisms, inflammation is the body’s most primitive and essential protective response against any external agent. Inflammation, however, not only causes various modern diseases such as cardiovascular disorders, neurological disorders, autoimmune diseases, metabolic syndrome, infectious diseases, and cancer but also shortens the healthy life expectancy. This review focuses on the onset of carcinogenesis due to chronic inflammation caused by pathogen infections and inhalation/ingestion of foreign substances. This study summarizes animal models associated with inflammation-related carcinogenesis by organ. By determining factors common to inflammatory carcinogenesis models, we examined strategies for the prevention and treatment of inflammatory carcinogenesis in humans. Abstract Inflammation-related carcinogenesis has long been known as one of the carcinogenesis patterns in humans. Common carcinogenic factors are inflammation caused by infection with pathogens or the uptake of foreign substances from the environment into the body. Inflammation-related carcinogenesis as a cause for cancer-related death worldwide accounts for approximately 20%, and the incidence varies widely by continent, country, and even region of the country and can be affected by economic status or development. Many novel approaches are currently available concerning the development of animal models to elucidate inflammation-related carcinogenesis. By learning from the oldest to the latest animal models for each organ, we sought to uncover the essential common causes of inflammation-related carcinogenesis. This review confirmed that a common etiology of organ-specific animal models that mimic human inflammation-related carcinogenesis is prolonged exudation of inflammatory cells. Genotoxicity or epigenetic modifications by inflammatory cells resulted in gene mutations or altered gene expression, respectively. Inflammatory cytokines/growth factors released from inflammatory cells promote cell proliferation and repair tissue injury, and inflammation serves as a “carcinogenic niche”, because these fundamental biological events are common to all types of carcinogenesis, not just inflammation-related carcinogenesis. Since clinical strategies are needed to prevent carcinogenesis, we propose the therapeutic apheresis of inflammatory cells as a means of eliminating fundamental cause of inflammation-related carcinogenesis.
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Affiliation(s)
- Futoshi Okada
- Division of Experimental Pathology, Faculty of Medicine, Tottori University, Yonago 683-8503, Japan; (R.I.); (K.G.); (M.O.)
- Chromosome Engineering Research Center, Tottori University, Yonago 683-8503, Japan
- Correspondence: ; Tel.: +81-859-38-6241
| | - Runa Izutsu
- Division of Experimental Pathology, Faculty of Medicine, Tottori University, Yonago 683-8503, Japan; (R.I.); (K.G.); (M.O.)
| | - Keisuke Goto
- Division of Experimental Pathology, Faculty of Medicine, Tottori University, Yonago 683-8503, Japan; (R.I.); (K.G.); (M.O.)
- Division of Gastrointestinal and Pediatric Surgery, Faculty of Medicine, Tottori University, Yonago 683-8503, Japan
| | - Mitsuhiko Osaki
- Division of Experimental Pathology, Faculty of Medicine, Tottori University, Yonago 683-8503, Japan; (R.I.); (K.G.); (M.O.)
- Chromosome Engineering Research Center, Tottori University, Yonago 683-8503, Japan
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22
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Dietary modulations of folic acid affect the development of diethylnitrosamine induced hepatocellular carcinoma in a rat model. J Mol Histol 2021; 52:335-350. [PMID: 33438102 DOI: 10.1007/s10735-020-09955-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 12/31/2020] [Indexed: 02/07/2023]
Abstract
The present study evaluated the role of dietary folate modulations in the development of hepatocellular carcinoma (HCC) in a rat model. Male Wistar rats were given diethylnitrosamine (DEN) carcinogen for a period of 18 weeks in addition to different folate modulations. Biochemical parameters were assayed and liver tissues were examined using various histopathological stains viz. Hematoxylin and eosin (H&E), Masson's trichrome, Immunohistochemistry (IHC) staining for arginase-1 and α-smooth muscle actin (SMA). Serum folate and hepatic folate stores were decreased and increased in folate deficiency (FD) and folate oversupplemented (FO) group respectively. Analysis of serum liver function tests revealed deranged liver functioning in all the groups. H&E staining of rat liver demonstrated vague nodularity from 2nd to 8th week, fibrosis from 10th to 15th week, cirrhosis and HCC from 16th to 18th week. Combining the observations of H&E with IHC for arginase-1, 14 (50%), 11 (39.3%) and 17 (58.6%) rats showed HCC positivity in FN (folate normal), FD and FO diets respectively. IHC for α-SMA depicted increased staining with progression of the disease from fibrosis to cirrhosis in all the dietary groups. Collectively, findings of all the histopathological stains, revealed increase in the number of cirrhotic cases and decrease in the number of HCC cases in FD group, indicating delayed progression of HCC with FD. Moreover, FO led to more number of HCC and reduction in the number of cirrhotic cases, signifying early progression of HCC.
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23
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Abstract
The incidence of hepatocellular cancer (HCC) is gradually rising. HCC occurs as a sequela to various chronic liver diseases and ensuing cirrhosis. There have been many therapies approved for unresectable HCC in the last 5 years, including immune checkpoint inhibitors, and the overall response rates have improved. However, there are many cases that do not respond, and personalized medicine is lacking, making HCC an unmet clinical need. Generation of appropriate animal models have been key to our understanding of HCC. Based on the overall concept of hepatocarcinogenesis, two major categories of animal models are discussed herein that can be useful to address specific questions. One category is described as the outside-in model of HCC and is based on the premise that it takes decades of hepatocyte injury, death, wound healing, and regeneration to eventually lead to DNA damage and mutations in a hepatocyte, which initiates tumorigenesis. Several animal models have been generated, which attempt to recapitulate this complex tissue damage and cellular interplay through genetics, diets, and toxins. The second category is the inside-out model of HCC, where clinically relevant genes can be coexpressed in a small subset of hepatocytes to yield a tumor, which matches HCC subsets in gene expression. This model has been made possible in part by the widely available molecular characterization of HCC, and in part by modalities like sleeping beauty transposon/transposase, Crispr/Cas9, and hydrodynamic tail vein injection. These two categories of HCC have distinct pros and cons, which are discussed in this Thinking Out Loud article.
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Affiliation(s)
- Satdarshan P. Monga
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh Medical Center and University of Pittsburgh, Pittsburgh, PA, USA
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh Medical Center and University of Pittsburgh, Pittsburgh, PA, USA
- Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh, Pittsburgh, PA, USA
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24
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Zhang XN, Meng FG, Wang YR, Liu SX, Zeng T. Transformed ALDH2 -/- hepatocytes by ethanol could serve as a useful tool for studying alcoholic hepatocarcinogenesis. Med Hypotheses 2020; 146:110366. [PMID: 33208242 DOI: 10.1016/j.mehy.2020.110366] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 10/16/2020] [Accepted: 10/26/2020] [Indexed: 02/06/2023]
Abstract
Alcohol is a well-recognized hepatic carcinogen. Alcohol is metabolized into genotoxic acetaldehyde in hepatocytes, which is catalyzed by aldehyde dehydrogenase 2 (ALDH2). The detailed underlying mechanisms of alcohol-related hepatocellular carcinoma (HCC) remains unclear, at least partially, due to the absence of appropriate experimental models. Current studies suggest that rodents are not good models of the most common liver diseases that trigger HCC including alcoholic liver injury. We hypothesize that ethanol could induce transformation of immortalized normal liver cells, which may serve as a versatile tool for studying alcoholic HCC. Besides, we believe that knockout of ALDH2 will help to shorten the time course of transformation, as ALDH2 deficiency will significantly increase the accumulation of acetaldehyde in hepatocytes. Using this model, the dynamic changes of carcinogenesis-related molecular events could be easily examined. Furthermore, the transformed cells isolated from soft agar could be inoculated to mice for studying invasion, metastasis, and also for screening prophylactics.
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Affiliation(s)
- Xiu-Ning Zhang
- Institute of Toxicology, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Fan-Ge Meng
- Institute of Toxicology, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Yi-Ran Wang
- Institute of Toxicology, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Shi-Xuan Liu
- Institute of Toxicology, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Tao Zeng
- Institute of Toxicology, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
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25
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Roles of peroxisome proliferator-activated receptor α in the pathogenesis of ethanol-induced liver disease. Chem Biol Interact 2020; 327:109176. [PMID: 32534989 DOI: 10.1016/j.cbi.2020.109176] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 06/02/2020] [Accepted: 06/09/2020] [Indexed: 12/18/2022]
Abstract
Alcoholic liver disease (ALD) is a progressively aggravated liver disease with high incidence in alcoholics. Ethanol-induced fat accumulation and the subsequent lipopolysaccharide (LPS)-driven inflammation bring liver from reversible steatosis, to irreversible hepatitis, fibrosis, cirrhosis, and even hepatocellular carcinoma. Peroxisome proliferator-activated receptor α (PPARα) is a member of the nuclear receptor superfamily of ligand-activated transcription factors and plays pivotal roles in the regulation of fatty acid homeostasis as well as the inflammation control in the liver. It has been well documented that PPARα activity and/or expression are downregulated in liver of mice exposed to ethanol, which is thought to be one of the prime contributors to ethanol-induced steatosis, hepatitis and fibrosis. This article summarizes the current evidences from in vitro and animal models for the critical roles of PPARα in the onset and progression of ALD. Importantly, it should be noted that the expression of PPARα in human liver is reported to be similar to that in mice, and PPARα expression is downregulated in the liver of patients with nonalcoholic fatty liver disease (NAFLD), a disease sharing many similarities with ALD. Therefore, clinical trials investigating the expression of PPARα in the liver of ALD patients and the efficacy of strong PPARα agonists for the prevention and treatment of ALD are warranted.
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26
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Wang Y, Zhang H, Chen Q, Jiao F, Shi C, Pei M, Lv J, Zhang H, Wang L, Gong Z. TNF-α/HMGB1 inflammation signalling pathway regulates pyroptosis during liver failure and acute kidney injury. Cell Prolif 2020; 53:e12829. [PMID: 32419317 PMCID: PMC7309595 DOI: 10.1111/cpr.12829] [Citation(s) in RCA: 145] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Revised: 04/21/2020] [Accepted: 04/24/2020] [Indexed: 12/24/2022] Open
Abstract
OBJECTIVE Acute kidney injury (AKI) is a common complication of acute liver failure (ALF). Pyroptosis is a necrosis type related to inflammation. This study aimed to investigate the role of TNF-α/HMGB1 pathway in pyroptosis during ALF and AKI. METHODS An ALF and AKI mouse model was generated using LPS/D-Gal, and a TNF-α inhibitor, CC-5013, was used to treat the mice. THP-1 cells were induced to differentiate into M1 macrophages, then challenged with either CC-5013 or an HMGB1 inhibitor, glycyrrhizin. pLVX-mCMVZsGreen-PGK-Puros plasmids containing TNF-α wild-type (WT), mutation A94T of TNF-α and mutation P84L of TNF-α were transfected into M1 macrophages. RESULTS Treatment with CC-5013 decreased the activation of TNF-α/HMGB1 pathway and pyroptosis in the treated mice and cells compared with the control mice and cells. CC-5013 also ameliorated liver and kidney pathological changes and improved liver and renal functions in treated mice, and the number of M1 macrophages in the liver and kidney tissues also decreased. The activation of TNF-α/HMGB1 pathway and pyroptosis increased in the M1 macrophage group compared with the normal group. Similarly, the activation of TNF-α/HMGB1 pathway and pyroptosis in the LPS + WT group also increased. By contrast, the activation of the TNF-α/HMGB1 pathway and pyroptosis decreased in the LPS + A94T and LPS + P84L groups. Moreover, glycyrrhizin inhibited pyroptosis. CONCLUSION The TNF-α/HMGB1 inflammation signalling pathway plays an important role in pyroptosis during ALF and AKI.
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Affiliation(s)
- Yao Wang
- Department of Infectious DiseasesRenmin Hospital of Wuhan UniversityWuhanChina
| | - Haiyue Zhang
- Department of Infectious DiseasesRenmin Hospital of Wuhan UniversityWuhanChina
| | - Qian Chen
- Department of Infectious DiseasesRenmin Hospital of Wuhan UniversityWuhanChina
| | - Fangzhou Jiao
- Department of Infectious DiseasesRenmin Hospital of Wuhan UniversityWuhanChina
| | - Chunxia Shi
- Department of Infectious DiseasesRenmin Hospital of Wuhan UniversityWuhanChina
| | - Maohua Pei
- Department of Infectious DiseasesRenmin Hospital of Wuhan UniversityWuhanChina
| | - Jian Lv
- Department of PharmacyRenmin Hospital of Wuhan UniversityWuhanChina
| | - Hong Zhang
- Department of PharmacyRenmin Hospital of Wuhan UniversityWuhanChina
| | - Luwen Wang
- Department of Infectious DiseasesRenmin Hospital of Wuhan UniversityWuhanChina
| | - Zuojiong Gong
- Department of Infectious DiseasesRenmin Hospital of Wuhan UniversityWuhanChina
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27
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Zhao J, O'Neil M, Schonfeld M, Komatz A, Weinman SA, Tikhanovich I. Hepatocellular Protein Arginine Methyltransferase 1 Suppresses Alcohol-Induced Hepatocellular Carcinoma Formation by Inhibition of Inducible Nitric Oxide Synthase. Hepatol Commun 2020; 4:790-808. [PMID: 32490317 PMCID: PMC7262284 DOI: 10.1002/hep4.1488] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Accepted: 01/29/2020] [Indexed: 12/17/2022] Open
Abstract
Alcohol is a well-established risk factor for hepatocellular carcinoma (HCC), but the mechanisms by which alcohol promotes liver cancer are not well understood. Studies suggest that ethanol may enhance tumor progression by increasing hepatocyte proliferation and through alcohol-induced liver inflammation. Protein arginine methyltransferase 1 (PRMT1) is the main enzyme responsible for cellular arginine methylation. Asymmetric dimethyl arginine, produced by PRMT1, is a potent inhibitor of nitric oxide synthases. PRMT1 is implicated in the development of several types of tumors and cardiovascular disease. Our previous work has shown that PRMT1 in the liver regulates hepatocyte proliferation and oxidative stress and protects from alcohol-induced liver injury. However, its role in HCC development remains controversial. In this study, we found that hepatocyte-specific PRMT1-knockout mice develop an increased number of tumors in an N-nitrosodiethylamine (DEN) alcohol model of liver tumorigenesis in mice. This effect was specific to the alcohol-related component because wild-type and knockout mice developed similar tumor numbers in the DEN model without the addition of alcohol. We found that in the presence of alcohol, the increase in tumor number was associated with increased proliferation in liver and tumor, increased WNT/β-catenin signaling, and increased inflammation. We hypothesized that increased inflammation was due to increased oxidative and nitrosative stress in knockout mice. By blocking excess nitric oxide production using an inducible nitric oxide synthase inhibitor, we reduced hepatocyte death and inflammation in the liver and prevented the increase in WNT/β-catenin signaling, proliferation, and tumor number in livers of knockout mice. Conclusion: PRMT1 is an important protection factor from alcohol-induced liver injury, inflammation, and HCC development.
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Affiliation(s)
- Jie Zhao
- Department of Internal Medicine University of Kansas Medical Center Kansas City KS
| | - Maura O'Neil
- Department of Pathology University of Kansas Medical Center Kansas City KS
| | - Michael Schonfeld
- Department of Internal Medicine University of Kansas Medical Center Kansas City KS
| | - Amberly Komatz
- Liver Center University of Kansas Medical Center Kansas City KS
| | - Steven A Weinman
- Department of Internal Medicine University of Kansas Medical Center Kansas City KS.,Liver Center University of Kansas Medical Center Kansas City KS
| | - Irina Tikhanovich
- Department of Internal Medicine University of Kansas Medical Center Kansas City KS
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28
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Zayed Mohamed N, Aly HF, moneim El-Mezayen HA, El-Salamony HE. Effect of co-administration of Bee honey and some chemotherapeutic drugs on dissemination of hepatocellular carcinoma in rats. Toxicol Rep 2019; 6:875-888. [PMID: 31516840 PMCID: PMC6727247 DOI: 10.1016/j.toxrep.2019.08.007] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2018] [Revised: 07/18/2019] [Accepted: 08/15/2019] [Indexed: 12/12/2022] Open
Abstract
Alternative and complimentary usage of the natural compound has raised hopes of finding curative options for liver hepatocarcinogenesis. In the present study, the curative effect of bee honey against diethylnitrosamine (DEN) (50 mg/kg) and carbon tetrachloride (CCl4) (2 mg/Kg)-induced hepatocellular carcinoma (HCC) in male rats in the presence or absence of some chemotherapeutic drugs, Cisplatin (Cis), Cyclophosphamide (CY) and 5- Fluorouracil (5-FU) were investigated. The obtained results demonstrated that treatment with DEN/CCl4 caused oxidative stress as assigned by the increase in malondialdehyde (MDA) and fall in glutathione (GSH) content. Meantime detraction in the antioxidants, including superoxide dismutase (SOD), catalase (CAT), glutathione-s-transferase (GST) and glutathione peroxidase (GPx) was observed. Also, the results showed induction of inflammation as reflected by an increase in the levels of both α- fetoprotein and α- fucosidase in the liver. This was accompanied by changes in the hepatic function biomarkers which characterized by the increased levels of transaminases (AST, ALT), alkaline phosphatase (ALP) and γ-Glutamyl transferase (γ-GT) and decrease in total protein content in the serum. In conclusion, the combination of the selected drugs and bee honey may be an effective chemo- preventive and therapeutic strategy for treating DEN and CCl4-induced HCC.
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Affiliation(s)
- Naima Zayed Mohamed
- Therapeutic Chemistry Department, Pharmaceutical and Drug Industries Research Division, National Research Centre (NRC), Giza, Egypt
| | - Hanan Farouk Aly
- Therapeutic Chemistry Department, Pharmaceutical and Drug Industries Research Division, National Research Centre (NRC), Giza, Egypt
| | | | - Hadeer E. El-Salamony
- Therapeutic Chemistry Department, Pharmaceutical and Drug Industries Research Division, National Research Centre (NRC), Giza, Egypt
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29
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Zhao J, O’Neil M, Vittal A, Weinman SA, Tikhanovich I. PRMT1-Dependent Macrophage IL-6 Production Is Required for Alcohol-Induced HCC Progression. Gene Expr 2019; 19:137-150. [PMID: 30236171 PMCID: PMC6466176 DOI: 10.3727/105221618x15372014086197] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Alcohol is a well-established risk factor for hepatocellular carcinoma, but the mechanisms are not well understood. Several studies suggested that alcohol promotes tumor growth by altering immune cell phenotypes in the liver. Arginine methylation is a common posttranslational modification generated mostly by a single protein, PRMT1. In myeloid cells PRMT1 is a key regulator of immune response. Myeloid-specific PRMT1 knockout mice are hyperresponsive to LPS and deficient in PPARγ-dependent macrophage M2 polarization. We aimed to define the role of myeloid PRMT1 in alcohol-associated liver tumor progression using a mouse model of DEN injection followed by Lieber-DeCarli alcohol liquid diet feeding. We found that PRMT1 knockout mice showed significantly lower expression of IL-10 and IL-6 cytokines in the liver and downstream STAT3 activation, which correlated with reduced number of surface tumors, reduced proliferation, and reduced number of M2 macrophages in the liver as well as within proliferating nodules. We found that blocking IL-6 signaling in alcohol-fed mice reduced the number of tumors and liver proliferation in wild-type mice but not in knockout mice suggesting that reduced IL-6 in PRMT1 knockout mice contributes to the protection from alcohol. Additionally, PRMT1 knockout did not show any protection in tumor formation in the absence of alcohol. Finally, we confirmed that this mechanism is relevant in humans. We found that PRMT1 expression in tumor-associated macrophages correlated with STAT3 activation in human HCC specimens. Taken together, these data suggest that the PRMT1-IL-6-STAT3 axis is an important mechanism of alcohol-associated tumor progression.
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Affiliation(s)
- Jie Zhao
- *Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA
| | - Maura O’Neil
- †Department of Pathology, University of Kansas Medical Center, Kansas City, KS, USA
| | - Anusha Vittal
- ‡Liver Center, University of Kansas Medical Center, Kansas City, KS, USA
| | - Steven A. Weinman
- *Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA
- ‡Liver Center, University of Kansas Medical Center, Kansas City, KS, USA
| | - Irina Tikhanovich
- *Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA
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Matsushita H, Takaki A. Alcohol and hepatocellular carcinoma. BMJ Open Gastroenterol 2019; 6:e000260. [PMID: 31139422 PMCID: PMC6505979 DOI: 10.1136/bmjgast-2018-000260] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Revised: 01/04/2019] [Accepted: 01/12/2019] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Alcohol is classified as a Group 1 carcinogen by the International Agency for Research on Cancer because it induces hepatocellular carcinoma (among other cancers) in humans. An excessive alcohol intake may result in fatty liver, acute/chronic hepatitis, and cirrhosis and eventually lead to hepatocellular carcinoma. It has been reported that alcohol abuse increases the relative risk of hepatocellular carcinoma by 3- to 10-fold. AIM AND METHODS To clarify the known mechanisms of alcohol-related carcinogenesis, we searched Pubmed using the terms alcohol and immune mechanism, alcohol and cancer, and immune mechanism and cancer and summarized the articles as a qualitative review. RESULTS From a clinical perspective, it is well known that alcohol interacts with other factors, such as smoking, viral hepatitis, and diabetes, leading to an increased risk of hepatocellular carcinoma. There are several possible mechanisms through which alcohol may induce liver carcinogenicity, including the mutagenic effects of acetaldehyde and the production of ROS due to the excessive hepatic deposition of iron. Furthermore, it has been reported that alcohol accelerates hepatitis C virus-induced liver tumorigenesis through TLR4 signaling. Despite intense investigations to elucidate the mechanisms, they remain poorly understood. CONCLUSION This review summarizes the recent findings of clinical and pathological studies that have investigated the carcinogenic effects of alcohol in the liver.
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Affiliation(s)
- Hiroshi Matsushita
- Department of Gastroenterology and Hepatology, Okayama University, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Akinobu Takaki
- Department of Gastroenterology and Hepatology, Okayama University, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
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31
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Lamas-Paz A, Hao F, Nelson LJ, Vázquez MT, Canals S, Gómez del Moral M, Martínez-Naves E, Nevzorova YA, Cubero FJ. Alcoholic liver disease: Utility of animal models. World J Gastroenterol 2018; 24:5063-5075. [PMID: 30568384 PMCID: PMC6288648 DOI: 10.3748/wjg.v24.i45.5063] [Citation(s) in RCA: 107] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Revised: 11/08/2018] [Accepted: 11/09/2018] [Indexed: 02/06/2023] Open
Abstract
Alcoholic liver disease (ALD) is a major cause of acute and chronic liver injury. Extensive evidence has been accumulated on the pathological process of ALD during the past decades. However, effective treatment options for ALD are very limited due to the lack of suitable in vivo models that recapitulate the full spectrum of ALD. Experimental animal models of ALD, particularly rodents, have been used extensively to mimic human ALD. An ideal animal model should recapitulate all aspects of the ALD process, including significant steatosis, hepatic neutrophil infiltration, and liver injury. A better strategy against ALD depends on clear diagnostic biomarkers, accurate predictor(s) of its progression and new therapeutic approaches to modulate stop or even reverse the disease. Numerous models employing rodent animals have been established in the last decades to investigate the effects of acute and chronic alcohol exposure on the initiation and progression of ALD. Although significant progress has been made in gaining better knowledge on the mechanisms and pathology of ALD, many features of ALD are unknown, and require further investigation, ideally with improved animal models that more effectively mimic human ALD. Although differences in the degree and stages of alcoholic liver injury inevitably exist between animal models and human ALD, the acquisition and translational relevance will be greatly enhanced with the development of new and improved animal models of ALD.
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Affiliation(s)
- Arantza Lamas-Paz
- Department of Immunology, Ophthalmology and ORL, Complutense University School of Medicine, Madrid 28040, Spain
- Yulia A Nevzovova, Francisco Javier Cubero, 12 de Octubre Health Research Institute (imas12), Madrid 28041, Spain
| | - Fengjie Hao
- Department of Immunology, Ophthalmology and ORL, Complutense University School of Medicine, Madrid 28040, Spain
- Yulia A Nevzovova, Francisco Javier Cubero, 12 de Octubre Health Research Institute (imas12), Madrid 28041, Spain
| | - Leonard J Nelson
- Institute for Bioengineering (IBioE), School of Engineering, Faraday Building, The University of Edinburgh, Edinburgh EH9 3 JL, Scotland, United Kingdom
| | - Maria Teresa Vázquez
- Department of Human Anatomy and Embryology, Complutense University School of Medicine, Madrid 28040, Spain
| | - Santiago Canals
- Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas, Universidad Miguel Hernández, San Juan de Alicante 03550, Spain
| | - Manuel Gómez del Moral
- Department of Cell Biology, Complutense University School of Medicine, Madrid 28040, Spain
| | - Eduardo Martínez-Naves
- Department of Immunology, Ophthalmology and ORL, Complutense University School of Medicine, Madrid 28040, Spain
- Yulia A Nevzovova, Francisco Javier Cubero, 12 de Octubre Health Research Institute (imas12), Madrid 28041, Spain
| | - Yulia A Nevzorova
- Department of Genetics, Physiology and Microbiology, Faculty of Biology, Universidad Complutense, Madrid 28040, Spain
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen 52062, Germany
| | - Francisco Javier Cubero
- Department of Immunology, Ophthalmology and ORL, Complutense University School of Medicine, Madrid 28040, Spain
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Brown ZJ, Heinrich B, Greten TF. Mouse models of hepatocellular carcinoma: an overview and highlights for immunotherapy research. Nat Rev Gastroenterol Hepatol 2018; 15:536-554. [PMID: 29904153 DOI: 10.1038/s41575-018-0033-6] [Citation(s) in RCA: 164] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Mouse models are the basis of preclinical and translational research in hepatocellular carcinoma (HCC). Multiple methods exist to induce tumour formation in mice, including genetically engineered mouse models, chemotoxic agents, intrahepatic or intrasplenic injection of tumour cells and xenograft approaches. Additionally, as HCC generally develops in the context of diseased liver, methods exist to induce liver disease in mice to mimic viral hepatitis, fatty liver disease, fibrosis, alcohol-induced liver disease and cholestasis. Similar to HCC in humans, response to therapy in mouse models is monitored with imaging modalities such as CT or MRI, as well as additional techniques involving bioluminescence. As immunotherapy is increasingly applied to HCC, mouse models for these approaches are required for preclinical data. In studying cancer immunotherapy, it is important to consider aspects of antitumour immune responses and to produce a model that mimics the complexity of the immune system. This Review provides an overview of the different mouse models of HCC, presenting techniques to prepare an HCC mouse model and discussing different approaches to help researchers choose an appropriate model for a specific hypothesis. Specific aspects of immunotherapy research in HCC and the applied mouse models in this field are also highlighted.
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Affiliation(s)
- Zachary J Brown
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Bernd Heinrich
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Tim F Greten
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
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33
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Guo F, Zheng K, Benedé-Ubieto R, Cubero FJ, Nevzorova YA. The Lieber-DeCarli Diet-A Flagship Model for Experimental Alcoholic Liver Disease. Alcohol Clin Exp Res 2018; 42:1828-1840. [DOI: 10.1111/acer.13840] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Accepted: 07/09/2018] [Indexed: 02/06/2023]
Affiliation(s)
- Feifei Guo
- Department of Genetics, Physiology and Microbiology; Faculty of Biology; Complutense University of Madrid; Madrid Spain
| | - Kang Zheng
- Department of Immunology, Ophthalmology & ORL; School of Medicine; Complutense University of Madrid; Madrid Spain
- 12 de Octubre Health Research Institute (imas12); Madrid Spain
| | - Raquel Benedé-Ubieto
- Department of Genetics, Physiology and Microbiology; Faculty of Biology; Complutense University of Madrid; Madrid Spain
| | - Francisco Javier Cubero
- Department of Immunology, Ophthalmology & ORL; School of Medicine; Complutense University of Madrid; Madrid Spain
- 12 de Octubre Health Research Institute (imas12); Madrid Spain
| | - Yulia A. Nevzorova
- Department of Genetics, Physiology and Microbiology; Faculty of Biology; Complutense University of Madrid; Madrid Spain
- Department of Internal Medicine III; University Hospital RWTH Aachen; Aachen Germany
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Kimura T, Tanaka N, Fujimori N, Sugiura A, Yamazaki T, Joshita S, Komatsu M, Umemura T, Matsumoto A, Tanaka E. Mild drinking habit is a risk factor for hepatocarcinogenesis in non-alcoholic fatty liver disease with advanced fibrosis. World J Gastroenterol 2018; 24:1440-1450. [PMID: 29632425 PMCID: PMC5889824 DOI: 10.3748/wjg.v24.i13.1440] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Revised: 03/03/2018] [Accepted: 03/10/2018] [Indexed: 02/06/2023] Open
Abstract
AIM The impact of mild drinking habit (less than 20 g/d of ethanol) on the clinical course of non-alcoholic fatty liver disease (NAFLD) has not been determined. We examined the influence of a mild drinking habit on liver carcinogenesis from NAFLD.
METHODS A total of 301 patients who had been diagnosed as having NAFLD by liver biopsy between 2003 and 2016 [median age: 56 years, 45% male, 56% with non-alcoholic steatohepatitis, 26% with advanced fibrosis (F3-4)] were divided into the mild drinking group with ethanol consumption of less than 20 g/d (mild drinking group, n = 93) and the non-drinking group (n = 208). Clinicopathological features at the time of liver biopsy and factors related to hepatocellular carcinoma (HCC) occurrence were compared between the groups.
RESULTS We observed significant differences in male prevalence (P = 0.01), platelet count (P = 0.04), and gamma-glutamyl transpeptidase (P = 0.02) between the test groups. Over 6 years of observation, the HCC appearance rate was significantly higher in the mild drinking group (6.5% vs 1.4%, P = 0.02). Multivariate survival analysis using Cox’s regression model revealed that hepatic advanced fibrosis (F3-4) (P < 0.01, risk ratio: 11.60), diabetes mellitus (P < 0.01, risk ratio: 89.50), and serum triglyceride (P = 0.04, risk ratio: 0.98) were factors significantly related to HCC in all NAFLD patients, while the effect of a drinking habit was marginal (P = 0.07, risk ratio: 4.43). In patients with advanced fibrosis (F3-4), however, a drinking habit (P = 0.04, risk ratio: 4.83), alpha-fetoprotein (P = 0.01, risk ratio: 1.23), and diabetes mellitus (P = 0.03, risk ratio: 12.00) were identified as significant contributors to HCC occurrence.
CONCLUSION A mild drinking habit appears to be a risk factor for hepatocarcinogenesis in NAFLD patients, especially those with advanced fibrosis.
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Affiliation(s)
- Takefumi Kimura
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Naoki Tanaka
- Department of Metabolic Regulation, Shinshu University Graduate School of Medicine, Matsumoto 390-8621, Japan
- Research Center for Agricultural Food Industry, Shinshu University, Matsumoto 390-8621, Japan
| | - Naoyuki Fujimori
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Ayumi Sugiura
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Tomoo Yamazaki
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Satoru Joshita
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Michiharu Komatsu
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Takeji Umemura
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Akihiro Matsumoto
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Eiji Tanaka
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
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Zhao J, Adams A, Roberts B, O'Neil M, Vittal A, Schmitt T, Kumer S, Cox J, Li Z, Weinman SA, Tikhanovich I. Protein arginine methyl transferase 1- and Jumonji C domain-containing protein 6-dependent arginine methylation regulate hepatocyte nuclear factor 4 alpha expression and hepatocyte proliferation in mice. Hepatology 2018; 67:1109-1126. [PMID: 29023917 PMCID: PMC5826837 DOI: 10.1002/hep.29587] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Revised: 09/13/2017] [Accepted: 10/02/2017] [Indexed: 12/27/2022]
Abstract
UNLABELLED Alcohol is a well-established risk factor for hepatocellular carcinoma (HCC), but the mechanisms by which it promotes liver cancer are not well understood. Several studies have shown that cellular protein arginine methylation is inhibited by alcohol. Arginine methylation is controlled by the reciprocal activity of protein arginine methyltransferases, primarily protein arginine methyl transferase 1 (PRMT1), and a demethylase Jumonji C domain-containing protein 6 (JMJD6). The aim of this study was to explore the role of arginine methylation changes in alcohol pathogenesis. We found that PRMT1 activity is inhibited in livers of mice fed with alcohol compared to pair-fed mice. Using hepatocyte-specific PRMT1 knockout mice, we identified that loss of PRMT1 results in enhanced hepatocyte proliferation and a 33% increase in liver size. This increased hepatocyte proliferation was associated with reduced expression of hepatocyte nuclear factor 4 alpha (Hnf4α), an important regulator of liver tumorigenesis. We found that PRMT1 regulates Hnf4α expression directly through arginine methylation at the (Hnf4α) promoter. In the absence of PRMT1, JMJD6 can demethylate the Hnf4α promoter and suppress its expression. We were able to restore Hnf4α expression and abolish the increase in hepatocyte proliferation by knockdown of JMJD6 in PRMT1 knockout mice. Knockdown of JMJD6 in alcohol-fed mice similarly increased Hnf4α expression. We then examined whether loss of arginine methylation might play a role in alcohol-associated liver cancers. We examined 25 human HCC specimens and found a strong correlation (R = 0.8; P < 0.01) between arginine methylation levels and Hnf4α expression in these specimens, suggesting that the above mechanism is relevant in patients. CONCLUSION Taken together, these data suggest that PRMT1 inhibition, such as induced by alcohol, may result in epigenetic changes leading to loss of Hnf4α. This effect may contribute to alcohol's ability to promote liver tumors. (Hepatology 2018;67:1109-1126).
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Affiliation(s)
- Jie Zhao
- Department of Internal Medicine, Kansas City, KS 66160, U.S.A
| | - Abby Adams
- Department of Internal Medicine, Kansas City, KS 66160, U.S.A,Liver Center, University of Kansas Medical Center, Kansas City, KS 66160, U.S.A
| | - Ben Roberts
- Liver Center, University of Kansas Medical Center, Kansas City, KS 66160, U.S.A
| | - Maura O'Neil
- Department of Pathology, Kansas City, KS 66160, U.S.A
| | - Anusha Vittal
- Department of Internal Medicine, Kansas City, KS 66160, U.S.A
| | | | - Sean Kumer
- Department of Surgery, Kansas City, KS 66160, U.S.A
| | - Josiah Cox
- Department of Internal Medicine, Kansas City, KS 66160, U.S.A
| | - Zhuan Li
- Department of Internal Medicine, Kansas City, KS 66160, U.S.A
| | - Steven A. Weinman
- Department of Internal Medicine, Kansas City, KS 66160, U.S.A,Liver Center, University of Kansas Medical Center, Kansas City, KS 66160, U.S.A
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Alcoholic Liver Disease Accelerates Early Hepatocellular Cancer in a Mouse Model. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1032:71-79. [PMID: 30362091 DOI: 10.1007/978-3-319-98788-0_5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
HCC is a rapidly increasing cancer worldwide. Most HCC rises in the setting of chronic and advanced liver disease caused by viral hepatitis, alcohol use, non-alcoholic liver disease or their combination. We found that in the mouse model, alcohol alone does not induce HCC, however, it can promote HCC development after a carcinogen exposure. Multiple mechanisms are involved in carcinogenesis and alcohol affects many of those including epithelial-mesenchymal transition, cancer stem marker expression and inflammation as evidenced in our HCC model.
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37
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Ratna A, Mandrekar P. Alcohol and Cancer: Mechanisms and Therapies. Biomolecules 2017; 7:E61. [PMID: 28805741 PMCID: PMC5618242 DOI: 10.3390/biom7030061] [Citation(s) in RCA: 80] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Revised: 08/07/2017] [Accepted: 08/08/2017] [Indexed: 12/14/2022] Open
Abstract
Several scientific and clinical studies have shown an association between chronic alcohol consumption and the occurrence of cancer in humans. The mechanism for alcohol-induced carcinogenesis has not been fully understood, although plausible events include genotoxic effects of acetaldehyde, cytochrome P450 2E1 (CYP2E1)-mediated generation of reactive oxygen species, aberrant metabolism of folate and retinoids, increased estrogen, and genetic polymorphisms. Here, we summarize the impact of alcohol drinking on the risk of cancer development and potential underlying molecular mechanisms. The interactions between alcohol abuse, anti-tumor immune response, tumor growth, and metastasis are complex. However, multiple studies have linked the immunosuppressive effects of alcohol with tumor progression and metastasis. The influence of alcohol on the host immune system and the development of possible effective immunotherapy for cancer in alcoholics are also discussed here. The conclusive biological effects of alcohol on tumor progression and malignancy have not been investigated extensively using an animal model that mimics the human disease. This review provides insights into cancer pathogenesis in alcoholics, alcohol and immune interactions in different cancers, and scope and future of targeted immunotherapeutic modalities in patients with alcohol abuse.
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Affiliation(s)
- Anuradha Ratna
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
| | - Pranoti Mandrekar
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
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Yan G, Wang X, Sun C, Zheng X, Wei H, Tian Z, Sun R. Chronic Alcohol Consumption Promotes Diethylnitrosamine-Induced Hepatocarcinogenesis via Immune Disturbances. Sci Rep 2017; 7:2567. [PMID: 28566719 PMCID: PMC5451469 DOI: 10.1038/s41598-017-02887-7] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2017] [Accepted: 04/19/2017] [Indexed: 12/13/2022] Open
Abstract
Chronic alcohol consumption increases the risk of hepatocellular carcinoma (HCC). However, little is known about the potential immunological mechanisms by which ethanol affects tumor progression. Here, adult male mice were administered multiple doses of diethylnitrosamine (DEN). Four and a half months later, the DEN-treated mice were placed on a liquid Lieber-DeCarli control diet or diet containing 5% ethanol for 2.5 months. At the end of the study, liver tissue samples were obtained to analyze pathology, gene expression, and hepatic mononuclear cells (MNCs). Results showed that ethanol feeding exacerbates the progression of hepatic tumors (characterized by the ratio of liver weight to body weight, and the tumor volume and diameter) in DEN-treated mice. Mechanistically, chronic alcohol consumption decreased the number of antitumor CD8+ T cells but increased the number of tumor-associated macrophages (TAMs) in the liver in DEN-initiated tumorigenesis. Besides, TAMs were prone to be M2 phenotype after alcohol consumption. Moreover, chronic alcohol consumption aggravated inflammation, fibrosis, and epithelial-mesenchymal transition (EMT) in the pathological process of HCC. These data demonstrate that chronic alcohol consumption exacerbates DEN-induced hepatocarcinogenesis by enhancing protumor immunity, impairing antitumor immunity and aggravating hepatic pathological injury. Targeting the immune system is a potential therapeutic regimen for alcohol-promoted HCC.
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Affiliation(s)
- Guoxiu Yan
- Institute of Immunology and CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui, 230027, China
| | - Xuefu Wang
- Institute of Immunology and CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui, 230027, China.
| | - Cheng Sun
- Institute of Immunology and CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui, 230027, China
| | - Xiaodong Zheng
- Institute of Immunology and CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui, 230027, China
| | - Haiming Wei
- Institute of Immunology and CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui, 230027, China.,Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui, 230027, China
| | - Zhigang Tian
- Institute of Immunology and CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui, 230027, China.,Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui, 230027, China
| | - Rui Sun
- Institute of Immunology and CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui, 230027, China. .,Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui, 230027, China.
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Magdaleno F, Blajszczak CC, Nieto N. Key Events Participating in the Pathogenesis of Alcoholic Liver Disease. Biomolecules 2017; 7:biom7010009. [PMID: 28134813 PMCID: PMC5372721 DOI: 10.3390/biom7010009] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Accepted: 01/20/2017] [Indexed: 12/12/2022] Open
Abstract
Alcoholic liver disease (ALD) is a leading cause of morbidity and mortality worldwide. It ranges from fatty liver to steatohepatitis, fibrosis, cirrhosis and hepatocellular carcinoma. The most prevalent forms of ALD are alcoholic fatty liver, alcoholic hepatitis (AH) and alcoholic cirrhosis, which frequently progress as people continue drinking. ALD refers to a number of symptoms/deficits that contribute to liver injury. These include steatosis, inflammation, fibrosis and cirrhosis, which, when taken together, sequentially or simultaneously lead to significant disease progression. The pathogenesis of ALD, influenced by host and environmental factors, is currently only partially understood. To date, lipopolysaccharide (LPS) translocation from the gut to the portal blood, aging, gender, increased infiltration and activation of neutrophils and bone marrow-derived macrophages along with alcohol plus iron metabolism, with its associated increase in reactive oxygen species (ROS), are all key events contributing to the pathogenesis of ALD. This review aims to introduce the reader to the concept of alcohol-mediated liver damage and the mechanisms driving injury.
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Affiliation(s)
- Fernando Magdaleno
- Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA.
| | - Chuck C Blajszczak
- Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA.
| | - Natalia Nieto
- Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA.
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