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Li W, Gao W, Yan S, Yang L, Zhu Q, Chu H. Gut Microbiota as Emerging Players in the Development of Alcohol-Related Liver Disease. Biomedicines 2024; 13:74. [PMID: 39857657 PMCID: PMC11761646 DOI: 10.3390/biomedicines13010074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2024] [Revised: 12/23/2024] [Accepted: 12/29/2024] [Indexed: 01/27/2025] Open
Abstract
The global incidence and mortality rates of alcohol-related liver disease are on the rise, reflecting a growing health concern worldwide. Alcohol-related liver disease develops due to a complex interplay of multiple reasons, including oxidative stress generated during the metabolism of ethanol, immune response activated by immunogenic substances, and subsequent inflammatory processes. Recent research highlights the gut microbiota's significant role in the progression of alcohol-related liver disease. In patients with alcohol-related liver disease, the relative abundance of pathogenic bacteria, including Enterococcus faecalis, increases and is positively correlated with the level of severity exhibited by alcohol-related liver disease. Supplement probiotics like Lactobacillus, as well as Bifidobacterium, have been found to alleviate alcohol-related liver disease. The gut microbiota is speculated to trigger specific signaling pathways, influence metabolite profiles, and modulate immune responses in the gut and liver. This research aimed to investigate the role of gut microorganisms in the onset and advancement of alcohol-related liver disease, as well as to uncover the underlying mechanisms by which the gut microbiota may contribute to its development. This review outlines current treatments for reversing gut dysbiosis, including probiotics, fecal microbiota transplantation, and targeted phage therapy. Particularly, targeted therapy will be a vital aspect of future alcohol-related liver disease treatment. It is to be hoped that this article will prove beneficial for the treatment of alcohol-related liver disease.
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Affiliation(s)
- Wei Li
- Wuhan Jinyintan Hospital, Tongji Medical College of Huazhong University of Science and Technology, Hubei Clinical Research Center for Infectious Diseases, Wuhan Research Center for Communicable Disease Diagnosis and Treatment, Chinese Academy of Medical Sciences, Joint Laboratory of Infectious Diseases and Health, Wuhan Institute of Virology and Wuhan Jinyintan Hospital, Chinese Academy of Sciences, Wuhan 430023, China;
| | - Wenkang Gao
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; (W.G.); (S.Y.); (L.Y.)
| | - Shengqi Yan
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; (W.G.); (S.Y.); (L.Y.)
| | - Ling Yang
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; (W.G.); (S.Y.); (L.Y.)
| | - Qingjing Zhu
- Wuhan Jinyintan Hospital, Tongji Medical College of Huazhong University of Science and Technology, Hubei Clinical Research Center for Infectious Diseases, Wuhan Research Center for Communicable Disease Diagnosis and Treatment, Chinese Academy of Medical Sciences, Joint Laboratory of Infectious Diseases and Health, Wuhan Institute of Virology and Wuhan Jinyintan Hospital, Chinese Academy of Sciences, Wuhan 430023, China;
| | - Huikuan Chu
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; (W.G.); (S.Y.); (L.Y.)
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Sánchez V, Baumann A, Kromm F, Yergaliyev T, Brandt A, Scholda J, Kopp F, Camarinha-Silva A, Bergheim I. Oral supplementation of choline attenuates the development of alcohol-related liver disease (ALD). Mol Med 2024; 30:181. [PMID: 39425011 PMCID: PMC11488139 DOI: 10.1186/s10020-024-00950-4] [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: 03/28/2024] [Accepted: 10/04/2024] [Indexed: 10/21/2024] Open
Abstract
BACKGROUND Chronic alcohol intake is associated with alterations of choline metabolism in various tissues. Here, we assessed if an oral choline supplementation attenuated the development of alcohol-related liver disease (ALD) in mice. METHODS Female C57BL/6 J mice (n = 8/group) were either pair-fed a liquid control diet, or a Lieber DeCarli liquid diet (5% ethanol) ± 2.7 g choline/kg diet for 29 days. Liver damage, markers of intestinal permeability and intestinal microbiota composition were determined. Moreover, the effects of choline on ethanol-induced intestinal permeability were assessed in an ex vivo model. RESULTS ALD development as determined by liver histology and assessing markers of inflammation (e.g., nitric oxide, interleukin 6 and 4-hydroxynonenal protein adducts) was attenuated by the supplementation of choline. Intestinal permeability in small intestine being significantly higher in ethanol-fed mice was at the level of controls in ethanol-fed mice receiving choline. In contrast, no effects of the choline supplementation were found on intestinal microbiota composition. Choline also significantly attenuated the ethanol-induced intestinal barrier dysfunction in small intestinal tissue ex vivo, an effect almost entirely abolished by the choline oxidase inhibitor dimbunol. CONCLUSION Our results suggest that an oral choline supplementation attenuates the development of ALD in mice and is related to a protection from intestinal barrier dysfunction.
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Affiliation(s)
- Victor Sánchez
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Josef-Holaubek-Platz 2 (UZA II), A-1090, Vienna, Austria
| | - Anja Baumann
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Josef-Holaubek-Platz 2 (UZA II), A-1090, Vienna, Austria
| | - Franziska Kromm
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Josef-Holaubek-Platz 2 (UZA II), A-1090, Vienna, Austria
| | - Timur Yergaliyev
- Livestock Microbial Ecology Department, Institute of Animal Science, University of Hohenheim, Stuttgart, Germany
| | - Annette Brandt
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Josef-Holaubek-Platz 2 (UZA II), A-1090, Vienna, Austria
| | - Julia Scholda
- Department of Pharmaceutical Sciences, Clinical Pharmacy Group, University of Vienna, Vienna, Austria
| | - Florian Kopp
- Department of Pharmaceutical Sciences, Clinical Pharmacy Group, University of Vienna, Vienna, Austria
| | - Amélia Camarinha-Silva
- Livestock Microbial Ecology Department, Institute of Animal Science, University of Hohenheim, Stuttgart, Germany
| | - Ina Bergheim
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Josef-Holaubek-Platz 2 (UZA II), A-1090, Vienna, Austria.
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Meijnikman AS, Nieuwdorp M, Schnabl B. Endogenous ethanol production in health and disease. Nat Rev Gastroenterol Hepatol 2024; 21:556-571. [PMID: 38831008 DOI: 10.1038/s41575-024-00937-w] [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] [Accepted: 04/23/2024] [Indexed: 06/05/2024]
Abstract
The gut microbiome exerts metabolic actions on distal tissues and organs outside the intestine, partly through microbial metabolites that diffuse into the circulation. The disruption of gut homeostasis results in changes to microbial metabolites, and more than half of the variance in the plasma metabolome can be explained by the gut microbiome. Ethanol is a major microbial metabolite that is produced in the intestine of nearly all individuals; however, elevated ethanol production is associated with pathological conditions such as metabolic dysfunction-associated steatotic liver disease and auto-brewery syndrome, in which the liver's capacity to metabolize ethanol is surpassed. In this Review, we describe the mechanisms underlying excessive ethanol production in the gut and the role of ethanol catabolism in mediating pathogenic effects of ethanol on the liver and host metabolism. We conclude by discussing approaches to target excessive ethanol production by gut bacteria.
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Affiliation(s)
| | - Max Nieuwdorp
- Department of Internal Medicine, Amsterdam University Medical Centers, Location AMC, Amsterdam, Netherlands
- Department of Experimental Vascular Medicine, Amsterdam University Medical Centers, Location AMC, Amsterdam, Netherlands
- Diabeter Centrum Amsterdam, Amsterdam, Netherlands
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, CA, USA.
- Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA.
- Center for Innovative Phage Applications and Therapeutics, University of California San Diego, La Jolla, CA, USA.
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Mukhopadhyay B, Marietta C, Shen PH, Oiseni A, Mirshahi F, Mazzu M, Hodgkinson C, Winkler E, Yuan Q, Miranda D, Kunos G, Sanyal AJ, Goldman D. A patient-based iPSC-derived hepatocyte model of alcohol-associated cirrhosis reveals bioenergetic insights into disease pathogenesis. Nat Commun 2024; 15:2869. [PMID: 38693144 PMCID: PMC11063145 DOI: 10.1038/s41467-024-47085-y] [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: 05/28/2023] [Accepted: 03/15/2024] [Indexed: 05/03/2024] Open
Abstract
Only ~20% of heavy drinkers develop alcohol cirrhosis (AC). While differences in metabolism, inflammation, signaling, microbiome signatures and genetic variations have been tied to the pathogenesis of AC, the key underlying mechanisms for this interindividual variability, remain to be fully elucidated. Induced pluripotent stem cell-derived hepatocytes (iHLCs) from patients with AC and healthy controls differ transcriptomically, bioenergetically and histologically. They include a greater number of lipid droplets (LDs) and LD-associated mitochondria compared to control cells. These pre-pathologic indicators are effectively reversed by Aramchol, an inhibitor of stearoyl-CoA desaturase. Bioenergetically, AC iHLCs have lower spare capacity, slower ATP production and their mitochondrial fuel flexibility towards fatty acids and glutamate is weakened. MARC1 and PNPLA3, genes implicated by GWAS in alcohol cirrhosis, show to correlate with lipid droplet-associated and mitochondria-mediated oxidative damage in AC iHLCs. Knockdown of PNPLA3 expression exacerbates mitochondrial deficits and leads to lipid droplets alterations. These findings suggest that differences in mitochondrial bioenergetics and lipid droplet formation are intrinsic to AC hepatocytes and can play a role in its pathogenesis.
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Affiliation(s)
- Bani Mukhopadhyay
- Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, 20892, USA
| | - Cheryl Marietta
- Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, 20892, USA
| | - Pei-Hong Shen
- Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, 20892, USA
| | - Abdul Oiseni
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298, USA
| | - Faridoddin Mirshahi
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298, USA
| | - Maria Mazzu
- Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, 20892, USA
| | - Colin Hodgkinson
- Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, 20892, USA
| | - Eli Winkler
- Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, 20892, USA
| | - Qiaoping Yuan
- Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, 20892, USA
| | - Daniel Miranda
- Aivia Machine Learning Team, Leica Microsystems, Inc, Deerfield, IL, USA
| | - George Kunos
- Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, 20892, USA
| | - Arun J Sanyal
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298, USA
| | - David Goldman
- Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, 20892, USA.
- Office of the Clinical Director, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, 20892, USA.
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Luo L, Ni J, Zhang J, Lin J, Chen S, Shen F, Huang Z. Toosendanin induces hepatotoxicity by restraining autophagy and lysosomal function through inhibiting STAT3/CTSC axis. Toxicol Lett 2024; 394:102-113. [PMID: 38460807 DOI: 10.1016/j.toxlet.2024.03.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 02/29/2024] [Accepted: 03/05/2024] [Indexed: 03/11/2024]
Abstract
Toosendanin (TSN) is the main active component in the traditional herb Melia toosendan Siebold & Zucc, which exhibits promising potential for development due to its diverse pharmacological properties. However, the hepatotoxicity associated with TSN needs further investigation. Previous research has implicated autophagy dysregulation in TSN-induced hepatotoxicity, yet the underlying mechanisms remain elusive. In this study, the mechanisms of signal transducer and activator of transcription 3 (STAT3) in TSN-induced autophagy inhibition and liver injury were explored using Stat3 knockout C57BL/6 mice and HepG2 cells. TSN decreased cell viability, increased lactate dehydrogenase (LDH) production in vitro, and elevated serum aspartate transaminase (AST) and alanine aminotransferase (ALT) levels as well as liver lesions in vivo, suggesting TSN had significant hepatotoxicity. TSN inhibited Janus kinase 2 (JAK2)/STAT3 pathway and the expression of cathepsin C (CTSC). Inhibition of STAT3 exacerbated TSN-induced autophagy inhibition and hepatic injury, whereas activation of STAT3 attenuated these effects of TSN. Mechanistically, STAT3 transcriptionally regulated the level of CTSC gene, which in turn affected autophagy and the process of liver injury. TSN-administered Stat3 knockout mice showed more severe hepatotoxicity, CTSC downregulation, and autophagy blockade than wildtype mice. In summary, TSN caused hepatotoxicity by inhibiting STAT3/CTSC axis-dependent autophagy and lysosomal function.
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Affiliation(s)
- Li Luo
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Jiajie Ni
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Jiahui Zhang
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Jinxian Lin
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Sixin Chen
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Feihai Shen
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China; School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China.
| | - Zhiying Huang
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
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Dos Santos AC, França TCS, Venzon L, Polli V, Polleti G, Trembulak E, Pilati SFM, da Silva LM. Are silymarin and N-acetylcysteine able to prevent liver damage mediated by multiple factors? Findings against ethanol plus LPS-induced liver injury in mice. J Biochem Mol Toxicol 2024; 38:e23560. [PMID: 37860953 DOI: 10.1002/jbt.23560] [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: 04/20/2023] [Revised: 09/11/2023] [Accepted: 10/05/2023] [Indexed: 10/21/2023]
Abstract
This study investigated the effect of N-acetylcysteine (NAC) and silymarin (SIL) in the liver of mice exposed to ethanol and lipopolysaccharides (LPS). Mice were divided into four groups (n = 6): naive, vehicle, NAC (200 mg/kg), and SIL (200 mg/kg). Treatments were given orally (po) once daily for 10 days. Liver injury was induced by administration of ethanol (30%, po) for 10 days, once daily, followed by a single administration of LPS (2 mg/kg, ip) 24 h before euthanasia. After the treatment period, animals were euthanized, and liver and blood samples were collected. NAC, but not SIL, prevented the increase in oxalacetic glutamic transaminase (OGT) and pyruvic glutamic transaminase (PGT) serum levels. NAC and SIL did not restore levels of reduced glutathione or hepatic malonaldehyde. The treatments with NAC or SIL showed no difference in the activity of glutathione S-transferase, superoxide dismutase, and catalase compared to vehicle group. Myeloperoxidase and N-acetylglucosaminidase activities are increased, as well as the IL-6 and IL-10 levels in the liver. The treatment with NAC, but not SIL, reduced the N-acetylglucosamines activity and the IL-6 and IL-10 amount in the liver. Histological findings revealed microsteatosis in the vehicle group, which was not prevented by SIL but was partially reduced in animals receiving NAC. Unlike other liver injury models, NAC (200 mg/kg) or SIL (200 mg/kg) did not positively affect antioxidant patterns in liver tissue of animals exposed to ethanol plus LPS, but NAC treatment displays anti-inflammatory properties in this model.
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Affiliation(s)
- Ana Caroline Dos Santos
- Postgraduate Program in Pharmaceutical Sciences, Universidade do Vale do Itajaí, Itajaí, Santa Catarina, Brazil
| | | | - Larissa Venzon
- Postgraduate Program in Pharmaceutical Sciences, Universidade do Vale do Itajaí, Itajaí, Santa Catarina, Brazil
| | - Vitor Polli
- Postgraduate Program in Pharmaceutical Sciences, Universidade do Vale do Itajaí, Itajaí, Santa Catarina, Brazil
| | - Gustavo Polleti
- Postgraduate Program in Pharmaceutical Sciences, Universidade do Vale do Itajaí, Itajaí, Santa Catarina, Brazil
| | - Erica Trembulak
- Postgraduate Program in Pharmaceutical Sciences, Universidade do Vale do Itajaí, Itajaí, Santa Catarina, Brazil
| | | | - Luísa Mota da Silva
- Postgraduate Program in Pharmaceutical Sciences, Universidade do Vale do Itajaí, Itajaí, Santa Catarina, Brazil
- LaFaTI-Laboratório de Farmacologia do Trato Gastrointestinal e suas Interações, Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil
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7
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Tian WS, Zhao J, Kim MK, Tae HJ, Kim IS, Ahn D, Hwang HP, Mao MX, Park BY. Veronica persica ameliorates acetaminophen-induced murine hepatotoxicity via attenuating oxidative stress and inflammation. Biomed Pharmacother 2023; 169:115898. [PMID: 37989029 DOI: 10.1016/j.biopha.2023.115898] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 11/13/2023] [Accepted: 11/14/2023] [Indexed: 11/23/2023] Open
Abstract
Excess acetaminophen (APAP) commonly causes severe acute liver injury (ALI), characterized by oxidative stress, pro-inflammatory responses, and hepatocyte damage. Veronica persica (VP) is a traditional medicine with antioxidant and anti-inflammatory properties. There is a paucity of information on its medicinal value, especially its potential mechanisms for alleviating ALI. This study aimed to clarify the ameliorative effects and intracellular mechanisms of VP on APAP-induced ALI via attenuating oxidative stress and inflammation. Mice were given VP for 7 days before exposure to APAP (300 mg/kg). The HPLC and radical scavenging assay found that VP contains 12 phenolic acids and 6 flavonoids, as well as show robust antioxidant capacity. In the APAP-induced ALI model, pre-treatment with VP significantly reduces APAP-induced hepatotoxicity by observing improved hepatocyte pathological injury and further confirmed by serum biochemical indicator. Also, the reduction of TUNEL-positive regions and the regulation of Bcl-2-associated X protein indicated that VP attenuates hepatocytotoxicity. Moreover, VP pre-intervention inhibits the formation of liver pro-inflammatory cytokines, the expression of inflammatory response genes, and increases in myeloperoxidase (MPO) in APAP-exposed mice. The elevated reduced glutathione (GSH) levels and decreased oxidative stress markers indicate that VP reduces APAP-promoted oxidative stress. Further study revealed that VP inhibited the phosphorylation of NF-κB/STAT3 cascade, blocked ERK and JNK phosphorylation, and activated AMP-activated protein kinase (AMPK). To sum up, this study demonstrated that VP exists hepatoprotective abilities on APAP-induced ALI, primarily by suppressing the phosphorylation of NF-κB/STAT3 cascade and ERK-JNK and inducing AMPK activation to alleviate oxidative stress and inflammation.
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Affiliation(s)
- Wei-Shun Tian
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, Henan, People's Republic of China; College of Veterinary Medicine and Institute of Animal Transplantation, Jeonbuk National University, Iksan, Jeollabuk-do 54596, Republic of Korea
| | - Jing Zhao
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, Henan, People's Republic of China
| | - Myung-Kon Kim
- Department of Food Science and Technology, Jeonbuk National University, Jeonju 54896, Republic of Korea
| | - Hyun-Jin Tae
- College of Veterinary Medicine and Institute of Animal Transplantation, Jeonbuk National University, Iksan, Jeollabuk-do 54596, Republic of Korea
| | - In-Shik Kim
- College of Veterinary Medicine and Institute of Animal Transplantation, Jeonbuk National University, Iksan, Jeollabuk-do 54596, Republic of Korea
| | - Dongchoon Ahn
- College of Veterinary Medicine and Institute of Animal Transplantation, Jeonbuk National University, Iksan, Jeollabuk-do 54596, Republic of Korea
| | - Hong Pil Hwang
- Department of Surgery of Jeonbuk National University Medical School and Hospital, Jeonju 54896, Republic of Korea
| | - Ming-Xian Mao
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, Henan, People's Republic of China
| | - Byung-Yong Park
- College of Veterinary Medicine and Institute of Animal Transplantation, Jeonbuk National University, Iksan, Jeollabuk-do 54596, Republic of Korea.
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Dou J, Cui H, Cui Z, Xuan M, Gao C, Li Z, Lian L, Nan J, Wu Y. Pterostilbene exerts cytotoxicity on activated hepatic stellate cells by inhibiting excessive proliferation through the crosstalk of Sirt1 and STAT3 pathways. Food Chem Toxicol 2023; 181:114042. [PMID: 37722617 DOI: 10.1016/j.fct.2023.114042] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 09/03/2023] [Accepted: 09/14/2023] [Indexed: 09/20/2023]
Abstract
Pterostilbene (PTE), a natural analogue of resveratrol, abundantly exists in blueberries and grapes and has several beneficial potentials against oxidative stress, inflammation, and cancer. In current study, we investigated the effects of PTE on hepatic fibrosis in vitro and in vivo. Activation of hepatic stellate cells (HSCs) is an initiating event in the initiation of hepatic fibrosis. MTT assay revealed that PTE (3.125-12.5 μM) displayed cytotoxicity on activated HSCs, no cytotoxicity on AML-12 and quiescent HSCs. PTE significantly inhibited the expressions of α-SMA, collagen Ⅰ and TIMP-1/MMP13 ratio; suppressed inflammatory cascade activation to reduce inflammatory cytokines release, such as Caspase-1, IL-1β and IL-6. PTE activated Sirt1 and decreased STAT3 phosphorylation, functioning as SRT1720 and Niclosamide. Sirt1 deficiency significantly elevated p-STAT3 expression, while STAT3 deficiency resulted in Sirt1 increasing and inhibited fibrosis and inflammatory cytokines expressions. In mice with hepatic fibrosis induced by thioacetamide (TAA), PTE significantly decreased ALT and AST activities, reduced fibrosis markers, STAT3 phosphorylation and activated Sirt1 expression. PTE showed cytotoxicity on activated HSCs to ameliorate hepatic fibrosis via regulating fibrogenesis, energy metabolism and inflammation and targeting the crosstalk of Sirt1 and STAT3. In conclusion, PTE could be potentially beneficial as a natural plant metabolite in preventing and treating hepatic fibrosis.
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Affiliation(s)
- Jiayi Dou
- Key Laboratory of Natural Medicines of the Changbai Mountain (Yanbian University), Ministry of Education, Key Laboratory for Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs, College of Pharmacy, Yanbian University, Yanji, Jilin Province, 133002, China
| | - Haozhen Cui
- Department of Chinese Traditional Medicine, Medical College, Yanbian University, Yanji, Jilin Province, 133002, China
| | - Zhenyu Cui
- Key Laboratory of Natural Medicines of the Changbai Mountain (Yanbian University), Ministry of Education, Key Laboratory for Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs, College of Pharmacy, Yanbian University, Yanji, Jilin Province, 133002, China
| | - Meiyan Xuan
- School of Pharmaceutical Sciences, Josai University, Sakado, Saitama, Japan
| | - Chong Gao
- Key Laboratory of Natural Medicines of the Changbai Mountain (Yanbian University), Ministry of Education, Key Laboratory for Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs, College of Pharmacy, Yanbian University, Yanji, Jilin Province, 133002, China
| | - Zhaoxu Li
- Key Laboratory of Natural Medicines of the Changbai Mountain (Yanbian University), Ministry of Education, Key Laboratory for Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs, College of Pharmacy, Yanbian University, Yanji, Jilin Province, 133002, China
| | - Lihua Lian
- Key Laboratory of Natural Medicines of the Changbai Mountain (Yanbian University), Ministry of Education, Key Laboratory for Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs, College of Pharmacy, Yanbian University, Yanji, Jilin Province, 133002, China
| | - Jixing Nan
- Key Laboratory of Natural Medicines of the Changbai Mountain (Yanbian University), Ministry of Education, Key Laboratory for Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs, College of Pharmacy, Yanbian University, Yanji, Jilin Province, 133002, China.
| | - Yanling Wu
- Key Laboratory of Natural Medicines of the Changbai Mountain (Yanbian University), Ministry of Education, Key Laboratory for Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs, College of Pharmacy, Yanbian University, Yanji, Jilin Province, 133002, China.
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Abstract
The steatotic diseases of metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-associated liver disease (ALD), and chronic hepatitis C (HCV) account for the majority of liver disease prevalence, morbidity, and mortality worldwide. While these diseases have distinct pathogenic and clinical features, dysregulated lipid droplet (LD) organelle biology represents a convergence of pathogenesis in all three. With increasing understanding of hepatocyte LD biology, we now understand the roles of LD proteins involved in these diseases but also how genetics modulate LD biology to either exacerbate or protect against the phenotypes associated with steatotic liver diseases. Here, we review the history of the LD organelle and its biogenesis and catabolism. We also review how this organelle is critical not only for the steatotic phenotype of liver diseases but also for their advanced phenotypes. Finally, we summarize the latest attempts and challenges of leveraging LD biology for therapeutic gain in steatotic diseases. In conclusion, the study of dysregulated LD biology may lead to novel therapeutics for the prevention of disease progression in the highly prevalent steatotic liver diseases of MASLD, ALD, and HCV.
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Affiliation(s)
- Joseph L Dempsey
- Division of Gastroenterology, Department of Medicine, School of Medicine, University of Washington, Seattle, Washington
| | - George N Ioannou
- Division of Gastroenterology, Department of Medicine, School of Medicine, University of Washington, Seattle, Washington
- Division of Gastroenterology, Veterans Affairs Puget Sound Healthcare System Seattle, Washington
| | - Rotonya M Carr
- Division of Gastroenterology, Department of Medicine, School of Medicine, University of Washington, Seattle, Washington
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10
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Patil VS, Harish DR, Sampat GH, Roy S, Jalalpure SS, Khanal P, Gujarathi SS, Hegde HV. System Biology Investigation Revealed Lipopolysaccharide and Alcohol-Induced Hepatocellular Carcinoma Resembled Hepatitis B Virus Immunobiology and Pathogenesis. Int J Mol Sci 2023; 24:11146. [PMID: 37446321 DOI: 10.3390/ijms241311146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 06/05/2023] [Accepted: 06/07/2023] [Indexed: 07/15/2023] Open
Abstract
Hepatitis B infection caused by the hepatitis B virus is a life-threatening cause of liver fibrosis, cirrhosis, and hepatocellular carcinoma. Researchers have produced multiple in vivo models for hepatitis B virus (HBV) and, currently, there are no specific laboratory animal models available to study HBV pathogenesis or immune response; nonetheless, their limitations prevent them from being used to study HBV pathogenesis, immune response, or therapeutic methods because HBV can only infect humans and chimpanzees. The current study is the first of its kind to identify a suitable chemically induced liver cirrhosis/HCC model that parallels HBV pathophysiology. Initially, data from the peer-reviewed literature and the GeneCards database were compiled to identify the genes that HBV and seven drugs (acetaminophen, isoniazid, alcohol, D-galactosamine, lipopolysaccharide, thioacetamide, and rifampicin) regulate. Functional enrichment analysis was performed in the STRING server. The network HBV/Chemical, genes, and pathways were constructed by Cytoscape 3.6.1. About 1546 genes were modulated by HBV, of which 25.2% and 17.6% of the genes were common for alcohol and lipopolysaccharide-induced hepatitis. In accordance with the enrichment analysis, HBV activates the signaling pathways for apoptosis, cell cycle, PI3K-Akt, TNF, JAK-STAT, MAPK, chemokines, NF-kappa B, and TGF-beta. In addition, alcohol and lipopolysaccharide significantly activated these pathways more than other chemicals, with higher gene counts and lower FDR scores. In conclusion, alcohol-induced hepatitis could be a suitable model to study chronic HBV infection and lipopolysaccharide-induced hepatitis for an acute inflammatory response to HBV.
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Affiliation(s)
- Vishal S Patil
- ICMR-National Institute of Traditional Medicine, Nehru Nagar, Belagavi 590010, India
- KLE College of Pharmacy, Belagavi, KLE Academy of Higher Education and Research, Belagavi 590010, India
| | - Darasaguppe R Harish
- ICMR-National Institute of Traditional Medicine, Nehru Nagar, Belagavi 590010, India
| | - Ganesh H Sampat
- ICMR-National Institute of Traditional Medicine, Nehru Nagar, Belagavi 590010, India
- KLE College of Pharmacy, Belagavi, KLE Academy of Higher Education and Research, Belagavi 590010, India
| | - Subarna Roy
- ICMR-National Institute of Traditional Medicine, Nehru Nagar, Belagavi 590010, India
| | - Sunil S Jalalpure
- KLE College of Pharmacy, Belagavi, KLE Academy of Higher Education and Research, Belagavi 590010, India
| | - Pukar Khanal
- KLE College of Pharmacy, Belagavi, KLE Academy of Higher Education and Research, Belagavi 590010, India
| | - Swarup S Gujarathi
- ICMR-National Institute of Traditional Medicine, Nehru Nagar, Belagavi 590010, India
- KLE College of Pharmacy, Belagavi, KLE Academy of Higher Education and Research, Belagavi 590010, India
| | - Harsha V Hegde
- ICMR-National Institute of Traditional Medicine, Nehru Nagar, Belagavi 590010, India
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11
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Yang H, Zhang P, Wang Q, Cheng K, Zhao Y. The research development of STAT3 in hepatic ischemia-reperfusion injury. Front Immunol 2023; 14:1066222. [PMID: 36761734 PMCID: PMC9902876 DOI: 10.3389/fimmu.2023.1066222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 01/10/2023] [Indexed: 01/25/2023] Open
Abstract
Ischemia-reperfusion injury (IRI) is a common complication of surgery, which can cause rapid deterioration of the liver function, increase the risk of graft rejection, and seriously affect the prognosis of patients. The signal transducer and activator of transcription 3 (STAT3) protein has been implicated in pathogenesis of IRI. STAT3 influences the mitochondria through multiple pathways and is also involved in apoptosis and other forms of programmed cell death. STAT3 is associated with Janus kinase (JAK), phosphoinositide-3 kinase (PI3K), and heme oxygenase-1 (HO-1) in liver IRI. The STAT3 pathway plays a dual role in IRI as it can also regulate lipid metabolism which may have potential for treating IRI fatty liver. In this review, we summarize research on the function of STAT3 in liver IRI to provide references for its application in the clinic.
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Affiliation(s)
| | | | | | | | - Yujun Zhao
- Engineering and Technology Research Center for Transplantation Medicine of National Health Comission, Third Xiangya Hospital, Central South University, Changsha, China
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12
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Dong H, Zhong W, Zhang W, Hao L, Guo W, Yue R, Sun X, Sun Z, Bataller R, Zhou Z. Loss of long-chain acyl-CoA synthetase 1 promotes hepatocyte death in alcohol-induced steatohepatitis. Metabolism 2023; 138:155334. [PMID: 36349655 DOI: 10.1016/j.metabol.2022.155334] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 09/07/2022] [Accepted: 10/14/2022] [Indexed: 11/06/2022]
Abstract
BACKGROUND Alcohol consumption has been shown to disrupt hepatic lipid homeostasis. Long-chain acyl-CoA synthetase 1 (ACSL1) critically regulates hepatic fatty acid metabolism and lipid homeostasis by channeling fatty acids to lipid metabolic pathways. However, it remains unclear how ACSL1 contributes to the development of alcohol-associated liver disease (ALD). METHODS We performed chronic alcohol feeding animal studies with hepatocyte-specific ACSL1 knockout (ACSL1Δhep) mice, hepatocyte-specific STAT5 knockout (STAT5Δhep) mice, and ACSL1Δhep based-STAT5B overexpression (Stat5b-OE) mice. Cell studies were conducted to define the causal role of ACSL1 deficiency in the pathogenesis of alcohol-induced liver injury. The clinical relevance of the STAT5-ACSL1 pathway was examined using liver tissues from patients with alcoholic hepatitis (AH) and normal subjects (Normal). RESULTS We found that chronic alcohol consumption reduced hepatic ACSL1 expression in AH patients and ALD mice. Hepatocyte-specific ACSL1 deletion exacerbated alcohol-induced liver injury by increasing free fatty acids (FFA) accumulation and cell death. Cell studies revealed that FFA elicited the translocation of BAX and p-MLKL to the lysosomal membrane, resulting in lysosomal membrane permeabilization (LMP) and thereby initiating lysosomal-mediated cell death pathway. Furthermore, we identified that the signal transducer and activator of transcription 5 (STAT5) is a novel transcriptional regulator of ACSL1. Deletion of STAT5 exacerbated alcohol-induced liver injury in association with downregulation of ACSL1, and reactivation of ACSL1 by STAT5 overexpression effectively ameliorated alcohol-induced liver injury. In addition, ACSL1 expression was positively correlated with STAT5 and negatively correlated with cell death was also validated in the liver of AH patients. CONCLUSIONS ACSL1 deficiency due to STAT5 inactivation critically mediates alcohol-induced lipotoxicity and cell death in the development of ALD. These findings provide insights into alcohol-induced liver injury.
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Affiliation(s)
- Haibo Dong
- Center for Translational Biomedical Research, the University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, USA
| | - Wei Zhong
- Center for Translational Biomedical Research, the University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, USA; Department of Nutrition, the University of North Carolina at Greensboro, Greensboro, NC, USA
| | - Wenliang Zhang
- Center for Translational Biomedical Research, the University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, USA
| | - Liuyi Hao
- Center for Translational Biomedical Research, the University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, USA
| | - Wei Guo
- Center for Translational Biomedical Research, the University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, USA
| | - Ruichao Yue
- Center for Translational Biomedical Research, the University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, USA
| | - Xinguo Sun
- Center for Translational Biomedical Research, the University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, USA
| | - Zhaoli Sun
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ramon Bataller
- Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Zhanxiang Zhou
- Center for Translational Biomedical Research, the University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, USA; Department of Nutrition, the University of North Carolina at Greensboro, Greensboro, NC, USA.
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13
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Han J, Lee C, Hur J, Jung Y. Current Therapeutic Options and Potential of Mesenchymal Stem Cell Therapy for Alcoholic Liver Disease. Cells 2022; 12:22. [PMID: 36611816 PMCID: PMC9818513 DOI: 10.3390/cells12010022] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/16/2022] [Accepted: 12/17/2022] [Indexed: 12/24/2022] Open
Abstract
Alcoholic liver disease (ALD) is a globally prevalent chronic liver disease caused by chronic or binge consumption of alcohol. The therapeutic efficiency of current therapies for ALD is limited, and there is no FDA-approved therapy for ALD at present. Various strategies targeting pathogenic events in the progression of ALD are being investigated in preclinical and clinical trials. Recently, mesenchymal stem cells (MSCs) have emerged as a promising candidate for ALD treatment and have been tested in several clinical trials. MSC-released factors have captured attention, as they have the same therapeutic function as MSCs. Herein, we focus on current therapeutic options, recently proposed strategies, and their limitations in ALD treatment. Also, we review the therapeutic effects of MSCs and those of MSC-related secretory factors on ALD. Although accumulating evidence suggests the therapeutic potential of MSCs and related factors in ALD, the mechanisms underlying their actions in ALD have not been well studied. Further investigations of the detailed mechanisms underlying the therapeutic role of MSCs in ALD are required to expand MSC therapies to clinical applications. This review provides information on current or possible treatments for ALD and contributes to our understanding of the development of effective and safe treatments for ALD.
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Affiliation(s)
- Jinsol Han
- Department of Integrated Biological Science, College of Natural Science, Pusan National University, Pusan 46241, Republic of Korea
| | - Chanbin Lee
- Department of Integrated Biological Science, College of Natural Science, Pusan National University, Pusan 46241, Republic of Korea
- Institute of Systems Biology, College of Natural Science, Pusan National University, Pusan 46241, Republic of Korea
| | - Jin Hur
- Department of Convergence Medicine, Pusan National University School of Medicine, Yangsan 50612, Republic of Korea
- PNU GRAND Convergence Medical Science Education Research Center, Pusan National University School of Medicine, Yangsan 50612, Republic of Korea
| | - Youngmi Jung
- Department of Integrated Biological Science, College of Natural Science, Pusan National University, Pusan 46241, Republic of Korea
- Department of Biological Sciences, College of Natural Science, Pusan National University, Pusan 46241, Republic of Korea
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14
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Yang W, Guo C, Herman JG, Zhu C, Lv H, Su X, Zhang L, Zhang M, Guo M. Epigenetic silencing of JAM3 promotes esophageal cancer development by activating Wnt signaling. Clin Epigenetics 2022; 14:164. [PMID: 36461092 PMCID: PMC9719220 DOI: 10.1186/s13148-022-01388-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Accepted: 11/27/2022] [Indexed: 12/03/2022] Open
Abstract
BACKGROUND The role of JAM3 in different tumors is controversial. The epigenetic regulation and the mechanism of JAM3 remain to be elucidated in human esophageal cancer (EC). METHODS Eleven EC cell lines, 49 cases of esophageal intraepithelial neoplasia (EIN) and 760 cases of primary EC samples were employed. Methylation-specific polymerase chain reaction, immunohistochemistry, MTT, western blot and xenograft mouse models were applied in this study. RESULTS The inverse association between RNA expression and promoter region methylation of JAM3 was found by analyzing 185 cases of EC samples extracted from the TCGA database (p < 0.05). JAM3 was highly expressed in KYSE450, KYSE520, TE1 and YES2 cells, low level expressed in KYSE70 cells and unexpressed in KYSE30, KYSE150, KYSE410, KYSE510, TE13 and BIC1 cells. JAM3 was unmethylated in KYSE450, KYSE520, TE1 and YES2 cells, partial methylated in KYSE70 cells and completely methylated in KYSE30, KYSE150, KYSE410, KYSE510, TE13 and BIC1 cells. The expression of JAM3 is correlated with methylation status. The levels of JAM3 were unchanged in KYSE450, KYSE520, TE1 and YES2 cells, increased in KYSE70 cells and restored expression in KYSE30, KYSE150, KYSE410, KYSE510, TE13 and BIC1 cells after 5-aza-2'-deoxycytidine treatment, suggesting that the expression of JAM3 is regulated by promoter region methylation. JAM3 was methylated in 26.5% (13/49) of EIN and 51.1% (388/760) of primary EC, and methylation of JAM3 was associated significantly with tumor differentiation and family history (all p < 0.05). Methylation of JAM3 is an independent prognostic factor of poor 5-year overall survival (p < 0.05). JAM3 suppresses cell proliferation, colony formation, migration and invasion and induces G1/S arrest and apoptosis in EC. Further study demonstrated that JAM3 suppressed EC cells and xenograft tumor growth by inhibiting Wnt/β-catenin signaling. CONCLUSION JAM3 is frequently methylated in human EC, and the expression of JAM3 is regulated by promoter region methylation. JAM3 methylation is an early detection and prognostic marker of EC. JAM3 suppresses EC growth both in vitro and in vivo by inhibiting Wnt signaling.
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Affiliation(s)
- Weili Yang
- grid.414252.40000 0004 1761 8894Department of Gastroenterology and Hepatology, Chinese PLA General Hospital, #28 Fuxing Road, Beijing, 100853 China
| | - Chao Guo
- grid.414252.40000 0004 1761 8894Laboratory Animal Center, Chinese PLA General Hospital, #28 Fuxing Road, Beijing, 100853 China
| | - James G. Herman
- grid.478063.e0000 0004 0456 9819The Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213 USA
| | - Cheng Zhu
- grid.414252.40000 0004 1761 8894Department of Gastroenterology and Hepatology, Chinese PLA General Hospital, #28 Fuxing Road, Beijing, 100853 China ,grid.216938.70000 0000 9878 7032Medical College of NanKai University, Tianjin, 300071 China
| | - Honghui Lv
- grid.414252.40000 0004 1761 8894Department of Gastroenterology and Hepatology, Chinese PLA General Hospital, #28 Fuxing Road, Beijing, 100853 China
| | - Xiaomo Su
- grid.414252.40000 0004 1761 8894Department of Gastroenterology and Hepatology, Chinese PLA General Hospital, #28 Fuxing Road, Beijing, 100853 China
| | - Lirong Zhang
- grid.207374.50000 0001 2189 3846Henan Key Laboratory for Esophageal Cancer Research, Zhengzhou University, 40 Daxue Road, Zhengzhou, 450052 Henan China
| | - Meiying Zhang
- grid.414252.40000 0004 1761 8894Department of Gastroenterology and Hepatology, Chinese PLA General Hospital, #28 Fuxing Road, Beijing, 100853 China
| | - Mingzhou Guo
- grid.414252.40000 0004 1761 8894Department of Gastroenterology and Hepatology, Chinese PLA General Hospital, #28 Fuxing Road, Beijing, 100853 China ,grid.207374.50000 0001 2189 3846Henan Key Laboratory for Esophageal Cancer Research, Zhengzhou University, 40 Daxue Road, Zhengzhou, 450052 Henan China
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15
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Alcohol-Related Liver Disease: An Overview on Pathophysiology, Diagnosis and Therapeutic Perspectives. Biomedicines 2022; 10:biomedicines10102530. [PMID: 36289791 PMCID: PMC9599689 DOI: 10.3390/biomedicines10102530] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 10/01/2022] [Accepted: 10/08/2022] [Indexed: 11/19/2022] Open
Abstract
Alcohol-related liver disease (ALD) refers to a spectrum of liver manifestations ranging from fatty liver diseases, steatohepatitis, and fibrosis/cirrhosis with chronic inflammation primarily due to excessive alcohol use. Currently, ALD is considered as one of the most prevalent causes of liver disease-associated mortality worldwide. Although the pathogenesis of ALD has been intensively investigated, the present understanding of its biomarkers in the context of early clinical diagnosis is not complete, and novel therapeutic targets that can significantly alleviate advanced forms of ALD are limited. While alcohol abstinence remains the primary therapeutic intervention for managing ALD, there are currently no approved medications for treating ALD. Furthermore, given the similarities and the differences between ALD and non-alcoholic fatty liver disease in terms of disease progression and underlying molecular mechanisms, numerous studies have demonstrated that many therapeutic interventions targeting several signaling pathways, including oxidative stress, inflammatory response, hormonal regulation, and hepatocyte death play a significant role in ALD treatment. Therefore, in this review, we summarized several key molecular targets and their modes of action in ALD progression. We also described the updated therapeutic options for ALD management with a particular emphasis on potentially novel signaling pathways.
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16
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Tang X, Li X, Li M, Zhong X, Fu W, Ao M, Xuan J. Enhanced US/CT/MR imaging of integrin αvβ3 for liver fibrosis staging in rat. Front Chem 2022; 10:996116. [PMID: 36262337 PMCID: PMC9574014 DOI: 10.3389/fchem.2022.996116] [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: 07/17/2022] [Accepted: 09/08/2022] [Indexed: 11/13/2022] Open
Abstract
Liver fibrosis is a global health challenge with high morbidity and mortality rates, and diagnostic sensitivity of liver fibrosis tests can be increased using multimodal molecular agents. We designed cyclic arginine-glycine-aspartic acid (cRGD)-modified nanoparticles (NPs) using ultrasound (US)/computed tomography (CT)/magnetic resonance (MR) triple-modality imaging to evaluate liver fibrosis stages. In vitro and in vivo studies were conducted using primary hepatic stellate cells (HSCs) and a rat model of liver fibrosis induced by carbon tetrachloride (CCl4). Our results showed cRGD-poly(lactic-co-glycolic acid)-Fe3O4-perfluorocarbon bromide (cRGD-PLGA-Fe3O4-PFOB) NPs were preferentially internalised by activated HSCs (aHSCs). The main cell types expressing integrin αvβ3 during liver fibrogenesis were the aHSCs. The protein levels of αv and β3 expressed on aHSCs increased with the progression of liver fibrosis. After intravenous injection of cRGD-PLGA-Fe3O4-PFOB NPs, the echo intensity (EI) values, CT values, and T2 values of liver parenchyma correlated well with liver fibrosis severity. cRGD-PLGA-Fe3O4-PFOB NPs as multifunction contrast agents showed great potential to reflect the degree of HSC activation and distinguish among different liver fibrotic stages. The ligand-directed and integrin αvβ3-mediated accumulation provides active and passive targeting capabilities, permitting the targeted multimodal imaging of cRGD-PLGA-Fe3O4-PFOB NPs, which delivers accurate non-invasive diagnosis and real-time monitoring of liver fibrosis development.
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Affiliation(s)
- Xueyao Tang
- Department of Ultrasound, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Department of Ultrasound, The Third People’s Hospital of Chengdu, Clinical College of Southwest Jiao Tong University, The Second Affiliated Chengdu Hospital of Chongqing Medical University, Chengdu, China
| | - Xuan Li
- Department of Ultrasound, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Department of Ultrasound, Sichuan Provincial People’s Hospital, Chengdu, China
| | - Mingxing Li
- Department of Ultrasound, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Xiaoling Zhong
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Wenguang Fu
- Academician (Expert) Workstation of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Meng Ao
- Department of Ultrasound, The Second Affiliated Hospital of Chongqing Medical University & Chongqing Key Laboratory of Ultrasound Molecular Imaging, Chongqing, China
- *Correspondence: Jiqing Xuan, ; Meng Ao,
| | - Jiqing Xuan
- Department of Ultrasound, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- *Correspondence: Jiqing Xuan, ; Meng Ao,
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17
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Yin F, Wu MM, Wei XL, Ren RX, Liu MH, Chen CQ, Yang L, Xie RQ, Jiang SY, Wang XF, Wang H. Hepatic NCoR1 deletion exacerbates alcohol-induced liver injury in mice by promoting CCL2-mediated monocyte-derived macrophage infiltration. Acta Pharmacol Sin 2022; 43:2351-2361. [PMID: 35149852 PMCID: PMC9433401 DOI: 10.1038/s41401-022-00863-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 01/07/2022] [Indexed: 02/06/2023]
Abstract
Nuclear receptor corepressor 1 (NCoR1) is a corepressor of the epigenetic regulation of gene transcription that has important functions in metabolism and inflammation, but little is known about its role in alcohol-associated liver disease (ALD). In this study, we developed mice with hepatocyte-specific NCoR1 knockout (NCoR1Hep-/-) using the albumin-Cre/LoxP system and investigated the role of NCoR1 in the pathogenesis of ALD and the underlying mechanisms. The traditional alcohol feeding model and NIAAA model of ALD were both established in wild-type and NCoR1Hep-/- mice. We showed that after ALD was established, NCoR1Hep-/- mice had worse liver injury but less steatosis than wild-type mice. We demonstrated that hepatocyte-specific loss of NCoR1 attenuated liver steatosis by promoting fatty acid oxidation by upregulating BMAL1 (a circadian clock component that has been reported to promote peroxisome proliferator activated receptor alpha (PPARα)-mediated fatty β-oxidation by upregulating de novo lipid synthesis). On the other hand, hepatocyte-specific loss of NCoR1 exacerbated alcohol-induced liver inflammation and oxidative stress by recruiting monocyte-derived macrophages via C-C motif chemokine ligand 2 (CCL2). In the mouse hepatocyte line AML12, NCoR1 knockdown significantly increased ethanol-induced CCL2 release. These results suggest that hepatocyte NCoR1 plays distinct roles in controlling liver inflammation and steatosis, which provides new insights into the development of treatments for steatohepatitis induced by chronic alcohol consumption.
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Affiliation(s)
- Fan Yin
- School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Miao-Miao Wu
- School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Xiao-Li Wei
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Rui-Xue Ren
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Meng-Hua Liu
- School of Pharmacy, Anhui Medical University, Hefei, 230032, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, 230032, China
| | - Chong-Qing Chen
- School of Pharmacy, Anhui Medical University, Hefei, 230032, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, 230032, China
| | - Liu Yang
- School of Pharmacy, Anhui Medical University, Hefei, 230032, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, 230032, China
| | - Rui-Qian Xie
- School of Pharmacy, Anhui Medical University, Hefei, 230032, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, 230032, China
| | - Shan-Yue Jiang
- School of Pharmacy, Anhui Medical University, Hefei, 230032, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, 230032, China
| | - Xue-Fu Wang
- School of Pharmacy, Anhui Medical University, Hefei, 230032, China.
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, 230032, China.
| | - Hua Wang
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, 230032, China.
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Zhou K, Yin F, Li Y, Ma C, Liu P, Xin Z, Ren R, Wei S, Khan M, Wang H, Zhang H. MicroRNA-29b ameliorates hepatic inflammation via suppression of STAT3 in alcohol-associated liver disease. Alcohol 2022; 99:9-22. [PMID: 34688828 DOI: 10.1016/j.alcohol.2021.10.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 09/11/2021] [Accepted: 10/18/2021] [Indexed: 02/08/2023]
Abstract
Alcohol-associated liver disease (ALD) is induced by chronic excessive alcohol consumption resulting in the clinical manifestations of steatosis, inflammation, and cirrhosis. MicroRNA-29b (miR-29b) is mainly expressed in hepatic nonparenchymal cells, and its expression level varies in different diseases. In this study, we aimed to determine the role of miR-29b in a mouse model of alcohol-associated liver disease. Wild-type (WT) and miR-29b knockout (miR-29b-/-) mice were fed a Lieber-DeCarli liquid diet containing 5% alcohol for 10 days, followed by gavage of a single dose of ethanol (5 g/kg body weight). Histology, immunoblotting, and biochemical analyses were then conducted for comparison. miR-29b expression was decreased in the livers of chronic-plus-binge ethanol-fed mice. Further analysis revealed that alcohol exposure exacerbated hepatic injury by significantly increasing serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, with decreased survival rates for miR-29b-/- mice. Results from the luciferase assay indicated that miR-29b negatively regulated the signal transducer and activator of transcription 3 (STAT3). Depletion of miR-29b led to an increase in STAT3 and more noticeable inflammation in the liver, whereas overexpression of miR-29b downregulated STAT3 and proinflammatory cytokine expression in primary mouse peritoneal macrophages. Taken together, these results demonstrate a novel association between miR-29b and ALD. miR-29b plays a hepatoprotective role in alcohol-induced inflammation and liver injury by targeting STAT3.
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19
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Das S, Ge X, Han H, Desert R, Song Z, Athavale D, Chen W, Gaskell H, Lantvit D, Guzman G, Nieto N. The Integrated "Multiomics" Landscape at Peak Injury and Resolution From Alcohol-Associated Liver Disease. Hepatol Commun 2022; 6:133-160. [PMID: 34558855 PMCID: PMC8710802 DOI: 10.1002/hep4.1793] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 07/06/2021] [Accepted: 07/07/2021] [Indexed: 01/09/2023] Open
Abstract
Alcohol-associated liver disease (ALD) is a significant clinical problem for which the most effective therapy is alcohol abstinence. The two aims of this study were, first, to identify the liver transcriptome, fecal microbiome, and portal serum metabolome at peak injury and during early and late resolution from ALD; and second, to integrate their interactions and understand better the pathogenesis of ALD. To provoke alcohol-induced liver injury, female and male wild-type mice were fed the control or ethanol Lieber-DeCarli diets for 6 weeks. To study early and late resolution, alcohol was withdrawn from the diet and mice were sacrificed after 3 and 14 days, respectively. At peak injury, there was increased signal transducer and activator of transcription (Stat3), Rho-GTPases, Tec kinase and glycoprotein VI (Gp6), and decreased peroxisome proliferator-activated receptor signaling. During resolution from ALD, there was up-regulation of vitamin D receptor/retinoid X receptor, toll-like receptor, p38 and Stat3, and down-regulation of liver X receptor signaling. Females showed significant changes in catabolic pathways, whereas males increased cellular stress, injury, and immune-response pathways that decreased during resolution. The bacterial genus Alistipes and the metabolite dipeptide glycyl-L-leucine increased at peak but decreased during resolution from ALD in both genders. Hepatic induction of mitogen-activated protein kinase (Map3k1) correlated with changes in the microbiome and metabolome at peak but was restored during ALD resolution. Inhibition of MAP3K1 protected from ALD in mice. Conclusion: Alcohol abstinence restores the liver transcriptome, fecal microbiome, and portal serum metabolome in a gender-specific manner. Integration of multiomics data identified Map3k1 as a key gene driving pathogenesis and resolution from ALD.
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Affiliation(s)
- Sukanta Das
- Department of PathologyUniversity of Illinois at ChicagoChicagoILUSA
| | - Xiaodong Ge
- Department of PathologyUniversity of Illinois at ChicagoChicagoILUSA
| | - Hui Han
- Department of PathologyUniversity of Illinois at ChicagoChicagoILUSA
| | - Romain Desert
- Department of PathologyUniversity of Illinois at ChicagoChicagoILUSA
| | - Zhuolun Song
- Department of PathologyUniversity of Illinois at ChicagoChicagoILUSA
| | - Dipti Athavale
- Department of PathologyUniversity of Illinois at ChicagoChicagoILUSA
| | - Wei Chen
- Department of PathologyUniversity of Illinois at ChicagoChicagoILUSA
| | - Harriet Gaskell
- Department of PathologyUniversity of Illinois at ChicagoChicagoILUSA
| | - Daniel Lantvit
- Department of PathologyUniversity of Illinois at ChicagoChicagoILUSA
| | - Grace Guzman
- Department of PathologyUniversity of Illinois at ChicagoChicagoILUSA
| | - Natalia Nieto
- Department of PathologyUniversity of Illinois at ChicagoChicagoILUSA
- Department of MedicineDivision of Gastroenterology and HepatologyUniversity of Illinois at ChicagoChicagoILUSA
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20
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Ali AL, Nailwal NP, Doshi GM. Emerging Role of Interleukins for the Assessment and Treatment of Liver Diseases. Endocr Metab Immune Disord Drug Targets 2021; 22:371-382. [PMID: 34819013 DOI: 10.2174/1871530321666211124102837] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 10/15/2021] [Accepted: 10/25/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND The most common liver diseases are fibrosis, alcoholic liver disease, non-alcoholic fatty disease, viral hepatitis, and hepatocellular carcinoma. These liver diseases account for approximately 2 million deaths per year worldwide, with cirrhosis accounting for 2.1% of the worldwide burden. The most widely used liver function tests for diagnosis are alanine transaminase, aspartate transaminase, serum proteins, serum albumin, and serum globulins, whereas antivirals and corticosteroids have been proven to be useful for the treatment of liver diseases. A major disadvantage of these diagnostic measures is the lack of specificity to a particular tissue or cell type, as these enzymes are common to one or more tissues. The major adverse effect of current treatment methods is drug resistance. To overcome these issues, interleukins have been investigated. The balance of these interleukins determines the outcome of an immune response. Interleukins are considered interesting therapeutic targets for the treatment of liver diseases. In this review, we summarize the current state of knowledge regarding interleukins in the diagnosis, treatment, and pathogenesis of different acute and chronic liver diseases. OBJECTIVE To understand the role of interleukins in the assessment and treatment of different types of liver diseases. METHODS A literature search was conducted using PubMed, Science Direct, and NCBI with the following keywords: Interleukins, Acute Liver Failure, Alcoholic Liver Disease, Non-Alcoholic Fatty Liver Disease, Liver Fibrosis, Hepatocellular Carcinoma, Inflammation, Liver injury, Hepatoprotective effect. Clinical trial data on these interleukins have been searched on Clinicaltrials.gov. RESULTS Existing literature and preclinical and clinical trial data demonstrate that interleukins play a crucial role in the pathogenesis of liver diseases. CONCLUSION Our findings indicate that IL-1, IL-6, IL-10, IL-17, IL-22, IL-35, and IL-37 are involved in the progression and control of various liver conditions via the regulation of cell signaling pathways. However, further investigation on the involvement of these interleukins is necessary for their use as a targeted therapy in liver diseases.
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Affiliation(s)
- Aaliya L Ali
- Department of Pharmacology, SVKM'S Dr. Bhanuben Nanavati College of Pharmacy, Mithibai Campus, Vile Parle (W), Mumbai-400056. India
| | - Namrata P Nailwal
- Department of Pharmacology, SVKM'S Dr. Bhanuben Nanavati College of Pharmacy, Mithibai Campus, Vile Parle (W), Mumbai-400056. India
| | - Gaurav M Doshi
- Department of Pharmacology, SVKM'S Dr. Bhanuben Nanavati College of Pharmacy, Mithibai Campus, Vile Parle (W), Mumbai-400056. India
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21
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Szántó M, Gupte R, Kraus WL, Pacher P, Bai P. PARPs in lipid metabolism and related diseases. Prog Lipid Res 2021; 84:101117. [PMID: 34450194 DOI: 10.1016/j.plipres.2021.101117] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 08/10/2021] [Accepted: 08/18/2021] [Indexed: 12/28/2022]
Abstract
PARPs and tankyrases (TNKS) represent a family of 17 proteins. PARPs and tankyrases were originally identified as DNA repair factors, nevertheless, recent advances have shed light on their role in lipid metabolism. To date, PARP1, PARP2, PARP3, tankyrases, PARP9, PARP10, PARP14 were reported to have multi-pronged connections to lipid metabolism. The activity of PARP enzymes is fine-tuned by a set of cholesterol-based compounds as oxidized cholesterol derivatives, steroid hormones or bile acids. In turn, PARPs modulate several key processes of lipid homeostasis (lipotoxicity, fatty acid and steroid biosynthesis, lipoprotein homeostasis, fatty acid oxidation, etc.). PARPs are also cofactors of lipid-responsive nuclear receptors and transcription factors through which PARPs regulate lipid metabolism and lipid homeostasis. PARP activation often represents a disruptive signal to (lipid) metabolism, and PARP-dependent changes to lipid metabolism have pathophysiological role in the development of hyperlipidemia, obesity, alcoholic and non-alcoholic fatty liver disease, type II diabetes and its complications, atherosclerosis, cardiovascular aging and skin pathologies, just to name a few. In this synopsis we will review the evidence supporting the beneficial effects of pharmacological PARP inhibitors in these diseases/pathologies and propose repurposing PARP inhibitors already available for the treatment of various malignancies.
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Affiliation(s)
- Magdolna Szántó
- Department Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032, Hungary
| | - Rebecca Gupte
- Laboratory of Signaling and Gene Regulation, Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Division of Basic Research, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - W Lee Kraus
- Laboratory of Signaling and Gene Regulation, Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Division of Basic Research, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Pal Pacher
- National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
| | - Peter Bai
- Department Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032, Hungary; MTA-DE Lendület Laboratory of Cellular Metabolism, Debrecen, 4032, Hungary; Research Center for Molecular Medicine, Faculty of Medicine, University of Debrecen, 4032, Hungary.
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22
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Pan XY, Wang L, You HM, Cheng M, Yang Y, Huang C, Li J. Alternative activation of macrophages by prostacyclin synthase ameliorates alcohol induced liver injury. J Transl Med 2021; 101:1210-1224. [PMID: 34112940 PMCID: PMC8367821 DOI: 10.1038/s41374-021-00531-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 12/19/2020] [Accepted: 12/19/2020] [Indexed: 12/13/2022] Open
Abstract
Alcoholic liver disease (ALD) is a major cause of chronic liver disease worldwide. Macrophages exhibit different functional states and are classified as classically activated (M1) and alternatively activated (M2) macrophages. However, the mechanisms that govern M1/M2 polarization in chronic ALD remain to be elucidated. Prostacyclin (PGI2) synthase (PTGIS) is an enzyme of the prostaglandin pathway which catalyzes the conversion of Prostaglandin H2 (PGH2) to PGI2. PTGIS has anti-inflammatory properties. However, the function of PTGIS in ALD has not yet been determined. In this study, we demonstrated that PTGIS was downregulated in ALD and forced PTGIS expression in vivo using recombinant adeno-associated viral vector-packed PTGIS overexpression plasmid, which alleviated the inflammatory response and suppressed the macrophage M1 phenotype in mice. Loss- and gain-of function-experiments demonstrated that forced PTGIS expression inhibited the macrophage switch to the M1 phenotype and promoted M2 polarization. Furthermore, we identified the genes regulated by PTGIS through RNA-sequencing (RNA-seq) analysis. Gene ontology and KEGG pathway analyses showed that PTGIS regulates many genes involved in the immune response and is enriched in the Janus kinase/signal transducers and activators of transcription (JAK/STAT) signal transduction pathway, which plays an important role in regulating macrophage polarization. The proteins interacting with JAKs were predicted using the STRING database. The overlap between the RNA-seq and the STRING database was interleukin-6; this indicated that it was involved in macrophage polarization regulated by JAK/STAT signaling. We further explored the microRNAs that could regulate the expression of PTGIS through TargetScan. The results of luciferase assay illustrated that the expression of PTGIS was regulated by miR-140-3p.1. These results imply that PTGIS plays a pivotal role in ALD, partly by influencing macrophage polarization.
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Affiliation(s)
- Xue-Yin Pan
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
- The key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Hefei, 230032, China
- Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Ling Wang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
- The key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Hefei, 230032, China
- Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Hong-Mei You
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
- The key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Hefei, 230032, China
- Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Miao Cheng
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
- The key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Hefei, 230032, China
- Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Yang Yang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
- The key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Hefei, 230032, China
- Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Cheng Huang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
- The key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Hefei, 230032, China
- Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Jun Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China.
- The key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Hefei, 230032, China.
- Institute for Liver Diseases of Anhui Medical University, Hefei, China.
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23
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The Gut Microbiota-Derived Immune Response in Chronic Liver Disease. Int J Mol Sci 2021; 22:ijms22158309. [PMID: 34361075 PMCID: PMC8347749 DOI: 10.3390/ijms22158309] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 07/29/2021] [Accepted: 07/30/2021] [Indexed: 02/06/2023] Open
Abstract
In chronic liver disease, the causative factor is important; however, recently, the intestinal microbiome has been associated with the progression of chronic liver disease and the occurrence of side effects. The immune system is affected by the metabolites of the microbiome, and diet is the primary regulator of the microbiota composition and function in the gut–liver axis. These metabolites can be used as therapeutic material, and postbiotics, in the future, can increase or decrease human immunity by modulating inflammation and immune reactions. Therefore, the excessive intake of nutrients and the lack of nutrition have important effects on immunity and inflammation. Evidence has been published indicating that microbiome-induced chronic inflammation and the consequent immune dysregulation affect the development of chronic liver disease. In this research paper, we discuss the overall trend of microbiome-derived substances related to immunity and the future research directions.
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24
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Yan J, Nie Y, Luo M, Chen Z, He B. Natural Compounds: A Potential Treatment for Alcoholic Liver Disease? Front Pharmacol 2021; 12:694475. [PMID: 34290612 PMCID: PMC8287649 DOI: 10.3389/fphar.2021.694475] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 06/23/2021] [Indexed: 12/12/2022] Open
Abstract
Excessive alcohol intake is a direct cause of alcoholic liver disease (ALD). ALD usually manifests as fatty liver in the initial stage and then develops into alcoholic hepatitis (ASH), fibrosis and cirrhosis. Severe alcoholism induces extensive hepatocyte death, liver failure, and even hepatocellular carcinoma (HCC). Currently, there are few effective clinical means to treat ALD, except for abstinence. Natural compounds are a class of compounds extracted from herbs with an explicit chemical structure. Several natural compounds, such as silymarin, quercetin, hesperidin, and berberine, have been shown to have curative effects on ALD without side effects. In this review, we pay particular attention to natural compounds and developing clinical drugs based on natural compounds for ALD, with the aim of providing a potential treatment for ALD.
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Affiliation(s)
- Junbin Yan
- The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China.,Key Laboratory of Integrative Chinese and Western Medicine for the Diagnosis and Treatment of Circulatory Diseases of Zhejiang Province, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Yunmeng Nie
- The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Minmin Luo
- The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China.,Key Laboratory of Integrative Chinese and Western Medicine for the Diagnosis and Treatment of Circulatory Diseases of Zhejiang Province, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Zhiyun Chen
- The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China.,Key Laboratory of Integrative Chinese and Western Medicine for the Diagnosis and Treatment of Circulatory Diseases of Zhejiang Province, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Beihui He
- The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China.,Key Laboratory of Integrative Chinese and Western Medicine for the Diagnosis and Treatment of Circulatory Diseases of Zhejiang Province, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
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25
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Lin L, Yang S, Xiao Z, Hong P, Sun S, Zhou C, Qian ZJ. The Inhibition Effect of the Seaweed Polyphenol, 7-Phloro-Eckol from Ecklonia Cava on Alcohol-Induced Oxidative Stress in HepG2/CYP2E1 Cells. Mar Drugs 2021; 19:158. [PMID: 33802989 PMCID: PMC8002839 DOI: 10.3390/md19030158] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 03/15/2021] [Accepted: 03/16/2021] [Indexed: 02/07/2023] Open
Abstract
The liver is vulnerable to oxidative stress-induced damage, which leads to many diseases, including alcoholic liver disease (ALD). Liver disease endanger people's health, and the incidence of ALD is increasing; therefore, prevention is very important. 7-phloro-eckol (7PE) is a seaweed polyphenol, which was isolated from Ecklonia cava in a previous study. In this study, the antioxidative stress effect of 7PE on HepG2/CYP2E1 cells was evaluated by alcohol-induced cytotoxicity, DNA damage, and expression of related inflammation and apoptosis proteins. The results showed that 7PE caused alcohol-induced cytotoxicity to abate, reduced the amount of reactive oxygen species (ROS) and nitric oxide (NO), and effectively inhibited DNA damage in HepG2/CYP2E1 cells. Additionally, the expression levels of glutathione (GSH), superoxide dismutase (SOD), B cell lymphoma 2 (Bcl-2), and Akt increased, while γ-glutamyltransferase (GGT), Bcl-2 related x (Bax), cleaved caspase-3, cleaved caspase-9, nuclear factor-κB (NF-κB), and JNK decreased. Finally, molecular docking proved that 7PE could bind to BCL-2 and GSH protein. These results indicate that 7PE can alleviate the alcohol-induced oxidative stress injury of HepG2 cells and that 7PE may have a potential application prospect in the future development of antioxidants.
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Affiliation(s)
- Liyuan Lin
- School of Chemistry and Environment, Shenzhen Institute of Guangdong Ocean University, College of Food Science and Technology, Guangdong Ocean University, Zhanjiang 524-088, China; (L.L.); (S.Y.); (Z.X.); (P.H.); (S.S.); (C.Z.)
- Southern Marine Science and Engineering Guangdong Laboratory, Zhanjiang 524-088, China
| | - Shengtao Yang
- School of Chemistry and Environment, Shenzhen Institute of Guangdong Ocean University, College of Food Science and Technology, Guangdong Ocean University, Zhanjiang 524-088, China; (L.L.); (S.Y.); (Z.X.); (P.H.); (S.S.); (C.Z.)
- Southern Marine Science and Engineering Guangdong Laboratory, Zhanjiang 524-088, China
| | - Zhenbang Xiao
- School of Chemistry and Environment, Shenzhen Institute of Guangdong Ocean University, College of Food Science and Technology, Guangdong Ocean University, Zhanjiang 524-088, China; (L.L.); (S.Y.); (Z.X.); (P.H.); (S.S.); (C.Z.)
- Southern Marine Science and Engineering Guangdong Laboratory, Zhanjiang 524-088, China
| | - Pengzhi Hong
- School of Chemistry and Environment, Shenzhen Institute of Guangdong Ocean University, College of Food Science and Technology, Guangdong Ocean University, Zhanjiang 524-088, China; (L.L.); (S.Y.); (Z.X.); (P.H.); (S.S.); (C.Z.)
- Southern Marine Science and Engineering Guangdong Laboratory, Zhanjiang 524-088, China
| | - Shengli Sun
- School of Chemistry and Environment, Shenzhen Institute of Guangdong Ocean University, College of Food Science and Technology, Guangdong Ocean University, Zhanjiang 524-088, China; (L.L.); (S.Y.); (Z.X.); (P.H.); (S.S.); (C.Z.)
| | - Chunxia Zhou
- School of Chemistry and Environment, Shenzhen Institute of Guangdong Ocean University, College of Food Science and Technology, Guangdong Ocean University, Zhanjiang 524-088, China; (L.L.); (S.Y.); (Z.X.); (P.H.); (S.S.); (C.Z.)
- Southern Marine Science and Engineering Guangdong Laboratory, Zhanjiang 524-088, China
| | - Zhong-Ji Qian
- School of Chemistry and Environment, Shenzhen Institute of Guangdong Ocean University, College of Food Science and Technology, Guangdong Ocean University, Zhanjiang 524-088, China; (L.L.); (S.Y.); (Z.X.); (P.H.); (S.S.); (C.Z.)
- Southern Marine Science and Engineering Guangdong Laboratory, Zhanjiang 524-088, China
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26
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Chiou YL, Chyau CC, Li TJ, Kuo CF, Kang YY, Chen CC, Ko WS. Hepatoprotective Effect of Antrodia cinnamomea Mycelium in Patients with Nonalcoholic Steatohepatitis: A Randomized, Double-Blind, Placebo-Controlled Trial. J Am Coll Nutr 2020; 40:349-357. [PMID: 32657670 DOI: 10.1080/07315724.2020.1779850] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Nonalcoholic steatohepatitis (NASH) has become a prominent liver disease in contemporary society because of the changing dieting styles. Complicated syndromes often accompanied by obesity and diabetes makes no standard treatment for NASH. Therefore, we investigated the potential role of Antrodia cinnamomea mycelium (ACM) as nutraceutical supplementation in the treatment of NASH in this 6-month randomized, double-blind, placebo-controlled study. METHOD 28 Participants were treated with three capsules per day containing either 420 mg of ACM or 420 mg of starch as a placebo. The participants were required to follow a predetermined regular visit to hospital every three months during the intervention period (6 months). During each study visit, subjects underwent anthropometric measurements and blood testing for biochemical analysis, immune function assay, inflammatory cytokines assay, and FibroMax test. RESULTS The ACM supplemented group had a significant improvement in steatosis and decreased in the inflammatory marker of TNF-α after three and six months. NASH patients who received ACM showed a significant decrease in the SteatoTest mean value from 0.66 at baseline to 0.49 at 6 months (p < 0.029) and the ActiTest mean value decreased from 0.46 at baseline to 0.30 at 6 months (p < 0.029). CONCLUSION This is the first clinical investigation that explores the hepatoprotective effect of A. cinnamomea mycelium in patients with NASH. No participants experienced any adverse events during the study, which suggested that ACM is a safe alternative treatment for NASH.
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Affiliation(s)
- Ya-Ling Chiou
- Department of Nutrition, Master Program of Biomedical Nutrition, Hungkuang University, Taichung City, Taiwan
| | - Charng-Cherng Chyau
- Research Institute of Biotechnology, Hungkuang University, Taichung City, Taiwan
| | - Tsung-Ju Li
- Biotech Research Institute, Grape King Bio Ltd, Taoyuan City, Taiwan
| | - Chia-Feng Kuo
- Department of Food Science, Nutrition, and Nutraceutical Biotechnology, Shih Chien University, Taipei City, Taiwan
| | - Yu-Yling Kang
- Department of Nutrition, Master Program of Biomedical Nutrition, Hungkuang University, Taichung City, Taiwan
| | - Chin-Chu Chen
- Biotech Research Institute, Grape King Bio Ltd, Taoyuan City, Taiwan.,Department of Food Science, Nutrition, and Nutraceutical Biotechnology, Shih Chien University, Taipei City, Taiwan.,Institute of Food Science and Technology, National Taiwan University, Taipei City, Taiwan
| | - Wang-Sheng Ko
- Department of Nutrition, Master Program of Biomedical Nutrition, Hungkuang University, Taichung City, Taiwan.,Department of Internal Medicine, Kuang-Tien General Hospital, Taichung City, Taiwan
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27
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Bharadwaj U, Kasembeli MM, Robinson P, Tweardy DJ. Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 to Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution. Pharmacol Rev 2020; 72:486-526. [PMID: 32198236 PMCID: PMC7300325 DOI: 10.1124/pr.119.018440] [Citation(s) in RCA: 213] [Impact Index Per Article: 42.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Before it was molecularly cloned in 1994, acute-phase response factor or signal transducer and activator of transcription (STAT)3 was the focus of intense research into understanding the mammalian response to injury, particularly the acute-phase response. Although known to be essential for liver production of acute-phase reactant proteins, many of which augment innate immune responses, molecular cloning of acute-phase response factor or STAT3 and the research this enabled helped establish the central function of Janus kinase (JAK) family members in cytokine signaling and identified a multitude of cytokines and peptide hormones, beyond interleukin-6 and its family members, that activate JAKs and STAT3, as well as numerous new programs that their activation drives. Many, like the acute-phase response, are adaptive, whereas several are maladaptive and lead to chronic inflammation and adverse consequences, such as cachexia, fibrosis, organ dysfunction, and cancer. Molecular cloning of STAT3 also enabled the identification of other noncanonical roles for STAT3 in normal physiology, including its contribution to the function of the electron transport chain and oxidative phosphorylation, its basal and stress-related adaptive functions in mitochondria, its function as a scaffold in inflammation-enhanced platelet activation, and its contributions to endothelial permeability and calcium efflux from endoplasmic reticulum. In this review, we will summarize the molecular and cellular biology of JAK/STAT3 signaling and its functions under basal and stress conditions, which are adaptive, and then review maladaptive JAK/STAT3 signaling in animals and humans that lead to disease, as well as recent attempts to modulate them to treat these diseases. In addition, we will discuss how consideration of the noncanonical and stress-related functions of STAT3 cannot be ignored in efforts to target the canonical functions of STAT3, if the goal is to develop drugs that are not only effective but safe. SIGNIFICANCE STATEMENT: Key biological functions of Janus kinase (JAK)/signal transducer and activator of transcription (STAT)3 signaling can be delineated into two broad categories: those essential for normal cell and organ development and those activated in response to stress that are adaptive. Persistent or dysregulated JAK/STAT3 signaling, however, is maladaptive and contributes to many diseases, including diseases characterized by chronic inflammation and fibrosis, and cancer. A comprehensive understanding of JAK/STAT3 signaling in normal development, and in adaptive and maladaptive responses to stress, is essential for the continued development of safe and effective therapies that target this signaling pathway.
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Affiliation(s)
- Uddalak Bharadwaj
- Department of Infectious Diseases, Infection Control & Employee Health, Division of Internal Medicine (U.B., M.M.K., P.R., D.J.T.), and Department of Molecular and Cellular Oncology (D.J.T.), University of Texas, MD Anderson Cancer Center, Houston, Texas
| | - Moses M Kasembeli
- Department of Infectious Diseases, Infection Control & Employee Health, Division of Internal Medicine (U.B., M.M.K., P.R., D.J.T.), and Department of Molecular and Cellular Oncology (D.J.T.), University of Texas, MD Anderson Cancer Center, Houston, Texas
| | - Prema Robinson
- Department of Infectious Diseases, Infection Control & Employee Health, Division of Internal Medicine (U.B., M.M.K., P.R., D.J.T.), and Department of Molecular and Cellular Oncology (D.J.T.), University of Texas, MD Anderson Cancer Center, Houston, Texas
| | - David J Tweardy
- Department of Infectious Diseases, Infection Control & Employee Health, Division of Internal Medicine (U.B., M.M.K., P.R., D.J.T.), and Department of Molecular and Cellular Oncology (D.J.T.), University of Texas, MD Anderson Cancer Center, Houston, Texas
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28
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Mohamed WR, Kotb AS, Abd El-Raouf OM, Mohammad Fikry E. Apigenin alleviated acetaminophen-induced hepatotoxicity in low protein-fed rats: Targeting oxidative stress, STAT3, and apoptosis signals. J Biochem Mol Toxicol 2020; 34:e22472. [PMID: 32048452 DOI: 10.1002/jbt.22472] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Revised: 11/28/2019] [Accepted: 01/31/2020] [Indexed: 02/06/2023]
Abstract
Apigenin (API) is a natural flavonoid abundant in fruits and vegetables. The present study was undertaken to evaluate the effect of protein malnutrition (PMN) on acetaminophen (APAP)-induced hepatotoxicity, together with the protective effects of API, in male Wistar albino rats. In total, 64 male rats were divided into eight groups. Silymarin (SIL) (100 mg/kg, PO) as a reference standard and API (50 mg/kg, PO) were given to normal and APAP-induced hepatic injury in low protein-fed rats. The present results revealed that PMN significantly potentiated APAP-induced hepatotoxicity. Interestingly, the administration of SIL and API alleviated the induced damage, as revealed by reduced serum alanine aminotransferase and aspartate aminotransferase activities along with a significant improvement of the histopathological damage. API suppressed inflammatory response by reducing the interleukin-1β level and signal transducer and activator of transcription 3 expressions along with attenuating oxidative stress as shown by a significant reduction in liver contents of malondialdehyde and nitrite/nitrate as well as restoration of hepatic content of reduced glutathione and superoxide dismutase activity. API also counteracted apoptosis through downregulation of caspase-3 expression level. In conclusion, PMN greatly potentiated the hepatotoxic effects of APAP, and API produced a multimechanistic hepatoprotective activity that can be attributed to its antioxidant, anti-inflammatory, and antiapoptotic effects.
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Affiliation(s)
- Wafaa R Mohamed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni Suef, Egypt
| | - Amr S Kotb
- Department of Pharmacology, National Organization for Drug Control and Research, Giza, Egypt
| | - Ola M Abd El-Raouf
- Department of Pharmacology, National Organization for Drug Control and Research, Giza, Egypt
| | - Ebtehal Mohammad Fikry
- Department of Pharmacology, National Organization for Drug Control and Research, Giza, Egypt
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Jeon S, Carr R. Alcohol effects on hepatic lipid metabolism. J Lipid Res 2020; 61:470-479. [PMID: 32029510 DOI: 10.1194/jlr.r119000547] [Citation(s) in RCA: 175] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Revised: 01/28/2020] [Indexed: 12/16/2022] Open
Abstract
Alcoholic liver disease (ALD) is the most prevalent type of chronic liver disease with significant morbidity and mortality worldwide. ALD begins with simple hepatic steatosis and progresses to alcoholic steatohepatitis, fibrosis, and cirrhosis. The severity of hepatic steatosis is highly associated with the development of later stages of ALD. This review explores the disturbances of alcohol-induced hepatic lipid metabolism through altered hepatic lipid uptake, de novo lipid synthesis, fatty acid oxidation, hepatic lipid export, and lipid droplet formation and catabolism. In addition, we review emerging data on the contributions of genetics and bioactive lipid metabolism in alcohol-induced hepatic lipid accumulation.
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Affiliation(s)
- Sookyoung Jeon
- Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA
| | - Rotonya Carr
- Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA
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Wan YM, Wu HM, Li YH, Xu ZY, Yang JH, Liu C, He YF, Wang MJ, Wu XN, Zhang Y. TSG-6 Inhibits Oxidative Stress and Induces M2 Polarization of Hepatic Macrophages in Mice With Alcoholic Hepatitis via Suppression of STAT3 Activation. Front Pharmacol 2020; 11:10. [PMID: 32116692 PMCID: PMC7010862 DOI: 10.3389/fphar.2020.00010] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2019] [Accepted: 01/07/2020] [Indexed: 12/19/2022] Open
Abstract
Tumor necrosis factor (TNF)-α-stimulated protein 6 (TSG-6) is a secreted protein with diverse tissue protective and anti-inflammatory properties. We aimed to investigate its effective in treating mice with alcoholic hepatitis (AH) and the associated mechanisms. AH was induced in 8-10 week female C57BL/6N mice by chronic-binge ethanol feeding for 10 days. Intraperitoneal (i.p.) injection of recombinant mouse TSG-6 or saline were performed in mice on day 10. Blood samples and hepatic tissues were collected on day 11. Biochemistry, liver histology, flow cytometry, and cytokine measurements were conducted. Compared to the normal control mice, the AH mice had significantly increased liver/body weight ratio, serum alanine aminotransferase (ALT) and aspartate aminotransferases (AST), hepatic total cholesterol (TC), triglyceride (TG), malondialdehyde (MDA), hepatic macrophage infiltration, serum and hepatic interleukin (IL)-6, and tumor necrosis factor (TNF)-α, which were markedly reduced by i.p. injection of rmTSG-6. Compared to the normal control mice, the hepatic glutathione (GSH), accumulation of M2 macrophages, serum, and hepatic IL-10 and TSG-6 were prominently reduced in the AH mice, which were significantly enhanced after i.p. injection of rmTSG-6. Compared to the normal control mice, hepatic activation of signal transducer and activator of transcription 3 (STAT3) was significantly induced, which was markedly suppressed by rmTSG-6 treatment. TSG-6 were effective for the treatment of AH mice, which might be associated with its ability in inhibiting hepatic oxidative stress and inducing hepatic M2 macrophages polarization via suppressing STAT3 activation.
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Affiliation(s)
- Yue-Meng Wan
- Gastroenterology Department, the 2 Affiliated Hospital of Kunming Medical University, Kunming, China
- Department of Occupational, Labor and Environmental Health, Public Health Institute of Kunming Medical University, Kunming, China
| | - Hua-Mei Wu
- Gastroenterology Department, the 2 Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Yu-Hua Li
- Gastroenterology Department, the 2 Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Zhi-Yuan Xu
- Gastroenterology Department, the 2 Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Jin-Hui Yang
- Gastroenterology Department, the 2 Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Chang Liu
- Department of Occupational, Labor and Environmental Health, Public Health Institute of Kunming Medical University, Kunming, China
| | - Yue-Feng He
- Department of Occupational, Labor and Environmental Health, Public Health Institute of Kunming Medical University, Kunming, China
| | - Men-Jie Wang
- Department of Occupational, Labor and Environmental Health, Public Health Institute of Kunming Medical University, Kunming, China
| | - Xi-Nan Wu
- Department of Occupational, Labor and Environmental Health, Public Health Institute of Kunming Medical University, Kunming, China
| | - Yuan Zhang
- The Biomedical Engineering Research Center, Kunming Medical University, Kunming, China
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31
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PTP1B promotes macrophage activation by regulating the NF-κB pathway in alcoholic liver injury. Toxicol Lett 2020; 319:11-21. [DOI: 10.1016/j.toxlet.2019.11.001] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Revised: 10/25/2019] [Accepted: 11/01/2019] [Indexed: 02/07/2023]
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Wan YM, Li ZQ, Zhou Q, Liu C, Wang MJ, Wu HX, Mu YZ, He YF, Zhang Y, Wu XN, Li YH, Xu ZY, Wu HM, Xu Y, Yang JH, Wang XF. Mesenchymal stem cells alleviate liver injury induced by chronic-binge ethanol feeding in mice via release of TSG6 and suppression of STAT3 activation. Stem Cell Res Ther 2020; 11:24. [PMID: 31931878 PMCID: PMC6958598 DOI: 10.1186/s13287-019-1547-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 12/10/2019] [Accepted: 12/29/2019] [Indexed: 12/20/2022] Open
Abstract
Background Mesenchymal stem cells (MSCs) are a population of pluripotent cells that might be used for treatment of liver disease. However, the efficacy of MSCs for mice with alcoholic hepatitis (AH) and its underlying mechanism remains unclear. Methods MSCs were isolated from the bone marrow (BM) of 4–6-week-old male C57BL/6 N mice. AH was induced in female mice by chronic-binge ethanol feeding for 10 days. The mice were given intraperitoneal injections of MSCs with or without transfection or AG490, recombinant mouse tumor necrosis factor (TNF)-α-stimulated gene/protein 6 (rmTSG-6), or saline at day 10. Blood samples and hepatic tissues were collected at day 11. Various assays such as biochemistry, histology, and flow cytometry were performed. Results MSCs reduced AH in mice, decreasing liver/body weight ratio, liver injury, blood and hepatic lipids, malondialdehyde, interleukin (IL)-6, and TNF-ɑ, but increasing glutathione, IL-10, and TSG-6, compared to control mice. Few MSCs engrafted into the inflamed liver. Knockdown of TSG-6 in MSCs significantly attenuated their effects, and injection of rmTSG-6 achieved similar effects to MSCs. The signal transducer and activator of transcription 3 (STAT3) was activated in mice with AH, and MSCs and rmTSG-6 inhibited the STAT3 activation. Injection of MSCs plus AG490 obtained more alleviation of liver injury than MSCs alone. Conclusions BM-MSCs injected into mice with AH do not engraft the liver, but they secrete TSG-6 to reduce liver injury and to inhibit STAT3 activation.
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Affiliation(s)
- Yue-Meng Wan
- Gastroenterology Department, The 2nd Affiliated Hospital of Kunming Medical University, Kunming City, 650101, Yunnan Province, China.,Public Health Institute of Kunming Medical University, Kunming City, 650500, Yunnan Province, China
| | - Zhi-Qiang Li
- Public Health Institute of Kunming Medical University, Kunming City, 650500, Yunnan Province, China
| | - Qiong Zhou
- Public Health Institute of Kunming Medical University, Kunming City, 650500, Yunnan Province, China
| | - Chang Liu
- Public Health Institute of Kunming Medical University, Kunming City, 650500, Yunnan Province, China
| | - Men-Jie Wang
- Public Health Institute of Kunming Medical University, Kunming City, 650500, Yunnan Province, China
| | - Hui-Xin Wu
- Public Health Institute of Kunming Medical University, Kunming City, 650500, Yunnan Province, China
| | - Yun-Zhen Mu
- Public Health Institute of Kunming Medical University, Kunming City, 650500, Yunnan Province, China
| | - Yue-Feng He
- Public Health Institute of Kunming Medical University, Kunming City, 650500, Yunnan Province, China
| | - Yuan Zhang
- The Biomedical Engineering Research Center, Kunming Medical University, Kunming, 650500, Yunnan, China
| | - Xi-Nan Wu
- Public Health Institute of Kunming Medical University, Kunming City, 650500, Yunnan Province, China.
| | - Yu-Hua Li
- Gastroenterology Department, The 2nd Affiliated Hospital of Kunming Medical University, Kunming City, 650101, Yunnan Province, China
| | - Zhi-Yuan Xu
- Gastroenterology Department, The 2nd Affiliated Hospital of Kunming Medical University, Kunming City, 650101, Yunnan Province, China
| | - Hua-Mei Wu
- Gastroenterology Department, The 2nd Affiliated Hospital of Kunming Medical University, Kunming City, 650101, Yunnan Province, China
| | - Ying Xu
- Gastroenterology Department, The 2nd Affiliated Hospital of Kunming Medical University, Kunming City, 650101, Yunnan Province, China
| | - Jin-Hui Yang
- Gastroenterology Department, The 2nd Affiliated Hospital of Kunming Medical University, Kunming City, 650101, Yunnan Province, China
| | - Xiao-Fang Wang
- Department of Pathology, The 2nd Affiliated Hospital of Kunming Medical University, Kunming City, 65010, Yunnan Province, China
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Mizrahi M, Ben Ya'acov A, Adar T, Levy Sklair M, Gaska S, Ilan Y. Oral Administration ofHoodia parvifloraAlleviates Insulin Resistance and Nonalcoholic Steatohepatitis. J Med Food 2019; 22:1189-1198. [DOI: 10.1089/jmf.2019.0093] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Affiliation(s)
- Meir Mizrahi
- Gastroenterology and Liver Units, Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel
| | - Ami Ben Ya'acov
- Gastroenterology and Liver Units, Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel
| | - Tomer Adar
- Gastroenterology and Liver Units, Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel
| | - Miriam Levy Sklair
- Department of Radiology, Hebrew University-Hadassah Medical Center, Jerusalem, Israel
| | - Svetlana Gaska
- Goldyne Savad Institute of Gene Therapy, Hebrew University-Hadassah Medical Center, Jerusalem, Israel
| | - Yaron Ilan
- Gastroenterology and Liver Units, Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel
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Weiss TS, Lupke M, Dayoub R, Geissler EK, Schlitt HJ, Melter M, Eggenhofer E. Augmenter of Liver Regeneration Reduces Ischemia Reperfusion Injury by Less Chemokine Expression, Gr-1 Infiltration and Oxidative Stress. Cells 2019; 8:cells8111421. [PMID: 31718093 PMCID: PMC6912457 DOI: 10.3390/cells8111421] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Revised: 11/08/2019] [Accepted: 11/10/2019] [Indexed: 12/14/2022] Open
Abstract
Hepatic ischemia reperfusion injury (IRI) is a major complication in liver resection and transplantation. Here, we analyzed the impact of recombinant human augmenter of liver regeneration (rALR), an anti-oxidative and anti-apoptotic protein, on the deleterious process induced by ischemia reperfusion (IR). Application of rALR reduced tissue damage (necrosis), levels of lipid peroxidation (oxidative stress) and expression of anti-oxidative genes in a mouse IRI model. Damage associated molecule pattern (DAMP) and inflammatory cytokines such as HMGB1 and TNFα, were not affected by rALR. Furthermore, we evaluated infiltration of inflammatory cells into liver tissue after IRI and found no change in CD3 or γδTCR positive cells, or expression of IL17/IFNγ by γδTCR cells. The quantity of Gr-1 positive cells (neutrophils), and therefore, myeloperoxidase activity, was lower in rALR-treated mice. Moreover, we found under hypoxic conditions attenuated ROS levels after ALR treatment in RAW264.7 cells and in primary mouse hepatocytes. Application of rALR also led to reduced expression of chemo-attractants like CXCL1, CXCL2 and CCl2 in hepatocytes. In addition, ALR expression was increased in IR mouse livers after 3 h and in biopsies from human liver transplants with minimal signs of tissue damage. Therefore, ALR attenuates IRI through reduced neutrophil tissue infiltration mediated by lower expression of key hepatic chemokines and reduction of ROS generation.
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Affiliation(s)
- Thomas S. Weiss
- University Children Hospital (KUNO), University Hospital Regensburg, 93053 Regensburg, Germany; (M.L.); (R.D.); (M.M.)
- Center for Liver Cell Research, University Hospital Regensburg, 93053 Regensburg, Germany
- Correspondence: ; Tel.: +49-9419442195
| | - Madeleine Lupke
- University Children Hospital (KUNO), University Hospital Regensburg, 93053 Regensburg, Germany; (M.L.); (R.D.); (M.M.)
| | - Rania Dayoub
- University Children Hospital (KUNO), University Hospital Regensburg, 93053 Regensburg, Germany; (M.L.); (R.D.); (M.M.)
| | - Edward K. Geissler
- Department of Surgery, University Hospital Regensburg, 93053 Regensburg, Germany; (E.K.G.); (H.J.S.); (E.E.)
| | - Hans J. Schlitt
- Department of Surgery, University Hospital Regensburg, 93053 Regensburg, Germany; (E.K.G.); (H.J.S.); (E.E.)
| | - Michael Melter
- University Children Hospital (KUNO), University Hospital Regensburg, 93053 Regensburg, Germany; (M.L.); (R.D.); (M.M.)
| | - Elke Eggenhofer
- Department of Surgery, University Hospital Regensburg, 93053 Regensburg, Germany; (E.K.G.); (H.J.S.); (E.E.)
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Lee C, Cheung ST. STAT3: An Emerging Therapeutic Target for Hepatocellular Carcinoma. Cancers (Basel) 2019; 11:cancers11111646. [PMID: 31731457 PMCID: PMC6895841 DOI: 10.3390/cancers11111646] [Citation(s) in RCA: 91] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 10/21/2019] [Accepted: 10/22/2019] [Indexed: 12/16/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a major global health problem and its treatment options have been limited. Signal transducer and activator of transcription 3 (STAT3) is a transcription factor important for various cellular processes. Overexpression and constitutive activation of STAT3 have been frequently found in HCC and associated with poor prognosis. Ample evidence has shown that STAT3 plays pivotal roles in the initiation, progression, metastasis and immune suppression of HCC. Thus, STAT3 has attracted attention as a novel therapeutic target in HCC. Clinical trials have investigated STAT3-targeted therapeutics either as monotherapy or in combination with chemotherapeutic agents, immune checkpoint inhibitors and alternative targeted drugs. Some of these studies have yielded encouraging results. Particularly, napabucasin—a cancer stemness inhibitor targeting STAT3-driven gene transcription—has stood out with its promising clinical efficacy and safety profile. Nonetheless, clinical investigations of STAT3-targeted therapies in HCC are limited and more efforts are strongly urged to evaluate their clinical performance in HCC. Here, we provide a comprehensive review of the roles of STAT3 in HCC and follow by comprehensive analysis of STAT3 targeted strategies.
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Affiliation(s)
- Carol Lee
- Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China;
| | - Siu Tim Cheung
- Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China;
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
- Correspondence: ; Tel.: +852-3505-1121
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Natarajan G, Perriotte-Olson C, Casey CA, Donohue TM, Talmon GA, Harris EN, Kabanov AV, Saraswathi V. Effect of nanoformulated copper/zinc superoxide dismutase on chronic ethanol-induced alterations in liver and adipose tissue. Alcohol 2019; 79:71-79. [PMID: 30611703 DOI: 10.1016/j.alcohol.2018.12.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Revised: 12/22/2018] [Accepted: 12/28/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND We previously reported that nanoformulated copper/zinc superoxide dismutase (Nano) attenuates non-alcoholic fatty liver disease and adipose tissue (AT) inflammation in obese animals. Here, we sought to determine whether Nano treatment attenuates alcohol-associated liver disease (AALD) and AT inflammation in alcohol-fed mice. METHODS We pre-treated E-47 cells (HepG2 cells that over-express CYP2E1) with native- or nano-superoxide dismutase (SOD) for 6 h, followed by treatment with ethanol and/or linoleic acid (LA), a free fatty acid. For in vivo studies, male C57BL/6 mice were fed the Lieber-DeCarli control or ethanol liquid diet for 4 weeks. The mice received Nano once every 2 days during the last 2 weeks of ethanol feeding. RESULTS Our in vitro studies revealed that Nano pretreatment reduced LA + ethanol-induced oxidative stress in E-47 cells. Our in vivo experiments showed that ethanol-fed Nano-treated mice had 22% lower hepatic triglyceride levels than mice fed ethanol alone. Nano-treated ethanol-fed mice also had 2-fold lower levels of Cd68 and similarly reduced levels of Ccl2 and Mmp12 mRNAs, than in untreated ethanol-fed mice. We also noted that ethanol feeding caused a remarkable increase in hepatic and/or plasma MCP-1 and CCR2 protein, which was blunted in ethanol + Nano-treated animals. The hepatic content of SREBP-1c, a transcription factor that promotes lipogenesis, was higher in ethanol-fed mice than controls but was attenuated in ethanol + Nano-treated animals. Further, livers of ethanol + Nano-treated mice had significantly higher levels of phosphorylated adenosine monophosphate-activated protein kinase (AMPK) than both control and ethanol-fed mice. In AT, the levels of Il6 mRNA, a hepatoprotective cytokine, and that of Arg1, a marker of anti-inflammatory macrophages, were significantly increased in ethanol + Nano-treated mice compared with control mice. CONCLUSION Our data indicate that Nano treatment attenuates ethanol-induced steatohepatitis and that this effect is associated with an apparent activation of AMPK signaling. Our data also suggest that Nano induces Arg1 and Il6 expression in AT, suggesting anti-inflammatory effects in this tissue.
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Affiliation(s)
- Gopalakrishnan Natarajan
- Department of Internal Medicine, Divisions of Diabetes, Endocrinology, and Metabolism, University of Nebraska Medical Center, Omaha, NE, United States
| | - Curtis Perriotte-Olson
- Department of Internal Medicine, Divisions of Diabetes, Endocrinology, and Metabolism, University of Nebraska Medical Center, Omaha, NE, United States
| | - Carol A Casey
- Department of Gastroenterology and Hepatology, University of Nebraska Medical Center, Omaha, NE, United States; VA Nebraska-Western Iowa Health Care System, Omaha, NE, United States
| | - Terrence M Donohue
- Department of Gastroenterology and Hepatology, University of Nebraska Medical Center, Omaha, NE, United States; VA Nebraska-Western Iowa Health Care System, Omaha, NE, United States
| | - Geoffrey A Talmon
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, United States
| | - Edward N Harris
- Department of Biochemistry, University of Nebraska at Lincoln, Lincoln, NE, United States
| | - Alexander V Kabanov
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Viswanathan Saraswathi
- Department of Internal Medicine, Divisions of Diabetes, Endocrinology, and Metabolism, University of Nebraska Medical Center, Omaha, NE, United States; VA Nebraska-Western Iowa Health Care System, Omaha, NE, United States.
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Yuan Q, Hou S, Zhai J, Tian T, Wu Y, Wu Z, He J, Chen Z, Zhang J. S100A4 promotes inflammation but suppresses lipid accumulation via the STAT3 pathway in chronic ethanol-induced fatty liver. J Mol Med (Berl) 2019; 97:1399-1412. [PMID: 31321478 DOI: 10.1007/s00109-019-01808-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2018] [Revised: 05/24/2019] [Accepted: 05/31/2019] [Indexed: 02/07/2023]
Abstract
S100A4, a member of the S100 calcium-binding protein family, has been identified in a subpopulation of liver macrophages and promotes liver fibrosis via hepatic stellate cell activation. However, the specific role of S100A4 in alcoholic liver disease (ALD) has not been well investigated. Here, S100A4 knockout (S100A4-/-) mice were used in a chronic-binge ethanol model for studying the role of S100A4 and its related molecular mechanism in ALD. S100A4 expression was increased in ethanol-induced liver tissues of wild-type (WT) mice. Macrophage-derived S100A4 promoted liver inflammation but suppressed lipid accumulation under the ethanol feeding condition. S100A4 deficiency promoted ethanol-induced liver injury and hepatic fat accumulation. Further mechanistic studies found that S100A4 inhibited liver fat accumulation mainly by activating the STAT3 pathway and downregulating lipogenic gene expression, especially that of SREBP-1c. In AML-12 cells, a STAT3 inhibitor abolished STAT3 levels and decreased the expression of SREBP1c. Furthermore, the administration of a neutralizing S100A4 antibody to WT mice significantly promoted ethanol-induced liver injury and fatty accumulation. Thus, S100A4 may represent a potential candidate target for the prevention and treatment of ethanol-induced fatty liver. In this study, we discovered the special role of S100A4 in alcoholic liver disease. S100A4 deficiency attenuated ethanol-induced hepatitis and promoted hepatic fat accumulation in ethanol-induced liver tissues. Further mechanistic studies have found that S100A4 promotes early alcoholic hepatitis mainly by activating the STAT3 pathway and its downstream proinflammatory gene expression. Interestingly, activation of the STAT3 pathway downregulates lipogenic gene expression, especially SREBP-1c. KEY MESSAGES: In this study, we discovered the special role of S100A4 in alcoholic liver disease. S100A4 deficiency attenuated ethanol-induced hepatitis and promoted hepatic fat accumulation in ethanol-induced liver tissues. Further mechanistic studies have found that S100A4 promotes early alcoholic hepatitis mainly by activating the STAT3 pathway and its downstream proinflammatory gene expression. Interestingly, activation of the STAT3 pathway downregulates lipogenic gene expression, especially SREBP-1c.
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Affiliation(s)
- Qi Yuan
- The College of Life Science and Bioengineering, Beijing Jiaotong University, No.3 Shangyuancun Road, Beijing, 100044, People's Republic of China
| | - Shasha Hou
- The College of Life Science and Bioengineering, Beijing Jiaotong University, No.3 Shangyuancun Road, Beijing, 100044, People's Republic of China
| | - Junfeng Zhai
- The Chinese Academy of Inspection and Quarantine, Beijing, People's Republic of China
| | - Tian Tian
- The College of Life Science and Bioengineering, Beijing Jiaotong University, No.3 Shangyuancun Road, Beijing, 100044, People's Republic of China
| | - Yingjie Wu
- The State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, People's Republic of China
| | - Zhenlong Wu
- The State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, People's Republic of China
| | - Jinsheng He
- The College of Life Science and Bioengineering, Beijing Jiaotong University, No.3 Shangyuancun Road, Beijing, 100044, People's Republic of China
| | - Zhinan Chen
- The College of Life Science and Bioengineering, Beijing Jiaotong University, No.3 Shangyuancun Road, Beijing, 100044, People's Republic of China.,The Cell Engineering Research Center and Department of Cell Biology, State Key Laboratory of Cancer, Fourth Military Medical University, Xi'an, People's Republic of China
| | - Jinhua Zhang
- The College of Life Science and Bioengineering, Beijing Jiaotong University, No.3 Shangyuancun Road, Beijing, 100044, People's Republic of China.
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Bhattacharjee S, Mejías-Luque R, Loffredo-Verde E, Toska A, Flossdorf M, Gerhard M, Prazeres da Costa C. Concomitant Infection of S. mansoni and H. pylori Promotes Promiscuity of Antigen-Experienced Cells and Primes the Liver for a Lower Fibrotic Response. Cell Rep 2019; 28:231-244.e5. [DOI: 10.1016/j.celrep.2019.05.108] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Revised: 01/29/2019] [Accepted: 05/29/2019] [Indexed: 12/12/2022] Open
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Li S, Tan HY, Wang N, Feng Y, Wang X, Feng Y. Recent Insights Into the Role of Immune Cells in Alcoholic Liver Disease. Front Immunol 2019; 10:1328. [PMID: 31244862 PMCID: PMC6581703 DOI: 10.3389/fimmu.2019.01328] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Accepted: 05/24/2019] [Indexed: 12/12/2022] Open
Abstract
Accumulating clinical and experimental evidences have demonstrated that both innate and adaptive immunity are involved in the pathogenesis of alcoholic liver disease (ALD), in which the role of immunity is to fuel the inflammation and to drive the progression of ALD. Various immune cells are implicated in the pathogenesis of ALD. The activation of innate immune cells induced by alcohol and adaptive immune response triggered by oxidative modification of hepatic constituents facilitate the persistent hepatic inflammation. Meanwhile, the suppressed antigen-presenting capability of various innate immune cells and impaired function of T cells may consequently lead to an increased risk of infection in the patients with advanced ALD. In this review, we summarized the significant recent findings of immune cells participating in ALD. The pathways and molecules involved in the regulation of specific immune cells, and novel mediators protecting the liver from alcoholic injury via affecting these cells are particularly highlighted. This review aims to update the knowledge about immunity in the pathogenesis of ALD, which may facilitate to enhancement of currently available interventions for ALD treatment.
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Affiliation(s)
- Sha Li
- Li Ka Shing Faculty of Medicine, School of Chinese Medicine, The University of Hong Kong, Hong Kong, China
| | - Hor-Yue Tan
- Li Ka Shing Faculty of Medicine, School of Chinese Medicine, The University of Hong Kong, Hong Kong, China
| | - Ning Wang
- Li Ka Shing Faculty of Medicine, School of Chinese Medicine, The University of Hong Kong, Hong Kong, China
| | - Yigang Feng
- Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Xuanbin Wang
- Laboratory of Chinese Herbal Pharmacology, Laboratory of Wudang Local Chinese Medicine Research, Oncology Center, Renmin Hospital, Hubei University of Medicine, Shiyan, China
| | - Yibin Feng
- Li Ka Shing Faculty of Medicine, School of Chinese Medicine, The University of Hong Kong, Hong Kong, China
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Choi WM, Kim MH, Jeong WI. Functions of hepatic non-parenchymal cells in alcoholic liver disease. LIVER RESEARCH 2019. [DOI: 10.1016/j.livres.2019.04.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Marentette JO, Wang M, Michel CR, Powell R, Zhang X, Reisdorph N, Fritz KS, Ju C. Multi-omics Analysis of Liver Infiltrating Macrophages Following Ethanol Consumption. Sci Rep 2019; 9:7776. [PMID: 31123328 PMCID: PMC6533323 DOI: 10.1038/s41598-019-43240-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2018] [Accepted: 11/28/2018] [Indexed: 02/07/2023] Open
Abstract
Alcoholic liver disease (ALD) is a significant health hazard and economic burden affecting approximately 10 million people in the United States. ALD stems from the production of toxic-reactive metabolites, oxidative stress and fat accumulation in hepatocytes which ultimately results in hepatocyte death promoting hepatitis and fibrosis deposition. Monocyte-derived infiltrating Ly6Chi and Ly6Clow macrophages are instrumental in perpetuating and resolving the hepatitis and fibrosis associated with ALD pathogenesis. In the present study we isolated liver infiltrating macrophages from mice on an ethanol diet and subjected them to metabolomic and proteomic analysis to provide a broad assessment of the cellular metabolite and protein differences between infiltrating macrophage phenotypes. We identified numerous differentially regulated metabolites and proteins between Ly6Chi and Ly6Clow macrophages. Bioinformatic analysis for pathway enrichment of the differentially regulated metabolites showed a significant number of metabolites involved in the processes of glycerophospholipid metabolism, arachidonic acid metabolism and phospholipid biosynthesis. From analysis of the infiltrating macrophage proteome, we observed a significant enrichment in the biological processes of antigen presentation, actin polymerization and organization, phagocytosis and apoptotic regulation. The data presented herein could yield exciting new research avenues for the analysis of signaling pathways regulating macrophage polarization in ALD.
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Affiliation(s)
- John O Marentette
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Meng Wang
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Cole R Michel
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Roger Powell
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Xing Zhang
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Nichole Reisdorph
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Kristofer S Fritz
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.
| | - Cynthia Ju
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.
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Lee C, Kim J, Wang S, Sung S, Kim N, Lee HH, Seo YS, Jung Y. Hepatoprotective Effect of Kombucha Tea in Rodent Model of Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis. Int J Mol Sci 2019; 20:2369. [PMID: 31086120 PMCID: PMC6539514 DOI: 10.3390/ijms20092369] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 05/03/2019] [Accepted: 05/08/2019] [Indexed: 12/15/2022] Open
Abstract
Kombucha tea (KT) has emerged as a substance that protects the liver from damage; however, its mechanisms of action on the fatty liver remain unclear. Therefore, we investigated the potential role of KT and its underlying mechanisms on nonalcoholic fatty liver disease (NAFLD). db/db mice that were fed methionine/choline-deficient (MCD) diets for seven weeks were treated for vehicle (M + V) or KT (M + K) and fed with MCD for four additional weeks. Histomorphological injury and increased levels of liver enzymes and lipids were evident in the M + V group, whereas these symptoms were ameliorated in the M + K group. The M + K group had more proliferating and less apoptotic hepatocytic cells than the M + V group. Lipid uptake and lipogenesis significantly decreased, and free fatty acid (FFA) oxidation increased in the M + K, when compared with the M + V group. With the reduction of hedgehog signaling, inflammation and fibrosis also declined in the M + K group. Palmitate (PA) treatment increased the accumulation of lipid droplets and decreased the viability of primary hepatocytes, whereas KT suppressed PA-induced damage in these cells by enhancing intracellular lipid disposal. These results suggest that KT protects hepatocytes from lipid toxicity by influencing the lipid metabolism, and it attenuates inflammation and fibrosis, which contributes to liver restoration in mice with NAFLD.
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Affiliation(s)
- Chanbin Lee
- Department of Integrated Biological Science, Pusan National University, 63-2 Pusandaehak-ro, Geumjeong-gu, Pusan 46241, Korea.
| | - Jieun Kim
- Department of Integrated Biological Science, Pusan National University, 63-2 Pusandaehak-ro, Geumjeong-gu, Pusan 46241, Korea.
| | - Sihyung Wang
- Department of Integrated Biological Science, Pusan National University, 63-2 Pusandaehak-ro, Geumjeong-gu, Pusan 46241, Korea.
| | - Sumi Sung
- Department of Integrated Biological Science, Pusan National University, 63-2 Pusandaehak-ro, Geumjeong-gu, Pusan 46241, Korea.
| | - Namgyu Kim
- Department of Integrated Biological Science, Pusan National University, 63-2 Pusandaehak-ro, Geumjeong-gu, Pusan 46241, Korea.
| | - Hyun-Hee Lee
- Department of Integrated Biological Science, Pusan National University, 63-2 Pusandaehak-ro, Geumjeong-gu, Pusan 46241, Korea.
| | - Young-Su Seo
- Department of Integrated Biological Science, Pusan National University, 63-2 Pusandaehak-ro, Geumjeong-gu, Pusan 46241, Korea.
- Department of Microbiological Sciences, Pusan National University, 63-2 Pusandaehak-ro, Geumjeong-gu, Pusan 46241, Korea.
| | - Youngmi Jung
- Department of Integrated Biological Science, Pusan National University, 63-2 Pusandaehak-ro, Geumjeong-gu, Pusan 46241, Korea.
- Department of Biological Sciences, Pusan National University, 63-2 Pusandaehak-ro, Geumjeong-gu, Pusan 46241, Korea.
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Stärkel P, Schnabl B, Leclercq S, Komuta M, Bataller R, Argemi J, Palma E, Chokshi S, Hellerbrand C, Maccioni L, Lanthier N, Leclercq I. Deficient IL-6/Stat3 Signaling, High TLR7, and Type I Interferons in Early Human Alcoholic Liver Disease: A Triad for Liver Damage and Fibrosis. Hepatol Commun 2019; 3:867-882. [PMID: 31334440 PMCID: PMC6601428 DOI: 10.1002/hep4.1364] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Accepted: 04/15/2019] [Indexed: 12/15/2022] Open
Abstract
Mechanisms underlying alcohol-induced liver injury and its progression still remain incompletely understood. Animal models can only address some aspects of the pathophysiology that requires studies directly in humans, which are scarce. We assessed liver inflammatory and immune responses at early stages of alcoholic liver disease in a unique cohort of alcohol-dependent patients undergoing a highly standardized alcohol withdrawal program. In active drinkers, quantitative real-time polymerase chain reaction revealed alcohol-induced activation of tumor necrosis factor alpha, interleukin (IL)-1β, and nuclear factor kappa B in liver tissue already at early disease stages. Double immunofluorescence staining indicated that this proinflammatory response was restricted to activated, CD68-positive macrophages. In parallel, down-regulation of IL-6, inhibition of the signal transducer and activator of transcription 3 (Stat3) pathway, as well as blunted cyclin D expression in hepatocytes, reduced proliferation and favored hepatocyte apoptosis. In addition, immunofluorescence and quantitative real-time polymerase chain reaction of liver tissue showed that alcohol also activated the toll-like receptor (TLR) 7-interferon (IFN) axis in hepatocytes, which was confirmed in alcohol-stimulated primary human hepatocytes and precision-cut liver slices in vitro. Activation of the TLR7-IFN axis strongly correlated with liver fibrosis markers and disease progression. Two weeks of abstinence attenuated the inflammatory response but did not allow recovery of the defective Stat3 pathway or effect on fibrosis-associated factors. Conclusion: In humans, inflammation, activation of the TLR7-IFN axis, and inhibition of Stat3-dependent repair mechanisms in early alcoholic liver disease pave the way for fibrosis development and ultimately disease progression.
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Affiliation(s)
- Peter Stärkel
- Department of Hepato-gastroenterology Cliniques Universitaires Saint-Luc Brussels Belgium.,Institute of Experimental and Clinical Research, Laboratory of Hepato-gastroenterology Université Catholique de Louvain Brussels Belgium
| | - Bernd Schnabl
- Department of Medicine University of California San Diego La Jolla CA
| | - Sophie Leclercq
- Institute of Neuroscience Université Catholique de Louvain Brussels Belgium
| | - Mina Komuta
- Department of Pathology Cliniques Universitaires Saint-Luc Brussels Belgium
| | - Ramon Bataller
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine University of Pittsburgh Medical Center, Pittsburgh Liver Research Center Pittsburgh PA
| | - Josepmaria Argemi
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine University of Pittsburgh Medical Center, Pittsburgh Liver Research Center Pittsburgh PA
| | - Elena Palma
- Institute of Hepatology Foundation for Liver Research London United Kingdom.,Faculty of Life Sciences & Medicine King's College London London United Kingdom
| | - Shilpa Chokshi
- Institute of Hepatology Foundation for Liver Research London United Kingdom.,Faculty of Life Sciences & Medicine King's College London London United Kingdom
| | - Claus Hellerbrand
- Institute of Biochemistry Friedrich-Alexander University Erlangen-Nürnberg Erlangen Germany
| | - Luca Maccioni
- Institute of Experimental and Clinical Research, Laboratory of Hepato-gastroenterology Université Catholique de Louvain Brussels Belgium
| | - Nicolas Lanthier
- Department of Hepato-gastroenterology Cliniques Universitaires Saint-Luc Brussels Belgium.,Institute of Experimental and Clinical Research, Laboratory of Hepato-gastroenterology Université Catholique de Louvain Brussels Belgium
| | - Isabelle Leclercq
- Institute of Experimental and Clinical Research, Laboratory of Hepato-gastroenterology Université Catholique de Louvain Brussels Belgium
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Wang M, Ma LJ, Yang Y, Xiao Z, Wan JB. n-3 Polyunsaturated fatty acids for the management of alcoholic liver disease: A critical review. Crit Rev Food Sci Nutr 2018; 59:S116-S129. [PMID: 30580553 DOI: 10.1080/10408398.2018.1544542] [Citation(s) in RCA: 106] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Excess alcohol exposure leads to alcoholic liver disease (ALD), a predominant cause of liver-related morbidity and mortality worldwide. In the past decade, increasing attention has been paid to understand the association between n-3 polyunsaturated fatty acids (n-3 PUFAs) and ALD. In this review, we summarize the metabolism of n-3 PUFAs, animal model of ALD, and the findings from recent studies determining the role of n-3 PUFAs in ALD as a possible treatment. The animal models of acute ethanol exposure, chronic ethanol exposure and chronic-plus-single binge ethanol feeding have been widely used to explore the impact of n-3 PUFAs. Although the results of studies regarding the role of n-3 PUFAs in ALD have been inconsistent or controversial, increasing evidence has demonstrated that n-3 PUFAs may be useful in alleviating alcoholic steatosis and alcohol-induced liver injury through multiple mechanisms, including decreased de novo lipogenesis and lipid mobilization from adipose tissue, enhanced mitochondrial fatty acid β-oxidation, reduced hepatic inflammation and oxidative stress, and promoted intestinal homeostasis, positively suggesting that n-3 PUFAs might be promising for the management of ALD. The oxidation of n-3 PUFAs ex vivo in an experimental diet was rarely considered in most n-3 PUFA-related studies, likely contributing to the inconsistent results. Thus, the role of n-3 PUFAs in ALD deserves greater research efforts and remains to be evaluated in randomized, placebo-controlled clinic trial. ABBREVIATION AA arachidonic acid ACC acetyl-CoA carboxylase ACLY ATP-citrate lyase ACO acyl-CoA oxidase ALA α-linolenic acid ALD alcoholic liver disease ALP alkaline phosphatase ALT alanine aminotransferase AMPK AMP-activated protein kinase AST aspartate aminotransferase ATGL adipose triglyceride lipase cAMP cyclic adenosine 3',5'-monophosphate COX cyclooxygenases CPT1 carnitine palmitoyltransferase 1 CYP2E1 cytochrome P450 2E1 DGAT2 diacylglycerol acyltransferase 2 DGLA dihomo-γ-linolenic acid DHA docosahexaenoic acid DPA docosapentaenoic acid DTA docosatetraenoic acid EPA eicosapentaenoic acid ER endoplasmic reticulum ETA eicosatetraenoic acid FAS fatty acid synthase FATPs fatty acid transporter proteins GLA,γ linolenic acid GPR120 G protein-coupled receptor 120 GSH glutathione; H&E haematoxylin-eosin; HO-1 heme oxygenase-1; HSL hormone-sensitive lipase; IL-6 interleukin-6 iNOS nitric oxide synthase LA linoleic acid LBP lipopolysaccharide binding protein LOX lipoxygenases LXR liver X receptor LXREs LXR response elements MCP-1 monocyte chemotactic protein-1 MTP microsomal triglyceride transfer protein MUFA monounsaturated fatty acids MyD88 myeloid differentiation factor 88 n-3 PUFAs omega-3 polyunsaturated fatty acid NAFLD nonalcoholic fatty liver disease NASH nonalcoholic steatohepatitis NF-κB transcription factor nuclear factor κB PDE3B phosphodiesterase 3B PPAR peroxisome proliferator-activated receptor ROS reactive oxygen species RXR retinoid X receptor SCD-1 stearyl CoA desaturase-1 SDA stearidonic acid SFA saturated fatty acids SIRT1 sirtuin 1 SOD superoxide dismutase SREBP sterol regulatory element-binding protein TB total bilirubin TC total cholesterol TG triacylglycerol TLR4 Toll-like receptor-4 TNF-α tumor necrosis factor-α VLDLR very low-density lipoprotein receptor WT wild type; ZO-1 zonula occludens-1.
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Affiliation(s)
- Meng Wang
- a State Key Laboratory of Quality Research in Chinese Medicine , Institute of Chinese Medical Sciences, University of Macau , Macao , China.,b Center for Drug Innovation and Discovery, College of Life Science, Hebei Normal University , Shijiazhuang , Hebei , China
| | - Li-Juan Ma
- a State Key Laboratory of Quality Research in Chinese Medicine , Institute of Chinese Medical Sciences, University of Macau , Macao , China
| | - Yan Yang
- c Department of Nutrition, School of Public Health , Sun Yat-Sen University , Guangzhou , China
| | - Zeyu Xiao
- d Collaborative Translational Medicine Collaborative Innovation Center, Department of Pharmacology and Chemical Biology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jian-Bo Wan
- a State Key Laboratory of Quality Research in Chinese Medicine , Institute of Chinese Medical Sciences, University of Macau , Macao , China
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Gao Y, Zhao H, Wang P, Wang J, Zou L. The roles of SOCS3 and STAT3 in bacterial infection and inflammatory diseases. Scand J Immunol 2018; 88:e12727. [PMID: 30341772 DOI: 10.1111/sji.12727] [Citation(s) in RCA: 93] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Revised: 10/11/2018] [Accepted: 10/13/2018] [Indexed: 12/27/2022]
Affiliation(s)
- Yu Gao
- Translational Neuroscience & Neural Regeneration and Repair Institute/Institute of Cell Therapy; The People's Hospital of China Three Gorges University; Yichang China
- Department of Microbiology, Tumor and Cell Biology; Karolinska Institutet; Stockholm Sweden
| | - Honglei Zhao
- Translational Neuroscience & Neural Regeneration and Repair Institute/Institute of Cell Therapy; The People's Hospital of China Three Gorges University; Yichang China
- Department of Oncology-Pathology; Karolinska Institutet; Stockholm Sweden
| | - Peng Wang
- Translational Neuroscience & Neural Regeneration and Repair Institute/Institute of Cell Therapy; The People's Hospital of China Three Gorges University; Yichang China
| | - Jun Wang
- Translational Neuroscience & Neural Regeneration and Repair Institute/Institute of Cell Therapy; The People's Hospital of China Three Gorges University; Yichang China
| | - Lili Zou
- Translational Neuroscience & Neural Regeneration and Repair Institute/Institute of Cell Therapy; The People's Hospital of China Three Gorges University; Yichang China
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Han JH, Ju JH, Lee YS, Park JH, Yeo IJ, Park MH, Roh YS, Han SB, Hong JT. Astaxanthin alleviated ethanol-induced liver injury by inhibition of oxidative stress and inflammatory responses via blocking of STAT3 activity. Sci Rep 2018; 8:14090. [PMID: 30237578 PMCID: PMC6148091 DOI: 10.1038/s41598-018-32497-w] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Accepted: 09/03/2018] [Indexed: 12/20/2022] Open
Abstract
Astaxanthin (AXT) is classified as a xanthophyll carotenoid compound which have broader functions including potent antioxidant, anti-inflammatory and neuroprotective properties. Considerable researches have demonstrated that AXT shows preventive and therapeutic properties against for Diabetes, Osteoarthritis and Rheumatoid Arthritis. However, the protective effect of AXT on liver disease has not yet been reported. In this study, we investigated effects of AXT on ethanol-induced liver injury in chronic plus binge alcohol feeding model. The hepatic steatosis and inflammation induced by ethanol administration were alleviated by AXT. Serum levels of aspartate transaminase and alanine transaminase were decreased in the livers of AXT administrated group. The ethanol-induced expression of cytochrome P450 2E1 (CYP2E1), pro-inflammatory proteins, cytokines, chemokines and reactive oxygen species (ROS) levels were also reduced in the livers of AXT administrated group. Moreover, ethanol-induced infiltration of neutrophils was decreased in the livers of AXT administrated group. Docking model and pull-down assay showed that AXT directly binds to the DNA binding site of STAT3. Moreover, AXT decreased STAT3 phosphorylation in the liver of AXT administration group. Therefore, these results suggest that AXT could prevent ethanol-induced hepatic injury via inhibition of oxidant and inflammatory responses via blocking of STAT3 activity.
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Affiliation(s)
- Ji Hye Han
- College of Pharmacy and Medical Research Center, Chungbuk National University, Osongsaengmyeong 1-ro, Osong-eup, Heungdeok-gu, Cheongju, Chungbuk, 28160, Republic of Korea
| | - Jung Heun Ju
- College of Pharmacy and Medical Research Center, Chungbuk National University, Osongsaengmyeong 1-ro, Osong-eup, Heungdeok-gu, Cheongju, Chungbuk, 28160, Republic of Korea
| | - Yong Sun Lee
- College of Pharmacy and Medical Research Center, Chungbuk National University, Osongsaengmyeong 1-ro, Osong-eup, Heungdeok-gu, Cheongju, Chungbuk, 28160, Republic of Korea
| | - Ju Ho Park
- College of Pharmacy and Medical Research Center, Chungbuk National University, Osongsaengmyeong 1-ro, Osong-eup, Heungdeok-gu, Cheongju, Chungbuk, 28160, Republic of Korea
| | - In Jun Yeo
- College of Pharmacy and Medical Research Center, Chungbuk National University, Osongsaengmyeong 1-ro, Osong-eup, Heungdeok-gu, Cheongju, Chungbuk, 28160, Republic of Korea
| | - Mi Hee Park
- College of Pharmacy and Medical Research Center, Chungbuk National University, Osongsaengmyeong 1-ro, Osong-eup, Heungdeok-gu, Cheongju, Chungbuk, 28160, Republic of Korea
| | - Yoon Seok Roh
- College of Pharmacy and Medical Research Center, Chungbuk National University, Osongsaengmyeong 1-ro, Osong-eup, Heungdeok-gu, Cheongju, Chungbuk, 28160, Republic of Korea
| | - Sang Bae Han
- College of Pharmacy and Medical Research Center, Chungbuk National University, Osongsaengmyeong 1-ro, Osong-eup, Heungdeok-gu, Cheongju, Chungbuk, 28160, Republic of Korea
| | - Jin Tae Hong
- College of Pharmacy and Medical Research Center, Chungbuk National University, Osongsaengmyeong 1-ro, Osong-eup, Heungdeok-gu, Cheongju, Chungbuk, 28160, Republic of Korea.
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Zhao J, Jiao Y, Song Y, Liu J, Li X, Zhang H, Yang J, Lu Y. Stanniocalcin 2 Ameliorates Hepatosteatosis Through Activation of STAT3 Signaling. Front Physiol 2018; 9:873. [PMID: 30038584 PMCID: PMC6046442 DOI: 10.3389/fphys.2018.00873] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Accepted: 06/19/2018] [Indexed: 12/18/2022] Open
Abstract
Stanniocalcin 2 (STC2), a secreted glycoprotein hormone, regulates many biological processes, including cell proliferation, apoptosis, tumorigenesis, and atherosclerosis. However, its role in hepatic triglyceride metabolism remains unknown. In the present study, we found that expression levels of STC2 were significantly reduced in the livers of leptin-deficient and high fat diet-induced obese mice. Systemic administration of STC2 recombinant protein or adenovirus-mediated overexpression of STC2 markedly attenuated hepatosteatosis and hypertriglyceridemia in obese mice. At the molecular level, we found that STC2 activated the STAT3 signaling pathway to inhibit lipogenic gene expression. Consistently, in vitro studies further showed that inhibition of STAT3 signaling abolished the anti-steatotic effects of STC2. Together, our results revealed an important role of STC2 in the regulation of hepatic triglyceride metabolism, which might provide a potential therapeutic target for the treatment of fatty liver and related metabolic disorders.
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Affiliation(s)
- Jiejie Zhao
- Department of Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yang Jiao
- Department of Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yuping Song
- Department of Endocrinology and Metabolism, Minhang Branch, Zhongshan Hospital, Central Hospital of Minhang District, Shanghai Minhang Hospital, Fudan University, Shanghai, China
| | - Jianmin Liu
- Department of Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaoying Li
- Department of Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Huijie Zhang
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jialin Yang
- Department of Endocrinology and Metabolism, Minhang Branch, Zhongshan Hospital, Central Hospital of Minhang District, Shanghai Minhang Hospital, Fudan University, Shanghai, China
| | - Yan Lu
- Department of Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
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Li B, Li D, Wang Y, Meng X, Sun X, Tian J, Shi L, Ma F. Schisantherin A alleviated alcohol-induced liver injury by the regulation of alcohol metabolism and NF-kB pathway. Exp Anim 2018; 67:451-461. [PMID: 29806627 PMCID: PMC6219874 DOI: 10.1538/expanim.18-0021] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Schisantherin A (SinA), one of the most abundant active ingredients of Schisandra chinensis, was reported to protect and benefit the liver, however, its effect on alcohol-induced liver injury (ALI) was still not clear. In the present study, an ALI mice model was induced by feeding mice an alcohol-containing liquid diet for four weeks. Then, 100 mg/kg or 200 mg/kg SinA was administered to mice every day by gavage for the last two weeks. Histopathological analysis showed that alcohol-induced liver lipid vacuoles were reduced by SinA. The activities of aspartate aminotransferase (AST, 61.90 ± 14.65 vs. 93.65 ± 20.50, 50.46 ± 13.21 vs. 93.65 ± 20.50) and alanine transaminase (ALT, 41.29 ± 9.20 vs. 64.04 ± 18.13, 36.52 ± 7.71 vs. 64.04 ± 18.13) in the serum of ALI mice were significantly reduced by 100 mg/kg or 200 mg/kg SinA when compared with control mice. Alcohol-induced oxidative stress and the inflammatory response in the liver were suppressed by SinA in a dose-dependent manner. Meanwhile, treatment with SinA decreased alcohol dehydrogenase (ADH) activity and increased acetaldehyde dehydrogenase (ALDH) activity in ALI mice. Alcohol-induced upregulation of CYP2E1 and CYP1A2 in the liver was inhibited by SinA. Further, SinA suppressed activation of the NF-kB pathway in ALI mice. In conclusion, our findings demonstrate that SinA is able to protect against ALI, and this may be, at least in part, caused by regulation of alcohol metabolism and the NF-kB pathway. Our data suggest a therapeutic potential of SinA in the treatment of ALI.
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Affiliation(s)
- Bin Li
- College of Food Science, Shenyang Agricultural University, Shenyang 110866, People's Republic of China
| | - Dongnan Li
- College of Food Science, Shenyang Agricultural University, Shenyang 110866, People's Republic of China
| | - Yuehua Wang
- College of Food Science, Shenyang Agricultural University, Shenyang 110866, People's Republic of China
| | - Xianjun Meng
- College of Food Science, Shenyang Agricultural University, Shenyang 110866, People's Republic of China
| | - Xiyun Sun
- College of Food Science, Shenyang Agricultural University, Shenyang 110866, People's Republic of China
| | - Jinlong Tian
- College of Food Science, Shenyang Agricultural University, Shenyang 110866, People's Republic of China
| | - Lin Shi
- College of Food Science, Shenyang Agricultural University, Shenyang 110866, People's Republic of China
| | - Fengming Ma
- College of Food Science, Shenyang Agricultural University, Shenyang 110866, People's Republic of China
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50
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Cheng CF, Pan TM. Monascus-fermented red mold dioscorea protects mice against alcohol-induced liver injury, whereas its metabolites ankaflavin and monascin regulate ethanol-induced peroxisome proliferator-activated receptor-γ and sterol regulatory element-binding transcription factor-1 expression in HepG2 cells. JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE 2018; 98:1889-1898. [PMID: 28902410 DOI: 10.1002/jsfa.8670] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/22/2017] [Revised: 09/04/2017] [Accepted: 09/05/2017] [Indexed: 06/07/2023]
Abstract
BACKGROUND Alcoholic hepatitis is a necroinflammatory process that is associated with fibrosis and leads to cirrhosis in 40% of cases. The hepatoprotective effects of red mold dioscorea (RMD) from Monascus purpureus NTU 568 were evaluated in vivo using a mouse model of chronic alcohol-induced liver disease (ALD). RESULTS ALD mice were orally administered vehicle (ALD group) or vehicle plus 307.5, 615.0 or 1537.5 mg kg-1 (1 ×, 2 × and 5 ×) RMD for 5 weeks. RMD lowered serum leptin, hepatic total cholesterol, free fatty acid and hepatic triglyceride levels and increased serum adiponectin, hepatic alcohol dehydrogenase and antioxidant enzyme levels. Furthermore, ankaflavin (AK) and monascin (MS), metabolites of RMD fermented with M. purpureus 568, induced peroxisome proliferator-activated receptor-γ expression and the concomitant suppression of ethanol-induced elevation of sterol regulatory element-binding transcription factor-1 and TG in HepG2 cells. CONCLUSION These results indicate the hepatoprotective effect of Monascus-fermented RMD. Moreover, AK and MS were identified as the active constituents of RMD for the first time and were shown to protect against ethanol-induced liver damage. © 2017 Society of Chemical Industry.
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Affiliation(s)
- Chih-Fu Cheng
- Department of Biochemical Science and Technology, College of Life Science, National Taiwan University, Taipei, Taiwan
| | - Tzu-Ming Pan
- Department of Biochemical Science and Technology, College of Life Science, National Taiwan University, Taipei, Taiwan
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