|
1
|
Feng ZG, Geng ZJ, Song Q, Hu H, Tan XY, Zeng SY, Zhou RY, Ma X, Liu Y, Zhang Y. Metabolomics based analysis reveals the therapeutic effects of Incarvillea arguta (Royle) Royle aqueous extract against alcohol-induced liver injury. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 140:156639. [PMID: 40085992 DOI: 10.1016/j.phymed.2025.156639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Revised: 03/08/2025] [Accepted: 03/11/2025] [Indexed: 03/16/2025]
Abstract
BACKGROUND Alcohol-induced liver injury (ALI) poses a significant threat to global human health. The Chinese Yi medicine Liangtoumao (LTM), which originated from the whole plant of Incarvillea arguta Royle (Royle), has been widely used by the Yi ethnic group to prevent and treat ALI and other liver diseases. However, its effectiveness and mechanisms are still under-researched. PURPOSE The objective of our research is to investigate the chemical composition of LTM aqueous extract, evaluate its potential therapeutic intervention effect on ALI, and explore its mechanisms in rat models. METHODS The chemical components and constituents of LTM aqueous extract migrating to the blood were analyzed by UPLC-Q-TOF/MS. Sprague-Dawley rats subjected to chronic binge alcohol exposure were utilized to establish chronic ALI models and evaluate the therapeutic effects of LTM aqueous extract. Serum and spatial metabolomics analyses were used to investigate potential mechanisms. RESULTS A total of 60 chemical components in LTM aqueous extract were identified, with 67 absorbed into the blood, including 29 original compounds and 38 metabolites. Treatment with LTM aqueous extract remarkably alleviated hepatic lesions in livers of ALI rats, improved liver function, reduced oxidative stress and inflammation. Serum metabolomics and hepatic spatial metabolomics identified 30 and 215 differential metabolites, respectively. Metabolic pathways of glyoxylate and dicarboxylate, glycerophospholipid, linoleic acid, taurine and hypotaurine, and cysteine and methionine were closely related to the hepaprotective effects of LTM. CONCLUSION Our research confirmed significant effects of LTM on ALI prevention and treatment for the first time. Metabolomic findings revealed that LTM significantly influences various aspects of lipid metabolism. This study supports expanded mechanism investigations of LTM and explores its possibility as a potential ALI therapy.
Collapse
Affiliation(s)
- Zi-Ge Feng
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; College of Pharmacy and Food, Southwest Minzu University, Chengdu 610225, China
| | - Zang-Jia Geng
- College of Pharmacy and Food, Southwest Minzu University, Chengdu 610225, China
| | - Qin Song
- College of Pharmacy and Food, Southwest Minzu University, Chengdu 610225, China
| | - Hu Hu
- College of Pharmacy and Food, Southwest Minzu University, Chengdu 610225, China
| | - Xiao-Yan Tan
- Chongqing Three Gorges Medical College, Chongqing 404120, China
| | - Shang-Yu Zeng
- Urban Vocational College of Sichuan, Chengdu 610110, China
| | - Rong-Yu Zhou
- College of Pharmacy and Food, Southwest Minzu University, Chengdu 610225, China
| | - Xiao Ma
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
| | - Yue Liu
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
| | - Yi Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
| |
Collapse
|
|
2
|
Khunger S, Mewara A, Kaur U, Duseja A, Ray P, Kalra N, Sharma N, Sehgal R. Toll-like receptor upregulation in liver and peripheral blood mononuclear cells of patients with amoebic liver abscess. Immunobiology 2025; 230:152869. [PMID: 39919544 DOI: 10.1016/j.imbio.2025.152869] [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: 05/21/2024] [Revised: 12/24/2024] [Accepted: 01/08/2025] [Indexed: 02/09/2025]
Abstract
AIM We aimed to understand the host and microbe interactions at the time of infection and inflammatory response in amoebic liver abscess (ALA) patients based on toll-like receptor (TLR) expression (mRNA), cytokine and IgG subtypes levels. METHODS AND RESULTS Liver aspirates from 100 ALA patients and 11 liver autopsy samples were used as negative controls. Blood samples from 100 ALA and 41 healthy individuals were collected. mRNA expression of TLR 1 to 9 genes was measured using reverse transcriptase polymerase chain reaction (RT-PCR). Serum cytokines level was quantified by flow cytometry. In-house ELISA for the analysis of IgG and its subtypes in the serum samples was performed. A total of 7 TLR genes (TLR1, TLR2, TLR4, TLR6, TLR7, TLR8 and TLR9) and 6 TLR genes (TLR1, TLR2, TLR3, TLR4, TLR5 and TLR8) were found to be elevated in liver aspirates and PBMCs respectively. Increased serum cytokine levels were observed in ALA patients vs. healthy controls. Interestingly, a significant increase in IgG and its subtypes (IgG1, IgG3 and IgG4) was found in the serum of ALA patients. CONCLUSION Increased levels of TLR, pro- and anti-inflammatory cytokines, IgG and its subtypes, are possibly linked with early-stage infection in ALA patients. IMPACT STATEMENT The role of TLRs in association with ALA might provide insights into new therapeutic strategies.
Collapse
Affiliation(s)
- Sandhya Khunger
- Department of Medical Parasitology, Postgraduate Institute of Medical Education and Research, Chandigarh, India; Department of Microbiology (FAHS), Shree Guru Gobind Singh Tricentenary (SGT) University, Gurugram, (Haryana) 122505,India
| | - Abhishek Mewara
- Department of Medical Parasitology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Upninder Kaur
- Department of Medical Parasitology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Ajay Duseja
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Pallab Ray
- Department of Medical Microbiology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Naveen Kalra
- Department of Radiodiagnosis and Imaging, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Navneet Sharma
- Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Rakesh Sehgal
- Department of Microbiology, Aarupadai Veed Medical College and Hospital, Vinayaka Mission's Research Foundation- DU, Pondicherry, India.
| |
Collapse
|
|
3
|
Yuan Y, Zhang Y, Hu C, Wang Z, Xu Q, Pan R, Li X, Christian M, Zhu P, Zhao J. Chrysanthemum extract mitigates high-fat diet-induced inflammation, intestinal barrier damage and gut microbiota disorder. Food Funct 2025; 16:1347-1359. [PMID: 39873557 DOI: 10.1039/d4fo04889j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2025]
Abstract
An effective intervention for obesity without side effects is needed. Chrysanthemum may be the preferred choice due to its influence in the improvement of glycolipid metabolism. This study assessed the efficacy of chrysanthemum and its flavonoids in mitigating high-fat diet (HFD) induced obesity, focusing on the integrity of the intestinal barrier, inflammation, and gut microbiota. Fifty male C57BL/6J mice were divided into 5 groups randomly: normal control (NC), HFD, HFD with chrysanthemum aqueous extract (CM), HFD with a low-dose flavonoid extract of chrysanthemum (FLL), and HFD with a high-dose flavonoid extract of chrysanthemum (FLH). The results showed that after 9 weeks of intervention with CM, FLL and FLH, the body weight and blood lipid levels of mice were reduced. The chrysanthemum treatment regimens down-regulated the gene expression and protein levels of TLR4, MyD88, TRAF6 and NF-κB, upregulated the gene expression levels of ZO-1 and occludin, and decreased the levels of LPS and diamine oxidase (DAO) in the serum. With CM, FLL and FLH, the levels of the inflammatory factors IL-1β, TNF-α, and IL-6 were decreased, and the abundance of pernicious bacteria Lachnoclostridium, Streptococcus and Enterococcus was decreased. Notably, the purified chrysanthemum flavonoid extract showed greater effects as compared to the CM. The study demonstrated that chrysanthemum extracts could achieve anti-obesity effects by strengthening the intestinal barrier function, relieving inflammation and modulating the gut microbial composition.
Collapse
Affiliation(s)
- Yiwei Yuan
- Institute of Food Nutrition and Quality Safety, College of Life Sciences, China Jiliang University, Hangzhou, Zhejiang, 310018, China.
| | - Yu Zhang
- Institute of Food Nutrition and Quality Safety, College of Life Sciences, China Jiliang University, Hangzhou, Zhejiang, 310018, China.
| | - Chunli Hu
- Food and Drug Inspection and Testing Center, Chunan, Zhejiang, 311700, China
| | - Zhenyu Wang
- Institute of Food Nutrition and Quality Safety, College of Life Sciences, China Jiliang University, Hangzhou, Zhejiang, 310018, China.
| | - Qianqian Xu
- Institute of Food Nutrition and Quality Safety, College of Life Sciences, China Jiliang University, Hangzhou, Zhejiang, 310018, China.
| | - Ruili Pan
- Institute of Food Nutrition and Quality Safety, College of Life Sciences, China Jiliang University, Hangzhou, Zhejiang, 310018, China.
| | - Xiaojun Li
- Doctor Innovation Workstation of Zhejiang Yifutang Tea Industry Co., Ltd, Tonglu, Zhejiang, 311500, China
| | - Mark Christian
- School of Science and Technology, Nottingham Trent University, Clifton, Nottingham, NG11 8NS, UK
| | - Peinan Zhu
- Qiandao Lake Pure Zhejiang Agricultural Development Co., Ltd, Chunan, Zhejiang, 311701, China
| | - Jin Zhao
- Institute of Food Nutrition and Quality Safety, College of Life Sciences, China Jiliang University, Hangzhou, Zhejiang, 310018, China.
- Doctor Innovation Workstation of Zhejiang Yifutang Tea Industry Co., Ltd, Tonglu, Zhejiang, 311500, China
| |
Collapse
|
|
4
|
da Silva Pereira ENG, Franco RLC, Santos RDCD, Daliry A. Statins and non-alcoholic fatty liver disease: A concise review. Biomed Pharmacother 2025; 183:117805. [PMID: 39755024 DOI: 10.1016/j.biopha.2024.117805] [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: 10/16/2024] [Revised: 12/12/2024] [Accepted: 12/28/2024] [Indexed: 01/06/2025] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a common hepatic manifestation of metabolic syndrome affecting 20-30 % of the adult population worldwide. This disease, which includes simple steatosis and non-alcoholic steatohepatitis, poses a significant risk for cardiovascular and metabolic diseases. Lifestyle modifications are crucial in the treatment of NAFLD; however, patient adherence remains challenging. As there is no specific treatment, drug repositioning is being researched as an alternative strategy. Statins, which are known for their cholesterol-lowering effects, are considered potential interventions for NAFLD. This review aimed to present the current understanding of the effects of statins on liver physiology in the context of NAFLD. The pathophysiology of NAFLD includes steatosis, inflammation, and fibrosis, which are exacerbated by dyslipidemia and insulin resistance. Statins, which inhibit 3-hydroxy-3-methylglutaryl-CoA reductase, have pleiotropic effects beyond cholesterol-lowering and affect pathways related to inflammation, fibrogenesis, oxidative stress, and microcirculation. Although clinical guidelines support the use of statins for dyslipidemia in patients with NAFLD, more studies are needed to demonstrate their efficacy in liver disease. This comprehensive review serves as a foundation for future studies on the therapeutic potential of statins in NAFLD.
Collapse
Affiliation(s)
| | - Rafaela Luiza Costa Franco
- Laboratory of Clinical and Experimental Physiopathology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil
| | - Rafaele Dantas Cruz Dos Santos
- Laboratory of Clinical and Experimental Physiopathology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil
| | - Anissa Daliry
- Laboratory of Clinical and Experimental Physiopathology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil
| |
Collapse
|
|
5
|
Bahriz HA, Abdelaziz RR, El-Kashef DH. Desloratadine mitigates hepatocellular carcinoma in rats: Possible contribution of TLR4/MYD88/NF-κB pathway. Toxicol Appl Pharmacol 2025; 495:117202. [PMID: 39672344 DOI: 10.1016/j.taap.2024.117202] [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: 04/28/2024] [Revised: 07/03/2024] [Accepted: 12/08/2024] [Indexed: 12/15/2024]
Abstract
Chemotherapeutic medication-induced systemic toxicity makes cancer treatment less effective. Thus, the need for drug repurposing, which aids in the development of safe and efficient cancer therapies, is urgent. The primary goal of this research was to assess desloratadine hepatoprotective abilities and its capacity to attenuate TLR4/MyD88/NF-κB inflammatory pathway in hepatocellular carcinoma (HCC) induced by thioacetamide (TAA). Male Sprague Dawely rats received TAA injections (200 mg/kg, i.p., 2 times/week) for 16 weeks. To confirm the development of HCC, liver function biomarkers and histopathological analysis were evaluated. Desloratadine (5 mg/kg, p.o.) was administered to rats in 2 treatment groups; HCC + DES 1 group received desloratadine with TAA for 1 month from week 13-16, HCC + DES 2 group received desloratadine with TAA for 2 months from week 9-16. Chronic TAA administration resulted in considerable overexpression of the profibrogenic cytokine TGF-β and elevation in protein expression of NF-κB besides levels of TLR4, MyD88, TRAF6, TAK1 and IL-1β. Desloratadine administration showed a significant improvement in liver function tests, as well as an increase in tissue antioxidant enzymes and an improvement in the liver's histopathological features. Collectively, desloratadine through modulating TLR4/MyD88/TRAF6/TAK1/NF-κB and acting as an antioxidant, is a promising treatment for HCC induced by TAA.
Collapse
Affiliation(s)
- Heba A Bahriz
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | - Rania R Abdelaziz
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
| | - Dalia H El-Kashef
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| |
Collapse
|
|
6
|
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.
Collapse
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.)
| |
Collapse
|
|
7
|
Hejazi S, Moosavi M, Molavinia S, Mansouri E, Azadnasab R, Khodayar MJ. Epicatechin ameliorates glucose intolerance and hepatotoxicity in sodium arsenite-treated mice. Food Chem Toxicol 2024; 192:114950. [PMID: 39182636 DOI: 10.1016/j.fct.2024.114950] [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: 06/03/2024] [Revised: 08/04/2024] [Accepted: 08/21/2024] [Indexed: 08/27/2024]
Abstract
Arsenic is a metalloid found in the environment that causes toxic effects in different organs, mainly the liver. This study aimed to investigate the protective effects of epicatechin (EC), a natural flavonol, on glucose intolerance (GI) and liver toxicity caused by sodium arsenite (SA) in mice. Our findings showed that SA exposure led to the development of GI. Liver tissue damage and decreased pancreatic Langerhans islet size were also observed in this study. Mice exposed to SA exhibited hepatic oxidative damage, indicated by reduced antioxidant markers (such as superoxide dismutase, catalase, glutathione peroxidase, and glutathione), along with elevated levels of thiobarbituric acid reactive substances. SA administration elevated the serum activities of liver enzymes alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase. Furthermore, notable increases in the levels of inflammatory and apoptotic markers (Toll-like receptor 4, nuclear factor-kappa B, tumor necrosis factor-α, nitric oxide, B-cell lymphoma-2, and cysteine aspartate-specific protease-3) were observed in the liver. Treatment of SA-exposed mice with EC considerably reversed these biochemical and histological changes. This study demonstrated the beneficial effects of EC in ameliorating SA-induced hyperglycemia and hepatotoxicity due to its ability to enhance the antioxidant system by modulating inflammation and apoptosis.
Collapse
Affiliation(s)
- Sara Hejazi
- Toxicology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mehrnoosh Moosavi
- Toxicology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; Department of Toxicology, School of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Shahrzad Molavinia
- Toxicology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Esrafil Mansouri
- Cellular and Molecular Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Reza Azadnasab
- Toxicology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mohammad Javad Khodayar
- Toxicology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; Department of Toxicology, School of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
| |
Collapse
|
|
8
|
Khaksari M, Pourali M, Rezaei Talabon S, Gholizadeh Navashenaq J, Bashiri H, Amiresmaili S. Protective effects of 17-β-estradiol on liver injury: The role of TLR4 signaling pathway and inflammatory response. Cytokine 2024; 181:156686. [PMID: 38991382 DOI: 10.1016/j.cyto.2024.156686] [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: 04/20/2024] [Revised: 06/23/2024] [Accepted: 06/25/2024] [Indexed: 07/13/2024]
Abstract
Liver injury, a major global health issue, stems from various causes such as alcohol consumption, nonalcoholic steatohepatitis, obesity, diabetes, metabolic syndrome, hepatitis, and certain medications. The liver's unique susceptibility to ischemia and hypoxia, coupled with the critical role of the gut-liver axis in inflammation, underscores the need for effective therapeutic interventions. The study highlights E2's interaction with estrogen receptors (ERs) and its modulation of the Toll-like receptor 4 (TLR4) signaling pathway as key mechanisms in mitigating liver injury. Activation of TLR4 leads to the release of pro-inflammatory cytokines and chemokines, exacerbating liver inflammation and injury. E2 down-regulates TLR4 expression, reduces oxidative stress, and inhibits pro-inflammatory cytokines, thereby protecting the liver. Both classic (ERα and ERβ) and non-classic [G protein-coupled estrogen receptor (GPER)] receptors are influenced by E2. ERα is particularly crucial for liver regeneration, preventing liver failure by promoting hepatocyte proliferation. Furthermore, E2 exerts anti-inflammatory, antioxidant, and anti-apoptotic effects by inhibiting cytokines such as IL-6, IL-1β, TNF-α, and IL-17, and by reducing lipid peroxidation and free radical damage. The article calls for further clinical research to validate these findings and to develop estrogen-based treatments for liver injuries. Overall, the research emphasizes the significant potential of E2 as a therapeutic agent for liver injuries. It advocates for extensive clinical studies to validate E2 hepatoprotective properties and develop effective estrogen-based treatments.
Collapse
Affiliation(s)
- Mohammad Khaksari
- Neuroscince and Endocrinology and Metabolism Research Centers, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | | | | | | | - Hamideh Bashiri
- Neuroscience Research Center, Institute of Neuropharmacology, Department of Physiology and Pharmacology, Afzalipour School of Medicine, Kerman University of Medical Sciences, Kerman, Ira
| | | |
Collapse
|
|
9
|
Lin YL, Cheng KC, Kao YF, Wu K, Chen JW, Nakthong S, Chen YC. Valorization of broiler edible byproducts: a chicken-liver hydrolysate with hepatoprotection against binge drinking. Poult Sci 2024; 103:104023. [PMID: 39002366 PMCID: PMC11298911 DOI: 10.1016/j.psj.2024.104023] [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: 03/24/2024] [Revised: 06/03/2024] [Accepted: 06/20/2024] [Indexed: 07/15/2024] Open
Abstract
Over 10,000 metric-ton broiler livers are produced annually in Taiwan. Concerning unpleasant odor and healthy issue, broiler livers are not attractive to consumers. Although the patented chicken-liver hydrolysates (CLHs) through pepsin digestion possess several biofunctionalities, there is no study on hepatoprotection of CLH-based formula capsule (GBHP01) against binge drinking (Whiskey, 50% Alc./Vol.). GBHP01 led to an accelerated blood-alcohol clearance in rats, as evidenced by lowering blood-alcohol increment within 0 to 4 h, increasing blood-alcohol decrement within 4 to 8 h, and smaller blood alcohol concentration areas under the curve (BAC AUC) in the 8-h period (p < 0.05). The ameliorative effects of GBHP01 against binge drinking in rats over 6 wk were attributed to accelerated alcohol metabolism by further increasing alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) activities while downregulating cytochrome P450 2E1 (CYP2E1) protein expression, elevating antioxidant capacity, decreasing zonula occludens-1 (ZO-1) protein decrement and serum endotoxin, and reducing inflammation related protein levels, that is, toll-like receptor 4 (TLR4) and mitogen-activated protein kinase (MAPK), and proinflammatory cytokines. The development of CLH supplements could not only enhance the added value of broiler livers through nutraceutical development but also offer a strategy to maximize the utilization of poultry processing residues, as shown in this study.
Collapse
Affiliation(s)
- Yi-Ling Lin
- Department of Animal Science and Technology, National Taiwan University, Taipei City 106037, Taiwan; Undergraduate and Graduate Programs of Nutrition Science, National Taiwan Normal University, Taipei City 116059, Taiwan
| | - Kuan-Chen Cheng
- Institute of Food Science and Technology, National Taiwan University, Taipei City 106319, Taiwan; Department of Optometry, Asia University, Taichung City 413305, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung City 404328, Taiwan
| | - Yi-Feng Kao
- Seafood Technology Division, Fisheries Research Institute, Ministry of Agriculture, Keelung City 202008, Taiwan
| | - Kang Wu
- Department of Animal Science and Technology, National Taiwan University, Taipei City 106037, Taiwan
| | - Jr-Wei Chen
- Department of Animal Industry, Ministry of Agriculture, Executive Yuan, Taipei City 100212, Taiwan
| | - Sasitorn Nakthong
- Department of Food Safety Innovation, Faculty of Agriculture at Kamphaeng Saen, Kasetsart University, Kamphaeng Saen Campus, Nakhon Pathom Province 73140, Thailand
| | - Yi-Chen Chen
- Department of Animal Science and Technology, National Taiwan University, Taipei City 106037, Taiwan; Master Program in Global Agriculture Technology and Genomic Science, International College, National Taiwan University, Taipei City 106319, Taiwan..
| |
Collapse
|
|
10
|
Ali FEM, Abdel-Reheim MA, Hassanein EHM, Abd El-Aziz MK, Althagafy HS, Badran KSA. Exploring the potential of drug repurposing for liver diseases: A comprehensive study. Life Sci 2024; 347:122642. [PMID: 38641047 DOI: 10.1016/j.lfs.2024.122642] [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: 02/09/2024] [Revised: 03/24/2024] [Accepted: 04/10/2024] [Indexed: 04/21/2024]
Abstract
Drug repurposing involves the investigation of existing drugs for new indications. It offers a great opportunity to quickly identify a new drug candidate at a lower cost than novel discovery and development. Despite the importance and potential role of drug repurposing, there is no specific definition that healthcare providers and the World Health Organization credit. Unfortunately, many similar and interchangeable concepts are being used in the literature, making it difficult to collect and analyze uniform data on repurposed drugs. This research was conducted based on understanding general criteria for drug repurposing, concentrating on liver diseases. Many drugs have been investigated for their effect on liver diseases even though they were originally approved (or on their way to being approved) for other diseases. Some of the hypotheses for drug repurposing were first captured from the literature and then processed further to test the hypothesis. Recently, with the revolution in bioinformatics techniques, scientists have started to use drug libraries and computer systems that can analyze hundreds of drugs to give a short list of candidates to be analyzed pharmacologically. However, this study revealed that drug repurposing is a potential aid that may help deal with liver diseases. It provides available or under-investigated drugs that could help treat hepatitis, liver cirrhosis, Wilson disease, liver cancer, and fatty liver. However, many further studies are needed to ensure the efficacy of these drugs on a large scale.
Collapse
Affiliation(s)
- Fares E M Ali
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut 71524, Egypt; Michael Sayegh, Faculty of Pharmacy, Aqaba University of Technology, Aqaba 77110, Jordan
| | - Mustafa Ahmed Abdel-Reheim
- Department of Pharmaceutical Sciences, College of Pharmacy, Shaqra University, Shaqra 11961, Saudi Arabia; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni Suef 62521, Egypt.
| | - Emad H M Hassanein
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut 71524, Egypt.
| | - Mostafa K Abd El-Aziz
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut 71524, Egypt
| | - Hanan S Althagafy
- Department of Biochemistry, Faculty of Science, University of Jeddah, Jeddah, Saudi Arabia
| | - Khalid S A Badran
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut 71524, Egypt
| |
Collapse
|
|
11
|
Grøndal SM, Tutusaus A, Boix L, Reig M, Blø M, Hodneland L, Gausdal G, Jackson A, Garcia de Frutos P, Lorens JB, Morales A, Marí M. Dynamic changes in immune cell populations by AXL kinase targeting diminish liver inflammation and fibrosis in experimental MASH. Front Immunol 2024; 15:1400553. [PMID: 38817615 PMCID: PMC11137289 DOI: 10.3389/fimmu.2024.1400553] [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: 03/13/2024] [Accepted: 04/23/2024] [Indexed: 06/01/2024] Open
Abstract
Background and aims Metabolic dysfunction-associated steatohepatitis (MASH) is a significant health concern with limited treatment options. AXL, a receptor tyrosine kinase activated by the GAS6 ligand, promotes MASH through activation of hepatic stellate cells and inflammatory macrophages. This study identified cell subsets affected by MASH progression and the effect of AXL inhibition. Methods Mice were fed chow or different fat-enriched diets to induce MASH, and small molecule AXL kinase inhibition with bemcentinib was evaluated. Gene expression was measured by qPCR. Time-of-flight mass cytometry (CyTOF) used single cells from dissociated livers, acquired on the Fluidigm Helios, and cell populations were studied using machine learning. Results In mice fed different fat-enriched diets, liver steatosis alone was insufficient to elevate plasma soluble AXL (sAXL) levels. However, in conjunction with inflammation, sAXL increases, serving as an early indicator of steatohepatitis progression. Bemcentinib, an AXL inhibitor, effectively reduced proinflammatory responses in MASH models, even before fibrosis appearance. Utilizing CyTOF analysis, we detected a decreased population of Kupffer cells during MASH while promoting infiltration of monocytes/macrophages and CD8+ T cells. Bemcentinib partially restored Kupffer cells, reduced pDCs and GzmB- NK cells, and increased GzmB+CD8+ T cells and LSECs. Additionally, AXL inhibition enhanced a subtype of GzmB+CD8+ tissue-resident memory T cells characterized by CX3CR1 expression. Furthermore, bemcentinib altered the transcriptomic landscape associated with MASH progression, particularly in TLR signaling and inflammatory response, exhibiting differential cytokine expression in the plasma, consistent with liver repair and decreased inflammation. Conclusion Our findings highlight sAXL as a biomarker for monitoring MASH progression and demonstrate that AXL targeting shifted liver macrophages and CD8+ T-cell subsets away from an inflammatory phenotype toward fibrotic resolution and organ healing, presenting a promising strategy for MASH treatment.
Collapse
Affiliation(s)
- Sturla Magnus Grøndal
- Department of Biomedicine, Centre for Cancer Biomarkers, University of Bergen, Bergen, Norway
| | - Anna Tutusaus
- Institute of Biomedical Research of Barcelona (IIBB-CSIC), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Barcelona Clinic Liver Cancer Center (BCLC), Hospital Clínic de Barcelona, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
| | - Loreto Boix
- Barcelona Clinic Liver Cancer Center (BCLC), Hospital Clínic de Barcelona, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
| | - Maria Reig
- Barcelona Clinic Liver Cancer Center (BCLC), Hospital Clínic de Barcelona, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
| | | | | | | | | | - Pablo Garcia de Frutos
- Institute of Biomedical Research of Barcelona (IIBB-CSIC), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Unidad Asociada (IMIM), Institute of Biomedical Research of Barcelona (IIBB-CSIC), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), ISCIII, Madrid, Spain
| | - James Bradley Lorens
- Department of Biomedicine, Centre for Cancer Biomarkers, University of Bergen, Bergen, Norway
- BerGenBio ASA, Bergen, Norway
| | - Albert Morales
- Institute of Biomedical Research of Barcelona (IIBB-CSIC), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Barcelona Clinic Liver Cancer Center (BCLC), Hospital Clínic de Barcelona, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
| | - Montserrat Marí
- Institute of Biomedical Research of Barcelona (IIBB-CSIC), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Barcelona Clinic Liver Cancer Center (BCLC), Hospital Clínic de Barcelona, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
| |
Collapse
|
|
12
|
Alghamdi W, Mosli M, Alqahtani SA. Gut microbiota in MAFLD: therapeutic and diagnostic implications. Ther Adv Endocrinol Metab 2024; 15:20420188241242937. [PMID: 38628492 PMCID: PMC11020731 DOI: 10.1177/20420188241242937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Accepted: 02/22/2024] [Indexed: 04/19/2024] Open
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD), formerly known as nonalcoholic fatty liver disease, is becoming a significant contributor to chronic liver disease globally, surpassing other etiologies, such as viral hepatitis. Prevention and early treatment strategies to curb its growing prevalence are urgently required. Recent evidence suggests that targeting the gut microbiota may help treat and alleviate disease progression in patients with MAFLD. This review aims to explore the complex relationship between MAFLD and the gut microbiota in relation to disease pathogenesis. Additionally, it delves into the therapeutic strategies targeting the gut microbiota, such as diet, exercise, antibiotics, probiotics, synbiotics, glucagon-like peptide-1 receptor agonists, and fecal microbiota transplantation, and discusses novel biomarkers, such as microbiota-derived testing and liquid biopsy, for their diagnostic and staging potential. Overall, the review emphasizes the urgent need for preventive and therapeutic strategies to address the devastating consequences of MAFLD at both individual and societal levels and recognizes that further exploration of the gut microbiota may open avenues for managing MAFLD effectively in the future.
Collapse
Affiliation(s)
- Waleed Alghamdi
- Division of Gastroenterology, Department of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mahmoud Mosli
- Division of Gastroenterology, Department of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Saleh A. Alqahtani
- Organ Transplant Center of Excellence, King Faisal Specialist Hospital & Research Center, Riyadh 11211, Saudi Arabia
- Division of Gastroenterology & Hepatology, Johns Hopkins University, Baltimore, MD, USA
| |
Collapse
|
|
13
|
Martínez-López S, Ángel-Gomis E, Gómez-Hurtado I, Fernández-Iglesias A, Morante J, Gracia-Sancho J, Boix P, Cubero FJ, Zapater P, Caparrós E, Francés R. Cirrhosis-downregulated LSECtin can be retrieved by cytokines, shifts the TLR-induced LSECs secretome and correlates with the hepatic Th response. Liver Int 2024; 44:996-1010. [PMID: 38293766 DOI: 10.1111/liv.15836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 12/07/2023] [Accepted: 12/26/2023] [Indexed: 02/01/2024]
Abstract
BACKGROUND AND AIMS We evaluated tolerogenic C-type lectin LSECtin loss in cirrhosis and its potential regulation by cytokines. METHODS Liver tissue from patients with cirrhosis and healthy controls, immortalised and generated LSECtin-CRISPR immortalised LSECs, and murine primary LSECs from the CCl4 model were handled. RESULTS LSECtin expression was reduced in liver tissue from cirrhotic patients, and it decreased from compensated to decompensated disease. Increased phosphorylation of MAPK, Akt and NFkB was observed upon LSECtin stimulation in LSEC murine cell line, showing a pattern of inflammatory and chemotactic cytokines either restrained (IL-10, CCL4) or unrestrained (TNF-α, IL-1β, IL-6, CCL2). CD44 attenuated whereas LAG-3 increased all substrates phosphorylation in combination with TLR4 and TLR2 ligands except for NFkB. TNF-α, IL-1 β, IL-6 and CCL2 were restrained by LSECtin crosslinking on TLRs studied. Conversely, IL-10 and CCL4 were upregulated, suggesting a LSECtin-TLRs synergistic effect. Also, LSECtin was significantly induced after IL-13 stimulation or combined with anti-inflammatory cytokines in cirrhotic and immortalised LSECs. Th17 and regulatory T cells were progressively increased in the hepatic tissue from compensated to decompensated patients. A significant inverse correlation was present between gene expression levels of CLEC4G/LSECtin and RORγT and FOXP3 in liver tissues. CONCLUSION LSECtin restrains TLR proinflammatory secretome induced on LSECs by interfering immune response control, survival and MAPKs signalling pathways. The cytokine-dependent induction of LSECtin and the association between LSECtin loss and Th17 cell subset expansion in the liver, provides a solid background for exploring LSECtin retrieval as a mechanism to reprogram LSEC homeostatic function hampered during cirrhosis.
Collapse
Affiliation(s)
- Sebastián Martínez-López
- Hepatic and Intestinal Immunobiology Group, Departamento de Medicina Clínica, Universidad Miguel Hernández, San Juan de Alicante, Spain
- IIS ISABIAL, Hospital General Universitario Dr. Balmis, Alicante, Spain
| | - Enrique Ángel-Gomis
- Hepatic and Intestinal Immunobiology Group, Departamento de Medicina Clínica, Universidad Miguel Hernández, San Juan de Alicante, Spain
- IIS ISABIAL, Hospital General Universitario Dr. Balmis, Alicante, Spain
| | - Isabel Gómez-Hurtado
- Hepatic and Intestinal Immunobiology Group, Departamento de Medicina Clínica, Universidad Miguel Hernández, San Juan de Alicante, Spain
- IIS ISABIAL, Hospital General Universitario Dr. Balmis, Alicante, Spain
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
| | - Anabel Fernández-Iglesias
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
- Liver Vascular Biology Research Group, IDIBAPS, Barcelona, Spain
| | - Javier Morante
- Instituto de Neurociencias, CSIC-UMH, San Juan de Alicante, Spain
| | - Jordi Gracia-Sancho
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
- Liver Vascular Biology Research Group, IDIBAPS, Barcelona, Spain
| | - Paula Boix
- Hepatic and Intestinal Immunobiology Group, Departamento de Medicina Clínica, Universidad Miguel Hernández, San Juan de Alicante, Spain
- IIS ISABIAL, Hospital General Universitario Dr. Balmis, Alicante, Spain
| | - Francisco J Cubero
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
- Department of Immunology, Ophthalmology and ENT, School of Medicine, Complutense University, Madrid, Spain
| | - Pedro Zapater
- Hepatic and Intestinal Immunobiology Group, Departamento de Medicina Clínica, Universidad Miguel Hernández, San Juan de Alicante, Spain
- IIS ISABIAL, Hospital General Universitario Dr. Balmis, Alicante, Spain
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
- Instituto IDIBE, Universidad Miguel Hernández, Elche, Spain
| | - Esther Caparrós
- Hepatic and Intestinal Immunobiology Group, Departamento de Medicina Clínica, Universidad Miguel Hernández, San Juan de Alicante, Spain
- IIS ISABIAL, Hospital General Universitario Dr. Balmis, Alicante, Spain
| | - Rubén Francés
- Hepatic and Intestinal Immunobiology Group, Departamento de Medicina Clínica, Universidad Miguel Hernández, San Juan de Alicante, Spain
- IIS ISABIAL, Hospital General Universitario Dr. Balmis, Alicante, Spain
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
- Instituto IDIBE, Universidad Miguel Hernández, Elche, Spain
| |
Collapse
|
|
14
|
Peng Y, Cui H, Shu C, Wei Z, Ni X, Liu J. Triclosan induces liver injury in long-life exposed mice via activation of TLR4/NF-κB/NLRP3 pathway. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2024; 273:116115. [PMID: 38377781 DOI: 10.1016/j.ecoenv.2024.116115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 02/06/2024] [Accepted: 02/13/2024] [Indexed: 02/22/2024]
Abstract
Triclosan (TCS) is a widely used synthetic, with broad-spectrum antibacterial properties found in both pharmaceuticals and personal care products. More specifically, it is hepatotoxic in rodents and exhibits differential effects in mice and humans. However, the mechanisms underlying TCS-induced liver toxicity have not been elucidated. This study examined the role of the toll-like receptor 4 (TLR4)/ nuclear factor kappa B (NF-κB)/ nod-like receptor protein 3 (NLRP3) pathway in TCS-exposed liver toxicity by established a long-life TCS-exposed mice liver injury model. The 24 C57BL/6 pregnant mice exposed to TCS (0, 50 and 100 mg/kg) every day during the gestation and nursing period. After weaning, the male mice were left to continue administrate with TCS until 8 weeks of age. Then, mice in each group were sacrificed for investigation. Long-life exposure to TCS resulted in a reduction of body weight in growth mice. TCS exposure caused the increase of serum ALT, AST and ALP. The situation of inflammatory cell infiltration, macrophage recruitment and collagen fiber deposition in TCS-exposed mice liver tissues were performed by histological analysis including hematoxylin-eosin, Masson, Sirius red, and immunohistochemistry staining. Protein expression levels in TLR4/NF-κB/NLRP3 pathway was measured through Western blot, and the NLRP3 inflammasome activation was measured using real-time quantitative PCR (RT-qPCR). The results showed that exposure to TCS elevated TLR4, myeloid differentiation factor 88 (Myd88), TNF receptor associated factor 6 (TRAF6), enhanced NF-κB activation, and affected NLRP3 inflammasome activation in mice liver. Collectively, these findings indicate that long-life exposure to TCS-induced mice by upregulating the TLR4-Myd88-TRAF6 pathway, activating the NF-κB signaling cascade, initiating the NLRP3 inflammasome pathway, and ultimately leading to liver injury, including inflammation, hepatocyte pyroptosis and hepatofibrosis. Henceforth, the TLR4/NF-κB/NLRP3 pathway may now provide a theoretical basis and valuable therapeutic targets for overcoming TCS-induced liver toxicity.
Collapse
Affiliation(s)
- Yuxuan Peng
- Department of Health Laboratory Technology, School of Public Health, China Medical University, Shenyang 110122, China
| | - He Cui
- Department of Health Laboratory Technology, School of Public Health, China Medical University, Shenyang 110122, China
| | - Chang Shu
- Department of Health Laboratory Technology, School of Public Health, China Medical University, Shenyang 110122, China
| | - Ziyun Wei
- Department of Health Laboratory Technology, School of Public Health, China Medical University, Shenyang 110122, China
| | - Xiao Ni
- Department of Health Laboratory Technology, School of Public Health, China Medical University, Shenyang 110122, China
| | - Jieyu Liu
- Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention (China Medical University), Ministry of Education, China; Department of Health Laboratory Technology, School of Public Health, China Medical University, Shenyang 110122, China.
| |
Collapse
|
|
15
|
Takenaka Y, Tanaka T, Otaki S, Kanbe A, Morita T, Yokoi K, Sekiguchi S, Nakamura K, Satoh H, Tojo T, Uchiumi F, Kitabatake K, Aoki S, Tsukimoto M. Amodiaquine Analogs Are Potent Inhibitors of Interleukin-6 Production Induced by Activation of Toll-Like Receptors Recognizing Pathogen Nucleic Acids. Biol Pharm Bull 2024; 47:2101-2118. [PMID: 39710379 DOI: 10.1248/bpb.b24-00639] [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] [Indexed: 12/24/2024]
Abstract
Excessive inflammatory responses to viral infections, known as cytokine storms, are caused by overactivation of endolysosomal Toll-like receptors (TLRs) (TLR3, TLR7, TLR8, and TLR9) and can be lethal, but no specific treatment is available. Some quinoline derivatives with antiviral activity were tried during the recent coronavirus disease 2019 (COVID-19) pandemic, but showed serious toxicity, and their efficacy for treating viral cytokine storms was not established. Here, in order to discover a low-toxicity quinoline derivative as a candidate for controlling virally induced inflammation, we synthesized a series of derivatives of amodiaquine (ADQ), a quinoline approved as an antimalarial, and tested their effects on TLRs-mediated production of inflammatory cytokines and cell viability in vitro. In J774.1 murine macrophages, ADQ inhibited interleukin-6 (IL-6) production induced by TLR3 agonist poly(I:C), TLR7 agonist imiquimod, and TLR9 agonist cytosine-phosphate-guanosine oligodeoxynucleotide (CpG ODN) with IC50 values of 2.43, 3.48, and 0.0359 µM, respectively, indicating that ADQ has a high inhibitory selectivity for TLR9 signaling. A structure-activity relationship study revealed that an appropriately substituted amino group on the phenol moiety and a halogen substituent on quinoline are important for potent anti-inflammatory activity and low cytotoxicity. ADQ analogs bearing N-butylethyl, N-3-fluoropiperidinyl, and N-4-fluoropiperidinyl groups in place of the N-diethyl group exhibited more potent activity and lower cytotoxicity than ADQ. ADQ and its analogs appear to inhibit the activity of TLRs recognizing pathogen nucleic acids via alkalinization of endolysosomes. Our results suggest that ADQ analogs are promising candidates as therapeutic agents for cytokine storms mediated by TLRs recognizing pathogen nucleic acid with reduced side effects.
Collapse
Affiliation(s)
- Yohei Takenaka
- Department of Radiation Biosciences, Graduate School of Pharmaceutical Sciences, Tokyo University of Science
| | - Tomohiro Tanaka
- Department of Bioorganic and Bioinorganic Chemistry, Graduate School of Pharmaceutical Sciences, Tokyo University of Science
- Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
| | - Shotaro Otaki
- Department of Bioorganic and Bioinorganic Chemistry, Graduate School of Pharmaceutical Sciences, Tokyo University of Science
| | - Azusa Kanbe
- Department of Bioorganic and Bioinorganic Chemistry, Graduate School of Pharmaceutical Sciences, Tokyo University of Science
| | - Tomoe Morita
- Department of Bioorganic and Bioinorganic Chemistry, Graduate School of Pharmaceutical Sciences, Tokyo University of Science
| | - Kenta Yokoi
- Department of Bioorganic and Bioinorganic Chemistry, Graduate School of Pharmaceutical Sciences, Tokyo University of Science
| | - Saki Sekiguchi
- Department of Bioorganic and Bioinorganic Chemistry, Graduate School of Pharmaceutical Sciences, Tokyo University of Science
| | - Koki Nakamura
- Department of Bioorganic and Bioinorganic Chemistry, Graduate School of Pharmaceutical Sciences, Tokyo University of Science
| | - Hidetoshi Satoh
- Department of Bioorganic and Bioinorganic Chemistry, Graduate School of Pharmaceutical Sciences, Tokyo University of Science
| | - Toshifumi Tojo
- Department of Bioorganic and Bioinorganic Chemistry, Graduate School of Pharmaceutical Sciences, Tokyo University of Science
- Research Institute for Science and Technology (RIST), Tokyo University of Science
| | - Fumiaki Uchiumi
- Department of Gene Regulation Graduate School of Pharmaceutical Sciences, Tokyo University of Science
| | - Kazuki Kitabatake
- Department of Radiation Biosciences, Graduate School of Pharmaceutical Sciences, Tokyo University of Science
| | - Shin Aoki
- Department of Bioorganic and Bioinorganic Chemistry, Graduate School of Pharmaceutical Sciences, Tokyo University of Science
- Research Institute for Science and Technology (RIST), Tokyo University of Science
- Research Institute for Biomedical Sciences (RIBS), Tokyo University of Science
| | - Mitsutoshi Tsukimoto
- Department of Radiation Biosciences, Graduate School of Pharmaceutical Sciences, Tokyo University of Science
- Research Institute for Science and Technology (RIST), Tokyo University of Science
| |
Collapse
|
|
16
|
Liu H, Li N, Kuang G, Gong X, Wang T, Hu J, Du H, Zhong M, Guo J, Xie Y, Xiang Y, Wu S, Yuan Y, Yin X, Wan J, Li K. Protectin D1 inhibits TLR4 signaling pathway to alleviate non-alcoholic steatohepatitis via upregulating IRAK-M. Free Radic Biol Med 2024; 210:42-53. [PMID: 37984750 DOI: 10.1016/j.freeradbiomed.2023.11.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 11/09/2023] [Accepted: 11/15/2023] [Indexed: 11/22/2023]
Abstract
Non-alcoholic steatohepatitis (NASH) is a prevalent metabolic disease, characterized by the hepatic steatosis, inflammation, and fibrosis, which is lack of effective treatment currently. Protectin D1 (PTD1), a lipid mediator from omega-3 fatty acid docosahexaenoic acid (DHA), has displayed wide pharmacological actions including anti-inflammation in a variety of diseases, but the role of PTD1 on NASH remains unclear. In this study, using the methionine and choline deficient (MCD) fed NASH model, we explored the effect and underlying mechanism of PTD1 on NASH in mice. Our results showed PTD1 improved MCD-induced steatosis, hepatocellular injury, inflammation and fibrosis. Furthermore, PTD1 inhibited MCD-induced activation of TLR4 downstream molecules (TAK1, p38 and p65) without affecting the levels of TLR4 and phosphorylated IRAK-1. Notably, the levels of IRAK-M protein and the binding between IRAK-M and TRAF6 in the liver were also increased by PTD1 in NASH mice. Moreover, IRAK-M knockout remarkedly reverted the beneficial effects of PTD1 on the NASH in mice. Thus, these results demonstrated that PTD1 could protect mice from NASH by inhibiting the activation of TLR4 downstream signaling pathway, which might be related to the upregulation of IRAK-M, indicating that PTD1 may provide a new treatment for NASH.
Collapse
Affiliation(s)
- Hao Liu
- Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, China; Department of Pharmacology, Chongqing Medical University, Chongqing, China
| | - Nana Li
- Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, China; Department of Pharmacology, Chongqing Medical University, Chongqing, China
| | - Ge Kuang
- Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, China; Department of Pharmacology, Chongqing Medical University, Chongqing, China
| | - Xia Gong
- Department of Anatomy, Chongqing Medical University, Chongqing, China
| | - Ting Wang
- Department of Orthopedics, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jun Hu
- Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, China; Department of Pharmacology, Chongqing Medical University, Chongqing, China
| | - Hui Du
- Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, China; Department of Pharmacology, Chongqing Medical University, Chongqing, China
| | - Minxuan Zhong
- Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, China
| | - Jiashi Guo
- Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, China; Department of Pharmacology, Chongqing Medical University, Chongqing, China
| | - Yao Xie
- Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, China; Department of Pharmacology, Chongqing Medical University, Chongqing, China
| | - Yang Xiang
- Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, China; Department of Pharmacology, Chongqing Medical University, Chongqing, China
| | - Shengwang Wu
- Department of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Yiling Yuan
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Xinru Yin
- Department of Gastroenterology, Institute of Surgery Research, Daping Hospital, Army Medical University, Chongqing, China
| | - Jingyuan Wan
- Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, China; Department of Pharmacology, Chongqing Medical University, Chongqing, China.
| | - Ke Li
- Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, China; Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
| |
Collapse
|
|
17
|
Wang T, Lu Z, Sun GF, He KY, Chen ZP, Qu XH, Han XJ. Natural Products in Liver Fibrosis Management: A Five-year Review. Curr Med Chem 2024; 31:5061-5082. [PMID: 38362686 DOI: 10.2174/0109298673288458240203064112] [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: 10/26/2023] [Revised: 01/11/2024] [Accepted: 01/23/2024] [Indexed: 02/17/2024]
Abstract
Liver fibrosis, characterized by the overproduction of extracellular matrix proteins within liver tissue, poses a rising global health concern. However, no approved antifibrotic drugs are currently available, highlighting the critical need for understanding the molecular mechanisms of liver fibrosis. This knowledge could not only aid in developing therapies but also enable early intervention, enhance disease prediction, and improve our understanding of the interaction between various underlying conditions and the liver. Notably, natural products used in traditional medicine systems worldwide and demonstrating diverse biochemical and pharmacological activities are increasingly recognized for their potential in treating liver fibrosis. This review aims to comprehensively understand liver fibrosis, emphasizing the molecular mechanisms and advancements in exploring natural products' antifibrotic potential over the past five years. It also acknowledges the challenges in their development and seeks to underscore their potency in enhancing patient prognosis and reducing the global burden of liver disease.
Collapse
Affiliation(s)
- Tao Wang
- Institute of Geriatrics, Jiangxi Provincial People's Hospital, the First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, 330006, P.R. China
| | - Zhuo Lu
- Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, P.R. China
| | - Gui-Feng Sun
- Institute of Geriatrics, Jiangxi Provincial People's Hospital, the First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, 330006, P.R. China
| | - Kai-Yi He
- Institute of Geriatrics, Jiangxi Provincial People's Hospital, the First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, 330006, P.R. China
| | - Zhi-Ping Chen
- Department of Critical Care Medicine, Jiangxi Provincial People's Hospital, the First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, 330006, P.R. China
| | - Xin-Hui Qu
- The Second Department of Neurology, Jiangxi Provincial People's Hospital, the First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, 330006, P.R. China
| | - Xiao-Jian Han
- Institute of Geriatrics, Jiangxi Provincial People's Hospital, the First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, 330006, P.R. China
- The Second Department of Neurology, Jiangxi Provincial People's Hospital, the First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, 330006, P.R. China
| |
Collapse
|
|
18
|
Malik JA, Kaur G, Agrewala JN. Revolutionizing medicine with toll-like receptors: A path to strengthening cellular immunity. Int J Biol Macromol 2023; 253:127252. [PMID: 37802429 DOI: 10.1016/j.ijbiomac.2023.127252] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2023] [Revised: 10/01/2023] [Accepted: 10/03/2023] [Indexed: 10/10/2023]
Abstract
Toll-like receptors play a vital role in cell-mediated immunity, which is crucial for the immune system's defense against pathogens and maintenance of homeostasis. The interaction between toll-like-receptor response and cell-mediated immunity is complex and essential for effectively eliminating pathogens and maintaining immune surveillance. In addition to pathogen recognition, toll-like receptors serve as adjuvants in vaccines, as molecular sensors, and recognize specific patterns associated with pathogens and danger signals. Incorporating toll-like receptor ligands into vaccines can enhance the immune response to antigens, making them potent adjuvants. Furthermore, they bridge the innate and adaptive immune systems and improve antigen-presenting cells' capacity to process and present antigens to T cells. The intricate signaling pathways and cross-talk between toll-like-receptor and T cell receptor (TCR) signaling emphasize their pivotal role in orchestrating effective immune responses against pathogens, thus facilitating the development of innovative vaccine strategies. This article provides an overview of the current understanding of toll-like receptor response and explores their potential clinical applications. By unraveling the complex mechanisms of toll-like-receptor signaling, we can gain novel insights into immune responses and potentially develop innovative therapeutic approaches. Ongoing investigations into the toll-like-receptor response hold promise in the future in enhancing our ability to combat infections, design effective vaccines, and improve clinical outcomes.
Collapse
Affiliation(s)
- Jonaid Ahmad Malik
- Immunology Laboratory, Department of Biomedical Engineering, Indian Institute of Technology, Ropar, Punjab 140001, India
| | - Gurpreet Kaur
- Immunology Laboratory, Department of Biomedical Engineering, Indian Institute of Technology, Ropar, Punjab 140001, India; Department of Biotechnology, Chandigarh Group of Colleges, Landran, Mohali, Punjab 140055, India
| | - Javed N Agrewala
- Immunology Laboratory, Department of Biomedical Engineering, Indian Institute of Technology, Ropar, Punjab 140001, India.
| |
Collapse
|
|
19
|
Gilanipour A, Teimoori A, Arabzadeh SA, Mollaie HR, Mousavi E. Toll-like receptor 7 and RIG-I-like receptors expression in peripheral blood mononuclear cells of naïve patients with hepatitis C. BMC Res Notes 2023; 16:344. [PMID: 37993939 PMCID: PMC10664272 DOI: 10.1186/s13104-023-06626-2] [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: 09/11/2023] [Accepted: 11/15/2023] [Indexed: 11/24/2023] Open
Abstract
BACKGROUND The proper function of Pattern Recognition Receptors (PRRs) as a part of the host immune system can eliminate numerous pathogens from the body. However, some viruses can manipulate PRRs to escape the innate immune system. As there is controversy in the activation of PRRs in patients infected with HCV, we decided to evaluate the gene expression changes of PRRs in HCV cases compared to the healthy control. METHODS In this study, the relative expression of Toll-like receptor 7, RIG-I, and MAD-5 in peripheral mononuclear blood cells of twenty HCV patients and twenty healthy controls of the same gender and age were analyzed by quantitative Real-time PCR. RESULTS Our results showed that the expression of RIG-I and MAD-5 significantly increased in HCV-infected samples compared to the controls (P value:0.01; P value:0.05), while the expression of TLR7 was similar between the case and the control group (P value:0.1). CONCLUSION It seems in suppressing HCV, RIG-I and MAD-5 receptors are likely to be more activated than TRL7 in HCV patients. The lack of TLR7 gene expression might reflect the defect of the host in the stimulation of the innate immune system through the TLR7 pathway.
Collapse
Affiliation(s)
- Atena Gilanipour
- Department of Medical Microbiology (Bacteriology and Virology), Afzalipour Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Ali Teimoori
- Department of Virology, Faculty of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Seyed Alimohammad Arabzadeh
- Department of Medical Microbiology (Bacteriology and Virology), Afzalipour Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Hamid Reza Mollaie
- Department of Medical Microbiology (Bacteriology and Virology), Afzalipour Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Elham Mousavi
- Department of Medical Microbiology (Bacteriology and Virology), Afzalipour Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran.
- Medical Mycology and Bacteriology Research Center, Kerman University of Medical Sciences, Kerman, Iran.
| |
Collapse
|
|
20
|
Banerjee P, Gaddam N, Chandler V, Chakraborty S. Oxidative Stress-Induced Liver Damage and Remodeling of the Liver Vasculature. THE AMERICAN JOURNAL OF PATHOLOGY 2023; 193:1400-1414. [PMID: 37355037 DOI: 10.1016/j.ajpath.2023.06.002] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Revised: 05/29/2023] [Accepted: 06/08/2023] [Indexed: 06/26/2023]
Abstract
As an organ critically important for targeting and clearing viruses, bacteria, and other foreign material, the liver operates via immune-tolerant, anti-inflammatory mechanisms indispensable to the immune response. Stress and stress-induced factors disrupt the homeostatic balance in the liver, inflicting tissue damage, injury, and remodeling. These factors include oxidative stress (OS) induced by viral infections, environmental toxins, drugs, alcohol, and diet. A recurrent theme seen among stressors common to multiple liver diseases is the induction of mitochondrial dysfunction, increased reactive oxygen species expression, and depletion of ATP. Inflammatory signaling additionally exacerbates the condition, generating a proinflammatory, immunosuppressive microenvironment and activation of apoptotic and necrotic mechanisms that disrupt the integrity of liver morphology. These pathways initiate signaling pathways that significantly contribute to the development of liver steatosis, inflammation, fibrosis, cirrhosis, and liver cancers. In addition, hypoxia and OS directly enhance angiogenesis and lymphangiogenesis in chronic liver diseases. Late-stage consequences of these conditions often narrow the outcomes for liver transplantation or result in death. This review provides a detailed perspective on various stress-induced factors and the specific focus on role of OS in different liver diseases with special emphasis on different molecular mechanisms. It also highlights how resultant changes in the liver vasculature correlate with pathogenesis.
Collapse
Affiliation(s)
- Priyanka Banerjee
- Department of Medical Physiology, Texas A&M Health Science Center, Bryan, Texas.
| | - Niyanshi Gaddam
- Department of Medical Physiology, Texas A&M Health Science Center, Bryan, Texas
| | - Vanessa Chandler
- Department of Medical Physiology, Texas A&M Health Science Center, Bryan, Texas
| | - Sanjukta Chakraborty
- Department of Medical Physiology, Texas A&M Health Science Center, Bryan, Texas.
| |
Collapse
|
|
21
|
Stojic J, Kukla M, Grgurevic I. The Intestinal Microbiota in the Development of Chronic Liver Disease: Current Status. Diagnostics (Basel) 2023; 13:2960. [PMID: 37761327 PMCID: PMC10528663 DOI: 10.3390/diagnostics13182960] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 09/06/2023] [Accepted: 09/11/2023] [Indexed: 09/29/2023] Open
Abstract
Chronic liver disease (CLD) is a significant global health burden, leading to millions of deaths annually. The gut-liver axis plays a pivotal role in this context, allowing the transport of gut-derived products directly to the liver, as well as biological compounds from the liver to the intestine. The gut microbiota plays a significant role in maintaining the health of the digestive system. A change in gut microbiome composition as seen in dysbiosis is associated with immune dysregulation, altered energy and gut hormone regulation, and increased intestinal permeability, contributing to inflammatory mechanisms and damage to the liver, irrespective of the underlying etiology of CLD. The aim of this review is to present the current knowledge about the composition of the intestinal microbiome in healthy individuals and those with CLD, including the factors that affect this composition, the impact of the altered microbiome on the liver, and the mechanisms by which it occurs. Furthermore, this review analyzes the effects of gut microbiome modulation on the course of CLD, by using pharmacotherapy, nutrition, fecal microbiota transplantation, supplements, and probiotics. This review opens avenues for the translation of knowledge about gut-liver interplay into clinical practice as an additional tool to fight CLD and its complications.
Collapse
Affiliation(s)
- Josip Stojic
- Department of Gastroenterology, Hepatology and Clinical Nutrition, University Hospital Dubrava, 10000 Zagreb, Croatia;
| | - Michał Kukla
- Department of Internal Medicine and Geriatrics, Faculty of Medicine, Jagellonian University Medical College, 31-688 Kraków, Poland;
- Department of Endoscopy, University Hospital, 30-688 Kraków, Poland
| | - Ivica Grgurevic
- Department of Gastroenterology, Hepatology and Clinical Nutrition, University Hospital Dubrava, 10000 Zagreb, Croatia;
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
- Faculty of Pharmacy and Biochemistry, University of Zagreb, 10000 Zagreb, Croatia
| |
Collapse
|
|
22
|
Zheng W, Yang L, Jiang S, Chen M, Li J, Liu Z, Wu Z, Gong J, Chen Y. Role of Kupffer cells in tolerance induction after liver transplantation. Front Cell Dev Biol 2023; 11:1179077. [PMID: 37601106 PMCID: PMC10435084 DOI: 10.3389/fcell.2023.1179077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Accepted: 07/24/2023] [Indexed: 08/22/2023] Open
Abstract
Currently, liver transplantation has reached a level of maturity where it is considered an effective treatment for end-stage liver disease and can significantly prolong the survival time of patients. However, acute and chronic rejection remain major obstacles to its efficacy. Although long-term use of immunosuppressants can prevent rejection, it is associated with serious side effects and significant economic burden for patients. Therefore, the investigation of induced immune tolerance holds crucial theoretical significance and socio-economic value. In fact, the establishment of immune tolerance in liver transplantation is intricately linked to the unique innate immune system of the liver. Kupffer cells, as a crucial component of this system, play a pivotal role in maintaining the delicate balance between inflammatory response and immune tolerance following liver transplantation. The important roles of different functions of Kupffer cells, such as phagocytosis, cell polarization, antigen presentation and cell membrane proteins, in the establishment of immune tolerance after transplantation is comprehensively summarized in this paper. Providing theoretical basis for further study and clinical application of Kupffer cells in liver transplantation.
Collapse
Affiliation(s)
- Weixiong Zheng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Lingxiang Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Shiming Jiang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Mingxiang Chen
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jinzheng Li
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zuojing Liu
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zhongjun Wu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jianping Gong
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yong Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| |
Collapse
|
|
23
|
Abd-Elhakim YM, Behairy A, Hashem MMM, Abo-El-Sooud K, El-Metwally AE, Hassan BA, Ali HA. Toll-like receptors and nuclear factor kappa B signaling pathway involvement in hepatorenal oxidative damage induced by some food preservatives in rats. Sci Rep 2023; 13:5938. [PMID: 37045926 PMCID: PMC10097866 DOI: 10.1038/s41598-023-32887-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Accepted: 04/04/2023] [Indexed: 04/14/2023] Open
Abstract
Chemical food preservatives are extensively found in various processed food products in the human environment. Hence, this study aimed to investigate the effect of long-term exposure to five food preservatives (potassium sorbate (PS), butylated hydroxyanisole (BHA), sodium benzoate (SB), calcium propionate (CP), and boric acid (BA)) on the liver and kidney in rats and the probable underlying mechanisms. For 90 days, sixty male albino rats were orally given either water (control), 0.09 mg/kg b.wt BHA, 4.5 mg/kg b.wt PS, 0.9 mg/kg b.wt SB, 0.16 mg/kg b.wt BA, or 0.18 mg/kg b.wt CP. Liver and kidney function tests were assessed. Hepatic and renal oxidative stress biomarkers were estimated. Histologic examination analysis of liver and kidney tissues was achieved. Toll-like receptors 2 and 4 (TLR-2 and TLR-4), tumor necrosis factor-alpha (TNF-α), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) mRNA expression levels were measured. The results revealed that long-term oral dosing of the five food preservatives resulted in significant increases in alkaline phosphatase, alanine transaminase, aspartate transaminase, urea, uric acid, and creatinine levels. There were significant reductions in hepatic and renal antioxidant enzymes, an increase in MDA concentrations, and pathological alterations in renal and hepatic tissues. The mRNA levels of TLR-4, TLR-2, NF-κB, and TNF-α were elevated in the food preservatives-exposed groups. Conclusively, the current findings revealed that long-term exposure to PS, BHA, SB, CP, and BA has a negative impact on liver and kidney function. Furthermore, these negative effects could be mediated via oxidative stress induction, inflammatory reactions, and cytokine production.
Collapse
Affiliation(s)
- Yasmina M Abd-Elhakim
- Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, 44519, Egypt.
| | - Amany Behairy
- Department of Physiology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, 44519, Egypt
| | - Mohamed M M Hashem
- Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, Giza, 12613, Egypt
| | - Khaled Abo-El-Sooud
- Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, Giza, 12613, Egypt
| | - Abeer E El-Metwally
- Pathology Department, Animal Reproduction Research Institute, Giza, 3514805, Egypt
| | - Bayan A Hassan
- Pharmacology Department, Faculty of Pharmacy, Future University, Cairo, 11835, Egypt
| | - Haytham A Ali
- Department of Biochemistry, Faculty of Veterinary Medicine, Zagazig University, Zagazig, 44519, Egypt
- Department of Biochemistry, Faculty of Science, University of Jeddah, Jeddah, 23218, Saudi Arabia
| |
Collapse
|
|
24
|
Takimoto Y, Chu PS, Nakamoto N, Hagihara Y, Mikami Y, Miyamoto K, Morikawa R, Teratani T, Taniki N, Fujimori S, Suzuki T, Koda Y, Ishihara R, Ichikawa M, Honda A, Kanai T. Myeloid TLR4 signaling promotes post-injury withdrawal resolution of murine liver fibrosis. iScience 2023; 26:106220. [PMID: 36876136 PMCID: PMC9982274 DOI: 10.1016/j.isci.2023.106220] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 08/25/2022] [Accepted: 02/13/2023] [Indexed: 02/18/2023] Open
Abstract
The fate of resolution of liver fibrosis after withdrawal of liver injury is still incompletely elucidated. Toll-like receptor 4 (TLR4) in tissue fibroblasts is pro-fibrogenic. After withdrawal of liver injury, we unexpectedly observed a significant delay of fibrosis resolution as TLR4 signaling was pharmacologically inhibited in vivo in two murine models. Single-cell transcriptome analysis of hepatic CD11b+ cells, main producers of matrix metalloproteinases (MMPs), revealed a prominent cluster of restorative Tlr4-expressing Ly6c2-low myeloid cells. Delayed resolution after gut sterilization suggested its microbiome-dependent nature. Enrichment of a metabolic pathway linking to a significant increase of bile salt hydrolase-possessing family Erysipelotrichaceae during resolution. Farnesoid X receptor-stimulating secondary bile acids including 7-oxo-lithocholic acids upregulated MMP12 and TLR4 in myeloid cells in vitro. Fecal material transplant in germ-free mice confirmed phenotypical correlations in vivo. These findings highlight a pro-fibrolytic role of myeloid TLR4 signaling after injury withdrawal and may provide targets for anti-fibrotic therapy.
Collapse
Affiliation(s)
- Yoichi Takimoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Po-Sung Chu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Nobuhiro Nakamoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Yuya Hagihara
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Yohei Mikami
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Kentaro Miyamoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.,Miyarisan Pharmaceutical Co., Ltd, Kita-ku, Tokyo 114-0016, Japan
| | - Rei Morikawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Toshiaki Teratani
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Nobuhito Taniki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Sota Fujimori
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.,Research Unit/Immunology and Inflammation, Sohyaku Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Kanagawa 227-0033, Japan
| | - Takahiro Suzuki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.,Miyarisan Pharmaceutical Co., Ltd, Kita-ku, Tokyo 114-0016, Japan
| | - Yuzo Koda
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.,Research Unit/Immunology and Inflammation, Sohyaku Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Kanagawa 227-0033, Japan
| | - Rino Ishihara
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Masataka Ichikawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Akira Honda
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokyo Medical University Ibaraki Medical Center, Inashiki-gun, Ibaraki 300-0395, Japan
| | - Takanori Kanai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| |
Collapse
|
|
25
|
Zhang N, Yao H, Zhang Z, Li Z, Chen X, Zhao Y, Ju R, He J, Pan H, Liu X, Lv Y. Ongoing involvers and promising therapeutic targets of hepatic fibrosis: The hepatic immune microenvironment. Front Immunol 2023; 14:1131588. [PMID: 36875101 PMCID: PMC9978172 DOI: 10.3389/fimmu.2023.1131588] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2022] [Accepted: 02/02/2023] [Indexed: 02/18/2023] Open
Abstract
Hepatic fibrosis is often secondary to chronic inflammatory liver injury. During the development of hepatic fibrosis, the damaged hepatocytes and activated hepatic stellate cells (HSCs) caused by the pathogenic injury could secrete a variety of cytokines and chemokines, which will chemotactic innate and adaptive immune cells of liver tissue and peripheral circulation infiltrating into the injury site, mediating the immune response against injury and promoting tissue reparation. However, the continuous release of persistent injurious stimulus-induced inflammatory cytokines will promote HSCs-mediated fibrous tissue hyperproliferation and excessive repair, which will cause hepatic fibrosis development and progression to cirrhosis even liver cancer. And the activated HSCs can secrete various cytokines and chemokines, which directly interact with immune cells and actively participate in liver disease progression. Therefore, analyzing the changes in local immune homeostasis caused by immune response under different pathological states will greatly enrich our understanding of liver diseases' reversal, chronicity, progression, and even deterioration of liver cancer. In this review, we summarized the critical components of the hepatic immune microenvironment (HIME), different sub-type immune cells, and their released cytokines, according to their effect on the development of progression of hepatic fibrosis. And we also reviewed and analyzed the specific changes and the related mechanisms of the immune microenvironment in different chronic liver diseases.Moreover, we retrospectively analyzed whether the progression of hepatic fibrosis could be alleviated by modulating the HIME.We aimed to elucidate the pathogenesis of hepatic fibrosis and provide the possibility for exploring the therapeutic targets for hepatic fibrosis.
Collapse
Affiliation(s)
- Nana Zhang
- Institute of Regenerative and Reconstructive Medicine, Med-X Institute, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Huimin Yao
- Institute of Regenerative and Reconstructive Medicine, Med-X Institute, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Zhixuan Zhang
- Institute of Regenerative and Reconstructive Medicine, Med-X Institute, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Zhuoqun Li
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Xue Chen
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Yan Zhao
- Institute of Regenerative and Reconstructive Medicine, Med-X Institute, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Ran Ju
- Institute of Regenerative and Reconstructive Medicine, Med-X Institute, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Jiayi He
- Institute of Regenerative and Reconstructive Medicine, Med-X Institute, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Heli Pan
- Institute of Regenerative and Reconstructive Medicine, Med-X Institute, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Xiaoli Liu
- Institute of Regenerative and Reconstructive Medicine, Med-X Institute, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Yi Lv
- Institute of Regenerative and Reconstructive Medicine, Med-X Institute, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| |
Collapse
|
|
26
|
Zhang J, Zao X, Zhang J, Guo Z, Jin Q, Chen G, Gan D, Du H, Ye Y. Is it possible to intervene early cirrhosis by targeting toll-like receptors to rebalance the intestinal microbiome? Int Immunopharmacol 2023; 115:109627. [PMID: 36577151 DOI: 10.1016/j.intimp.2022.109627] [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: 11/01/2022] [Revised: 12/13/2022] [Accepted: 12/19/2022] [Indexed: 12/27/2022]
Abstract
Cirrhosis is a progressive chronic liver disease caused by one or more causes and characterized by diffuse fibrosis, pseudolobules, and regenerated nodules. Once progression to hepatic decompensation, the function of the liver and other organs is impaired and almost impossible to reverse and recover, which often results in hospitalization, impaired quality of life, and high mortality. However, in the early stage of cirrhosis, there seems to be a possibility of cirrhosis reversal. The development of cirrhosis is related to the intestinal microbiota and activation of toll-like receptors (TLRs) pathways, which could regulate cell proliferation, apoptosis, expression of the hepatomitogen epiregulin, and liver inflammation. Targeting regulation of intestinal microbiota and TLRs pathways could affect the occurrence and development of cirrhosis and its complications. In this paper, we first reviewed the dynamic change of intestinal microbiota and TLRs during cirrhosis progression. And further discussed the interaction between them and potential therapeutic targets to reverse early staged cirrhosis.
Collapse
Affiliation(s)
- Jiaxin Zhang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China; Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
| | - Xiaobin Zao
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China; Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
| | - Jiaying Zhang
- School of Mechanical Engineering and Automation, Beihang University, Beijing, China
| | - Ziwei Guo
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Qian Jin
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Guang Chen
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China; Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
| | - Da'nan Gan
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China; Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
| | - Hongbo Du
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China; Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
| | - Yong'an Ye
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China; Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China.
| |
Collapse
|
|
27
|
Lee KC, Wu PS, Lin HC. Pathogenesis and treatment of non-alcoholic steatohepatitis and its fibrosis. Clin Mol Hepatol 2023; 29:77-98. [PMID: 36226471 PMCID: PMC9845678 DOI: 10.3350/cmh.2022.0237] [Citation(s) in RCA: 89] [Impact Index Per Article: 44.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Accepted: 10/11/2022] [Indexed: 02/02/2023] Open
Abstract
The initial presentation of non-alcoholic steatohepatitis (NASH) is hepatic steatosis. The dysfunction of lipid metabolism within hepatocytes caused by genetic factors, diet, and insulin resistance causes lipid accumulation. Lipotoxicity, oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum stress would further contribute to hepatocyte injury and death, leading to inflammation and immune dysfunction in the liver. During the healing process, the accumulation of an excessive amount of fibrosis might occur while healing. During the development of NASH and liver fibrosis, the gut-liver axis, adipose-liver axis, and renin-angiotensin system (RAS) may be dysregulated and impaired. Translocation of bacteria or its end-products entering the liver could activate hepatocytes, Kupffer cells, and hepatic stellate cells, exacerbating hepatic steatosis, inflammation, and fibrosis. Bile acids regulate glucose and lipid metabolism through Farnesoid X receptors in the liver and intestine. Increased adipose tissue-derived non-esterified fatty acids would aggravate hepatic steatosis. Increased leptin also plays a role in hepatic fibrogenesis, and decreased adiponectin may contribute to hepatic insulin resistance. Moreover, dysregulation of peroxisome proliferator-activated receptors in the liver, adipose, and muscle tissues may impair lipid metabolism. In addition, the RAS may contribute to hepatic fatty acid metabolism, inflammation, and fibrosis. The treatment includes lifestyle modification, pharmacological therapy, and non-pharmacological therapy. Currently, weight reduction by lifestyle modification or surgery is the most effective therapy. However, vitamin E, pioglitazone, and obeticholic acid have also been suggested. In this review, we will introduce some new clinical trials and experimental therapies for the treatment of NASH and related fibrosis.
Collapse
Affiliation(s)
- Kuei-Chuan Lee
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan,Department of Medicine, National Yang Ming Chiao Tung University School of Medicine, Taipei, Taiwan,Corresponding author : Kuei-Chuan Lee Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, 201, Section 2, Shih-Pai Road, Taipei 11217, Taiwan Tel: +886 2 2871 2121, Fax: +886 2 2873 9318, E-mail:
| | - Pei-Shan Wu
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan,Department of Medicine, National Yang Ming Chiao Tung University School of Medicine, Taipei, Taiwan,Endoscopy Center for Diagnosis and Treatment, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Han-Chieh Lin
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan,Department of Medicine, National Yang Ming Chiao Tung University School of Medicine, Taipei, Taiwan,Corresponding author : Kuei-Chuan Lee Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, 201, Section 2, Shih-Pai Road, Taipei 11217, Taiwan Tel: +886 2 2871 2121, Fax: +886 2 2873 9318, E-mail:
| |
Collapse
|
|
28
|
Tourkochristou E, Assimakopoulos SF, Thomopoulos K, Marangos M, Triantos C. NAFLD and HBV interplay - related mechanisms underlying liver disease progression. Front Immunol 2022; 13:965548. [PMID: 36544761 PMCID: PMC9760931 DOI: 10.3389/fimmu.2022.965548] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 11/15/2022] [Indexed: 12/08/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) and Hepatitis B virus infection (HBV) constitute common chronic liver diseases with worldwide distribution. NAFLD burden is expected to grow in the coming decade, especially in western countries, considering the increased incidence of diabetes and obesity. Despite the organized HBV vaccinations and use of anti-viral therapies globally, HBV infection remains endemic and challenging public health issue. As both NAFLD and HBV have been associated with the development of progressive fibrosis, cirrhosis and hepatocellular carcinoma (HCC), the co-occurrence of both diseases has gained great research and clinical interest. The causative relationship between NAFLD and HBV infection has not been elucidated so far. Dysregulated fatty acid metabolism and lipotoxicity in NAFLD disease seems to initiate activation of signaling pathways that enhance pro-inflammatory responses and disrupt hepatocyte cell homeostasis, promoting progression of NAFLD disease to NASH, fibrosis and HCC and can affect HBV replication and immune encountering of HBV virus, which may further have impact on liver disease progression. Chronic HBV infection is suggested to have an influence on metabolic changes, which could lead to NAFLD development and the HBV-induced inflammatory responses and molecular pathways may constitute an aggravating factor in hepatic steatosis development. The observed altered immune homeostasis in both HBV infection and NAFLD could be associated with progression to HCC development. Elucidation of the possible mechanisms beyond HBV chronic infection and NAFLD diseases, which could lead to advanced liver disease or increase the risk for severe complications, in the case of HBV-NAFLD co-existence is of high clinical significance in the context of designing effective therapeutic targets.
Collapse
Affiliation(s)
- Evanthia Tourkochristou
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Stelios F. Assimakopoulos
- Division of Infectious Diseases, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Konstantinos Thomopoulos
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Markos Marangos
- Division of Infectious Diseases, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| |
Collapse
|
|
29
|
Pezzino S, Sofia M, Faletra G, Mazzone C, Litrico G, La Greca G, Latteri S. Gut-Liver Axis and Non-Alcoholic Fatty Liver Disease: A Vicious Circle of Dysfunctions Orchestrated by the Gut Microbiome. BIOLOGY 2022; 11:1622. [PMID: 36358323 PMCID: PMC9687983 DOI: 10.3390/biology11111622] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Revised: 11/03/2022] [Accepted: 11/04/2022] [Indexed: 09/24/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a prevalent, multifactorial, and poorly understood liver disease with an increasing incidence worldwide. NAFLD is typically asymptomatic and coupled with other symptoms of metabolic syndrome. The prevalence of NAFLD is rising in tandem with the prevalence of obesity. In the Western hemisphere, NAFLD is one of the most prevalent causes of liver disease and liver transplantation. Recent research suggests that gut microbiome dysbiosis may play a significant role in the pathogenesis of NAFLD by dysregulating the gut-liver axis. The so-called "gut-liver axis" refers to the communication and feedback loop between the digestive system and the liver. Several pathological mechanisms characterized the alteration of the gut-liver axis, such as the impairment of the gut barrier and the increase of the intestinal permeability which result in endotoxemia and inflammation, and changes in bile acid profiles and metabolite levels produced by the gut microbiome. This review will explore the role of gut-liver axis disruption, mediated by gut microbiome dysbiosis, on NAFLD development.
Collapse
Affiliation(s)
| | | | | | | | | | | | - Saverio Latteri
- Department of Surgical Sciences and Advanced Technologies “G. F. Ingrassia”, Cannizzaro Hospital, University of Catania, 95126 Catania, Italy
| |
Collapse
|
|
30
|
Guo X, Li Y, Wang W, Wang L, Hu S, Xiao X, Hu C, Dai Y, Zhang Y, Li Z, Li J, Ma X, Zeng J. The construction of preclinical evidence for the treatment of liver fibrosis with quercetin: A systematic review and meta-analysis. Phytother Res 2022; 36:3774-3791. [PMID: 35918855 DOI: 10.1002/ptr.7569] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Revised: 07/06/2022] [Accepted: 07/06/2022] [Indexed: 12/09/2022]
Abstract
Quercetin (3,3',4',5,7-pentahydroxyflavone), a flavonoid, is widely found in fruits and vegetables and exerts broad-spectrum pharmacological effects in the liver. Many studies have explored the bioactivity of quercetin in the treatment of liver fibrosis. Hence, through a systematic review and biological mechanism evaluation, this study aimed to construct a body of preclinical evidence for the treatment of liver fibrosis using quercetin. The literature used in this study was mainly obtained from four databases, and the SYRCLE list (10 items) was used to evaluate the quality of the included literature. A meta-analysis of HA, LN, and other indicators was performed via STATA 15.0 software. Subgroup analyses based on animal species and model protocol were performed to further obtain detailed results. Moreover, the therapeutic mechanism of quercetin was summarized in a directed network form based on a comprehensive search of the literature. After screening, a total of 14 articles (comprising 15 studies) involving 254 animals were included. The results from the analysis showed that the corresponding liver function indexes, such as the levels of HA and LN, were significantly improved in the quercetin group compared with the model group, and liver function, such as the levels of AST and ALT, were also improved in the quercetin group. The species- and model-based subgroup analyses of AST and ALT revealed that quercetin exerts a significant effect. The therapeutic mechanism of quercetin was shown to be related to multiple pathways involving anti-inflammatory and antioxidant activities and lipid accumulation, including regulation of the TGF-β, α-SMA, ROS, and P-AMPK pathways. The results showed that quercetin exerts an obvious effect on liver fibrosis, and more prominent improvement effects on liver function and liver fibrosis indicators were obtained with a dose of 5-200 mg during a treatment course ranging from 4 to 8 weeks. Quercetin might be a promising therapeutic for liver fibrosis.
Collapse
Affiliation(s)
- Xiaochuan Guo
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yuanyuan Li
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Acupuncture and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Weizheng Wang
- School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Luyao Wang
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Sihan Hu
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Acupuncture and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiaolin Xiao
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Caiyu Hu
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yao Dai
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yiheng Zhang
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Ziyu Li
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Junlin Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiao Ma
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jinhao Zeng
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| |
Collapse
|
|
31
|
Roy N, Nadda N, Kumar H, Prasad C, Kumar Jha J, Pandey HC, Vanamail P, Saraya A, Balhara YPS, Shalimar, Nayak B. Pattern recognition receptor CD14 gene polymorphisms in alcohol use disorder patients and its Influence on liver disease susceptibility. Front Immunol 2022; 13:975027. [PMID: 36238273 PMCID: PMC9551314 DOI: 10.3389/fimmu.2022.975027] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Accepted: 08/15/2022] [Indexed: 11/13/2022] Open
Abstract
Background Alcohol use disorders (AUDs) leading to liver disease is major concern over other spectrum of disorder. Excessive alcohol consumption resulting in leaky gut syndrome is attributed to alcohol-induced liver injury through portal translocation of bacterial endotoxin. Susceptibility to alcoholic liver disease (ALD) in AUD patients could be dependent upon genes responsible for inflammation and alcohol metabolism. The pattern recognition receptor CD14 gene is a major player in endotoxin-mediated inflammation and susceptibility to ALD. This study investigated the genetic association of CD14 polymorphisms and other mechanisms relevant to altered inflammatory responses leading to ALD. Methods Patients with alcohol use disorder with ALD (n = 128) and without liver disease (ALC, n = 184) and controls without alcohol use disorder (NALC, n = 152) from North India were enrolled. The CD4 gene polymorphisms in the North Indian population were evaluated by RFLP and sequencing. Secretory CD14 (sCD14), LBP, TLR4, MD2, TNFα, IL1b, IFNγ, IL6, IL10, and IL4 levels in serum were measured by ELISA among groups. The influence of polymorphisms on CD14 gene promoter activity and circulatory bacterial DNA level was determined. Results The CD14 gene promoter and exonic region SNPs were found to be monomorphic, except for SNP rs2569190 for the North Indian population. The genetic association of SNP rs2569190(C/T) with the risk of developing ALD was found significant for TT genotype [ORTT, 95% CI = 2.19, 1.16–4.13 for ALD vs. ALC and OR, 2.09, 1.18–3.72 for ALD vs. NALC]. An increased sCD14 level was observed in AUD patients compared to NALC control. Increased levels of LBP, TLR4, TNFα, IL1β, IFNγ, and IL6 and reduced levels of MD2, IL10, and IL4 were observed among the ALD patients compared to the other two control groups. Elevated levels of pro-inflammatory and reduced levels of anti-inflammatory cytokines were observed in the risk genotype TT groups of ALD patients and the ALC group compared to NALC. Promoter activity was observed in the intronic region flanking SNPs and risk genotype can influence reporter activity, indicating CD14 gene expression. Conclusion Enhanced CD14 expression associated with inflammatory responses increases susceptibility to ALD in the TT genotype of AUD patients.
Collapse
|
|
32
|
Ohira H, Oikawa D, Kurokawa Y, Aoki Y, Omura A, Kiyomoto K, Nakagawa W, Mamoto R, Fujioka Y, Nakayama T. Suppression of colonic oxidative stress caused by chronic ethanol administration and attenuation of ethanol-induced colitis and gut leakiness by oral administration of sesaminol in mice. Food Funct 2022; 13:9285-9298. [PMID: 35968694 DOI: 10.1039/d1fo04120g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Chronic consumption of excess ethanol is one of the major risk factors for colorectal cancer (CRC), and the pathogenesis of ethanol-related CRC (ER-CRC) involves ethanol-induced oxidative-stress and inflammation in the colon and rectum, as well as gut leakiness. In this study, we hypothesised that oral administration of sesaminol, a sesame lignan, lowers the risk of ER-CRC because we found that it is a strong antioxidant with very low prooxidant activity. This hypothesis was examined using a mouse model, in which 2.0% v/v ethanol was administered ad libitum for 2 weeks with or without oral gavage with sesaminol (2.5 mg per day). Oral sesaminol administration suppressed the ethanol-induced colonic lesions and the ethanol-induced elevation of the colonic levels of oxidative stress markers (8-hydroxy-2'-deoxyguanosine, malondialdehyde, and 4-hydroxyalkenals). It consistently suppressed the chronic ethanol-induced expressions of cytochrome P450-2E1 and inducible nitric oxide synthase and upregulated heme oxygenase-1 expression, probably via the nuclear factor erythroid-derived 2-like 2 pathway in the mouse colon. Oral sesaminol administration also suppressed the chronic ethanol-induced elevation of colonic inflammation marker levels, such as those of tumour necrosis factor-α, interleukin-6, and monocyte chemoattractant protein-1, probably via the nuclear factor-kappa B pathway. Moreover, it prevented the chronic ethanol-induced gut leakiness by restoring tight junction proteins, giving rise to lower plasma endotoxin levels compared with those of ethanol-administered mice. All of these results suggest that dietary supplementation of sesaminol may lower the risk of ER-CRC by suppressing each of the above-mentioned steps in ER-CRC pathogenesis.
Collapse
Affiliation(s)
- Hideo Ohira
- Division of Clinical Nutrition, Faculty of Nutrition, Kobe Gakuin University, Kobe 651-2180, Japan
| | - Daiki Oikawa
- Department of Biomolecular Engineering, Graduate School of Engineering, Tohoku University, Sendai, Miyagi 980-8579, Japan
| | - Yoichi Kurokawa
- Faculty of Bioscience, Fukui Prefectural University, Fukui 910-1195, Japan
| | - Yuichi Aoki
- Tohoku University Tohoku Medical Megabank Organization, Seiryo 2-1, Sendai, Miyagi 980-8573, Japan
| | - Ayano Omura
- Kiyomoto Co., Ltd., 6-1633 Totoro-cho, Nobeoka, Miyazaki 889-0595, Japan
| | - Kunio Kiyomoto
- Kiyomoto Co., Ltd., 6-1633 Totoro-cho, Nobeoka, Miyazaki 889-0595, Japan
| | - Wao Nakagawa
- Division of Clinical Nutrition, Faculty of Nutrition, Kobe Gakuin University, Kobe 651-2180, Japan
| | - Rie Mamoto
- Division of Clinical Nutrition, Faculty of Nutrition, Kobe Gakuin University, Kobe 651-2180, Japan
| | - Yoshio Fujioka
- Division of Clinical Nutrition, Faculty of Nutrition, Kobe Gakuin University, Kobe 651-2180, Japan
| | - Toru Nakayama
- Department of Biomolecular Engineering, Graduate School of Engineering, Tohoku University, Sendai, Miyagi 980-8579, Japan
| |
Collapse
|
|
33
|
Ajoolabady A, Aslkhodapasandhokmabad H, Zhou Y, Ren J. Epigenetic modification in alcohol‐related liver diseases. Med Res Rev 2022; 42:1463-1491. [DOI: 10.1002/med.21881] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 01/21/2022] [Accepted: 01/30/2022] [Indexed: 12/13/2022]
Affiliation(s)
- Amir Ajoolabady
- School of Pharmacy University of Wyoming College of Health Sciences Laramie Wyoming USA
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases Zhongshan Hospital Fudan University Shanghai China
| | | | - Yuan Zhou
- Department of Biomedical Informatics, School of Basic Medical Sciences Peking University Beijing China
| | - Jun Ren
- School of Pharmacy University of Wyoming College of Health Sciences Laramie Wyoming USA
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases Zhongshan Hospital Fudan University Shanghai China
- Department of Laboratory Medicine and Pathology University of Washington Seattle Washington USA
| |
Collapse
|
|
34
|
Abstract
Non-alcoholic fatty liver disease is comprised of either simple steatosis (non-alcoholic fatty liver) or a more advanced inflammatory and fibrogenic stage (non-alcoholic steatohepatitis [NASH]). NASH affects a growing proportion of the global adult and pediatric population, leading to rising rates of liver fibrosis and hepatocellular carcinoma. NASH is a multifactorial disease that is part of a systemic metabolic disorder. Here, we provide an overview of the metabolic underpinnings of NASH pathogenesis and established drivers of inflammation and fibrosis. Clarification of underlying fibrogenic and inflammatory mechanisms will advance the development of novel treatment strategies as there are no approved therapies at present. We discuss emerging experimental approaches and potential novel investigational strategies derived from animal models including the inflammasome, epigenetic reprogramming, Hippo signaling, Notch signaling, engineered T cells to remove fibrogenic HSCs, and HSC-specific targeting therapies. Recently completed and ongoing clinical trials and antifibrotics are discussed, illuminating the growing expectation that one or more therapies will yield clinical benefit in NASH in the coming years.
Collapse
Affiliation(s)
- Youngmin A. Lee
- Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Scott L. Friedman
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| |
Collapse
|
|
35
|
Zhou Y, Zhang P, Zheng X, Ye C, Li M, Bian P, Fan C, Zhang Y. miR-155 regulates pro- and anti-inflammatory cytokine expression in human monocytes during chronic hepatitis C virus infection. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1618. [PMID: 34926662 PMCID: PMC8640902 DOI: 10.21037/atm-21-2620] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 08/27/2021] [Indexed: 12/15/2022]
Abstract
Background Hepatitis C virus (HCV) dysregulates innate and adaptive immune responses while monocytes (M) play a crucial role in linking innate and adaptive immunity to control viral infection. A transcription factor T-bet is upregulated to dampen M functions via the c-Jun N-terminal kinase (JNK) pathway, followed by enhanced Tim-3 expression in chronic HCV infection. However, the molecular mechanisms that control the expression in M are yet unknown. miR-155 has been implicated as a key regulator controlling diverse biological processes through posttranscriptional repression, but the influences of miR-155 on these regulators and effectors still need to be studied. Methods Forty HCV-infected patients and 40 healthy subjects (HS) were recruited, THP-1 cells (human acute monocyte leukemia cell line) were cultured with HCV-infected Huh 7.5 cells. The expression levels of miR-155 and JNK1/JNK2/JNK3 were measured by real-time RT-PCR. IL-10/IL-12 was detected by flow cytometry. THP-1 cells were transfected with mimics-155 and negative control, SOCS1, p-STAT1, p65, p-smad, p-p38, and p-JNK were measured by Western blot. TNF-α levels were measured by ELISA. Student’s t-test was used in statistics. Results The study showed that miR-155 was upregulated in CD14+ M in HCV-infected patients compared to healthy subjects (P<0.05). Moreover, the upregulation of miR-155 in CD14+ M from HCV-infected patients induced TNF-α production and JNK gene expression, which, in turn, led to T-bet upregulation. Also, miR-155 upregulation in CD14+ M of HCV-infected patients increased the IL-12 and decreased the IL-10 production. Conclusions The obtained results indicated that miR-155 upregulation in M during HCV infection enhances the activation of TNF-α and JNK pathways, promotes the expression of transcription factor T-bet, and triggers pro- and anti-inflammatory mediators. Together, these data reveal new information regarding the mechanisms of chronic HCV infection.
Collapse
Affiliation(s)
- Yun Zhou
- Department of Infectious Diseases, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Peixin Zhang
- Department of Infectious Diseases, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Xuyang Zheng
- Department of Infectious Diseases, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Chuantao Ye
- Department of Infectious Diseases, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Mengyuan Li
- Department of Infectious Diseases, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Peiyu Bian
- Department of Infectious Diseases, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Chao Fan
- Department of Infectious Diseases, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Ying Zhang
- Department of Infectious Diseases, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| |
Collapse
|
|
36
|
Center SA, Randolph JF, Warner KL, McDonough SP, Lucy JM, Sapa KC. Bacterial culture and immunohistochemical detection of bacteria and endotoxin in cats with suppurative cholangitis-cholangiohepatitis syndrome. J Am Vet Med Assoc 2021; 260:194-211. [PMID: 34936576 DOI: 10.2460/javma.20.10.0552] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVE To characterize the frequency and type of bacterial infection by culture- and immunohistochemical (IHC)-based methods and determine the impact of infection on clinical features and survival time in cats with suppurative cholangitis-cholangiohepatitis syndrome (S-CCHS). ANIMALS 168 client-owned cats with S-CCHS (cases). PROCEDURES Clinical features, bacterial culture results, culture-inoculate sources, and survival details were recorded. Cases were subcategorized by comorbidity (extrahepatic bile duct obstruction, cholelithiasis, cholecystitis, ductal plate malformation, biopsy-confirmed inflammatory bowel disease, and biopsy-confirmed pancreatitis) or treatment by cholecystectomy or cholecystoenterostomy. Culture results, bacterial isolates, Gram-stain characteristics, and IHC staining were compared among comorbidities. Lipoteichoic acid IHC staining detected gram-positive bacterial cell wall components, and toll-like receptor expression IHC reflected pathologic endotoxin (gram-negative bacteria) exposure. RESULTS Clinical features were similar among cases except for more frequent abdominal pain and lethargy in cats with positive culture results and pyrexia, abdominal pain, and hepatomegaly for cats with polymicrobial infections. Bacteria were cultured in 93 of 135 (69%) cats, with common isolates including Enterococcus spp and Escherichia coli. IHC staining was positive in 142 of 151 (94%) cats (lipoteichoic acid, 107/142 [75%]; toll-like receptor 4, 99/142 [70%]). With in-parallel interpretation of culture and IHC-based bacterial detection, 154 of 166 (93%) cats had bacterial infections (gram-positive, 118/154 [77%]; gram-negative, 111/154 [72%]; polymicrobial, 79/154 [51%]). Greater frequency of bacterial isolation occurred with combined tissue, bile, and crushed cholelith inoculates. Infection and gram-positive bacterial isolates were associated with significantly shorter long-term survival times. CLINICAL RELEVANCE S-CCHS was associated with bacterial infection, pathologic endotoxin exposure, and frequent polymicrobial infection in cats. Combined tissue inoculates improved culture detection of associated bacteria.
Collapse
Affiliation(s)
- Sharon A Center
- Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY
| | - John F Randolph
- Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY
| | - Karen L Warner
- Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY
| | - Sean P McDonough
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY
| | | | - Kirk C Sapa
- Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY
| |
Collapse
|
|
37
|
Marongiu L, Landry JJM, Rausch T, Abba ML, Delecluse S, Delecluse H, Allgayer H. Metagenomic analysis of primary colorectal carcinomas and their metastases identifies potential microbial risk factors. Mol Oncol 2021; 15:3363-3384. [PMID: 34328665 PMCID: PMC8637581 DOI: 10.1002/1878-0261.13070] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 07/09/2021] [Accepted: 07/29/2021] [Indexed: 12/18/2022] Open
Abstract
The paucity of microbiome studies at intestinal tissues has contributed to a yet limited understanding of potential viral and bacterial cofactors of colorectal cancer (CRC) carcinogenesis or progression. We analysed whole-genome sequences of CRC primary tumours, their corresponding metastases and matched normal tissue for sequences of viral, phage and bacterial species. Bacteriome analysis showed Fusobacterium nucleatum, Streptococcus sanguinis, F. Hwasookii, Anaerococcus mediterraneensis and further species enriched in primary CRCs. The primary CRC of one patient was enriched for F. alocis, S. anginosus, Parvimonas micra and Gemella sp. 948. Enrichment of Escherichia coli strains IAI1, SE11, K-12 and M8 was observed in metastases together with coliphages enterobacteria phage φ80 and Escherichia phage VT2φ_272. Virome analysis showed that phages were the most preponderant viral species (46%), the main families being Myoviridae, Siphoviridae and Podoviridae. Primary CRCs were enriched for bacteriophages, showing five phages (Enterobacteria, Bacillus, Proteus, Streptococcus phages) together with their pathogenic hosts in contrast to normal tissues. The most frequently detected, and Blast-confirmed, viruses included human endogenous retrovirus K113, human herpesviruses 7 and 6B, Megavirus chilensis, cytomegalovirus (CMV) and Epstein-Barr virus (EBV), with one patient showing EBV enrichment in primary tumour and metastases. EBV was PCR-validated in 80 pairs of CRC primary tumour and their corresponding normal tissues; in 21 of these pairs (26.3%), it was detectable in primary tumours only. The number of viral species was increased and bacterial species decreased in CRCs compared with normal tissues, and we could discriminate primary CRCs from metastases and normal tissues by applying the Hutcheson t-test on the Shannon indices based on viral and bacterial species. Taken together, our results descriptively support hypotheses on microorganisms as potential (co)risk factors of CRC and extend putative suggestions on critical microbiome species in CRC metastasis.
Collapse
Affiliation(s)
- Luigi Marongiu
- Department of Experimental Surgery – Cancer MetastasisMedical Faculty MannheimRuprecht‐Karls University of HeidelbergMannheimGermany
| | | | - Tobias Rausch
- Genomics Core FacilityEuropean Molecular Biology Laboratory (EMBL)HeidelbergGermany
| | - Mohammed L. Abba
- Department of Experimental Surgery – Cancer MetastasisMedical Faculty MannheimRuprecht‐Karls University of HeidelbergMannheimGermany
| | | | | | - Heike Allgayer
- Department of Experimental Surgery – Cancer MetastasisMedical Faculty MannheimRuprecht‐Karls University of HeidelbergMannheimGermany
| |
Collapse
|
|
38
|
Getachew A, Hussain M, Huang X, Li Y. Toll-like receptor 2 signaling in liver pathophysiology. Life Sci 2021; 284:119941. [PMID: 34508761 DOI: 10.1016/j.lfs.2021.119941] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 08/19/2021] [Accepted: 08/30/2021] [Indexed: 12/24/2022]
Abstract
Chronic liver diseases (CLD) are among the major cause of mortality and morbidity worldwide. Despite current achievements in the area of hepatitis virus, chronic alcohol abuse and high-fat diet are still fueling an epidemic of severe liver disease, for which, an effective therapy has yet not been discovered. In particular, the therapeutic regimens that could prevent the progression of fibrosis and, in turn, aid cirrhotic liver to develop a robust regenerative capability are intensively needed. To this context, a better understanding of the signaling pathways regulating hepatic disease development may be of critical value. In general, the liver responds to various insults with an orchestrated healing process involving variety of signaling pathways. One such pathway is the TLR2 signaling pathway, which essentially regulates adult liver pathogenesis and thus has emerged as an attractive target to treat liver disease. TLR2 is expressed by different liver cells, including Kupffer cells (KCs), hepatocytes, and hepatic stellate cells (HSCs). From a pathologic perspective, the crosstalk between antigens and TLR2 may preferentially trigger a distinctive set of signaling mechanisms in these liver cells and, thereby, induce the production of inflammatory and fibrogenic cytokines that can initiate and prolong liver inflammation, ultimately leading to fibrosis. In this review, we summarize the currently available evidence regarding the role of TLR2 signaling in hepatic disease progression. We first elaborate its pathological involvement in liver-disease states, such as inflammation, fibrosis, and cirrhosis. We then discuss how therapeutic targeting of this pathway may help to alleviate its disease-related functioning.
Collapse
Affiliation(s)
- Anteneh Getachew
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; University of Chinese Academy of Sciences, Beijing 100049, China; Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Muzammal Hussain
- Center for Chemical Biology and Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Xinping Huang
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; University of Chinese Academy of Sciences, Beijing 100049, China; Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Yinxiong Li
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; University of Chinese Academy of Sciences, Beijing 100049, China; Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510005, China.
| |
Collapse
|
|
39
|
Zhao C, Cui X, Zhao Y, Qian B, Zhang N, Xin L, Ha C, Yang J, Wang X, Gao X. Impact of hepatocyte-specific deletion of staphylococcal nuclease and tudor domain containing 1 (SND1) on liver insulin resistance and acute liver failure of mice. Bioengineered 2021; 12:7360-7375. [PMID: 34608846 PMCID: PMC8806720 DOI: 10.1080/21655979.2021.1974653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022] Open
Abstract
Although our previous research shows an ameliorated high-fat diet (HFD)-induced hepatic steatosis and insulin resistance in global SND1 transgenic mice, the involvement of SND1 loss-of-function in hepatic metabolism remains elusive. Herein, we aim to explore the potential impact of hepatocyte-specific SND1 deletion on insulin-resistant mice. As SND1 is reported to be linked to inflammatory response, the pathobiological feature of acute liver failure (ALF) is also investigated. Hence, we construct the conditional liver knockout (LKO) mice of SND1 for the first time. Under the condition of HFD, the absence of hepatic SND1 affects the weight of white adipose tissue, but not the gross morphology, body weight, cholesterol level, liver weight, and hepatic steatosis of mice. Furthermore, we fail to observe significant differences in either HFD-induced insulin resistance or lipopolysaccharide/D-galactosamine-induced (LPS/D-GaIN) ALF between LKO and wild type (WT) mice in terms of inflammation and tissue damage. Compared with negative controls, there is no differential SND1 expression in various species of sample with insulin resistance or ALF, based on several gene expression omnibus datasets, including GSE23343, GSE160646, GSE120243, GSE48794, GSE13271, GSE151268, GSE62026, GSE120652, and GSE38941. Enrichment result of SND1-binding partners or related genes indicates a sequence of issues related to RNA or lipid metabolism, but not glucose homeostasis or hepatic failure. Overall, hepatic SND1 is insufficient to alter the phenotypes of hepatic insulin resistance and acute liver failure in mice. The SND1 in various organs is likely to cooperate in regulating glucose homeostasis by affecting the expression of lipid metabolism-related RNA transcripts during stress.
Collapse
Affiliation(s)
- Chunyan Zhao
- Department of Biochemistry and Molecular Biology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.,Key Laboratory of Immune Microenvironment and Disease, Ministry of Education, Key Laboratory of Cellular and Molecular Immunology in Tianjin, Excellent Talent Project, Tianjin Medical University, Tianjin, China
| | - Xiaoteng Cui
- Department of Biochemistry and Molecular Biology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.,Key Laboratory of Immune Microenvironment and Disease, Ministry of Education, Key Laboratory of Cellular and Molecular Immunology in Tianjin, Excellent Talent Project, Tianjin Medical University, Tianjin, China.,Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Department of Neurosurgery, Tianjin Medical University General Hospital and Key Laboratory of Neurotrauma, Variation, and Regeneration, Ministry of Education and Tianjin Municipal Government, Tianjin, China
| | - Yan Zhao
- Department of Biochemistry and Molecular Biology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.,Key Laboratory of Immune Microenvironment and Disease, Ministry of Education, Key Laboratory of Cellular and Molecular Immunology in Tianjin, Excellent Talent Project, Tianjin Medical University, Tianjin, China
| | - Baoxin Qian
- Department of Biochemistry and Molecular Biology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.,Key Laboratory of Immune Microenvironment and Disease, Ministry of Education, Key Laboratory of Cellular and Molecular Immunology in Tianjin, Excellent Talent Project, Tianjin Medical University, Tianjin, China.,Department of Gastroenterology and Hepatology, The Third Central Clinical College of Tianjin Medical University, Tianjin Third Central Hospital, Tianjin, China
| | - Nan Zhang
- Department of Biochemistry and Molecular Biology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.,Key Laboratory of Immune Microenvironment and Disease, Ministry of Education, Key Laboratory of Cellular and Molecular Immunology in Tianjin, Excellent Talent Project, Tianjin Medical University, Tianjin, China
| | - Lingbiao Xin
- Department of Biochemistry and Molecular Biology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.,Key Laboratory of Immune Microenvironment and Disease, Ministry of Education, Key Laboratory of Cellular and Molecular Immunology in Tianjin, Excellent Talent Project, Tianjin Medical University, Tianjin, China
| | - Chuanbo Ha
- Department of Biochemistry and Molecular Biology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.,Key Laboratory of Immune Microenvironment and Disease, Ministry of Education, Key Laboratory of Cellular and Molecular Immunology in Tianjin, Excellent Talent Project, Tianjin Medical University, Tianjin, China
| | - Jie Yang
- Department of Biochemistry and Molecular Biology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.,Key Laboratory of Immune Microenvironment and Disease, Ministry of Education, Key Laboratory of Cellular and Molecular Immunology in Tianjin, Excellent Talent Project, Tianjin Medical University, Tianjin, China
| | - Xinting Wang
- Department of Biochemistry and Molecular Biology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.,Key Laboratory of Immune Microenvironment and Disease, Ministry of Education, Key Laboratory of Cellular and Molecular Immunology in Tianjin, Excellent Talent Project, Tianjin Medical University, Tianjin, China
| | - Xingjie Gao
- Department of Biochemistry and Molecular Biology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.,Key Laboratory of Immune Microenvironment and Disease, Ministry of Education, Key Laboratory of Cellular and Molecular Immunology in Tianjin, Excellent Talent Project, Tianjin Medical University, Tianjin, China
| |
Collapse
|
|
40
|
Kessoku T, Kobayashi T, Tanaka K, Yamamoto A, Takahashi K, Iwaki M, Ozaki A, Kasai Y, Nogami A, Honda Y, Ogawa Y, Kato S, Imajo K, Higurashi T, Hosono K, Yoneda M, Usuda H, Wada K, Saito S, Nakajima A. The Role of Leaky Gut in Nonalcoholic Fatty Liver Disease: A Novel Therapeutic Target. Int J Mol Sci 2021; 22:ijms22158161. [PMID: 34360923 PMCID: PMC8347478 DOI: 10.3390/ijms22158161] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 07/26/2021] [Accepted: 07/28/2021] [Indexed: 02/06/2023] Open
Abstract
The liver directly accepts blood from the gut and is, therefore, exposed to intestinal bacteria. Recent studies have demonstrated a relationship between gut bacteria and nonalcoholic fatty liver disease (NAFLD). Approximately 10–20% of NAFLD patients develop nonalcoholic steatohepatitis (NASH), and endotoxins produced by Gram-negative bacilli may be involved in NAFLD pathogenesis. NAFLD hyperendotoxicemia has intestinal and hepatic factors. The intestinal factors include impaired intestinal barrier function (leaky gut syndrome) and dysbiosis due to increased abundance of ethanol-producing bacteria, which can change endogenous alcohol concentrations. The hepatic factors include hyperleptinemia, which is associated with an excessive response to endotoxins, leading to intrahepatic inflammation and fibrosis. Clinically, the relationship between gut bacteria and NAFLD has been targeted in some randomized controlled trials of probiotics and other agents, but the results have been inconsistent. A recent randomized, placebo-controlled study explored the utility of lubiprostone, a treatment for constipation, in restoring intestinal barrier function and improving the outcomes of NAFLD patients, marking a new phase in the development of novel therapies targeting the intestinal barrier. This review summarizes recent data from studies in animal models and randomized clinical trials on the role of the gut–liver axis in NAFLD pathogenesis and progression.
Collapse
Affiliation(s)
- Takaomi Kessoku
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
- Department of Palliative Medicine, Yokohama City University Hospital, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
- Correspondence: ; Tel.: +81-45-787-2640; Fax: +81-45-784-3546
| | - Takashi Kobayashi
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
| | - Kosuke Tanaka
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
- Department of Palliative Medicine, Yokohama City University Hospital, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
| | - Atsushi Yamamoto
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
| | - Kota Takahashi
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
| | - Michihiro Iwaki
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
- Department of Palliative Medicine, Yokohama City University Hospital, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
| | - Anna Ozaki
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
| | - Yuki Kasai
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
| | - Asako Nogami
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
| | - Yasushi Honda
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
- Department of Palliative Medicine, Yokohama City University Hospital, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
| | - Yuji Ogawa
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
| | - Shingo Kato
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
| | - Kento Imajo
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
| | - Takuma Higurashi
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
| | - Kunihiro Hosono
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
| | - Masato Yoneda
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
| | - Haruki Usuda
- Department of Pharmacology, Shimane University Faculty of Medicine, 89-1 Enyacho, Izumo, Shimane 693-8501, Japan; (H.U.); (K.W.)
| | - Koichiro Wada
- Department of Pharmacology, Shimane University Faculty of Medicine, 89-1 Enyacho, Izumo, Shimane 693-8501, Japan; (H.U.); (K.W.)
| | - Satoru Saito
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
| | - Atsushi Nakajima
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (T.K.); (K.T.); (A.Y.); (K.T.); (M.I.); (A.O.); (Y.K.); (A.N.); (Y.H.); (Y.O.); (S.K.); (K.I.); (T.H.); (K.H.); (M.Y.); (S.S.); (A.N.)
| |
Collapse
|
|
41
|
Hydroxychloroquine (HCQ) Modulates Autophagy and Oxidative DNA Damage Stress in Hepatocellular Carcinoma to Overcome Sorafenib Resistance via TLR9/SOD1/hsa-miR-30a-5p/Beclin-1 Axis. Cancers (Basel) 2021; 13:cancers13133227. [PMID: 34203465 PMCID: PMC8267639 DOI: 10.3390/cancers13133227] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 06/23/2021] [Accepted: 06/24/2021] [Indexed: 12/12/2022] Open
Abstract
Sorafenib is used for treating advanced hepatocellular carcinoma (HCC), but some patients acquire sorafenib resistance. We investigated the mechanisms underlying acquired sorafenib resistance in HCC cells and targeted them to re-sensitize them to sorafenib. In silico analysis indicated that toll-like receptor (TLR)-9 was significantly overexpressed, and that miRNA (hsa-miR-30a-5p) was downregulated in sorafenib-resistant HCC cells, which modulated HCC cell proliferation, oxidative stress, and apoptosis. TLR9 overexpression increased HCC cell proliferation, whereas TLR9 inhibition from hydroxychloroquine (HCQ) decreased HCC cell proliferation, tumor growth, oxidative stress marker (SOD1), and the formation of autophagosome bodies (reduced ATG5 and Beclin-1 expression). Moreover, HCQ treatment reduced epithelial-mesenchymal transition, leading to decreased clonogenicity, migratory ability, and invasiveness. HCQ targeted and reduced the self-renewal capacity phenotype by inhibiting tumorsphere generation. Both in vitro and in vivo results demonstrated the synergistic effect of the HCQ-sorafenib combination on sorafenib-resistant HCC (Huh7-SR) cells, increasing their sensitivity to treatment by modulating TLR9, autophagy (ATG5 and Beclin-1), oxidative stress (SOD1), and apoptosis (c-caspase3) expression and thus overcoming the drug resistance. This study's findings indicate that TLR9 overexpression occurs in sorafenib-resistant HCC cells and that its downregulation aids HCC suppression. Moreover, HCQ treatment significantly increases sorafenib's effect on sorafenib-resistant HCC cells.
Collapse
|
|
42
|
Benedé‐Ubieto R, Estévez‐Vázquez O, Guo F, Chen C, Singh Y, Nakaya HI, Gómez del Moral M, Lamas‐Paz A, Morán L, López‐Alcántara N, Reissing J, Bruns T, Avila MA, Santamaría E, Mazariegos MS, Woitok MM, Haas U, Zheng K, Juárez I, Martín‐Villa JM, Asensio I, Vaquero J, Peligros MI, Argemi J, Bataller R, Ampuero J, Romero Gómez M, Trautwein C, Liedtke C, Bañares R, Cubero FJ, Nevzorova YA. An Experimental DUAL Model of Advanced Liver Damage. Hepatol Commun 2021; 5:1051-1068. [PMID: 34141989 PMCID: PMC8183170 DOI: 10.1002/hep4.1698] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 01/22/2021] [Accepted: 02/07/2021] [Indexed: 12/11/2022] Open
Abstract
Individuals exhibiting an intermediate alcohol drinking pattern in conjunction with signs of metabolic risk present clinical features of both alcohol-associated and metabolic-associated fatty liver diseases. However, such combination remains an unexplored area of great interest, given the increasing number of patients affected. In the present study, we aimed to develop a preclinical DUAL (alcohol-associated liver disease plus metabolic-associated fatty liver disease) model in mice. C57BL/6 mice received 10% vol/vol alcohol in sweetened drinking water in combination with a Western diet for 10, 23, and 52 weeks (DUAL model). Animals fed with DUAL diet elicited a significant increase in body mass index accompanied by a pronounced hypertrophy of adipocytes, hypercholesterolemia, and hyperglycemia. Significant liver damage was characterized by elevated plasma alanine aminotransferase and lactate dehydrogenase levels, extensive hepatomegaly, hepatocyte enlargement, ballooning, steatosis, hepatic cell death, and compensatory proliferation. Notably, DUAL animals developed lobular inflammation and advanced hepatic fibrosis. Sequentially, bridging cirrhotic changes were frequently observed after 12 months. Bulk RNA-sequencing analysis indicated that dysregulated molecular pathways in DUAL mice were similar to those of patients with steatohepatitis. Conclusion: Our DUAL model is characterized by obesity, glucose intolerance, liver damage, prominent steatohepatitis and fibrosis, as well as inflammation and fibrosis in white adipose tissue. Altogether, the DUAL model mimics all histological, metabolic, and transcriptomic gene signatures of human advanced steatohepatitis, and therefore serves as a preclinical tool for the development of therapeutic targets.
Collapse
Affiliation(s)
- Raquel Benedé‐Ubieto
- Department of Physiology, Genetics and MicrobiologyFaculty of BiologyComplutense University MadridMadridSpain
- Department of Immunology, Ophthalmology and ENTComplutense University School of MedicineMadridSpain
| | - Olga Estévez‐Vázquez
- Department of Physiology, Genetics and MicrobiologyFaculty of BiologyComplutense University MadridMadridSpain
- Department of Immunology, Ophthalmology and ENTComplutense University School of MedicineMadridSpain
| | - Feifei Guo
- Department of Immunology, Ophthalmology and ENTComplutense University School of MedicineMadridSpain
| | - Chaobo Chen
- Department of Immunology, Ophthalmology and ENTComplutense University School of MedicineMadridSpain
| | - Youvika Singh
- Department of Clinical and Toxicological AnalysesSchool of Pharmaceutical SciencesUniversity of São PauloSão PauloBrazil
| | - Helder I. Nakaya
- Department of Clinical and Toxicological AnalysesSchool of Pharmaceutical SciencesUniversity of São PauloSão PauloBrazil
- Scientific Platform PasteurUniversity of São PauloSão PauloBrazil
| | | | - Arantza Lamas‐Paz
- Department of Immunology, Ophthalmology and ENTComplutense University School of MedicineMadridSpain
| | - Laura Morán
- Department of Immunology, Ophthalmology and ENTComplutense University School of MedicineMadridSpain
| | - Nuria López‐Alcántara
- Department of Immunology, Ophthalmology and ENTComplutense University School of MedicineMadridSpain
- Institute for Endocrinology and DiabetesCenter of Brain Behavior & MetabolismUniversity of LübeckLübeckGermany
| | - Johanna Reissing
- Department of Internal Medicine IIIUniversity Hospital RWTHAachenGermany
| | - Tony Bruns
- Department of Internal Medicine IIIUniversity Hospital RWTHAachenGermany
| | - Matías A. Avila
- Hepatology ProgramCIMAUniversity of NavarraPamplonaSpain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y DigestivasInstituto de Salud Carlos IIIMadridSpain
- Instituto de Investigaciones Sanitarias de NavarraPamplonaSpain
| | - Eva Santamaría
- Hepatology ProgramCIMAUniversity of NavarraPamplonaSpain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y DigestivasInstituto de Salud Carlos IIIMadridSpain
| | - Marina S. Mazariegos
- Department of Immunology, Ophthalmology and ENTComplutense University School of MedicineMadridSpain
| | | | - Ute Haas
- Department of Internal Medicine IIIUniversity Hospital RWTHAachenGermany
| | - Kang Zheng
- Department of Immunology, Ophthalmology and ENTComplutense University School of MedicineMadridSpain
- 12 de Octubre Health Research InstituteMadridSpain
- Department of AnesthesiologyZhongda HospitalSchool of MedicineSoutheast UniversityNanjingChina
| | - Ignacio Juárez
- Department of Immunology, Ophthalmology and ENTComplutense University School of MedicineMadridSpain
| | - José Manuel Martín‐Villa
- Department of Immunology, Ophthalmology and ENTComplutense University School of MedicineMadridSpain
- Instituto de Investigación Sanitaria Gregorio MarañónMadridSpain
| | - Iris Asensio
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y DigestivasInstituto de Salud Carlos IIIMadridSpain
- Instituto de Investigación Sanitaria Gregorio MarañónMadridSpain
- Servicio de Aparato DigestivoHospital General Universitario Gregorio MarañónMadridSpain
| | - Javier Vaquero
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y DigestivasInstituto de Salud Carlos IIIMadridSpain
- Instituto de Investigación Sanitaria Gregorio MarañónMadridSpain
- Servicio de Aparato DigestivoHospital General Universitario Gregorio MarañónMadridSpain
| | - Maria Isabel Peligros
- Servicio de Anatomía PatológicaHospital General Universitario Gregorio MarañónMadridSpain
| | - Josepmaria Argemi
- Division of Gastroenterology, Hepatology and NutritionCenter for Liver DiseasesUniversity of PittsburghPittsburghPAUSA
- Liver UnitClinica Universidad de Navarra, University of NavarraPamplonaSpain
- Hepatology ProgramCentro de Investigación Médica AplicadaUniversidad de NavarraPamplonaSpain
| | - Ramón Bataller
- Division of Gastroenterology, Hepatology and NutritionCenter for Liver DiseasesUniversity of PittsburghPittsburghPAUSA
- Pittsburgh Liver Research CenterUniversity of PittsburghPittsburghPAUSA
| | - Javier Ampuero
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y DigestivasInstituto de Salud Carlos IIIMadridSpain
- Biomedical Research Networking Center in Hepatic and Digestive DiseasesInstituto de Biomedicina de SevillaHospital Universitario Virgen del Rocío de SevillaUniversity of SevillaSevillaSpain
| | - Manuel Romero Gómez
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y DigestivasInstituto de Salud Carlos IIIMadridSpain
- Biomedical Research Networking Center in Hepatic and Digestive DiseasesInstituto de Biomedicina de SevillaHospital Universitario Virgen del Rocío de SevillaUniversity of SevillaSevillaSpain
| | | | - Christian Liedtke
- Department of Internal Medicine IIIUniversity Hospital RWTHAachenGermany
| | - Rafael Bañares
- Department of Immunology, Ophthalmology and ENTComplutense University School of MedicineMadridSpain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y DigestivasInstituto de Salud Carlos IIIMadridSpain
- Instituto de Investigación Sanitaria Gregorio MarañónMadridSpain
- Servicio de Aparato DigestivoHospital General Universitario Gregorio MarañónMadridSpain
| | - Francisco Javier Cubero
- Department of Immunology, Ophthalmology and ENTComplutense University School of MedicineMadridSpain
- 12 de Octubre Health Research InstituteMadridSpain
| | - Yulia A. Nevzorova
- Department of Immunology, Ophthalmology and ENTComplutense University School of MedicineMadridSpain
- Department of Internal Medicine IIIUniversity Hospital RWTHAachenGermany
- 12 de Octubre Health Research InstituteMadridSpain
| |
Collapse
|
|
43
|
Li R, Mao Z, Ye X, Zuo T. Human Gut Microbiome and Liver Diseases: From Correlation to Causation. Microorganisms 2021; 9:1017. [PMID: 34066850 PMCID: PMC8151257 DOI: 10.3390/microorganisms9051017] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 04/25/2021] [Accepted: 04/30/2021] [Indexed: 02/06/2023] Open
Abstract
The important role of human gut microbiota in liver diseases has long been recognized as dysbiosis and the translocation of certain microbes from the gut to liver. With the development of high-throughput DNA sequencing, the complexity and integrity of the gut microbiome in the whole spectrum of liver diseases is emerging. Specific patterns of gut microbiota have been identified in liver diseases with different causes, including alcoholic, non-alcoholic, and virus induced liver diseases, or even at different stages, ranging from steatohepatitis, fibrosis, cirrhosis, to hepatocellular carcinoma. At the same time, the mechanism of how microbiota contributes to liver diseases goes beyond the traditional function of the gut-liver axis which could lead to liver injury and inflammation. With the application of proteomics, metabolomics, and modern molecular technologies, more microbial metabolites and the complicated interaction of microbiota with host immunity come into our understanding in the liver pathogenesis. Germ-free animal models serve as a workhorse to test the function of microbiota and their derivatives in liver disease models. Here, we review the current evidence on the relationship between gut microbiota and liver diseases, and the mechanisms underlying this phenotype. In addition to original liver diseases, gut microbiota might also affect liver injury in systemic disorders involving multiple organs, as in the case of COVID-19 at a severe state. A better understanding of the gut microbial contribution to liver diseases might help us better benefit from this guest-host relationship and pave the way for novel therapies.
Collapse
Affiliation(s)
- Rui Li
- Department of Geriatrics, Zhongnan Hospital of Wuhan University, Wuhan 430070, China;
| | - Zhengsheng Mao
- Department of Neurology, Wuhan Fourth Hospital, Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430074, China;
| | - Xujun Ye
- Department of Geriatrics, Zhongnan Hospital of Wuhan University, Wuhan 430070, China;
| | - Tao Zuo
- Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-Sen University, Sun Yat-Sen University, Guangzhou 510000, China
| |
Collapse
|
|
44
|
Getachew A, Abbas N, You K, Yang Z, Hussain M, Huang X, Cheng Z, Tan S, Tao J, Yu X, Chen Y, Yang F, Pan T, Xu Y, Xu G, Zhuang Y, Wu F, Li Y. SAA1/TLR2 axis directs chemotactic migration of hepatic stellate cells responding to injury. iScience 2021; 24:102483. [PMID: 34113824 PMCID: PMC8169952 DOI: 10.1016/j.isci.2021.102483] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 04/03/2021] [Accepted: 04/25/2021] [Indexed: 12/14/2022] Open
Abstract
Hepatic stellate cells (HSCs) are crucial for liver injury repair and cirrhosis. However, the mechanism of chemotactic recruitment of HSCs into injury loci is still largely unknown. Here, we demonstrate that serum amyloid A1 (SAA1) acts as a chemokine recruiting HSCs toward injury loci signaling via TLR2, a finding proven by gene manipulation studies in cell and mice models. The mechanistic investigations revealed that SAA1/TLR2 axis stimulates the Rac GTPases through PI3K-dependent pathways and induces phosphorylation of MLC (pSer19). Genetic deletion of TLR2 and pharmacological inhibition of PI3K diminished the phosphorylation of MLCpSer19 and migration of HSCs. In brief, SAA1 serves as a hepatic endogenous chemokine for the TLR2 receptor on HSCs, thereby initiating PI3K-dependent signaling and its effector, Rac GTPases, which consequently regulates actin filament remodeling and cell directional migration. Our findings provide novel targets for anti-fibrosis drug development.
SAA1 serves as a chemokine to guide migration of HSCs toward injury locus TLR2 acts as a functional receptor for SAA1 in HSCs SAA1/TLR2 axis-mediated migration of HSCs operates through PI3K/Rac1 signaling SAA1/TLR2 axis provides a link for the cross talk between hepatocytes and HSCs
Collapse
Affiliation(s)
- Anteneh Getachew
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China.,University of China Academy of Sciences, Beijing 100049, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Nasir Abbas
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China.,University of China Academy of Sciences, Beijing 100049, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Kai You
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Zhen Yang
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China.,University of China Academy of Sciences, Beijing 100049, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Muzammal Hussain
- University of China Academy of Sciences, Beijing 100049, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Xinping Huang
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China.,University of China Academy of Sciences, Beijing 100049, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Ziqi Cheng
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China.,University of China Academy of Sciences, Beijing 100049, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Shenglin Tan
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China.,University of China Academy of Sciences, Beijing 100049, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Jiawang Tao
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China.,University of China Academy of Sciences, Beijing 100049, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Xiaorui Yu
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China.,University of China Academy of Sciences, Beijing 100049, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Yan Chen
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Fan Yang
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Tingcai Pan
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Yingying Xu
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Guosheng Xu
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Yuanqi Zhuang
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - FeiMa Wu
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Yinxiong Li
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China.,University of China Academy of Sciences, Beijing 100049, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510005, China
| |
Collapse
|
|
45
|
Kairaluoma V, Kemi N, Huhta H, Pohjanen VM, Helminen O. Prognostic role of TLR4 and TLR2 in hepatocellular carcinoma. Acta Oncol 2021; 60:554-558. [PMID: 33502274 DOI: 10.1080/0284186x.2021.1877346] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Affiliation(s)
- Valtteri Kairaluoma
- Cancer and Translational Medicine Research Unit, Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland
| | - Niko Kemi
- Cancer and Translational Medicine Research Unit, Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland
| | - Heikki Huhta
- Cancer and Translational Medicine Research Unit, Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland
| | - Vesa-Matti Pohjanen
- Cancer and Translational Medicine Research Unit, Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland
| | - Olli Helminen
- Cancer and Translational Medicine Research Unit, Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland
| |
Collapse
|
|
46
|
Translational Approaches with Antioxidant Phytochemicals against Alcohol-Mediated Oxidative Stress, Gut Dysbiosis, Intestinal Barrier Dysfunction, and Fatty Liver Disease. Antioxidants (Basel) 2021; 10:antiox10030384. [PMID: 33806556 PMCID: PMC8000766 DOI: 10.3390/antiox10030384] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 02/25/2021] [Accepted: 02/25/2021] [Indexed: 12/12/2022] Open
Abstract
Emerging data demonstrate the important roles of altered gut microbiomes (dysbiosis) in many disease states in the peripheral tissues and the central nervous system. Gut dysbiosis with decreased ratios of Bacteroidetes/Firmicutes and other changes are reported to be caused by many disease states and various environmental factors, such as ethanol (e.g., alcohol drinking), Western-style high-fat diets, high fructose, etc. It is also caused by genetic factors, including genetic polymorphisms and epigenetic changes in different individuals. Gut dysbiosis, impaired intestinal barrier function, and elevated serum endotoxin levels can be observed in human patients and/or experimental rodent models exposed to these factors or with certain disease states. However, gut dysbiosis and leaky gut can be normalized through lifestyle alterations such as increased consumption of healthy diets with various fruits and vegetables containing many different kinds of antioxidant phytochemicals. In this review, we describe the mechanisms of gut dysbiosis, leaky gut, endotoxemia, and fatty liver disease with a specific focus on the alcohol-associated pathways. We also mention translational approaches by discussing the benefits of many antioxidant phytochemicals and/or their metabolites against alcohol-mediated oxidative stress, gut dysbiosis, intestinal barrier dysfunction, and fatty liver disease.
Collapse
|
|
47
|
Eguchi A, Iwasa M, Tamai Y, Tempaku M, Takamatsu S, Miyoshi E, Hasegawa H, Kobayashi Y, Takei Y. Branched-chain amino acids protect the liver from cirrhotic injury via suppression of activation of lipopolysaccharide-binding protein, toll-like receptor 4, and signal transducer and activator of transcription 3, as well as Enterococcus faecalis translocation. Nutrition 2021; 86:111194. [PMID: 33743328 DOI: 10.1016/j.nut.2021.111194] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 12/18/2020] [Accepted: 01/30/2021] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Branched-chain amino acids (BCAAs) are used as nutritional support and for improving prognosis in liver cirrhosis. Here we investigate the molecular mechanisms of BCAA treatment and liver damage focused on pathways related to lipopolysaccharide-binding protein (LBP). METHODS Serum LBP levels were measured in cirrhotic patients and in cirrhotic rats treated with BCAA to examine the correlation between liver function and survival. In cirrhotic rats, liver damage, Enterococcus faecalis translocation, serum capsular polysaccharide, and intestinal tight junction levels were assessed. Damaged HepG2 cells were cultured with BCAA-supplemented, BCAA-deficient, or control amino acid medium, followed by examination of LBP expression. RESULTS Serum LBP levels were significantly increased in deceased patients individuals with liver cirrhosis. The survival rate in patients with lower serum LBP (<3.48 μg/mL) was significantly improved. In BCAA-treated rat liver samples, protein expression of LBP, toll-like receptor 4 (TLR4), and phosphorylated signal transduction and activator of transcription 3 (STAT3) were significantly reduced. Also in BCAA-treated rats, intestinal zonula occludens gene expression was increased, whereas hepatic translocation of E. faecalis and serum capsular polysaccharide levels were reduced. In damaged HepG2 cells, lipopolysaccharide-induced elevation of LBP expression was rapidly and strongly repressed in BCAA-enriched medium. CONCLUSIONS Serum LBP level is a prognostic biomarker in liver cirrhosis. BCAA treatment reduced translocation of E. faecalis through intestinal tight junction recovery and reduced LBP expression in the liver, which repressed activation of LBP, toll-like receptor 4, and signal transduction and activator of transcription 3. Our findings suggest that BCAA supplementation protects the liver from damage via multiple pathways.
Collapse
Affiliation(s)
- Akiko Eguchi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Mie University, Tsu, Japan; Japan Science and Technology Agency, Precursory Research for Embryonic Science and Technology, Kawaguchi, Japan
| | - Motoh Iwasa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Mie University, Tsu, Japan.
| | - Yasuyuki Tamai
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Mie University, Tsu, Japan
| | - Mina Tempaku
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Mie University, Tsu, Japan
| | - Shinji Takamatsu
- Department of Molecular Biochemistry and Clinical Investigation, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Eiji Miyoshi
- Department of Molecular Biochemistry and Clinical Investigation, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Hiroshi Hasegawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Mie University, Tsu, Japan
| | - Yoshinao Kobayashi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Mie University, Tsu, Japan; Center for Physical and Mental Health, Graduate School of Medicine, Mie University, Tsu, Japan
| | - Yoshiyuki Takei
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Mie University, Tsu, Japan
| |
Collapse
|
|
48
|
Ruf B, Heinrich B, Greten TF. Immunobiology and immunotherapy of HCC: spotlight on innate and innate-like immune cells. Cell Mol Immunol 2021; 18:112-127. [PMID: 33235387 PMCID: PMC7852696 DOI: 10.1038/s41423-020-00572-w] [Citation(s) in RCA: 206] [Impact Index Per Article: 51.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 09/29/2020] [Indexed: 12/24/2022] Open
Abstract
Immune-based therapies such as immune checkpoint inhibitors have revolutionized the systemic treatment of various cancer types. The therapeutic application of monoclonal antibodies targeting inhibitory pathways such as programmed cell death-1(PD-1)/programmed cell death ligand 1 (PD-L1) and CTLA-4 to cells of the adaptive immune system has recently been shown to generate meaningful improvement in the clinical outcome of hepatocellular carcinoma (HCC). Nevertheless, current immunotherapeutic approaches induce durable responses in only a subset of HCC patients. Since immunologic mechanisms such as chronic inflammation due to chronic viral hepatitis or alcoholic and nonalcoholic fatty liver disease play a crucial role in the initiation, development, and progression of HCC, it is important to understand the underlying mechanisms shaping the unique tumor microenvironment of liver cancer. The liver is an immunologic organ with large populations of innate and innate-like immune cells and is exposed to bacterial, viral, and fungal antigens through the gut-liver axis. Here, we summarize and highlight the role of these cells in liver cancer and propose strategies to therapeutically target them. We also discuss current immunotherapeutic strategies in HCC and outline recent advances in our understanding of how the therapeutic potential of these agents might be enhanced.
Collapse
Affiliation(s)
- Benjamin Ruf
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Malignancies Branch, Centre for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Bernd Heinrich
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Malignancies Branch, Centre for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Tim F Greten
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Malignancies Branch, Centre for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
- NCI CCR Liver Cancer Program, National Institutes of Health, Bethesda, MD, 20892, USA.
| |
Collapse
|
|
49
|
Zhang Q, Ma C, Duan Y, Heinrich B, Rosato U, Diggs LP, Ma L, Roy S, Fu Q, Brown ZJ, Wabitsch S, Thovarai V, Fu J, Feng D, Ruf B, Cui LL, Subramanyam V, Frank KM, Wang S, Kleiner DE, Ritz T, Rupp C, Gao B, Longerich T, Kroemer A, Wang XW, Ruchirawat M, Korangy F, Schnabl B, Trinchieri G, Greten TF. Gut Microbiome Directs Hepatocytes to Recruit MDSCs and Promote Cholangiocarcinoma. Cancer Discov 2020; 11:1248-1267. [PMID: 33323397 DOI: 10.1158/2159-8290.cd-20-0304] [Citation(s) in RCA: 156] [Impact Index Per Article: 31.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 10/14/2020] [Accepted: 12/10/2020] [Indexed: 02/07/2023]
Abstract
Gut dysbiosis is commonly observed in patients with cirrhosis and chronic gastrointestinal disorders; however, its effect on antitumor immunity in the liver is largely unknown. Here we studied how the gut microbiome affects antitumor immunity in cholangiocarcinoma. Primary sclerosing cholangitis (PSC) or colitis, two known risk factors for cholangiocarcinoma which promote tumor development in mice, caused an accumulation of CXCR2+ polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC). A decrease in gut barrier function observed in mice with PSC and colitis allowed gut-derived bacteria and lipopolysaccharide to appear in the liver and induced CXCL1 expression in hepatocytes through a TLR4-dependent mechanism and an accumulation of CXCR2+ PMN-MDSCs. In contrast, neomycin treatment blocked CXCL1 expression and PMN-MDSC accumulation and inhibited tumor growth even in the absence of liver disease or colitis. Our study demonstrates that the gut microbiome controls hepatocytes to form an immunosuppressive environment by increasing PMN-MDSCs to promote liver cancer. SIGNIFICANCE: MDSCs have been shown to be induced by tumors and suppress antitumor immunity. Here we show that the gut microbiome can control accumulation of MDSCs in the liver in the context of a benign liver disease or colitis.See related commentary by Chagani and Kwong, p. 1014.This article is highlighted in the In This Issue feature, p. 995.
Collapse
Affiliation(s)
- Qianfei Zhang
- Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Chi Ma
- Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Yi Duan
- Department of Medicine, University of California, San Diego, La Jolla, California.,Department of Medicine, VA San Diego Healthcare System, San Diego, California
| | - Bernd Heinrich
- Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Umberto Rosato
- Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Laurence P Diggs
- Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Lichun Ma
- Laboratory of Human Carcinogenesis, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Soumen Roy
- Cancer and Inflammation Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Qiong Fu
- Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Zachary J Brown
- Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Simon Wabitsch
- Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Vishal Thovarai
- Cancer and Inflammation Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Jianyang Fu
- Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Dechun Feng
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland
| | - Benjamin Ruf
- Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Linda L Cui
- Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Varun Subramanyam
- Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Karen M Frank
- Microbiology Service, Department of Laboratory Medicine, Clinical Center, NIH, Bethesda, Maryland
| | - Sophie Wang
- Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | | | - Thomas Ritz
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.,Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany
| | - Christian Rupp
- Department of Gastroenterology, University Hospital of Heidelberg, Heidelberg, Germany
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland
| | - Thomas Longerich
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Alexander Kroemer
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, District of Columbia
| | - Xin Wei Wang
- Laboratory of Human Carcinogenesis, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.,NCI-CCR Liver Cancer Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Mathuros Ruchirawat
- Laboratory of Chemical Carcinogenesis, Chulabhorn Research Institute, Bangkok, Thailand.,Center of Excellence on Environmental Health and Toxicology, Office of the Higher Education Commission, Ministry of Education, Bangkok, Thailand
| | - Firouzeh Korangy
- Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Bernd Schnabl
- Department of Medicine, University of California, San Diego, La Jolla, California.,Department of Medicine, VA San Diego Healthcare System, San Diego, California
| | - Giorgio Trinchieri
- Cancer and Inflammation Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Tim F Greten
- Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland. .,NCI-CCR Liver Cancer Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| |
Collapse
|
|
50
|
Jennison E, Byrne CD. The role of the gut microbiome and diet in the pathogenesis of non-alcoholic fatty liver disease. Clin Mol Hepatol 2020; 27:22-43. [PMID: 33291863 PMCID: PMC7820212 DOI: 10.3350/cmh.2020.0129] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 08/12/2020] [Indexed: 02/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease, with a prevalence that is increasing in parallel with the global rise in obesity and type 2 diabetes mellitus. The pathogenesis of NAFLD is complex and multifactorial, involving environmental, genetic and metabolic factors. The role of the diet and the gut microbiome is gaining interest as a significant factor in NAFLD pathogenesis. Dietary factors induce alterations in the composition of the gut microbiome (dysbiosis), commonly reflected by a reduction of the beneficial species and an increase in pathogenic microbiota. Due to the close relationship between the gut and liver, altering the gut microbiome can affect liver functions; promoting hepatic steatosis and inflammation. This review summarises the current evidence supporting an association between NAFLD and the gut microbiome and dietary factors. The review also explores potential underlying mechanisms underpinning these associations and whether manipulation of the gut microbiome is a potential therapeutic strategy to prevent or treat NAFLD.
Collapse
Affiliation(s)
- Erica Jennison
- Department of Chemical Pathology, Southampton General Hospital, University Hospital Southampton, Southampton, UK
| | - Christopher D Byrne
- Department of Nutrition and Metabolism, Faculty of Medicine, University of Southampton, Southampton, UK.,Southampton National Institute for Health Research Biomedical Research Centre, Southampton General Hospital, University Hospital Southampton, Southampton, UK
| |
Collapse
|