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Wang X, Wang Z, Liu Z, Huang F, Pan Z, Zhang Z, Liu T. Nutritional strategies in oncology: The role of dietary patterns in modulating tumor progression and treatment response. Biochim Biophys Acta Rev Cancer 2025; 1880:189322. [PMID: 40228747 DOI: 10.1016/j.bbcan.2025.189322] [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: 02/10/2025] [Revised: 04/08/2025] [Accepted: 04/10/2025] [Indexed: 04/16/2025]
Abstract
Dietary interventions can influence tumor growth by restricting tumor-specific nutritional requirements, altering the nutrient availability in the tumor microenvironment, or enhancing the cytotoxicity of anticancer drugs. Metabolic reprogramming of tumor cells, as a significant hallmark of tumor progression, has a profound impact on immune regulation, severely hindering tumor eradication. Dietary interventions can modify tumor metabolic processes to some extent, thereby further improving the efficacy of tumor treatment. In this review, we emphasize the impact of dietary patterns on tumor progression. By exploring the metabolic differences of nutrients in normal cells versus cancer cells, we further clarify how dietary patterns influence cancer treatment. We also discuss the effects of dietary patterns on traditional treatments such as immunotherapy, chemotherapy, radiotherapy, and the gut microbiome, thereby underscoring the importance of precision nutrition.
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Affiliation(s)
- Xueying Wang
- Department of Oncological Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province 150000, China
| | - Zeyao Wang
- Department of Oncological Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province 150000, China
| | - Zihan Liu
- Department of Oncological Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province 150000, China
| | - Fanxuan Huang
- Department of Oncological Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province 150000, China
| | - Zhaoyu Pan
- Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Hunan, China
| | - Zhiren Zhang
- Departments of Cardiology and Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University, NHC Key Laboratory of Cell Transplantation, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin, China; Departments of Cardiology and Pharmacy and Breast Cancer surgery, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Heilongjiang Key Laboratory for Metabolic Disorder and Cancer Related Cardiovascular Diseases, Harbin, China.
| | - Tong Liu
- Department of Oncological Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province 150000, China; Departments of Cardiology and Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University, NHC Key Laboratory of Cell Transplantation, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin, China.
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2
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Ge Z, Wu Q, Lv C, He Q. The Roles of T Cells in the Development of Metabolic Dysfunction-Associated Steatohepatitis. Immunology 2025. [PMID: 40414629 DOI: 10.1111/imm.13943] [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: 12/04/2024] [Revised: 02/28/2025] [Accepted: 04/28/2025] [Indexed: 05/27/2025] Open
Abstract
Metabolic dysfunction-associated steatohepatitis (MASH), the progressed period of metabolic dysfunction-associated steatotic liver disease (MASLD), is a multifaceted liver disease characterised by inflammation and fibrosis that develops from simple steatosis, even contributing to hepatocellular carcinoma and death. MASH involves several immune cell-mediated inflammation and fibrosis, where T cells play a crucial role through the release of pro-inflammatory cytokines and pro-fibrotic factors. This review discusses the complex role of various T cell subsets in the pathogenesis of MASH and highlights the progress of ongoing clinical trials involving T cell-targeted MASH therapies.
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Affiliation(s)
- Zhifa Ge
- Department of General Surgery, Nanjing First Hospital, The Affiliated Nanjing Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Qingwei Wu
- Department of General Surgery, Nanjing First Hospital, The Affiliated Nanjing Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Chengyu Lv
- Department of General Surgery, Nanjing First Hospital, The Affiliated Nanjing Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Qifeng He
- Department of General Surgery, Nanjing First Hospital, The Affiliated Nanjing Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
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3
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Jee YM, Lee JY, Ryu T. Chronic Inflammation and Immune Dysregulation in Metabolic-Dysfunction-Associated Steatotic Liver Disease Progression: From Steatosis to Hepatocellular Carcinoma. Biomedicines 2025; 13:1260. [PMID: 40427086 PMCID: PMC12109540 DOI: 10.3390/biomedicines13051260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2025] [Revised: 05/16/2025] [Accepted: 05/19/2025] [Indexed: 05/29/2025] Open
Abstract
Background/Objectives: Metabolic-dysfunction-associated steatotic liver disease (MASLD) progresses from hepatic steatosis to hepatocellular carcinoma (HCC) as a result of systemic immunometabolic dysfunction. This review summarizes the key roles of the innate and adaptive immune mechanisms driving hepatic injury, fibrogenesis, and carcinogenesis in MASLD. Methods: A comprehensive literature review was performed using PubMed to identify relevant published studies. Eligible articles included original research and clinical studies addressing immunological and metabolic mechanisms in MASLD, as well as emerging therapeutic strategies. Results: We highlight the roles of cytokine networks, the gut-liver axis, and immune cell reprogramming. Emerging therapeutic strategies, including cytokine inhibitors, anti-fibrotic agents, metabolic modulators, and nutraceuticals, offer several indications for attenuating MASLD progression and reducing the prevalence of extrahepatic manifestations. Conclusions: Given the heterogeneity of MASLD, personalized combination-based approaches targeting both inflammation and metabolic stress are essential for effective disease management and the prevention of systemic complications.
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Affiliation(s)
- Young-Min Jee
- Department of Family Medicine, Soonchunhyang University Seoul Hospital, Seoul 04401, Republic of Korea;
- Department of Family Medicine, Graduate School of Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Jeong-Yoon Lee
- Department of Neurology, Soonchunhyang University Seoul Hospital, Seoul 04401, Republic of Korea;
- Department of Translational Medicine, Graduate School of Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Tom Ryu
- Department of Internal Medicine, Institute for Digestive Research, Digestive Disease Center, Soonchunhyang University College of Medicine, Seoul 04401, Republic of Korea
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4
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Rigual MDM, Angulo-Aguado M, Zagorac S, Álvarez-Díaz R, Benítez-Mondéjar M, Yi F, Martínez-Garay C, Santos-de-Frutos K, Kim E, Campos-Olivas R, Djouder N. Macrophages harness hepatocyte glutamate to boost liver regeneration. Nature 2025; 641:1005-1016. [PMID: 40140584 DOI: 10.1038/s41586-025-08778-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Accepted: 02/12/2025] [Indexed: 03/28/2025]
Abstract
Liver regeneration after hepatectomy follows accurate coordination with the body's specific requirements1-3. However, the molecular mechanisms, factors and particular hepatocyte population influencing its efficiency remain unclear. Here we report on a unique regeneration mechanism involving unconventional RPB5 prefoldin interactor 1 (URI1), which exclusively colocalizes with, binds to and activates glutamine synthase (GS) in pericentral hepatocytes. Genetic GS or URI1 depletion in mouse pericentral hepatocytes increases circulating glutamate levels, accelerating liver regeneration after two-third hepatectomy. Conversely, mouse hepatocytic URI1 overexpression hinders liver restoration, which can be reversed by elevating glutamate through supplementation or genetic GS depletion. Glutamate metabolically reprograms bone-marrow-derived macrophages, stabilizing HIF1α, which transcriptionally activates WNT3 to promote YAP1-dependent hepatocyte proliferation, boosting liver regeneration. GS regulation by URI1 is a mechanism that maintains optimal glutamate levels, probably to spatiotemporally fine-tune liver growth in accordance with the body's homeostasis and nutrient supply. Accordingly, in acute and chronic injury models, including in cirrhotic mice with low glutamate levels and in early mortality after liver resection, as well as in mice undergoing 90% hepatectomy, glutamate addition enhances hepatocyte proliferation and survival. Furthermore, URI1 and GS expression co-localize in human hepatocytes and correlate with WNT3 in immune cells across liver disease stages. Glutamate supplementation may therefore support liver regeneration, benefiting patients awaiting transplants or recovering from hepatectomy.
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Affiliation(s)
- María Del Mar Rigual
- Growth Factors, Nutrients and Cancer Group, Molecular Oncology Programme, Centro Nacional Investigaciones Oncológicas (CNIO), Madrid, Spain
| | - Mariana Angulo-Aguado
- Growth Factors, Nutrients and Cancer Group, Molecular Oncology Programme, Centro Nacional Investigaciones Oncológicas (CNIO), Madrid, Spain
| | - Sladjana Zagorac
- Growth Factors, Nutrients and Cancer Group, Molecular Oncology Programme, Centro Nacional Investigaciones Oncológicas (CNIO), Madrid, Spain
| | - Ruth Álvarez-Díaz
- Bioinformatic Unit, Centro Nacional Investigaciones Oncológicas (CNIO), Madrid, Spain
| | - Marta Benítez-Mondéjar
- Growth Factors, Nutrients and Cancer Group, Molecular Oncology Programme, Centro Nacional Investigaciones Oncológicas (CNIO), Madrid, Spain
| | - Fengming Yi
- Growth Factors, Nutrients and Cancer Group, Molecular Oncology Programme, Centro Nacional Investigaciones Oncológicas (CNIO), Madrid, Spain
| | - Carlos Martínez-Garay
- Growth Factors, Nutrients and Cancer Group, Molecular Oncology Programme, Centro Nacional Investigaciones Oncológicas (CNIO), Madrid, Spain
| | - Karla Santos-de-Frutos
- Growth Factors, Nutrients and Cancer Group, Molecular Oncology Programme, Centro Nacional Investigaciones Oncológicas (CNIO), Madrid, Spain
| | - Eunjeong Kim
- Growth Factors, Nutrients and Cancer Group, Molecular Oncology Programme, Centro Nacional Investigaciones Oncológicas (CNIO), Madrid, Spain
- KNU G-LAMP Research Center, KNU Institute of Basic Sciences, BK21 FOUR KNU Creative BioResearch Group, Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu, South Korea
| | - Ramón Campos-Olivas
- Spectroscopy and Nuclear Magnetic Resonance Unit, Structural Biology Programme, Centro Nacional Investigaciones Oncológicas (CNIO), Madrid, Spain
| | - Nabil Djouder
- Growth Factors, Nutrients and Cancer Group, Molecular Oncology Programme, Centro Nacional Investigaciones Oncológicas (CNIO), Madrid, Spain.
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Wu JS, He YQ, Wei YY, Ma XY, Zhang XY, He J, Wang LL, He JX, Han Y, Lin ZN, Lin YC. Evaluation of the efficacy of cell-penetrating monoclonal antibodies targeting intracellular p-NLRP3 S295 in alleviating hepatotoxicant-induced NAFLD. Int J Biol Macromol 2025; 308:142696. [PMID: 40169050 DOI: 10.1016/j.ijbiomac.2025.142696] [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: 08/19/2024] [Revised: 03/27/2025] [Accepted: 03/29/2025] [Indexed: 04/03/2025]
Abstract
NOD-like receptor protein 3 (NLRP3) is a key driver of hepatotoxicant-induced nonalcoholic fatty liver disease (NAFLD). Phosphorylation of NLRP3 at serine 295 (p-NLRP3S295) is crucial for pyroptosis. Monoclonal antibodies (mAbs) have been designed to target extracellular molecules or cell membrane surface receptors and have achieved progress in NAFLD treatment. However, research on mAbs targeting intracellular biomarkers for NAFLD treatment remains limited. In this study, aflatoxin B1 (AFB1), lipopolysaccharide (LPS) combined with ATP, or palmitic acid (PA) were used to induce p-NLRP3S295-dependent pyroptosis and inflammation mediated by lipotoxicity in hepatocytes in vitro. We generated a specific anti-p-NLRP3S295 mAb (14C7) and internalized it into hepatocytes via an enhanced TAT-based intracellular delivery system (eTAT), which inhibited p-NLRP3S295-dependent pyroptosis and inflammation in hepatocytes subjected to simulated lipotoxic injury and in the livers of NAFLD mice. The recombinant mAb@p-NLRP3S295 expression system was constructed with 14C7. The intracellularly expressed recombinant monoclonal antibody (R-mAb) efficiently blocked p-NLRP3S295-dependent pyroptosis and inflammation in hepatocytes exposed to hepatotoxicant through the proteasome degradation pathway mediated by tripartite motif-containing 40 (TRIM40). In conclusion, this study presents a novel approach for the targeted inhibition of p-NLRP3S295 through intracellular recombinant mAbs, offering new insights into the treatment of hepatotoxicant-related NAFLD via specific intracellular targeting.
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Affiliation(s)
- Jia-Shen Wu
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Yu-Qiao He
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Yue-Yue Wei
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Xin-Yu Ma
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Xin-Yu Zhang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Jie He
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Lei-Lei Wang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Jia-Xin He
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Yu Han
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Zhong-Ning Lin
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, School of Public Health, Xiamen University, Xiamen 361102, China.
| | - Yu-Chun Lin
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, School of Public Health, Xiamen University, Xiamen 361102, China.
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6
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Wu Q, Yang Y, Lin S, Geller DA, Yan Y. The microenvironment in the development of MASLD-MASH-HCC and associated therapeutic in MASH-HCC. Front Immunol 2025; 16:1569915. [PMID: 40370443 PMCID: PMC12074932 DOI: 10.3389/fimmu.2025.1569915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2025] [Accepted: 04/08/2025] [Indexed: 05/16/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a series of obesity-related metabolic liver diseases, ranging from relatively benign hepatic steatosis to metabolic-associated steatohepatitis (MASH). With the changes in lifestyle, its incidence and prevalence have risen to epidemic proportions globally. In recent years, an increasing amount of evidence has indicated that the hepatic microenvironment is involved in the pathophysiological processes of MASH-induced liver fibrosis and the formation of hepatocellular carcinoma (HCC). The hepatic microenvironment is composed of various parenchymal and non-parenchymal cells, which communicate with each other through various factors. In this review, we focus on the changes in hepatocytes, cholangiocytes, liver sinusoidal endothelial cells (LSECs), hepatic stellate cells (HSCs), Kupffer cells (KC), dendritic cells (DC), neutrophils, monocytes, T and B lymphocytes, natural killer cells (NK), natural killer T cells (NKT), mucosal-associated invariant T cells (MAIT), γδT cells, and gut microbiota during the progression of MASLD. Furthermore, we discuss promising therapeutic strategies targeting the microenvironment of MASLD-MASH-HCC.
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Affiliation(s)
- Qiulin Wu
- Department of General Surgery, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Yan Yang
- Department of General Surgery, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Shixun Lin
- Department of General Surgery, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - David A. Geller
- Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
| | - Yihe Yan
- Department of General Surgery, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
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7
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Luo J, Chen K, Nong X. Potential regulation of artesunate on bone metabolism through suppressing inflammatory infiltration in type 2 diabetes mellitus. Immunopharmacol Immunotoxicol 2025; 47:147-158. [PMID: 39762719 DOI: 10.1080/08923973.2024.2444953] [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: 01/24/2024] [Accepted: 12/15/2024] [Indexed: 03/29/2025]
Abstract
OBJECTIVE Osteoimmunology is an emerging field that explores the interplay between bone and the immune system. The immune system plays a critical role in the pathogenesis of diabetes and significantly affects bone homeostasis. Artesunate, a first-line treatment for malaria, is known for its low toxicity and multifunctional properties. Increasing evidence suggests that artesunate possesses anti-inflammatory, immunoregulatory, and osteogenic effects. This review aims to explore the relationship between immune regulation and bone metabolism in type 2 diabetes (T2DM) and to investigate the potential therapeutic application of artesunate. METHODS This review systematically examines literature from PubMed/Medline, Elsevier, Web of Science, Embase, the International Diabetes Federation, and other relevant databases. RESULTS This review synthesizes evidence from multiple sources to delineate the relationship between T lymphocytes and T2DM, the regulation of T lymphocyte subsets in bone metabolism, and the effects of artesunate on both T lymphocytes and bone metabolism. Recent studies suggest a bidirectional regulatory relationship between T2DM and T lymphocytes (CD4+ T and CD8+ T) during the onset and progression of the disease, with inflammatory and anti-inflammatory cytokines serving as key mediators. T lymphocyte subsets and their cytokines play a pivotal role in regulating osteogenesis and osteoclastogenesis in pathological conditions. Furthermore, artesunate has shown promise in modulating inflammatory infiltration and bone metabolism. CONCLUSION The accumulated evidence indicates that artesunate exerts regulatory effects on bone metabolism in T2DM by influencing T lymphocyte differentiation.
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Affiliation(s)
- Jinghong Luo
- Department of Oral & Maxillofacial Surgery, College of Stomatology, Guangxi Medical University, Nanning, Guangxi, China
| | - Kun Chen
- Department of Oral & Maxillofacial Surgery, College of Stomatology, Guangxi Medical University, Nanning, Guangxi, China
| | - Xiaolin Nong
- Department of Oral & Maxillofacial Surgery, College of Stomatology, Guangxi Medical University, Nanning, Guangxi, China
- Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Medical University, Nanning, Guangxi, China
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8
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Zhou H, Gizlenci M, Xiao Y, Martin F, Nakamori K, Zicari EM, Sato Y, Tullius SG. Obesity-associated Inflammation and Alloimmunity. Transplantation 2025; 109:588-596. [PMID: 39192462 PMCID: PMC11868468 DOI: 10.1097/tp.0000000000005183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/29/2024]
Abstract
Obesity is a worldwide health problem with a rapidly rising incidence. In organ transplantation, increasing numbers of patients with obesity accumulate on waiting lists and undergo surgery. Obesity is in general conceptualized as a chronic inflammatory disease, potentially impacting alloimmune response and graft function. Here, we summarize our current understanding of cellular and molecular mechanisms that control obesity-associated adipose tissue inflammation and provide insights into mechanisms affecting transplant outcomes, emphasizing on the beneficial effects of weight loss on alloimmune responses.
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Affiliation(s)
- Hao Zhou
- Division of Transplant Surgery & Transplant Surgery Research Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States
| | - Merih Gizlenci
- Division of Transplant Surgery & Transplant Surgery Research Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States
- Department of General, Visceral, Cancer and Transplant Surgery, University Hospital of Cologne, Cologne, Germany
| | - Yao Xiao
- Division of Transplant Surgery & Transplant Surgery Research Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States
| | - Friederike Martin
- Division of Transplant Surgery & Transplant Surgery Research Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States
- Department of Surgery, CVK/CCM, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Keita Nakamori
- Division of Transplant Surgery & Transplant Surgery Research Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States
- Department of Urology, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka, Japan
| | - Elizabeth M. Zicari
- Division of Transplant Surgery & Transplant Surgery Research Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States
- Faculté de Pharmacie, Université Paris Cité, Paris, France
| | - Yuko Sato
- Division of Transplant Surgery & Transplant Surgery Research Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States
| | - Stefan G. Tullius
- Division of Transplant Surgery & Transplant Surgery Research Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States
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Dabbaghizadeh A, Dion J, Maali Y, Fouda A, Bédard N, Evaristo G, Hassan GS, Tchervenkov J, Shoukry NH. Novel RORγt inverse agonists limit IL-17-mediated liver inflammation and fibrosis. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2025:vkaf014. [PMID: 40073158 DOI: 10.1093/jimmun/vkaf014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Accepted: 01/16/2025] [Indexed: 03/14/2025]
Abstract
Liver fibrosis is a global health problem. IL-17A has proven profibrogenic properties in liver disease making it an interesting therapeutic target. IL-17A is regulated by RORγt and produced by Th17 CD4+ and γδ-T cells. We hypothesized that blocking IL-17A production will limit fibrosis progression by reducing recruitment of inflammatory cells. Herein, we tested the therapeutic potential of 2 novel RORγt inverse agonists (2,3 derivatives of 4,5,6,7-tetrahydro-benzothiophene) in a mouse model of CCl4-induced liver injury. C57BL/6 mice received 2 weekly injections of CCl4 for 4 weeks. As of week 3, mice were treated with the 2 novel inverse agonists (TF-S10 and TF-S14) and GSK805 as a positive control. Mice treated with the inverse agonists showed reduced immune cells infiltrate around the portal and central veins. TF-S14 significantly reduced AST levels (P < 0.05), and all inhibitors led to an improvement in relative liver weight (liver index). Flow cytometry analysis demonstrated that all inhibitors reduced the numbers of intrahepatic lymphocytes (CD4+, CD8+, and γδ-T cells, P < 0.05), and myeloid (CD11b+) cells (P = 0.04), most significantly eosinophils (P < 0.05). Furthermore, IL-17A production by CD4+ and γδ-T cells was diminished (P < 0.05 and P < 0. 01, respectively). Finally, livers from inhibitors-treated mice showed decreased markers of hepatic stellate cell activation (desmin and ɑ-smooth muscle actin [ɑ-SMA]) and significantly reduced expression of the profibrogenic genes (Col1a1, Acta, Loxl2, and Tgfβ) (P < 0.001). This was accompanied by diminished collagen deposition as measured by Picrosirius Red staining (P < 0.001). In conclusion, our results suggest that inhibition of the IL-17A pathway could be a promising therapeutic strategy for liver fibrosis.
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Affiliation(s)
- Afrooz Dabbaghizadeh
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada
- Département de Microbiologie, Infectiologie et Immunologie, Faculté de médecine, Université de Montréal, Montréal, QC, Canada
| | - Jessica Dion
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada
| | - Yousef Maali
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada
- Département de Microbiologie, Infectiologie et Immunologie, Faculté de médecine, Université de Montréal, Montréal, QC, Canada
| | - Ahmed Fouda
- Division of Surgical and Interventional Science, Department of Surgery, McGill University, Montreal, QC, Canada
- Division of General Surgery, Section of Transplant Surgery, Department of Surgery, McGill University, Montreal, QC, Canada
- Research Institute of the McGill University Health Centre, Montréal, QC, Canada
- McGill University Health Centre, Montréal, QC, Canada
| | - Nathalie Bédard
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada
| | - Gertruda Evaristo
- Department of Pathology, McGill University Health Centre, Montreal, QC, Canada
| | - Ghada S Hassan
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada
| | - Jean Tchervenkov
- Division of Surgical and Interventional Science, Department of Surgery, McGill University, Montreal, QC, Canada
- Division of General Surgery, Section of Transplant Surgery, Department of Surgery, McGill University, Montreal, QC, Canada
| | - Naglaa H Shoukry
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada
- Département de médecine, Faculté de Médecine, Université de Montréal, Montréal, QC, Canada
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10
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Ren S, Zhang Y, Wang X, Su J, Wang X, Yuan Z, He X, Guo S, Chen Y, Deng S, Wu X, Li M, Du F, Zhao Y, Shen J, Hu W, Li X, Xiao Z. Emerging insights into the gut microbiota as a key regulator of immunity and response to immunotherapy in hepatocellular carcinoma. Front Immunol 2025; 16:1526967. [PMID: 40070843 PMCID: PMC11893557 DOI: 10.3389/fimmu.2025.1526967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Accepted: 02/10/2025] [Indexed: 03/14/2025] Open
Abstract
The gut microbiota, a complex microbial ecosystem closely connected to the liver via the portal vein, has emerged as a critical regulator of liver health and disease. Numerous studies have underscored its role in the onset and progression of liver disorders, including alcoholic liver disease, metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction-associated steatohepatitis (MASH), liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). This review provides a comprehensive overview of current insights into the influence of the gut microbiota on HCC progression, particularly its effects on immune cells within the HCC tumor microenvironment (TME). Furthermore, we explore the potential of gut microbiota-targeted interventions, such as antibiotics, probiotics, prebiotics, and fecal microbiota transplantation (FMT), to modulate the immune response and improve outcomes of immunotherapy in HCC. By synthesizing insights from recent studies, this review aims to highlight microbiota-based strategies that may enhance immunotherapy outcomes, advancing personalized approaches in HCC treatment.
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Affiliation(s)
- Siqi Ren
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Yinping Zhang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Xingyue Wang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Jiahong Su
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Xiang Wang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Zijun Yuan
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Xinyu He
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Sipeng Guo
- Research and Experiment Center, Sichuan College of Traditional Chinese Medicine, Mianyang, China
| | - Yu Chen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Shuai Deng
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Xu Wu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Mingxing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Fukuan Du
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Yueshui Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Jing Shen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Wei Hu
- Department of Gastroenterology, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong, China
| | - Xiaobing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Zhangang Xiao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Research and Experiment Center, Sichuan College of Traditional Chinese Medicine, Mianyang, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, China
- South Sichuan Institute of Translational Medicine, Luzhou, China
- Gulin Traditional Chinese Medicine Hospital, Luzhou, China
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11
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Vizioli G, Nicoletti A, Feliciani D, Funaro B, Zileri Dal Verme L, Ponziani FR, Zocco MA, Gasbarrini A, Gabrielli M. Immunotherapy and MASLD-Related HCC: Should We Reconsider the Role of Etiology in the Therapeutic Approach to HCC? APPLIED SCIENCES 2025; 15:2279. [DOI: 10.3390/app15052279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/21/2025]
Abstract
Hepatocellular carcinoma (HCC) accounts for 90% of primary liver cancers and typically arises in the context of chronic liver disease. With the increasing prevalence of metabolic disorders, metabolic dysfunction-associated steatotic liver disease (MASLD) has become the leading cause of chronic liver disease and the most rapidly increasing cause of HCC. The role of dysfunctional innate and adaptive immune responses in the development and progression of HCC is well-established, prompting numerous trials to evaluate the efficacy of immune checkpoint inhibitors (ICIs) in targeting tumor cells. These trials have yielded promising results, and ICIs, in combination with anti-vascular endothelial growth factor (VEGF) monoclonal antibodies, are now approved as first-line therapy for patients with metastatic or unresectable HCC, irrespective of the underlying liver disease. Notably, MASLD itself is characterized by immune system dysfunction, as metabolic inflammation plays a central role in its onset and progression. However, clinical studies and post-hoc analyses suggest that immunotherapy may be less effective in MASLD-associated HCC compared to viral-related HCC. This emerging evidence raises the question of whether the underlying liver disease influences the therapeutic response to ICIs in HCC. It may be time to consider tailoring therapeutic strategies for HCC based on the specific etiological, histological, and genotypical subgroups.
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Affiliation(s)
- Giuseppina Vizioli
- Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Alberto Nicoletti
- Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Daniela Feliciani
- Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Barbara Funaro
- Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Lorenzo Zileri Dal Verme
- Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Francesca Romana Ponziani
- Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Maria Assunta Zocco
- Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Antonio Gasbarrini
- Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Maurizio Gabrielli
- Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
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12
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Lei Y, Tao S, Yang Y, Xie F, Xie W. Association between prognostic nutritional index and all-cause mortality and cardiovascular disease mortality in American adults with non-alcoholic fatty liver disease. Front Nutr 2025; 12:1526801. [PMID: 39996009 PMCID: PMC11847695 DOI: 10.3389/fnut.2025.1526801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Accepted: 01/21/2025] [Indexed: 02/26/2025] Open
Abstract
Background The current research was to investigate the relationship between prognostic nutritional index (PNI) and mortality, with a focus on all-cause and cardiovascular disease (CVD) mortality, for those with non-alcoholic fatty liver disease (NAFLD). Methods Data from 20,142 patients who participated in the National Health and Nutrition Examination Survey (NHANES), which was carried out between 2005 and 2014, were included in this research. To examine the relationship between PNI and both all-cause and cardiovascular mortality, we employed weighted Cox regression models with multiple variables. Kaplan-Meier survival curves were utilized to visualize the survival distribution across different levels of PNI. The non-linear association between PNI and mortality was addressed through penalized spline smoothing. Subgroup analyses were conducted to examine the potential influence of relevant clinical variables on the relationship between PNI and mortality. The precision of PNI in forecasting the outcome of survival was assessed as well using time-dependent receiver operating characteristic curve (ROC) analysis. Results Kaplan-Meier analysis linked higher PNI to significantly reduced all-cause and CVD mortality. Multivariable Cox models demonstrated that increasing PNI consistently lowered mortality risks. With a threshold value of 50.5, the link between PNI and mortality showed a non-linear pattern after adjusting for confounding factors. Subgroup analyses confirmed robust associations, particularly in race, education, BMI, and fibrosis. Time-dependent ROC analysis highlighted the strong predictive performance of PNI across various time points. Conclusion PNI played a significant role as an effective predictor of prognosis in individuals diagnosed with NAFLD.
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Affiliation(s)
- Yuqing Lei
- Affiliated Guangdong Hospital of Integrated Traditional Chinese and Western Medicine of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Foshan, Guangdong, China
| | - Shaohong Tao
- Affiliated Guangdong Hospital of Integrated Traditional Chinese and Western Medicine of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Foshan, Guangdong, China
| | - Yubo Yang
- Nanhai Hospital of Traditional Chinese Medicine, Jinan University, Foshan, Guangdong, China
| | - Fang Xie
- Department of Liver Disease, Jinling Hospital Affiliated to Medical College of Nanjing University, Nanjing, Jiangsu, China
| | - Weining Xie
- Guangdong Provincial Hospital of Integrated Traditional Chinese and Western Medicine, Foshan, Guangdong, China
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13
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Zheng J, Wang S, Xia L, Sun Z, Chan KM, Bernards R, Qin W, Chen J, Xia Q, Jin H. Hepatocellular carcinoma: signaling pathways and therapeutic advances. Signal Transduct Target Ther 2025; 10:35. [PMID: 39915447 PMCID: PMC11802921 DOI: 10.1038/s41392-024-02075-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 09/18/2024] [Accepted: 11/14/2024] [Indexed: 02/09/2025] Open
Abstract
Liver cancer represents a major global health concern, with projections indicating that the number of new cases could surpass 1 million annually by 2025. Hepatocellular carcinoma (HCC) constitutes around 90% of liver cancer cases and is primarily linked to factors incluidng aflatoxin, hepatitis B (HBV) and C (HCV), and metabolic disorders. There are no obvious symptoms in the early stage of HCC, which often leads to delays in diagnosis. Therefore, HCC patients usually present with tumors in advanced and incurable stages. Several signaling pathways are dis-regulated in HCC and cause uncontrolled cell propagation, metastasis, and recurrence of HCC. Beyond the frequently altered and therapeutically targeted receptor tyrosine kinase (RTK) pathways in HCC, pathways involved in cell differentiation, telomere regulation, epigenetic modification and stress response also provide therapeutic potential. Investigating the key signaling pathways and their inhibitors is pivotal for achieving therapeutic advancements in the management of HCC. At present, the primary therapeutic approaches for advanced HCC are tyrosine kinase inhibitors (TKI), immune checkpoint inhibitors (ICI), and combination regimens. New trials are investigating combination therapies involving ICIs and TKIs or anti-VEGF (endothelial growth factor) therapies, as well as combinations of two immunotherapy regimens. The outcomes of these trials are expected to revolutionize HCC management across all stages. Here, we provide here a comprehensive review of cellular signaling pathways, their therapeutic potential, evidence derived from late-stage clinical trials in HCC and discuss the concepts underlying earlier clinical trials, biomarker identification, and the development of more effective therapeutics for HCC.
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Affiliation(s)
- Jiaojiao Zheng
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Siying Wang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Lei Xia
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Zhen Sun
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Kui Ming Chan
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, PR China
| | - René Bernards
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
- Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Wenxin Qin
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Jinhong Chen
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, PR China.
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
| | - Haojie Jin
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
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14
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Kim J, Seki E. Inflammation and Immunity in Liver Neoplasms: Implications for Future Therapeutic Strategies. Mol Cancer Ther 2025; 24:188-199. [PMID: 39365846 PMCID: PMC11794036 DOI: 10.1158/1535-7163.mct-23-0726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Revised: 07/28/2024] [Accepted: 08/09/2024] [Indexed: 10/06/2024]
Abstract
Over the past two decades, the "hallmarks of cancer" have revolutionized cancer research and highlighted the crucial roles of inflammation and immunity. Protumorigenic inflammation promotes cancer development along with inhibition of antitumor immunity, shaping the tumor microenvironment (TME) toward a tumor-permissive state and further enhancing the malignant potential of cancer cells. This immunosuppressive TME allows tumors to evade immunosurveillance. Thus, understanding the complex interplay between tumors and the immune system within the TME has become pivotal, especially with the advent of immunotherapy. Although immunotherapy has achieved notable success in many malignancies, primary liver cancer, particularly hepatocellular carcinoma, presents unique challenges. The hepatic immunosuppressive environment poses obstacles to the effectiveness of immunotherapy, along with high mortality rates and limited treatment options for patients with liver cancer. In this review, we discuss current understanding of the complex immune-mediated mechanisms underlying liver neoplasms, focusing on hepatocellular carcinoma and liver metastases. We describe the molecular and cellular heterogeneity within the TME, highlighting how this presents unique challenges and opportunities for immunotherapy in liver cancers. By unraveling the immune landscape of liver neoplasms, this review aims to contribute to the development of more effective therapeutic interventions, ultimately improving clinical outcomes for patients with liver cancer.
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Affiliation(s)
- Jieun Kim
- Karsh Division of Gastroenterology Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Ekihiro Seki
- Karsh Division of Gastroenterology Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
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15
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Ramadan A, Kaddah M, Shousha H, El-Kassas M. Personalized treatment approaches in hepatocellular carcinoma. Arab J Gastroenterol 2025; 26:122-128. [PMID: 39765390 DOI: 10.1016/j.ajg.2024.08.003] [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: 02/24/2024] [Revised: 07/13/2024] [Accepted: 08/24/2024] [Indexed: 03/16/2025]
Abstract
Personalized medicine is an emerging field that provides novel approaches to disease's early diagnosis, prevention, treatment, and prognosis based on the patient's criteria in gene expression, environmental factors, lifestyle, and diet. To date, hepatocellular carcinoma (HCC) is a significant global health burden, with an increasing incidence and significant death rates, despite advancements in surveillance, diagnosis, and therapeutic approaches. The majority of HCC lesions develop in patients with liver cirrhosis, carrying the risks of mortality associated with both the tumor burden and the cirrhosis. New therapeutic agents involving immune checkpoint inhibitors and targeted agents have been developed for sequential or concomitant application for advanced HCC but only a tiny percentage of patients benefit from each approach. Moreover, clinicians encounter difficulties determining the most appropriate regimen for each patient. This emphasizes the need for a personalized treatment approach. In other words, patients should no longer undergo treatment based on their tumor's histology but depending on the distinct molecular targets specific to their tumor biology. However, the utilization of precision medicine in managing HCC is still challenging. This review aims to discuss the role of personalized medicine in diagnosing, managing, and defining the prognosis of HCC. We also discuss the role of liquid biopsy and their clinical applications for immunotherapies in HCC. More clinical studies are still necessary to improve the precision of biomarkers used in the treatment decision for patients with HCC.
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Affiliation(s)
- Ahmed Ramadan
- Endemic Medicine Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Mona Kaddah
- Endemic Medicine Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Hend Shousha
- Endemic Medicine Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Mohamed El-Kassas
- Endemic Medicine Department, Faculty of Medicine, Helwan University, Cairo, Egypt; Liver Disease Research Center, College of Medicine, King Saud University, Riyadh 11411, Saudi Arabia.
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16
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Štaflová K, Zábranský A, Pichová I. Evaluation of the role of unconventional prefoldin RPB5 interactor (URI1) in hepatitis B virus infection. Virol J 2025; 22:7. [PMID: 39794779 PMCID: PMC11721529 DOI: 10.1186/s12985-024-02617-2] [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: 07/25/2024] [Accepted: 12/19/2024] [Indexed: 01/13/2025] Open
Abstract
Hepatitis B virus (HBV) infection can cause liver disease and lead to hepatocellular carcinoma (HCC). To better understand the factors involved in viral infection and pathogenesis and to develop novel therapies, it is crucial to investigate virus-host interactions. HBV infection has been shown to increase the expression of the unconventional prefoldin RPB5 interactor (URI1), a cellular protein that promotes liver tumorigenesis and HCC metastasis. Our study investigated the role of URI1 in HBV infection in vitro. Although previous reports have suggested that URI1 may act as an HBV restriction factor, our results showed that URI1 silencing or overexpression did not affect HBV replication in HepG2-NTCP cells. In primary human hepatocytes, URI1 knockdown modestly reduced HBV markers but did not significantly alter acute infection. Supporting the premise that URI1 is a promising therapeutic target for HCC, our findings show that URI1 knockdown does not enhance HBV infection in an acute infection model. This suggests that URI1 may be a viable therapeutic target for patients with HBV-associated HCC without increasing HBV-related complications.
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Affiliation(s)
- Karolína Štaflová
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic
| | - Aleš Zábranský
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic
| | - Iva Pichová
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic.
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17
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Tang Z, Wei C, Deng X, Lin Q, Hu Q, Li S, Wang J, Wu Y, Liu D, Fang M, Zhan T. Serum proteomic and metabolomic profiling of hepatocellular carcinoma patients co-infected with Clonorchis sinensis. Front Immunol 2025; 15:1489077. [PMID: 39840062 PMCID: PMC11746118 DOI: 10.3389/fimmu.2024.1489077] [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: 08/31/2024] [Accepted: 12/10/2024] [Indexed: 01/23/2025] Open
Abstract
Background Clonorchis sinensis (C. sinensis) infection is a significant risk factor for hepatocellular carcinoma (HCC), yet its underlying mechanisms remain poorly understood. This study aimed to investigate the impact of C. sinensis infection on the serum proteomic and metabolomic profiling of HCC patients, focusing on the potential mechanisms. Method A retrospective clinical analysis was conducted on 1121 HCC patients, comparing those with and without C. sinensis infection. The influence of C. sinensis on serum proteome and metabolome in HCC was further assessed. Result C. sinensis infection correlated with a younger age at cancer onset, male predominance, advanced cancer stage, liver cirrhosis, and microvascular invasion in HCC patients. It also associated with shorter overall survival (OS) and recurrence-free survival (RFS). The levels of blood lipids (e.g., APO-A, HDL-C, and TG) were significantly altered after C. sinensis infection. Proteomic and metabolomic analyses revealed metabolic reprogramming caused by C. sinensis, with excessive depletion of argininosuccinate synthase (ASS) and D-glucose as potential factors in C. sinensis-associated HCC malignancy. Key molecules ILF2, CNN2, OLFM4, NOTCH3, and LysoPA were implicated in HCC progression. Furthermore, C. sinensis triggered inflammation, insulin resistance, and pro-tumor immune escape, and exacerbated the complication of degenerative diseases. Conclusion This study not only provides compelling evidence for elucidating the mechanisms underlying C. sinensis-mediated HCC development but also identifies potential therapeutic targets for HCC patients co-infected with C. sinensis.
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Affiliation(s)
- Zeli Tang
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Guangxi Medical University, Nanning, China
- Key Laboratory of Longevity and Aging-related Diseases of Chinese Ministry of Education, Guangxi Medical University, Nanning, China
- Key Laboratory of Basic Research on Regional Diseases, Education Department of Guangxi Zhuang Autonomous Region, Guangxi Medical University, Nanning, China
| | - Caibiao Wei
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Xueling Deng
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Guangxi Medical University, Nanning, China
| | - Qiumei Lin
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Qiping Hu
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Guangxi Medical University, Nanning, China
- Key Laboratory of Longevity and Aging-related Diseases of Chinese Ministry of Education, Guangxi Medical University, Nanning, China
- Key Laboratory of Basic Research on Regional Diseases, Education Department of Guangxi Zhuang Autonomous Region, Guangxi Medical University, Nanning, China
| | - Shitao Li
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Guangxi Medical University, Nanning, China
| | - Jilong Wang
- Department of Parasitology, School of Basic Medical Sciences, Guangxi Medical University, Nanning, China
| | - Yuhong Wu
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Guangxi Medical University, Nanning, China
| | - Dengyu Liu
- Key Laboratory of Longevity and Aging-related Diseases of Chinese Ministry of Education, Guangxi Medical University, Nanning, China
- Key Laboratory of Basic Research on Regional Diseases, Education Department of Guangxi Zhuang Autonomous Region, Guangxi Medical University, Nanning, China
- Department of Parasitology, School of Basic Medical Sciences, Guangxi Medical University, Nanning, China
| | - Min Fang
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, China
- Engineering Research Center for Tissue & Organ Injury and Repair Medicine, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Tingzheng Zhan
- Key Laboratory of Longevity and Aging-related Diseases of Chinese Ministry of Education, Guangxi Medical University, Nanning, China
- Key Laboratory of Basic Research on Regional Diseases, Education Department of Guangxi Zhuang Autonomous Region, Guangxi Medical University, Nanning, China
- Department of Parasitology, School of Basic Medical Sciences, Guangxi Medical University, Nanning, China
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18
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Tang S, Wu S, Zhang W, Ma L, Zuo L, Wang H. Immunology and treatments of fatty liver disease. Arch Toxicol 2025; 99:127-152. [PMID: 39692857 DOI: 10.1007/s00204-024-03920-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Accepted: 11/26/2024] [Indexed: 12/19/2024]
Abstract
Alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) are two major chronic liver diseases worldwide. The triggers for fatty liver can be derived from external sources such as adipose tissue, the gut, personal diet, and genetics, or internal sources, including immune cell responses, lipotoxicity, hepatocyte death, mitochondrial dysfunction, and extracellular vesicles. However, their pathogenesis varies to some extent. This review summarizes various immune mechanisms and therapeutic targets associated with these two types of fatty liver disease. It describes the gut-liver axis and adipose tissue-liver crosstalk, as well as the roles of different immune cells (both innate and adaptive immune cells) in fatty liver disease. Additionally, mitochondrial dysfunction, extracellular vesicles, microRNAs (miRNAs), and gastrointestinal hormones are also related to the pathogenesis of fatty liver. Understanding the pathogenesis of fatty liver and corresponding therapeutic strategies provides a new perspective for developing novel treatments for fatty liver disease.
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Affiliation(s)
- Sainan Tang
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, Anhui, China
- Laboratory of Molecular Biology, Department of Biochemistry, School of Basic Medical Science, Anhui Medical University, Hefei, 230022, Anhui, China
| | - Shanshan Wu
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, Anhui, China
- Department of Gastroenterology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, Anhui, China
| | - Wenzhe Zhang
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, Anhui, China
- The First College of Clinical Medicine, Anhui Medical University, Hefei, Anhui, China
| | - Lili Ma
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, Anhui, China
- The First College of Clinical Medicine, Anhui Medical University, Hefei, Anhui, China
| | - Li Zuo
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, Anhui, China.
- Laboratory of Molecular Biology, Department of Biochemistry, School of Basic Medical Science, Anhui Medical University, Hefei, 230022, Anhui, China.
| | - Hua Wang
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China.
- Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, Anhui, China.
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19
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Grazioso TP, del Mar Rigual M, Perna C, Caleiras EJ, Djouder N. Cold exposure reinstates NAD + levels and attenuates hepatocellular carcinoma. Cell Stress 2024; 8:125-139. [PMID: 39781363 PMCID: PMC11708783 DOI: 10.15698/cst2024.12.302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 12/03/2024] [Accepted: 12/05/2024] [Indexed: 01/12/2025] Open
Abstract
Cold exposure has been historically used for medicinal purposes, but its benefits and associated mechanisms in mammalian organisms still remain unclear. Here, we explore the chemoprotective properties of cold temperature using a mouse model of hepatocellular carcinoma (HCC) that recapitulates several human features. Chronic cold exposure is shown to prolong lifespan in diseased mice, enhance liver health, and suppress the development of aggressive HCC, preventing hepatocellular hypertrophy, high-grade oval cell hyperplasia, liver steatosis, and aberrant hepatocyte hyperproliferation. Mechanistically, exposure to cold temperatures reinstates NAD+ levels in the HCC mouse models that originally exhibited low NAD+ levels, a contributing process to the development of liver tumors. These findings uncover the role of cold therapy to attenuate HCC development and potentially other existing malignancies involving NAD+ modulation.
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Affiliation(s)
- Tatiana P Grazioso
- Growth Factors, Nutrients and Cancer Group, Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO)Madrid, ES28029Spain
- Instituto de Investigación Sanitaria HM Hospitales (IISHM)MadridSpain
- Laboratory of Innovation in Oncology, Gynecological, Genitourinary and Skin Cancer Unit, HM CIOCC, Centro Integral Oncológico Clara Campal, Hospital Universitario HM Sanchinarro, HM HospitalesMadrid, ES-28050Spain
| | - Maria del Mar Rigual
- Growth Factors, Nutrients and Cancer Group, Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO)Madrid, ES28029Spain
| | - Cristian Perna
- Department of Pathology, Hospital Universitario Ramón y Cajal, IRYCISMadrid, ES28034Spain
- Universidad de AlcaláMadrid, ES28801Spain
| | | | - Nabil Djouder
- Growth Factors, Nutrients and Cancer Group, Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO)Madrid, ES28029Spain
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20
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Ezz-Eldin YM, El-Din Ewees MG, Khalaf MM, Azouz AA. Modulation of SIRT6 related signaling pathways of p-AKT/mTOR and NRF2/HO-1 by memantine contributes to curbing the progression of tamoxifen/HFD-induced MASH in rats. Eur J Pharmacol 2024; 984:177069. [PMID: 39442744 DOI: 10.1016/j.ejphar.2024.177069] [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: 07/08/2024] [Revised: 10/02/2024] [Accepted: 10/20/2024] [Indexed: 10/25/2024]
Abstract
Metabolic dysfunction-associated steatohepatitis (MASH) is a chronic liver disorder marked by hepatic fat accumulation and inflammatory infiltrates which may evolve to cirrhosis. Clinical studies have demonstrated the higher risk of MASH development after tamoxifen (TAM) therapy, especially in obese patients. Therefore, we aimed to evaluate MASH induction by TAM combined with high fat diet (HFD) and the potential interference of memantine (MEMA) with MASH progression via modulation of SIRT6 and its related signaling pathways. MASH was induced in female Wistar rats by co-administration of TAM (25 mg/kg/day, p.o.) and HFD for 5 weeks. Liver function biomarkers, tissue triglyceride and cholesterol, MASH scoring, SIRT6 with its related signals, and lipid synthesis/oxidation markers were estimated. By comparison to MASH group, MEMA improved liver function indices (ALT, AST, ALP, albumin) and reduced the progression of MASH, evidenced by decreased accumulation of lipids in hepatic tissue, improved histological features, and reduced MASH scoring. MEMA enhanced hepatic SIRT6 and downregulated p-AKT/mTOR signaling, that subsequently reduced expressions of the lipid synthesis biomarkers (SREBP1c, SCD), while elevating the lipid oxidation markers (PPAR-α, CPT1). Moreover, MEMA enhanced NRF2/HO-1 signaling, with subsequently improved antioxidant defense and pro-inflammatory/anti-inflammatory cytokines balance. Analysis of SIRT6 correlations with p-AKT/mTOR, NRF2/HO-1, SREBP1c, and PPAR-α further confirmed our results. Consequently, we conclude that MEMA could interfere with MASH progression, at least in part, via enhanced SIRT6 expression and modulation of its related p-AKT/mTOR and NRF2/HO-1 signaling pathways, eventually reducing liver steatosis and inflammation. That could be a promising therapeutic modality for curbing MASH progression.
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Affiliation(s)
- Yousra M Ezz-Eldin
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514, Egypt; Department of Pharmacology & Toxicology, Faculty of Pharmacy, Nahda University, Beni-Suef, Egypt
| | | | - Marwa M Khalaf
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514, Egypt
| | - Amany A Azouz
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514, Egypt.
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21
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Taberner-Cortés A, Aguilar-Ballester M, Jiménez-Martí E, Hurtado-Genovés G, Martín-Rodríguez RM, Herrero-Cervera A, Vinué Á, Martín-Vañó S, Martínez-Hervás S, González-Navarro H. Treatment with 1.25% cholesterol enriched diet produces severe fatty liver disease characterized by advanced fibrosis and inflammation and impaired autophagy in mice. J Nutr Biochem 2024; 134:109711. [PMID: 39111707 DOI: 10.1016/j.jnutbio.2024.109711] [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: 01/07/2024] [Revised: 07/15/2024] [Accepted: 07/26/2024] [Indexed: 09/06/2024]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is reaching pandemic proportions due to overnutrition. The understanding of advanced stages that recapitulate the human pathology is of great importance to get a better mechanistic insight. We hypothesized that feeding of WT (C57BL) mice with a diet containing a high content of fat (21%), sugar (41.5%) and 1.25% of cholesterol (called from now on high fat, sucrose and cholesterol diet, HFSCD) will reproduce the characteristics of disease severity. Analysis of 16 weeks HFSCD-fed mice demonstrated increased liver weight and plasmatic liver damage markers compared with control diet (CD)-fed mice. HFSCD-fed mice developed greater hepatic triglyceride, cholesterol and NEFA content, inflammation and NAFLD activity score (NAS) indicating an advanced disease. HFSCD-fed mice displayed augmented hepatic total CD3+ T and Th9 lymphocytes, as well as reduced Th2 lymphocytes and CD206 anti-inflammatory macrophages. Moreover, T cells and anti-inflammatory macrophages correlated positively and inversely, respectively, with intrahepatic cholesterol content. Consistently, circulating cytotoxic CD8+ T lymphocytes, Th1, and B cell levels were elevated in HFSCD-fed WT mice. Hepatic and adipose tissue expression analysis demonstrated changes in fibrotic and metabolic genes related with cholesterol, triglycerides, and fatty acid synthesis in HFSCD-fed WT. These mice also exhibited reduced antioxidant capacity and autophagy and elevated ERK signaling pathway activation and CHOP levels. Our results indicate that the feeding with a cholesterol-enriched diet in WT mice produces an advanced NAFLD stage with fibrosis, characterized by deficient autophagy and ER stress along with inflammasome activation partially via ERK pathway activation.
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Affiliation(s)
| | | | - Elena Jiménez-Martí
- Metabolic Diseases Group, INCLIVA Biomedical Research Institute, Valencia, Spain; Biochemistry and Molecular Biology Department, Faculty of Medicine, University of Valencia, Valencia, Spain
| | - Gema Hurtado-Genovés
- Metabolic Diseases Group, INCLIVA Biomedical Research Institute, Valencia, Spain
| | | | | | - Ángela Vinué
- Metabolic Diseases Group, INCLIVA Biomedical Research Institute, Valencia, Spain
| | - Susana Martín-Vañó
- Metabolic Diseases Group, INCLIVA Biomedical Research Institute, Valencia, Spain
| | - Sergio Martínez-Hervás
- Metabolic Diseases Group, INCLIVA Biomedical Research Institute, Valencia, Spain; Endocrinology and Nutrition Department Clinic Hospital and Department of Medicine, University of Valencia, Valencia, Spain; Metabolic Diseases Group, CIBER de Diabetes y Enfermedades Metabólicas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
| | - Herminia González-Navarro
- Metabolic Diseases Group, INCLIVA Biomedical Research Institute, Valencia, Spain; Biochemistry and Molecular Biology Department, Faculty of Medicine, University of Valencia, Valencia, Spain; Metabolic Diseases Group, CIBER de Diabetes y Enfermedades Metabólicas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.
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22
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Elaimy AL, El-Derany MO, James J, Wang Z, Pearson AN, Holcomb EA, Huber AK, Gijón M, Bell HN, Sanghvi VR, Frankel TL, Su GL, Tapper EB, Tai AW, Ramnath N, Centonze CP, Dobrosotskaya I, Moeller JA, Bryant AK, Elliott DA, Choi E, Evans JR, Cuneo KC, Fitzgerald TJ, Wahl DR, Morgan MA, Chang DT, Wicha MS, Lawrence TS, Shah YM, Green MD. SLC4A11 mediates ammonia import and promotes cancer stemness in hepatocellular carcinoma. JCI Insight 2024; 9:e184826. [PMID: 39287988 PMCID: PMC11601557 DOI: 10.1172/jci.insight.184826] [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: 07/12/2024] [Accepted: 09/12/2024] [Indexed: 09/19/2024] Open
Abstract
End-stage liver disease is marked by portal hypertension, systemic elevations in ammonia, and development of hepatocellular carcinoma (HCC). While these clinical consequences of cirrhosis are well described, it remains poorly understood whether hepatic insufficiency and the accompanying elevations in ammonia contribute to HCC carcinogenesis. Using preclinical models, we discovered that ammonia entered the cell through the transporter SLC4A11 and served as a nitrogen source for amino acid and nucleotide biosynthesis. Elevated ammonia promoted cancer stem cell properties in vitro and tumor initiation in vivo. Enhancing ammonia clearance reduced HCC stemness and tumor growth. In patients, elevations in serum ammonia were associated with an increased incidence of HCC. Taken together, this study forms the foundation for clinical investigations using ammonia-lowering agents as potential therapies to mitigate HCC incidence and aggressiveness.
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Affiliation(s)
| | - Marwa O. El-Derany
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA
- Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | | | | | - Ashley N. Pearson
- Department of Radiation Oncology and
- Graduate Program in Immunology, University of Michigan, Ann Arbor, Michigan, USA
| | - Erin A. Holcomb
- Department of Radiation Oncology and
- Graduate Program in Immunology, University of Michigan, Ann Arbor, Michigan, USA
| | | | - Miguel Gijón
- Cayman Chemical Company, Ann Arbor, Michigan, USA
| | - Hannah N. Bell
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA
| | - Viraj R. Sanghvi
- Department of Medicine, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York City, New York, USA
| | | | - Grace L. Su
- Department of Surgery and
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
- Gastroenterology Section, Department of Internal Medicine, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan, USA
| | - Elliot B. Tapper
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
- Gastroenterology Section, Department of Internal Medicine, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan, USA
| | - Andrew W. Tai
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
- Gastroenterology Section, Department of Internal Medicine, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan, USA
- Department of Microbiology and Immunology
| | - Nithya Ramnath
- Division of Hematology and Oncology, Department of Internal Medicine, and
| | | | | | | | - Alex K. Bryant
- Department of Radiation Oncology and
- Department of Radiation Oncology, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan, USA
| | - David A. Elliott
- Department of Radiation Oncology and
- Department of Radiation Oncology, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan, USA
| | - Enid Choi
- Department of Radiation Oncology and
- Department of Radiation Oncology, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan, USA
| | | | | | - Thomas J. Fitzgerald
- Department of Radiation Oncology, UMass Chan Medical School, Worcester, Massachusetts, USA
| | | | | | | | - Max S. Wicha
- Division of Hematology and Oncology, Department of Internal Medicine, and
| | | | - Yatrik M. Shah
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA
| | - Michael D. Green
- Department of Radiation Oncology and
- Department of Microbiology and Immunology
- Department of Radiation Oncology, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan, USA
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23
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Coste SC, Hilda Orășan O, Cozma A, Negrean V, Alexescu TG, Perne MG, Ciulei G, Hangan AC, Lucaciu RL, Iancu M, Procopciuc LM. Allelic, Genotypic, and Haplotypic Analysis of Cytokine IL17A, IL17F, and Toll-like Receptor TLR4 Gene Polymorphisms in Metabolic-Dysfunction-Associated Steatotic Liver Disease: Insights from an Exploratory Study. Life (Basel) 2024; 14:1327. [PMID: 39459627 PMCID: PMC11509161 DOI: 10.3390/life14101327] [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: 08/15/2024] [Revised: 10/11/2024] [Accepted: 10/16/2024] [Indexed: 10/28/2024] Open
Abstract
(1) Background: Interleukin 17 (IL17) and toll-like receptor 4 (TLR4) elevate the risk of metabolic and liver diseases. (2) Methods: This study's objective was to explore the association of IL17 and TLR4 gene polymorphisms with MASLD susceptibility and test their effect on serum IL17 and TLR4 levels. A total of 43 patients with MASLD (MASH/MAFL) and 38 healthy individuals were genotyped for IL17F-A7488G, IL17A-G197A, TLR4-Asp299Gly, and TLR4-Thr399Ile polymorphisms using PCR-RFLP. ELISA methods determined IL17F, IL17A, and TLR4 serum levels. (3) Conclusions: Patients carrying the variant genotypes (A/G + G/G) of IL17-A7448G (OR = 5.25), (G/A + A/A) of IL17-G197A (OR = 10.57), (Asp/Gly + Gly/Gly) of TLR4-Asp299Gly (OR = 3.52), or (Thr/Ile + Ile/Ile) of TLR4-Thr399Ile (OR = 9.87) had significantly increased odds of MASH. Genotype (G/A + A/A) of IL17-G197A was significantly associated with the odds of MAFL (p = 0.0166). Allele A of the IL17-G197A polymorphism was significantly related to increased odds of MAFL (OR = 4.13, p = 0.0133). In contrast, allele A of IL17-G197A (OR = 5.41, p = 0.008), allele Gly of TLR4-Asp299Gly (OR = 3.19, p = 0.046), and allele Ile of TLR4-Thr399Ile (OR = 6.94, p = 0.008) polymorphisms were significantly related to an increased risk of MASH. Allele A of IL17A-G197A, allele Gly of TLR4-Asp299Gly, and allele Ile of TLR4-Thr399Ile gene polymorphisms were significantly associated with the increased odds of MASLD. In patients with MASLD, we found significant influence from the IL17A-G197A gene polymorphism on IL17F levels (p = 0.0343).
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Affiliation(s)
- Sorina-Cezara Coste
- 4th Department of Internal Medicine, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (S.-C.C.); (O.H.O.); (A.C.); (V.N.); (T.G.A.); (M.G.P.); (G.C.)
| | - Olga Hilda Orășan
- 4th Department of Internal Medicine, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (S.-C.C.); (O.H.O.); (A.C.); (V.N.); (T.G.A.); (M.G.P.); (G.C.)
| | - Angela Cozma
- 4th Department of Internal Medicine, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (S.-C.C.); (O.H.O.); (A.C.); (V.N.); (T.G.A.); (M.G.P.); (G.C.)
| | - Vasile Negrean
- 4th Department of Internal Medicine, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (S.-C.C.); (O.H.O.); (A.C.); (V.N.); (T.G.A.); (M.G.P.); (G.C.)
| | - Teodora Gabriela Alexescu
- 4th Department of Internal Medicine, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (S.-C.C.); (O.H.O.); (A.C.); (V.N.); (T.G.A.); (M.G.P.); (G.C.)
| | - Mirela Georgiana Perne
- 4th Department of Internal Medicine, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (S.-C.C.); (O.H.O.); (A.C.); (V.N.); (T.G.A.); (M.G.P.); (G.C.)
| | - George Ciulei
- 4th Department of Internal Medicine, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (S.-C.C.); (O.H.O.); (A.C.); (V.N.); (T.G.A.); (M.G.P.); (G.C.)
| | - Adriana Corina Hangan
- Department of Inorganic Chemistry, Faculty of Pharmacy, “Iuliu-Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania;
| | - Roxana Liana Lucaciu
- Department of Pharmaceutical Biochemistry and Clinical Laboratory, Faculty of Pharmacy, “Iuliu-Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania;
| | - Mihaela Iancu
- 11th Department of Medical Education, Medical Informatics and Biostatistics, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Lucia-Maria Procopciuc
- Department of Molecular Sciences, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania;
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24
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Hu T, Liu CH, Lei M, Zeng Q, Li L, Tang H, Zhang N. Metabolic regulation of the immune system in health and diseases: mechanisms and interventions. Signal Transduct Target Ther 2024; 9:268. [PMID: 39379377 PMCID: PMC11461632 DOI: 10.1038/s41392-024-01954-6] [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: 03/27/2024] [Revised: 07/18/2024] [Accepted: 08/11/2024] [Indexed: 10/10/2024] Open
Abstract
Metabolism, including glycolysis, oxidative phosphorylation, fatty acid oxidation, and other metabolic pathways, impacts the phenotypes and functions of immune cells. The metabolic regulation of the immune system is important in the pathogenesis and progression of numerous diseases, such as cancers, autoimmune diseases and metabolic diseases. The concept of immunometabolism was introduced over a decade ago to elucidate the intricate interplay between metabolism and immunity. The definition of immunometabolism has expanded from chronic low-grade inflammation in metabolic diseases to metabolic reprogramming of immune cells in various diseases. With immunometabolism being proposed and developed, the metabolic regulation of the immune system can be gradually summarized and becomes more and more clearer. In the context of many diseases including cancer, autoimmune diseases, metabolic diseases, and many other disease, metabolic reprogramming occurs in immune cells inducing proinflammatory or anti-inflammatory effects. The phenotypic and functional changes of immune cells caused by metabolic regulation further affect and development of diseases. Based on experimental results, targeting cellular metabolism of immune cells becomes a promising therapy. In this review, we focus on immune cells to introduce their metabolic pathways and metabolic reprogramming, and summarize how these metabolic pathways affect immune effects in the context of diseases. We thoroughly explore targets and treatments based on immunometabolism in existing studies. The challenges of translating experimental results into clinical applications in the field of immunometabolism are also summarized. We believe that a better understanding of immune regulation in health and diseases will improve the management of most diseases.
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Affiliation(s)
- Tengyue Hu
- West China School of clinical medical, West China Second University Hospital, Sichuan University, Chengdu, China
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
- Laboratory of Infectious and Liver Diseases, Institution of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Chang-Hai Liu
- West China School of clinical medical, West China Second University Hospital, Sichuan University, Chengdu, China
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
- Laboratory of Infectious and Liver Diseases, Institution of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Min Lei
- West China School of clinical medical, West China Second University Hospital, Sichuan University, Chengdu, China
- National Center for Birth Defect Monitoring, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, China
- State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Qingmin Zeng
- West China School of clinical medical, West China Second University Hospital, Sichuan University, Chengdu, China
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
- Laboratory of Infectious and Liver Diseases, Institution of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Li Li
- Division of Renal and endocrinology, Qin Huang Hospital, Xi'an, China
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China.
- Laboratory of Infectious and Liver Diseases, Institution of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China.
- State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, China.
| | - Nannan Zhang
- West China School of clinical medical, West China Second University Hospital, Sichuan University, Chengdu, China.
- National Center for Birth Defect Monitoring, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, China.
- State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, China.
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25
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Yan M, Man S, Ma L, Guo L, Huang L, Gao W. Immunological mechanisms in steatotic liver diseases: An overview and clinical perspectives. Clin Mol Hepatol 2024; 30:620-648. [PMID: 38988278 PMCID: PMC11540396 DOI: 10.3350/cmh.2024.0315] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Revised: 07/10/2024] [Accepted: 07/10/2024] [Indexed: 07/12/2024] Open
Abstract
Steatotic liver diseases (SLD) are the principal worldwide cause of cirrhosis and end-stage liver cancer, affecting nearly a quarter of the global population. SLD includes metabolic dysfunction-associated alcoholic liver disease (MetALD) and metabolic dysfunction-associated steatotic liver disease (MASLD), resulting in asymptomatic liver steatosis, fibrosis, cirrhosis and associated complications. The immune processes include gut dysbiosis, adiposeliver organ crosstalk, hepatocyte death and immune cell-mediated inflammatory processes. Notably, various immune cells such as B cells, plasma cells, dendritic cells, conventional CD4+ and CD8+ T cells, innate-like T cells, platelets, neutrophils and macrophages play vital roles in the development of MetALD and MASLD. Immunological modulations targeting hepatocyte death, inflammatory reactions and gut microbiome include N-acetylcysteine, selonsertib, F-652, prednisone, pentoxifylline, anakinra, JKB-121, HA35, obeticholic acid, probiotics, prebiotics, antibiotics and fecal microbiota transplantation. Understanding the immunological mechanisms underlying SLD is crucial for advancing clinical therapeutic strategies.
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Affiliation(s)
- Mengyao Yan
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Microbiology, Ministry of Education, Tianjin Key Laboratory of Industry Microbiology, National and Local United Engineering Lab of Metabolic Control Fermentation Technology, China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science & Technology, Tianjin, China
| | - Shuli Man
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Microbiology, Ministry of Education, Tianjin Key Laboratory of Industry Microbiology, National and Local United Engineering Lab of Metabolic Control Fermentation Technology, China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science & Technology, Tianjin, China
| | - Long Ma
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Microbiology, Ministry of Education, Tianjin Key Laboratory of Industry Microbiology, National and Local United Engineering Lab of Metabolic Control Fermentation Technology, China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science & Technology, Tianjin, China
| | - Lanping Guo
- National Resource Center for Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Luqi Huang
- National Resource Center for Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Wenyuan Gao
- Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Weijin Road, Tianjin, China
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26
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Argenziano ME, Kim MN, Montori M, Di Bucchianico A, Balducci D, Ahn SH, Svegliati Baroni G. Epidemiology, pathophysiology and clinical aspects of Hepatocellular Carcinoma in MAFLD patients. Hepatol Int 2024; 18:922-940. [PMID: 39012579 DOI: 10.1007/s12072-024-10692-4] [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: 02/03/2024] [Accepted: 04/24/2024] [Indexed: 07/17/2024]
Abstract
Hepatocellular carcinoma (HCC) is undergoing a transformative shift, with metabolic-associated fatty liver disease (MAFLD) emerging as a dominant etiology. Diagnostic criteria for MAFLD involve hepatic steatosis and metabolic dysregulation. Globally, MAFLD prevalence stands at 38.77%, significantly linked to the escalating rates of obesity. Epidemiological data indicate a dynamic shift in the major etiologies of hepatocellular carcinoma (HCC), transitioning from viral to metabolic liver diseases. Besides the degree of liver fibrosis, several modifiable lifestyle risk factors, such as type 2 diabetes, obesity, alcohol use, smoking, and HBV, HCV infection contribute to the pathogenesis of HCC. Moreover gut microbiota and genetic variants may contribute to HCC development.The pathophysiological link between MAFLD and HCC involves metabolic dysregulation, impairing glucose and lipid metabolism, inflammation and oxidative stress. Silent presentation poses challenges in early MAFLD-HCC diagnosis. Imaging, biopsy, and AI-assisted techniques aid diagnosis, while HCC surveillance in non-cirrhotic MAFLD patients remains debated.ITA.LI.CA. group proposes a survival-based algorithm for treatment based on Barcelona clinic liver cancer (BCLC) algorithm. Liver resection, transplantation, ablation, and locoregional therapies are applied based on the disease stage. Systemic treatments is promising, with initial immunotherapy results indicating a less favorable response in MAFLD-related HCC.Adopting lifestyle interventions and chemopreventive measures with medications, including aspirin, metformin, and statins, constitute promising approaches for the primary prevention of HCC.Prognosis is influenced by multiple factors, with MAFLD-HCC associated with prolonged survival. Emerging diagnostic biomarkers and epigenomic markers, show promising results for early HCC detection in the MAFLD population.
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Affiliation(s)
- Maria Eva Argenziano
- Clinic of Gastroenterology, Hepatology, and Emergency Digestive Endoscopy, Università Politecnica Delle Marche, 60126,, Ancona, Italy
- Faculty of Medicine and Health Sciences, University of Ghent, Ghent, Belgium
| | - Mi Na Kim
- Department of Internal Medicine, Yonsei University College of Medicine, 50 Yonsei-Ro, Seodaemun-Gu, Seoul, 03722, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea
| | - Michele Montori
- Clinic of Gastroenterology, Hepatology, and Emergency Digestive Endoscopy, Università Politecnica Delle Marche, 60126,, Ancona, Italy
| | - Alessandro Di Bucchianico
- Clinic of Gastroenterology, Hepatology, and Emergency Digestive Endoscopy, Università Politecnica Delle Marche, 60126,, Ancona, Italy
| | - Daniele Balducci
- Clinic of Gastroenterology, Hepatology, and Emergency Digestive Endoscopy, Università Politecnica Delle Marche, 60126,, Ancona, Italy
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, 50 Yonsei-Ro, Seodaemun-Gu, Seoul, 03722, Republic of Korea.
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea.
- Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea.
| | - Gianluca Svegliati Baroni
- Liver Disease and Transplant Unit, Obesity Center, Azienda Ospedaliero-Universitaria Delle Marche, Polytechnic University of Marche, Ancona, Italy
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27
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Xie Z, Li Y, Cheng L, Huang Y, Rao W, Shi H, Li J. Potential therapeutic strategies for MASH: from preclinical to clinical development. LIFE METABOLISM 2024; 3:loae029. [PMID: 39872142 PMCID: PMC11749562 DOI: 10.1093/lifemeta/loae029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 06/16/2024] [Accepted: 07/05/2024] [Indexed: 01/03/2025]
Abstract
Current treatment paradigms for metabolic dysfunction-associated steatohepatitis (MASH) are based primarily on dietary restrictions and the use of existing drugs, including anti-diabetic and anti-obesity medications. Given the limited number of approved drugs specifically for MASH, recent efforts have focused on promising strategies that specifically target hepatic lipid metabolism, inflammation, fibrosis, or a combination of these processes. In this review, we examined the pathophysiology underlying the development of MASH in relation to recent advances in effective MASH therapy. Particularly, we analyzed the effects of lipogenesis inhibitors, nuclear receptor agonists, glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists, fibroblast growth factor mimetics, and combinatorial therapeutic approaches. We summarize these targets along with their preclinical and clinical candidates with the ultimate goal of optimizing the therapeutic prospects for MASH.
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Affiliation(s)
- Zhifu Xie
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Yufeng Li
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Long Cheng
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yidan Huang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Wanglin Rao
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- University of Chinese Academy of Sciences, Beijing 100049, China
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, Zhejiang 310024, China
| | - Honglu Shi
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Jingya Li
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- University of Chinese Academy of Sciences, Beijing 100049, China
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, Zhejiang 310024, China
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Coste SC, Orășan OH, Cozma A, Negrean V, Sitar-Tăut AV, Filip GA, Hangan AC, Lucaciu RL, Iancu M, Procopciuc LM. Metabolic Dysfunction-Associated Steatotic Liver Disease: The Associations between Inflammatory Markers, TLR4, and Cytokines IL-17A/F, and Their Connections to the Degree of Steatosis and the Risk of Fibrosis. Biomedicines 2024; 12:2144. [PMID: 39335657 PMCID: PMC11430745 DOI: 10.3390/biomedicines12092144] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Revised: 09/14/2024] [Accepted: 09/19/2024] [Indexed: 09/30/2024] Open
Abstract
Background: The pathogenesis of MASLD (metabolic dysfunction-associated steatotic liver disease) is driven by environmental, genetic, metabolic, immune, and inflammatory factors. IL-17 and TLR4 determine hepatic steatosis, inflammation, and finally fibrosis. Objectives: To explore the associations between the plasma levels of inflammatory markers, TLR4, and the cytokines IL17A/F, as well as their connections with the degree of hepatic steatosis and the risk of hepatic fibrosis (defined by the FIB-4 score) in MASLD patients. Methods: The study cohort included 80 patients diagnosed with MASLD. The IL-17A/F and TLR4 serum concentrations were determined using the ELISA method. Results: We found a significant difference in the CAR levels (C-reactive protein to albumin ratio) when comparing MASLD patients with severe steatosis to those with mild/moderate steatosis (Student's t test, t (71) = 2.32, p = 0.023). The PIV (pan-immune inflammatory value) was positively correlated with the SII (systemic immune inflammation index), (r = 0.86, p < 0.0001) and the CAR (r = 0.41, p = 0.033) in MASLD patients with severe steatosis. In contrast, increased values of the LMR (lymphocyte to monocyte ratio) were significantly associated, with decreased levels of the SII (ρ = -0.38, p = 0.045). We also found a positive correlation between the CAR and the SII (r = 0.41, p = 0.028). In patients with mild/moderate steatosis, a significant positive correlation was observed between the SII and IL17A (r = 0.36, p = 0.010), the PIV and the CAR (r = 0.29, p = 0.011), the PIV and the SII (r = 0.87, p < 0.0001) and the PIV and IL17A (r = 0.3, p = 0.036). A negative correlation was observed between the LMR and the SII (r = -0.55, p < 0.0001) and the CAR and IL17F (r = -0.37, p = 0.011). Regarding the inflammatory markers, the PIV (336.4 vs. 228.63, p = 0.0107), and the SII (438.47 vs. 585.39, p = 0.0238) had significantly lower levels in patients with an intermediate-high risk of hepatic fibrosis as compared with the patients with a low risk of hepatic fibrosis. The PNI (prognostic nutritional index) (47.16 vs. 42.41, p = 0.0392) had significantly different levels in patients with the likelihood of hepatic fibrosis than those with a low risk of hepatic fibrosis. Conclusions: Regarding the inflammatory markers, the PIV and the SII hold promise as biomarkers for discriminating between MASLD patients with an intermediate-high risk and those with a low risk of hepatic fibrosis. Our findings underscore the role of IL-17A and its potential relationship with inflammatory markers in MASLD pathogenesis and the progression to hepatic fibrosis.
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Affiliation(s)
- Sorina-Cezara Coste
- 4th Department of Internal Medicine, Faculty of Medicine, "Iuliu Hațieganu" University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Olga Hilda Orășan
- 4th Department of Internal Medicine, Faculty of Medicine, "Iuliu Hațieganu" University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Angela Cozma
- 4th Department of Internal Medicine, Faculty of Medicine, "Iuliu Hațieganu" University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Vasile Negrean
- 4th Department of Internal Medicine, Faculty of Medicine, "Iuliu Hațieganu" University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Adela-Viviana Sitar-Tăut
- 4th Department of Internal Medicine, Faculty of Medicine, "Iuliu Hațieganu" University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Gabriela Adriana Filip
- Department of Anatomy and Embryology, Faculty of Medicine, "Iuliu Hațieganu" University of Medicine and Pharmacy, 400006 Cluj-Napoca, Romania
| | - Adriana Corina Hangan
- Department of Inorganic Chemistry, Faculty of Pharmacy, "Iuliu Hațieganu" University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Roxana Liana Lucaciu
- Department of Pharmaceutical Biochemistry and Clinical Laboratory, Faculty of Pharmacy, "Iuliu Hațieganu" University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Mihaela Iancu
- 11th Department of Medical Education, Medical Informatics and Biostatistics, "Iuliu Hațieganu" University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Lucia Maria Procopciuc
- Department of Molecular Sciences, "Iuliu Hațieganu" University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania
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Fang Z, Liu C, Yu X, Yang K, Yu T, Ji Y, Liu C. Identification of neutrophil extracellular trap-related biomarkers in non-alcoholic fatty liver disease through machine learning and single-cell analysis. Sci Rep 2024; 14:21085. [PMID: 39256536 PMCID: PMC11387488 DOI: 10.1038/s41598-024-72151-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Accepted: 09/04/2024] [Indexed: 09/12/2024] Open
Abstract
Non-alcoholic Fatty Liver Disease (NAFLD), noted for its widespread prevalence among adults, has become the leading chronic liver condition globally. Simultaneously, the annual disease burden, particularly liver cirrhosis caused by NAFLD, has increased significantly. Neutrophil Extracellular Traps (NETs) play a crucial role in the progression of this disease and are key to the pathogenesis of NAFLD. However, research into the specific roles of NETs-related genes in NAFLD is still a field requiring thorough investigation. Utilizing techniques like AddModuleScore, ssGSEA, and WGCNA, our team conducted gene screening to identify the genes linked to NETs in both single-cell and bulk transcriptomics. Using algorithms including Random Forest, Support Vector Machine, Least Absolute Shrinkage, and Selection Operator, we identified ZFP36L2 and PHLDA1 as key hub genes. The pivotal role of these genes in NAFLD diagnosis was confirmed using the training dataset GSE164760. This study identified 116 genes linked to NETs across single-cell and bulk transcriptomic analyses. These genes demonstrated enrichment in immune and metabolic pathways. Additionally, two NETs-related hub genes, PHLDA1 and ZFP36L2, were selected through machine learning for integration into a prognostic model. These hub genes play roles in inflammatory and metabolic processes. scRNA-seq results showed variations in cellular communication among cells with different expression patterns of these key genes. In conclusion, this study explored the molecular characteristics of NETs-associated genes in NAFLD. It identified two potential biomarkers and analyzed their roles in the hepatic microenvironment. These discoveries could aid in NAFLD diagnosis and management, with the ultimate goal of enhancing patient outcomes.
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Affiliation(s)
- Zhihao Fang
- Department of General Surgery, Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Changxu Liu
- Department of General Surgery, Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Xiaoxiao Yu
- Department of General Surgery, Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Kai Yang
- Department of General Surgery, Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Tianqi Yu
- Department of General Surgery, Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Yanchao Ji
- Department of General Surgery, Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Chang Liu
- Department of General Surgery, Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.
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Gujarathi R, Franses JW, Pillai A, Liao CY. Targeted therapies in hepatocellular carcinoma: past, present, and future. Front Oncol 2024; 14:1432423. [PMID: 39267840 PMCID: PMC11390354 DOI: 10.3389/fonc.2024.1432423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Accepted: 08/13/2024] [Indexed: 09/15/2024] Open
Abstract
Targeted therapies are the mainstay of systemic therapies for patients with advanced, unresectable, or metastatic hepatocellular carcinoma. Several therapeutic targets, such as c-Met, TGF-β, and FGFR, have been evaluated in the past, though results from these clinical studies failed to show clinical benefit. However, these remain important targets for the future with novel targeted agents and strategies. The Wnt/β-catenin signaling pathway, c-Myc oncogene, GPC3, PPT1 are exciting novel targets, among others, currently undergoing evaluation. Through this review, we aim to provide an overview of previously evaluated and potentially novel therapeutic targets and explore their continued relevance in ongoing and future studies for HCC.
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Affiliation(s)
- Rushabh Gujarathi
- Section of Hematology and Oncology, Department of Medicine, University of Chicago, Chicago, IL, United States
| | - Joseph W Franses
- Section of Hematology and Oncology, Department of Medicine, University of Chicago, Chicago, IL, United States
| | - Anjana Pillai
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, University of Chicago, Chicago, IL, United States
| | - Chih-Yi Liao
- Section of Hematology and Oncology, Department of Medicine, University of Chicago, Chicago, IL, United States
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Abdelnabi MN, Hassan GS, Shoukry NH. Role of the type 3 cytokines IL-17 and IL-22 in modulating metabolic dysfunction-associated steatotic liver disease. Front Immunol 2024; 15:1437046. [PMID: 39156888 PMCID: PMC11327067 DOI: 10.3389/fimmu.2024.1437046] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Accepted: 07/12/2024] [Indexed: 08/20/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) comprises a spectrum of liver diseases that span simple steatosis, metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis and may progress to cirrhosis and cancer. The pathogenesis of MASLD is multifactorial and is driven by environmental, genetic, metabolic and immune factors. This review will focus on the role of the type 3 cytokines IL-17 and IL-22 in MASLD pathogenesis and progression. IL-17 and IL-22 are produced by similar adaptive and innate immune cells such as Th17 and innate lymphoid cells, respectively. IL-17-related signaling is upregulated during MASLD resulting in increased chemokines and proinflammatory cytokines in the liver microenvironment, enhanced recruitment of myeloid cells and T cells leading to exacerbation of inflammation and liver disease progression. IL-17 may also act directly by activating hepatic stellate cells resulting in increased fibrosis. In contrast, IL-22 is a pleiotropic cytokine with a dominantly protective signature in MASLD and is currently being tested as a therapeutic strategy. IL-22 also exhibits beneficial metabolic effects and abrogates MASH-related inflammation and fibrosis development via inducing the production of anti-oxidants and anti-apoptotic factors. A sex-dependent effect has been attributed to both cytokines, most importantly to IL-22 in MASLD or related conditions. Altogether, IL-17 and IL-22 are key effectors in MASLD pathogenesis and progression. We will review the role of these two cytokines and cells that produce them in the development of MASLD, their interaction with host factors driving MASLD including sexual dimorphism, and their potential therapeutic benefits.
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Affiliation(s)
- Mohamed N. Abdelnabi
- Centre de Recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
- Département de microbiologie, infectiologie et immunologie, Faculté de médecine, Université de Montréal, Montréal, QC, Canada
| | - Ghada S. Hassan
- Centre de Recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
| | - Naglaa H. Shoukry
- Centre de Recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
- Département de médecine, Faculté de médecine, Université de Montréal, Montréal, QC, Canada
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Cebi M, Yilmaz Y. Immune system dysregulation in the pathogenesis of non-alcoholic steatohepatitis: unveiling the critical role of T and B lymphocytes. Front Immunol 2024; 15:1445634. [PMID: 39148730 PMCID: PMC11324455 DOI: 10.3389/fimmu.2024.1445634] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Accepted: 07/22/2024] [Indexed: 08/17/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD), characterized by the excessive accumulation of fat within the cytoplasm of hepatocytes (exceeding 5% of liver weight) in individuals without significant alcohol consumption, has rapidly evolved into a pressing global health issue, affecting approximately 25% of the world population. This condition, closely associated with obesity, type 2 diabetes, and the metabolic syndrome, encompasses a spectrum of liver disorders ranging from simple steatosis without inflammation to non-alcoholic steatohepatitis (NASH) and cirrhotic liver disease. Recent research has illuminated the complex interplay between metabolic and immune responses in the pathogenesis of NASH, underscoring the critical role played by T and B lymphocytes. These immune cells not only contribute to necroinflammatory changes in hepatic lobules but may also drive the onset and progression of liver fibrosis. This narrative review aims to provide a comprehensive exploration of the effector mechanisms employed by T cells, B cells, and their respective subpopulations in the pathogenesis of NASH. Understanding the immunological complexity of NASH holds profound implications for the development of targeted immunotherapeutic strategies to combat this increasingly prevalent and burdensome metabolic liver disease.
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Affiliation(s)
- Merve Cebi
- Department of Medical Biology, School of Medicine, Recep Tayyip Erdoğan University, Rize, Türkiye
| | - Yusuf Yilmaz
- Department of Gastroenterology, School of Medicine, Recep Tayyip Erdoğan University, Rize, Türkiye
- The Global NASH Council, Washington, DC, United States
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Kim J, Seki E. Unveiling the cancer risk nexus of the steatotic liver. Trends Endocrinol Metab 2024; 35:708-719. [PMID: 38531699 PMCID: PMC11321945 DOI: 10.1016/j.tem.2024.02.017] [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: 01/09/2024] [Revised: 02/28/2024] [Accepted: 02/28/2024] [Indexed: 03/28/2024]
Abstract
Steatotic liver, characterized by the accumulation of fat in the liver, poses significant health risks including metabolic dysfunction-associated steatotic liver disease (MASLD) and an elevated risk of primary liver cancer. Emerging evidence indicates a robust association between steatotic liver and increased susceptibility to extrahepatic primary cancers and their metastases. The deposition of fat induces dynamic changes in hepatic microenvironments, thereby fostering inflammation and immune responses that enhance liver metastasis from extrahepatic primary cancers. This review explores the impact of steatotic liver on hepatic carcinogenesis and metastasis from extrahepatic cancers, with a specific focus on hepatocyte-derived factors and the immune microenvironment. By emphasizing novel conclusions, this article underscores the timely relevance of understanding these intricate connections.
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Affiliation(s)
- Jieun Kim
- Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Ekihiro Seki
- Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
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Gallo R, Teijeiro A, Angulo-Aguado M, Djouder N. IL-17A produced by POMC neurons regulates diet-induced obesity. iScience 2024; 27:110259. [PMID: 39027371 PMCID: PMC11255842 DOI: 10.1016/j.isci.2024.110259] [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] [Received: 04/27/2023] [Revised: 08/29/2023] [Accepted: 06/10/2024] [Indexed: 07/20/2024] Open
Abstract
Overeating leads to obesity, a low-grade inflammatory condition involving interleukin-17A (IL-17A). While pro-opiomelanocortin (POMC) neurons regulate feeding, their connection with IL-17A is not well understood. To impair IL-17A signaling in POMC neurons, IL-17A receptor (Il17ra) was deleted by crossing IL17ra-flox and Pomc-Cre mice. Despite effective deletion, these mice showed no differences in body weight or adiposity compared to control mice, challenging the idea that IL-17A induces obesity through POMC neuron regulation. However, both groups exhibited reduced weight gain and adiposity upon high-fat diet compared to mice carrying only the floxed alleles, suggesting independent effects of Pomc-Cre transgene on body weight. Further analysis reveals that POMC neurons express IL-17A, and reduction in number of POMC neurons in Pomc-Cre mice could be linked to decreased IL-17A expression, which correlates with reduced adipocyte gene expression associated with obesity. Our data underscore an unexpected crosstalk between IL-17A-producing POMC neurons and the endocrine system in obesity regulation.
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Affiliation(s)
- Rosa Gallo
- Growth Factors, Nutrients and Cancer Group, Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas, CNIO, 28029 Madrid, Spain
| | - Ana Teijeiro
- Growth Factors, Nutrients and Cancer Group, Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas, CNIO, 28029 Madrid, Spain
| | - Mariana Angulo-Aguado
- Growth Factors, Nutrients and Cancer Group, Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas, CNIO, 28029 Madrid, Spain
| | - Nabil Djouder
- Growth Factors, Nutrients and Cancer Group, Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas, CNIO, 28029 Madrid, Spain
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Zheng Y, Zhao L, Xiong Z, Huang C, Yong Q, Fang D, Fu Y, Gu S, Chen C, Li J, Zhu Y, Liu J, Liu F, Li Y. Ursolic acid targets secreted phosphoprotein 1 to regulate Th17 cells against metabolic dysfunction-associated steatotic liver disease. Clin Mol Hepatol 2024; 30:449-467. [PMID: 38623614 PMCID: PMC11261229 DOI: 10.3350/cmh.2024.0047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 04/12/2024] [Accepted: 04/15/2024] [Indexed: 04/17/2024] Open
Abstract
BACKGROUND/AIMS Metabolic dysfunction-associated steatotic liver disease (MASLD) has become an increasingly important health challenge, with a substantial rise linked to changing lifestyles and global obesity. Ursolic acid, a natural pentacyclic triterpenoid, has been explored for its potential therapeutic effects. Given its multifunctional bioactive properties, this research further revealed the pharmacological mechanisms of ursolic acid on MASLD. METHODS Drug target chips and bioinformatics analysis were combined in this study to explore the potential therapeutic effects of ursolic acid on MASLD. Molecular docking simulations, surface plasmon resonance analyses, pull-down experiments, and co-immunoprecipitation assays were used to verify the direct interactions. Gene knockdown mice were generated, and high-fat diets were used to validate drug efficacy. Furthermore, initial CD4+ T cells were isolated and stimulated to demonstrate our findings. RESULTS In this study, the multifunctional extracellular matrix phosphorylated glycoprotein secreted phosphoprotein 1 (SPP1) was investigated, highlighting its capability to induce Th17 cell differentiation, amplifying inflammatory cascades, and subsequently promoting the evolution of MASLD. In addition, this study revealed that in addition to the canonical TGF-β/IL-6 cytokine pathway, SPP1 can directly interact with ITGB1 and CD44, orchestrating Th17 cell differentiation via their joint downstream ERK signaling pathway. Remarkably, ursolic acid intervention notably suppressed the protein activity of SPP1, suggesting a promising avenue for ameliorating the immunoinflammatory trajectory in MASLD progression. CONCLUSION Ursolic acid could improve immune inflammation in MASLD by modulating SPP1-mediated Th17 cell differentiation via the ERK signaling pathway, which is orchestrated jointly by ITGB1 and CD44, emerging as a linchpin in this molecular cascade.
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Affiliation(s)
- Yiyuan Zheng
- Department of Gastroenterology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lina Zhao
- Department of Gastroenterology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zhekun Xiong
- Department of Spleen, Stomach and Hepatobiliary, Zhongshan Hospital of Traditional Chinese Medicine, Zhongshan, China
| | - Chaoyuan Huang
- Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Gastroenterology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
| | - Qiuhong Yong
- Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- The First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Dan Fang
- Medical Affairs Department, Ton-Bridge Medical Technology Co., Ltd., Zhuhai, China
| | - Yugang Fu
- Department of Gastroenterology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Simin Gu
- Department of Gastroenterology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Chong Chen
- Department of Gastroenterology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jiacheng Li
- Department of Gastroenterology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yingying Zhu
- Department of Gastroenterology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jing Liu
- Department of Gastroenterology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Fengbin Liu
- Department of Gastroenterology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yong Li
- Department of Gastroenterology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Miao Y, Li Z, Feng J, Lei X, Shan J, Qian C, Li J. The Role of CD4 +T Cells in Nonalcoholic Steatohepatitis and Hepatocellular Carcinoma. Int J Mol Sci 2024; 25:6895. [PMID: 39000005 PMCID: PMC11240980 DOI: 10.3390/ijms25136895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 06/14/2024] [Accepted: 06/19/2024] [Indexed: 07/14/2024] Open
Abstract
Hepatocellular carcinoma (HCC) has become the fourth leading cause of cancer-related deaths worldwide; annually, approximately 830,000 deaths related to liver cancer are diagnosed globally. Since early-stage HCC is clinically asymptomatic, traditional treatment modalities, including surgical ablation, are usually not applicable or result in recurrence. Immunotherapy, particularly immune checkpoint blockade (ICB), provides new hope for cancer therapy; however, immune evasion mechanisms counteract its efficiency. In addition to viral exposure and alcohol addiction, nonalcoholic steatohepatitis (NASH) has become a major cause of HCC. Owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance, NASH-associated HCC patients respond much less efficiently to ICB treatment than do patients with other etiologies. In addition, abnormal inflammation contributes to NASH progression and NASH-HCC transition, as well as to HCC immune evasion. Therefore, uncovering the detailed mechanism governing how NASH-associated immune cells contribute to NASH progression would benefit HCC prevention and improve HCC immunotherapy efficiency. In the following review, we focused our attention on summarizing the current knowledge of the role of CD4+T cells in NASH and HCC progression, and discuss potential therapeutic strategies involving the targeting of CD4+T cells for the treatment of NASH and HCC.
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Affiliation(s)
- Yadi Miao
- School of Medicine, Chongqing University, Chongqing 400030, China
| | - Ziyong Li
- School of Medicine, Chongqing University, Chongqing 400030, China
| | - Juan Feng
- Center for Precision Medicine of Cancer, Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing 400030, China
| | - Xia Lei
- School of Medicine, Chongqing University, Chongqing 400030, China
| | - Juanjuan Shan
- School of Medicine, Chongqing University, Chongqing 400030, China
- Center for Precision Medicine of Cancer, Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing 400030, China
| | - Cheng Qian
- School of Medicine, Chongqing University, Chongqing 400030, China
- Center for Precision Medicine of Cancer, Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing 400030, China
| | - Jiatao Li
- School of Medicine, Chongqing University, Chongqing 400030, China
- Center for Precision Medicine of Cancer, Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing 400030, China
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Teshima R, Saito-Sasaki N, Sawada Y. Generalized Pustular Psoriasis and Systemic Organ Dysfunctions. Int J Mol Sci 2024; 25:6270. [PMID: 38892457 PMCID: PMC11172751 DOI: 10.3390/ijms25116270] [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: 04/29/2024] [Revised: 06/02/2024] [Accepted: 06/04/2024] [Indexed: 06/21/2024] Open
Abstract
This review explores the intricate relationship between generalized pustular psoriasis (GPP) and various systemic diseases, shedding light on the broader impacts of this severe skin condition beyond its primary dermatological manifestations. GPP is identified as not only a profound contributor to skin pathology but also a significant risk factor for systemic diseases affecting cardiovascular, hepatic, renal, pulmonary, and skeletal systems, as well as associated with an increased incidence of anemia, depression, anxiety, and arthritis. The research highlights the complex interplay of cytokines, particularly IL-17 and IL-36, which are central to the pathophysiology of GPP and implicated in the exacerbation of systemic conditions. Key findings indicate a higher incidence of cardiovascular events in GPP patients compared to those with other severe forms of psoriasis, notably with a stronger correlation between myocardial infarction history and GPP development. Liver disturbances, frequently reversible upon psoriasis remission, suggest a cytokine-mediated link to hepatic health. Renal dysfunction appears elevated in GPP sufferers, with IL-17 and IL-36 potentially driving renal fibrosis. Similarly, interstitial lung disease and osteoporosis in GPP patients underscore the systemic reach of inflammatory processes initiated in the skin. The associations with anemia, depression, anxiety, and arthritis further complicate the clinical management of GPP, requiring a multidisciplinary approach. The study concludes that managing GPP effectively requires a holistic approach that addresses both the cutaneous and systemic dimensions of the disease, advocating for continued research into the mechanisms that connect GPP with broader health implications to refine therapeutic strategies.
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Affiliation(s)
| | | | - Yu Sawada
- Department of Dermatology, University of Occupational and Environmental Health, Kitakyushu 807-8555, Japan
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Yaseen MM, Abuharfeil NM, Darmani H. MDSC expansion during HIV infection: regulators, ART and immune reconstitution. Genes Immun 2024; 25:242-253. [PMID: 38605259 DOI: 10.1038/s41435-024-00272-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 04/03/2024] [Accepted: 04/05/2024] [Indexed: 04/13/2024]
Abstract
Myeloid-derived suppressor cells (MDSCs) become expanded in different pathological conditions including human immunodeficiency virus (HIV) infection and this may worsen the disease status and accelerate disease progression. In HIV infection, MDSCs suppress anti-HIV immune responses and hamper immune reconstitution. Understanding the factors and mechanisms of MDSC expansion during HIV infection is central to understanding the pathophysiology of HIV infection. This may pave the way to developing new therapeutic targets or strategies. In this work we addressed (i) the mechanisms that regulate MDSC expansion, (ii) the impact of antiretroviral therapy (ART) on the frequency of MDSCs during HIV infection; (iii) the impact of MDSCs on immune reconstitution during successful ART; and (iv) the potential of MDSCs as a therapeutic target.
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Affiliation(s)
- Mahmoud Mohammad Yaseen
- Department of Biotechnology and Genetic Engineering, Faculty of Science and Arts, Jordan University of Science and Technology, P.O. Box 3030, Irbid, 22110, Jordan.
| | - Nizar Mohammad Abuharfeil
- Department of Biotechnology and Genetic Engineering, Faculty of Science and Arts, Jordan University of Science and Technology, P.O. Box 3030, Irbid, 22110, Jordan
| | - Homa Darmani
- Department of Biotechnology and Genetic Engineering, Faculty of Science and Arts, Jordan University of Science and Technology, P.O. Box 3030, Irbid, 22110, Jordan
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Popov J, Despot T, Avelar Rodriguez D, Khan I, Mech E, Khan M, Bojadzija M, Pai N. Implications of Microbiota and Immune System in Development and Progression of Metabolic Dysfunction-Associated Steatotic Liver Disease. Nutrients 2024; 16:1668. [PMID: 38892602 PMCID: PMC11175128 DOI: 10.3390/nu16111668] [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: 05/10/2024] [Revised: 05/23/2024] [Accepted: 05/27/2024] [Indexed: 06/21/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent type of liver disease worldwide. The exact pathophysiology behind MASLD remains unclear; however, it is thought that a combination of factors or "hits" act as precipitants for disease onset and progression. Abundant evidence supports the roles of diet, genes, metabolic dysregulation, and the intestinal microbiome in influencing the accumulation of lipids in hepatocytes and subsequent progression to inflammation and fibrosis. Currently, there is no cure for MASLD, but lifestyle changes have been the prevailing cornerstones of management. Research is now focusing on the intestinal microbiome as a potential therapeutic target for MASLD, with the spotlight shifting to probiotics, antibiotics, and fecal microbiota transplantation. In this review, we provide an overview of how intestinal microbiota interact with the immune system to contribute to the pathogenesis of MASLD and metabolic dysfunction-associated steatohepatitis (MASH). We also summarize key microbial taxa implicated in the disease and discuss evidence supporting microbial-targeted therapies in its management.
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Affiliation(s)
- Jelena Popov
- Boston Combined Residency Program, Boston Children’s Hospital & Boston Medical Center, Boston, MA 02115, USA;
| | - Tijana Despot
- College of Medicine and Health, University College Cork, T12 YN60 Cork, Ireland; (T.D.); (I.K.)
| | - David Avelar Rodriguez
- Department of Pediatric Gastroenterology, Hepatology & Nutrition, The Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1E8, Canada;
| | - Irfan Khan
- College of Medicine and Health, University College Cork, T12 YN60 Cork, Ireland; (T.D.); (I.K.)
| | - Eugene Mech
- School of Medicine, University College Dublin, D04 C1P1 Dublin, Ireland;
| | - Mahrukh Khan
- Department of Pediatrics, Faculty of Health Sciences, McMaster University, Hamilton, ON L8S 4L8, Canada;
- Department of Medical Sciences, Faculty of Health Sciences, McMaster University, Hamilton, ON L8S 4L8, Canada
| | - Milan Bojadzija
- Department of Internal Medicine, Subotica General Hospital, 24000 Subotica, Serbia;
| | - Nikhil Pai
- Department of Pediatrics, Faculty of Health Sciences, McMaster University, Hamilton, ON L8S 4L8, Canada;
- Division of Gastroenterology, Hepatology and Nutrition, McMaster Children’s Hospital, Hamilton, ON L8S 4L8, Canada
- Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Division of Gastroenterology, Hepatology, and Nutrition, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
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Feng F, Zhao Y. Hepatocellular Carcinoma: Prevention, Diagnosis, and Treatment. Med Princ Pract 2024; 33:414-423. [PMID: 38772352 PMCID: PMC11460940 DOI: 10.1159/000539349] [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: 11/05/2023] [Accepted: 05/14/2024] [Indexed: 05/23/2024] Open
Abstract
Hepatocellular carcinoma (HCC), the most prevalent form of liver cancer globally, poses a substantial health burden. Influenced by risk factors such as hepatitis B or C virus infections, chronic consumption of alcohol, and metabolic dysfunction, its exact etiology likely involves a complex interplay between viral infection, hepatocyte mutations, and chronic liver diseases like cirrhosis and metabolic dysfunction-associated steatohepatitis, and demographic variables like sex, race, and age. Disease stage significantly impacts the prognosis of HCC. There is significant potential for life-saving and socioeconomic benefits through the implementation of surveillance programs and the introduction of low-cost screening measures for high-risk groups; these screening measures include ultrasound imaging and blood tests. Treatment options for HCC encompass liver resection, transplantation, transarterial chemoembolization, radiation therapy, chemotherapy, targeted therapy, and immunotherapy. Despite therapeutic advances, treating advanced HCC remains challenging, emphasizing the need for continued efforts in prevention, early detection, and development of treatments to improve prognosis and long-term survival.
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Affiliation(s)
- Fei Feng
- Ultrasound Medicine, The First Hospital of Lanzhou University, Lanzhou, China,
| | - Yue Zhao
- Department of Gastroenterology, The First Hospital of Lanzhou University, Key Laboratory for Gastrointestinal Disease of Gansu Province, Lanzhou, China
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Sun D, Li W, Ding D, Tan K, Ding W, Wang Z, Fu S, Hou G, Zhou WP, Gu F. IL-17a promotes hepatocellular carcinoma by increasing FAP expression in hepatic stellate cells via activation of the STAT3 signaling pathway. Cell Death Discov 2024; 10:230. [PMID: 38740736 DOI: 10.1038/s41420-024-01995-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 04/22/2024] [Accepted: 04/26/2024] [Indexed: 05/16/2024] Open
Abstract
Studies have shown that hepatic stellate cells (HSCs) and interleukin-17a (IL-17a) play important roles in liver tumorigenesis. In addition, fibroblast activation protein-α (FAP) has been shown to be a key regulator of hepatic stellate cell activation. In this study, in vivo and in vitro experiments were performed to verify the promoting effects of IL-17a administration, IL-17a overexpression, and FAP upregulation in HSCs on liver fibrosis and liver tumorigenesis. The cleavage under targets & release using nuclease (CUT&RUN) technique was used to verify the binding status of STAT3 to the FAP promoter. The in vitro studies showed that IL-17a activated HSCs and promoted HCC development and progression. FAP and IL-17a overexpression also activated HSCs, promoted HCC cell proliferation and migration, and inhibited HCC cell apoptosis. The in vivo studies suggested that IL-17a and FAP overexpression in HSCs facilitated liver tumor development and progression. The CUT&RUN results indicated that FAP expression was regulated by STAT3, which could bind to the FAP promoter region and regulate its transcription status. We concluded that IL-17a promoted HCC by increasing FAP expression in HSCs via activation of the STAT3 signaling pathway.
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Affiliation(s)
- Dapeng Sun
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, 225 Changhai Road, Shanghai, 200438, China
| | - Wen Li
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, 225 Changhai Road, Shanghai, 200438, China
| | - Dongyang Ding
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, 225 Changhai Road, Shanghai, 200438, China
| | - Kunjiang Tan
- The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, 200438, China
| | - Wenbin Ding
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, 225 Changhai Road, Shanghai, 200438, China
| | - Zongyan Wang
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, 225 Changhai Road, Shanghai, 200438, China
| | - Siyuan Fu
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, 225 Changhai Road, Shanghai, 200438, China
| | - Guojun Hou
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, 225 Changhai Road, Shanghai, 200438, China
| | - Wei-Ping Zhou
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, 225 Changhai Road, Shanghai, 200438, China.
| | - Fangming Gu
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, 225 Changhai Road, Shanghai, 200438, China.
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Papadopoulos G, Giannousi E, Avdi AP, Velliou RI, Nikolakopoulou P, Chatzigeorgiou A. Τ cell-mediated adaptive immunity in the transition from metabolic dysfunction-associated steatohepatitis to hepatocellular carcinoma. Front Cell Dev Biol 2024; 12:1343806. [PMID: 38774646 PMCID: PMC11106433 DOI: 10.3389/fcell.2024.1343806] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Accepted: 04/22/2024] [Indexed: 05/24/2024] Open
Abstract
Metabolic dysfunction-associated steatohepatitis (MASH) is the progressed version of metabolic dysfunction-associated steatotic liver disease (MASLD) characterized by inflammation and fibrosis, but also a pathophysiological "hub" that favors the emergence of liver malignancies. Current research efforts aim to identify risk factors, discover disease biomarkers, and aid patient stratification in the context of MASH-induced hepatocellular carcinoma (HCC), the most prevalent cancer among MASLD patients. To investigate the tumorigenic transition in MASH-induced HCC, researchers predominantly exploit preclinical animal-based MASH models and studies based on archived human biopsies and clinical trials. Recapitulating the immune response during tumor development and progression is vital to obtain mechanistic insights into MASH-induced HCC. Notably, the advanced complexity behind MASLD and MASH pathogenesis shifted the research focus towards innate immunity, a fundamental element of the hepatic immune niche that is usually altered robustly in the course of liver disease. During the last few years, however, there has been an increasing interest for deciphering the role of adaptive immunity in MASH-induced HCC, particularly regarding the functions of the various T cell populations. To effectively understand the specific role of T cells in MASH-induced HCC development, scientists should urgently fill the current knowledge gaps in this field. Pinpointing the metabolic signature, sketching the immune landscape, and characterizing the cellular interactions and dynamics of the specific T cells within the MASH-HCC liver are essential to unravel the mechanisms that adaptive immunity exploits to enable the emergence and progression of this cancer. To this end, our review aims to summarize the current state of research regarding the T cell functions linked to MASH-induced HCC.
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Affiliation(s)
- Grigorios Papadopoulos
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Eirini Giannousi
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Aikaterini P. Avdi
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Rallia-Iliana Velliou
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Polyxeni Nikolakopoulou
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
- Department of Neuroscience, Karolinska Institute, Stockholm, Sweden
- Center for the Advancement of Integrated Medical and Engineering Sciences (AIMES), Karolinska Institute and KTH Royal Institute of Technology, Stockholm, Sweden
| | - Antonios Chatzigeorgiou
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
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Lin Z, Zhang J, Duan T, Yang J, Yang Y. Trefoil factor 3 can stimulate Th17 cell response in the development of type 2 diabetes mellitus. Sci Rep 2024; 14:10340. [PMID: 38710764 PMCID: PMC11074263 DOI: 10.1038/s41598-024-60426-7] [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: 01/09/2024] [Accepted: 04/23/2024] [Indexed: 05/08/2024] Open
Abstract
This study aims to evaluate the role of trefoil factor 3 (TFF3) peptides in type 2 diabetes mellitus (T2DM) from an inflammatory perspective. The focus was on exploring how TFF3 affects the function of T cells. TFF3 overexpression model was constructed using lentivirus in Jurkat cell lines. We evaluated the impact of TFF3 on the proliferation, apoptosis, and IL-17A levels of Jurkat cells cultured in high glucose. The T2DM model was induced in TFF3 knockout (KO) mice through streptozotocin combined with high-fat diet. The measurements included glucose tolerance, insulin tolerance, inflammation markers, Th17 cell proportion, and pancreatic pathological changes. The T2DM modeling led to splenomegaly in mice, and increased expression of TFF3 in their spleens. Overexpression of TFF3 increased the proportion of IL-17+ T cells and the levels of Th17-related cytokines in Jurkat cells. There was no difference in body weight and blood glucose levels between wild-type and TFF3 KO mice. However, T2DM mice lacking the TFF3 gene showed improved glucose utilization, ameliorated pancreatic pathology, decreased inflammation levels, and reduced Th17 cell ratio. TFF3 may be involved in the chronic inflammatory immune response in T2DM. Its mechanism may be related to the regulation of the RORγt/IL-17 signaling pathway and its impact on T cell proliferation and apoptosis.
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Affiliation(s)
- Ziyang Lin
- Key Laboratory of Glucolipid Metabolic Diseases of the Ministry of Education, Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, The Institute of Chinese Medicinal Sciences, Science and Technology Building, Guangzhou Higher Education Mega Centre, Guangdong Pharmaceutical University, 280 Wai Huan Dong Road, Guangzhou, 510006, People's Republic of China
| | - Jinyuan Zhang
- Key Laboratory of Glucolipid Metabolic Diseases of the Ministry of Education, Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, The Institute of Chinese Medicinal Sciences, Science and Technology Building, Guangzhou Higher Education Mega Centre, Guangdong Pharmaceutical University, 280 Wai Huan Dong Road, Guangzhou, 510006, People's Republic of China
| | - Tingting Duan
- Guangdong Nephrotic Drug Engineering Technology Research Center, Institute of Consun Co. for Chinese Medicine in Kidney Diseases, Guangdong Consun Pharmaceutical Group, Guangzhou, People's Republic of China
| | - Junzheng Yang
- Guangdong Nephrotic Drug Engineering Technology Research Center, Institute of Consun Co. for Chinese Medicine in Kidney Diseases, Guangdong Consun Pharmaceutical Group, Guangzhou, People's Republic of China.
| | - Yiqi Yang
- Key Laboratory of Glucolipid Metabolic Diseases of the Ministry of Education, Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, The Institute of Chinese Medicinal Sciences, Science and Technology Building, Guangzhou Higher Education Mega Centre, Guangdong Pharmaceutical University, 280 Wai Huan Dong Road, Guangzhou, 510006, People's Republic of China.
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Kodama T, Takehara T. Molecular Genealogy of Metabolic-associated Hepatocellular Carcinoma. Semin Liver Dis 2024; 44:147-158. [PMID: 38499207 PMCID: PMC11245329 DOI: 10.1055/a-2289-2298] [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] [Indexed: 03/20/2024]
Abstract
This review examines the latest epidemiological and molecular pathogenic findings of metabolic-associated hepatocellular carcinoma (HCC). Its increasing prevalence is a significant concern and reflects the growing burden of obesity and metabolic diseases, including metabolic dysfunction-associated steatotic liver disease, formerly known as nonalcoholic fatty liver disease, and type 2 diabetes. Metabolic-associated HCC has unique molecular abnormality and distinctive gene expression patterns implicating aberrations in bile acid, fatty acid metabolism, oxidative stress, and proinflammatory pathways. Furthermore, a notable frequency of single nucleotide polymorphisms in genes such as patatin-like phospholipase domain-containing 3, transmembrane 6 superfamily member 2, glucokinase regulator, and membrane-bound O-acyltransferase domain-containing 7 has been observed. The tumor immune microenvironment of metabolic-associated HCC is characterized by unique phenotypes of macrophages, neutrophils, and T lymphocytes. Additionally, the pathogenesis of metabolic-associated HCC is influenced by abnormal lipid metabolism, insulin resistance, and dysbiosis. In conclusion, deciphering the intricate interactions among metabolic processes, genetic predispositions, inflammatory responses, immune regulation, and microbial ecology is imperative for the development of novel therapeutic and preventative measures against metabolic-associated HCC.
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Affiliation(s)
- Takahiro Kodama
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
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Hazari Y, Chevet E, Bailly-Maitre B, Hetz C. ER stress signaling at the interphase between MASH and HCC. Hepatology 2024:01515467-990000000-00844. [PMID: 38626349 DOI: 10.1097/hep.0000000000000893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2024] [Accepted: 03/28/2024] [Indexed: 04/18/2024]
Abstract
HCC is the most frequent primary liver cancer with an extremely poor prognosis and often develops on preset of chronic liver diseases. Major risk factors for HCC include metabolic dysfunction-associated steatohepatitis, a complex multifactorial condition associated with abnormal endoplasmic reticulum (ER) proteostasis. To cope with ER stress, the unfolded protein response engages adaptive reactions to restore the secretory capacity of the cell. Recent advances revealed that ER stress signaling plays a critical role in HCC progression. Here, we propose that chronic ER stress is a common transversal factor contributing to the transition from liver disease (risk factor) to HCC. Interventional strategies to target the unfolded protein response in HCC, such as cancer therapy, are also discussed.
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Affiliation(s)
- Younis Hazari
- Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile
- Faculty of Medicine, Biomedical Neuroscience Institute (BNI), University of Chile, Santiago, Chile
- Center for Geroscience, Brain Health and Metabolism (GERO), Santiago, Chile
- Department of Biotechnology, University of Kashmir, Srinagar, India
| | - Eric Chevet
- Inserm U1242, University of Rennes, Rennes, France
- Centre de Lutte Contre le Cancer Eugène Marquis, Rennes, France
| | - Béatrice Bailly-Maitre
- Institut National de la Santé et de la Recherche Médicale (INSERM) UMR1065, Université Côte d'Azur (UCA), Centre Méditerranéen de Médecine Moléculaire (C3M), 06204 Nice, France Team "Metainflammation and Hematometabolism", Metabolism Department, France
- Université Côte d'Azur, INSERM, U1065, C3M, 06200 Nice, France
| | - Claudio Hetz
- Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile
- Faculty of Medicine, Biomedical Neuroscience Institute (BNI), University of Chile, Santiago, Chile
- Center for Geroscience, Brain Health and Metabolism (GERO), Santiago, Chile
- Buck Institute for Research on Aging, Novato, California, USA
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Mateu-Arrom L, Puig L. Choosing the right biologic treatment for moderate-to-severe plaque psoriasis: the impact of comorbidities. Expert Rev Clin Pharmacol 2024; 17:363-379. [PMID: 38603464 DOI: 10.1080/17512433.2024.2340552] [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: 11/29/2023] [Accepted: 03/01/2024] [Indexed: 04/13/2024]
Abstract
INTRODUCTION Psoriasis is a chronic inflammatory skin disease often associated with several comorbidities, such as psoriatic arthritis, inflammatory bowel disease, obesity, diabetes mellitus or cardiovascular diseases, infections, or cancer, among others. With the progressive aging of the population, a growing number of patients with psoriasis can be expected to present multiple comorbidities. Currently, there is a wide range of biological treatments available for moderate to severe psoriasis, including tumor necrosis alpha (TNF) inhibitors, IL12/23 inhibitor, IL17 inhibitors, and IL23 inhibitors. AREAS COVERED This review aims to describe the specific characteristics of these drugs in relation to psoriasis comorbidities, in order to facilitate decision-making in clinical practice. EXPERT OPINION Some of the biological treatments can influence comorbidities, in some cases even improving them. Therefore, comorbidities are a key factor when deciding on one biological treatment over another. The development of new drugs is expanding the therapeutic arsenal for psoriasis. A high level of expertise in the field with a detailed knowledge of the characteristics of every drug is imperative to provide personalized medicine.
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Affiliation(s)
- Laura Mateu-Arrom
- Department of Dermatology, Hospital de la Santa Creu i Sant Pau, Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Lluis Puig
- Department of Dermatology, Hospital de la Santa Creu i Sant Pau, Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), Universitat Autònoma de Barcelona, Barcelona, Spain
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Li Z, Wang S, Xu Q, Su X, Wang Y, Wang L, Zhang Y. The double roles of T cell-mediated immune response in the progression of MASLD. Biomed Pharmacother 2024; 173:116333. [PMID: 38479177 DOI: 10.1016/j.biopha.2024.116333] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2024] [Revised: 02/21/2024] [Accepted: 02/22/2024] [Indexed: 03/27/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease(MASLD), formerly known as non-alcoholic fatty liver disease(NAFLD), has become a major cause of chronic liver disease and a significant risk factor for hepatocellular carcinoma, which poses a huge burden on global public health and economy. MASLD includes steatotic liver disease, steatohepatitis, and cirrhosis, and the latter two cause great harm to human health and life, even complicated with liver cancer. Immunologic mechanism plays a major role in promoting its development into hepatitis and cirrhosis. Now more and more evidences show that T cells play an important role in the progression of MASLD. In this review, we discuss the double roles of T cells in MASLD from the perspective of T cell response pathways, as well as new evidences regarding the possible application of immunomodulatory therapy in MASH.
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Affiliation(s)
- Zigan Li
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250033, China
| | - Shujun Wang
- Department of Medical Parasitology, Wannan Medical College, Wuhu 241000, China
| | - Qinchen Xu
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250033, China
| | - Xin Su
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250033, China
| | - Yunshan Wang
- Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province 250021, China
| | - Lina Wang
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250033, China.
| | - Yong Zhang
- Shandong Provincial Third Hospital Affiliated to Shandong University, Jinan, Shandong Province 250031, China.
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Niedecker RW, Delaney JA, Doyle MF, Sparks AD, Sitlani CM, Buzkova P, Zeb I, Tracy RP, Psaty BM, Budoff MJ, Olson NC. Investigating peripheral blood monocyte and T-cell subsets as non-invasive biomarkers for asymptomatic hepatic steatosis: results from the Multi-Ethnic Study of Atherosclerosis. Front Immunol 2024; 15:1243526. [PMID: 38596669 PMCID: PMC11002077 DOI: 10.3389/fimmu.2024.1243526] [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: 06/20/2023] [Accepted: 03/11/2024] [Indexed: 04/11/2024] Open
Abstract
Background Circulating immune cells have gained interest as biomarkers of hepatic steatosis. Data on the relationships between immune cell subsets and early-stage steatosis in population-based cohorts are limited. Methods This study included 1,944 asymptomatic participants of the Multi-Ethnic Study of Atherosclerosis (MESA) with immune cell phenotyping and computed tomography measures of liver fat. Participants with heavy alcohol use were excluded. A liver-to-spleen ratio Hounsfield units (HU) <1.0 and liver attenuation <40 HU were used to diagnose liver fat presence and >30% liver fat content, respectively. Logistic regression estimated cross-sectional associations of immune cell subsets with liver fat parameters adjusted for risk factors. We hypothesized that higher proportions of non-classical monocytes, Th1, Th17, and memory CD4+ T cells, and lower proportions of classical monocytes and naive CD4+ T cells, were associated with liver fat. Exploratory analyses evaluated additional immune cell phenotypes (n = 19). Results None of the hypothesized cells were associated with presence of liver fat. Higher memory CD4+ T cells were associated with >30% liver fat content, but this was not significant after correction for multiple hypothesis testing (odds ratio (OR): 1.31, 95% confidence interval (CI): 1.03, 1.66). In exploratory analyses unadjusted for multiple testing, higher proportions of CD8+CD57+ T cells were associated with liver fat presence (OR: 1.21, 95% CI: 1.02, 1.44) and >30% liver fat content (OR: 1.34, 95% CI: 1.07, 1.69). Conclusions Higher circulating memory CD4+ T cells may reflect liver fat severity. CD8+CD57+ cells were associated with liver fat presence and severity, but replication of findings is required.
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Affiliation(s)
- Rhys W. Niedecker
- Department of Pathology and Laboratory Medicine, Larner College of Medicine, University of Vermont, Burlington, VT, United States
| | - Joseph A. Delaney
- General Internal Medicine, University of Washington, Seattle, WA, United States
| | - Margaret F. Doyle
- Department of Pathology and Laboratory Medicine, Larner College of Medicine, University of Vermont, Burlington, VT, United States
| | - Andrew D. Sparks
- Department of Medical Biostatistics, Larner College of Medicine, University of Vermont, Burlington, VT, United States
| | - Colleen M. Sitlani
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, United States
| | - Petra Buzkova
- Department of Biostatistics, University of Washington School of Public Health, Seattle, WA, United States
| | - Irfan Zeb
- Department of Medicine, West Virginia University Heart and Vascular Institute, Morgantown, WV, United States
| | - Russell P. Tracy
- Department of Pathology and Laboratory Medicine, Larner College of Medicine, University of Vermont, Burlington, VT, United States
- Department of Biochemistry, Larner College of Medicine, University of Vermont, Burlington, VT, United States
| | - Bruce M. Psaty
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, United States
- Department of Epidemiology, University of Washington, Seattle, WA, United States
- Department of Health Systems and Population Health, University of Washington, Seattle, WA, United States
| | - Matthew J. Budoff
- Lundquist Institute at Harbor-UCLA Medical Center, Torrance, CA, United States
| | - Nels C. Olson
- Department of Pathology and Laboratory Medicine, Larner College of Medicine, University of Vermont, Burlington, VT, United States
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Xiao YL, Gong Y, Qi YJ, Shao ZM, Jiang YZ. Effects of dietary intervention on human diseases: molecular mechanisms and therapeutic potential. Signal Transduct Target Ther 2024; 9:59. [PMID: 38462638 PMCID: PMC10925609 DOI: 10.1038/s41392-024-01771-x] [Citation(s) in RCA: 44] [Impact Index Per Article: 44.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 02/05/2024] [Accepted: 02/18/2024] [Indexed: 03/12/2024] Open
Abstract
Diet, serving as a vital source of nutrients, exerts a profound influence on human health and disease progression. Recently, dietary interventions have emerged as promising adjunctive treatment strategies not only for cancer but also for neurodegenerative diseases, autoimmune diseases, cardiovascular diseases, and metabolic disorders. These interventions have demonstrated substantial potential in modulating metabolism, disease trajectory, and therapeutic responses. Metabolic reprogramming is a hallmark of malignant progression, and a deeper understanding of this phenomenon in tumors and its effects on immune regulation is a significant challenge that impedes cancer eradication. Dietary intake, as a key environmental factor, can influence tumor metabolism. Emerging evidence indicates that dietary interventions might affect the nutrient availability in tumors, thereby increasing the efficacy of cancer treatments. However, the intricate interplay between dietary interventions and the pathogenesis of cancer and other diseases is complex. Despite encouraging results, the mechanisms underlying diet-based therapeutic strategies remain largely unexplored, often resulting in underutilization in disease management. In this review, we aim to illuminate the potential effects of various dietary interventions, including calorie restriction, fasting-mimicking diet, ketogenic diet, protein restriction diet, high-salt diet, high-fat diet, and high-fiber diet, on cancer and the aforementioned diseases. We explore the multifaceted impacts of these dietary interventions, encompassing their immunomodulatory effects, other biological impacts, and underlying molecular mechanisms. This review offers valuable insights into the potential application of these dietary interventions as adjunctive therapies in disease management.
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Affiliation(s)
- Yu-Ling Xiao
- Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Yue Gong
- Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Ying-Jia Qi
- Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Zhi-Ming Shao
- Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Yi-Zhou Jiang
- Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
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He R, Guan C, Zhao X, Yu L, Cui Y. Expression of immune related genes and possible regulatory mechanisms in different stages of non-alcoholic fatty liver disease. Front Immunol 2024; 15:1364442. [PMID: 38524129 PMCID: PMC10957650 DOI: 10.3389/fimmu.2024.1364442] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Accepted: 02/26/2024] [Indexed: 03/26/2024] Open
Abstract
Background Non-alcoholic fatty liver disease (NAFLD), which includes simple steatosis (SS) and non-alcoholic steatohepatitis (NASH), is a significant contributor to liver disease on a global scale. The change of immunity-related genes (IRGs) expression level leads to different immune infiltrations. However, the expression of IRGs and possible regulatory mechanisms involved in NAFLD remain unclear. The objective of our research is to investigate crucial genes linked to the development of NAFLD and the transition from SS to NASH. Methods Dataset GSE89632, which includes healthy controls, SS patients, and NASH patients, was obtained using the GEO database. To examine the correlation between sets of genes and clinical characteristics, we employed weighted gene co-expression network analysis (WGCNA) and differential expression analysis. Hub genes were extracted using a network of protein-protein interactions (PPI) and three different machine learning algorithms. To validate the findings, another dataset that is publicly accessible and mice that were subjected to a high-fat diet (HFD) or MCD diet were utilized. Furthermore, the ESTIMATE algorithm and ssGSEA were employed to investigate the immune landscape in the normal versus SS group and SS versus NASH group, additionally, the relationship between immune infiltration and the expression of hub genes was also examined. Results A total of 28 immune related key genes were selected. Most of these genes expressed reverse patterns in the initial and progressive stages of NAFLD. GO and KEGG analyses showed that they were focused on the cytokine related pathways and immune cell activation and chemotaxis. After screening by various algorithms, we obtained two hub genes, including JUN and CCL20. Validation of these findings was confirmed by analyzing gene expression patterns in both the validation dataset and the mouse model. Ultimately, two hub genes were discovered to have a significant correlation with the infiltration of immune cells. Conclusion We proposed that there were dynamic changes in the expression levels of IRGs in different stages of NAFLD disease, which led to different immune landscapes in SS and NASH. The findings of our research could serve as a guide for the accurate management of various phases of NAFLD.
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Affiliation(s)
| | | | | | - Liang Yu
- Department of Pancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Yunfu Cui
- Department of Pancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
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