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Wang D, Miao J, Zhang L, Zhang L. Research advances in the diagnosis and treatment of MASLD/MASH. Ann Med 2025; 57. [DOI: 10.1080/07853890.2024.2445780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 12/01/2024] [Accepted: 12/02/2024] [Indexed: 01/06/2025] Open
Affiliation(s)
- Dekai Wang
- Department of General Practice, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Jinxian Miao
- Department of General Practice, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Lihua Zhang
- Department of General Practice, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Lin Zhang
- Department of General Practice, The First Affiliated Hospital of Kunming Medical University, Kunming, China
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Qian Z, Chen S, Liao X, Xie J, Xu Y, Zhong H, Ou L, Zuo X, Xu X, Peng J, Wu J, Cai S. Decreased intestinal abundance of Akkermansia muciniphila is associated with metabolic disorders among people living with HIV. Ann Med 2025; 57:2474730. [PMID: 40052450 PMCID: PMC11892071 DOI: 10.1080/07853890.2025.2474730] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 02/11/2025] [Accepted: 02/12/2025] [Indexed: 03/12/2025] Open
Abstract
BACKGROUND Previous studies have shown changes in gut microbiota after human immunodeficiency virus (HIV) infection, but there is limited research linking the gut microbiota of people living with HIV (PLWHIV) to metabolic diseases. METHODS A total of 103 PLWHIV were followed for 48 weeks of anti-retroviral therapy (ART), with demographic and clinical data collected. Gut microbiome analysis was conducted using metagenomic sequencing of fecal samples from 12 individuals. Nonalcoholic fatty liver disease (NAFLD) was diagnosed based on controlled attenuation parameter (CAP) values of 238 dB/m from liver fibro-scans. Participants were divided based on the presence of metabolic disorders, including NAFLD, overweight, and hyperlipidemia. Akkermansia abundance in stool samples was measured using RT-qPCR, and Pearson correlation and logistic regression were applied for analysis. RESULTS Metagenomic sequencing revealed a significant decline in gut Akkermansia abundance in PLWHIV with NAFLD. STAMP analysis of public datasets confirmed this decline after HIV infection, while KEGG pathway analysis identified enrichment of metabolism-related genes. A prospective cohort study with 103 PLWHIV followed for 48 weeks validated these findings. Akkermansia abundance was significantly lower in participants with NAFLD, overweight, and hyperlipidemia at baseline, and it emerged as an independent predictor of NAFLD and overweight. Negative correlations were observed between Akkermansia abundance and both CAP values and body mass index (BMI) at baseline and at week 48. At the 48-week follow-up, Akkermansia remained a predictive marker for NAFLD. CONCLUSIONS Akkermansia abundance was reduced in PLWHIV with metabolic disorders and served as a predictive biomarker for NAFLD progression over 48 weeks of ART.
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Affiliation(s)
- Zhe Qian
- Second Department of Elderly Respiratory, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangdong Provincial Geriatrics Institute, Southern Medical University, Guangzhou, China
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Suling Chen
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaoyang Liao
- Second Department of Elderly Respiratory, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangdong Provincial Geriatrics Institute, Southern Medical University, Guangzhou, China
| | - Jingfang Xie
- Department of Geriatrics, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangdong Provincial Geriatrics Institute, Southern Medical University, Guangzhou, China
| | - Yuyuan Xu
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Huiqun Zhong
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Lang Ou
- Department of hepatobiliary surgery, Affiliated Nanhua Hospital, University of South China, Hengyang, China
| | - Xiang Zuo
- Division of Hepatobiliopancreatic Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xuwen Xu
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jie Peng
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jian Wu
- Second Department of Elderly Respiratory, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangdong Provincial Geriatrics Institute, Southern Medical University, Guangzhou, China
- School of Medicine, South China University of Technology, Guangzhou, China
| | - Shaohang Cai
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Darbà J, Ascanio M. Hepatocellular carcinoma: what are the differential costs compared to the general population? J Med Econ 2025; 28:471-478. [PMID: 40126406 DOI: 10.1080/13696998.2025.2484073] [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: 01/23/2025] [Revised: 03/20/2025] [Accepted: 03/21/2025] [Indexed: 03/25/2025]
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC), which accounts for about 90% of all primary liver cancer cases, is the fifth most common malignancy and the second leading cause of cancer-related mortality worldwide. This study aims to analyse the differential costs of HCC-related hospital admissions compared to the general population in Spain. METHODS A retrospective multicenter study analyzed inpatient admissions from a Spanish national discharge database, covering 90% of hospitals between 2010 and 2022. HCC-related admissions were identified using ICD-9 and ICD-10 codes, while control admissions were selected from the general population in the same database without an HCC diagnosis. The direct hospitalization cost was included, covering medical examinations, procedures, medications, surgeries, personnel and equipment. Statistical methods, including nearest-neighbor matching, propensity score matching, and a generalized linear model, were used to estimate differential costs and to ensure comparability based on age, gender, and Charlson Comorbidity Index (CCI). RESULTS A total of 199,670 HCC-related hospital admissions and 200,000 control admissions were analyzed. Most HCC-related admissions involved male patients (78%) aged 66-85 years, with an average CCI of 5.18. HCC-related admissions incurred significantly higher costs, with an estimated differential cost of €1,303.68 using GLM, €1,804.25 via propensity score matching, and €1,767.77 using nearest-neighbor matching. Total costs per HCC admission ranged between €1,000 and €31,000. CONCLUSIONS HCC-related hospital admissions impose a significantly higher economic burden due to the complexity of care. Given the high mortality and resource utilization, advancements in early detection, treatment, and cost-effective interventions are needed to improve patient outcomes and reduce healthcare costs.
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Affiliation(s)
- Josep Darbà
- Department of Economics, Universitat de Barcelona, Barcelona, Spain
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Du W, Zou ZP, Ye BC, Zhou Y. Gut microbiota and associated metabolites: key players in high-fat diet-induced chronic diseases. Gut Microbes 2025; 17:2494703. [PMID: 40260760 PMCID: PMC12026090 DOI: 10.1080/19490976.2025.2494703] [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: 01/03/2025] [Revised: 02/26/2025] [Accepted: 04/11/2025] [Indexed: 04/24/2025] Open
Abstract
Excessive intake of dietary fats is strongly associated with an increased risk of various chronic diseases, such as obesity, diabetes, hepatic metabolic disorders, cardiovascular disease, chronic intestinal inflammation, and certain cancers. A significant portion of the adverse effects of high-fat diet on disease risk is mediated through modifications in the gut microbiota. Specifically, high-fat diets are linked to reduced microbial diversity, an overgrowth of gram-negative bacteria, an elevated Firmicutes-to-Bacteroidetes ratio, and alterations at various taxonomic levels. These microbial alterations influence the intestinal metabolism of small molecules, which subsequently increases intestinal permeability, exacerbates inflammatory responses, disrupts metabolic functions, and impairs signal transduction pathways in the host. Consequently, diet-induced changes in the gut microbiota play a crucial role in the initiation and progression of chronic diseases. This review explores the relationship between high-fat diets and gut microbiota, highlighting their roles and underlying mechanisms in the development of chronic metabolic diseases. Additionally, we propose probiotic interventions may serve as a promising adjunctive therapy to counteract the negative effects of high-fat diet-induced alterations in gut microbiota composition.
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Affiliation(s)
- Wei Du
- Laboratory of Biosystems and Microanalysis, State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China
| | - Zhen-Ping Zou
- Laboratory of Biosystems and Microanalysis, State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China
| | - Bang-Ce Ye
- Laboratory of Biosystems and Microanalysis, State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China
| | - Ying Zhou
- Laboratory of Biosystems and Microanalysis, State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China
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Zhang DY, Li D, Chen SJ, Zhang LJ, Zhu XL, Chen FD, Chen C, Wang Q, Du Y, Xiong JX, Huang SM, Zhang XD, Lv YT, Zeng F, Chen RX, Huang X, Mao F, Zhou S, Yao Q, Huang Y, Chen R, Mo Y, Xie Y, Jiang YH, Chen Z, Mo CY, Chen JJ, Bai FH. Bacteroides uniformis-generated hexadecanedioic acid ameliorates metabolic-associated fatty liver disease. Gut Microbes 2025; 17:2508433. [PMID: 40413726 DOI: 10.1080/19490976.2025.2508433] [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: 03/11/2025] [Revised: 04/28/2025] [Accepted: 05/14/2025] [Indexed: 05/27/2025] Open
Abstract
Gut microbiota exerts a pivotal influence on the development of Metabolic Associated Fatty Liver Disease (MAFLD), although the specific contributions of individual bacterial strains and their metabolites remain poorly defined. We conducted stool shotgun metagenomic sequencing and plasma untargeted metabolomics in a large prospective cohort comprising 120 MAFLD patients and 120 matched healthy controls. The mechanisms and microbial-derived metabolites involved in MAFLD were further investigated through multi-omics analyses in vitro and in vivo. Distinct differences were identified in both the microbial community structure and metabolomic profiles between MAFLD patients and healthy controls. Bacteroides uniformis (B. uniformis) was the most significantly depleted species in MAFLD and negatively correlated with hepatic steatosis and BMI. MAFLD was characterized by marked disruptions in fatty acid and amino acid metabolism. Combined analysis of metabolomic and metagenomic data achieved high diagnostic accuracy for MAFLD and hepatic steatosis severity (AUC = 0.93). Transplantation of fecal microbiota from MAFLD subjects into ABX mice led to the onset of MAFLD-like symptoms, whereas B. uniformis administration alleviate disease progression by inhibiting intestinal fat absorption, FFA from eWAT influx into liver via the gut-liver axis, and IRE1α-XBP1s-mediated flipogenesis and ferroptosis, as confirmed by hepatic transcriptomic and proteomic analyses. Hexadecanedioic acid (HDA), potentially identified as a key metabolite produced by B. uniformis, ameliorated MAFLD symptoms. Mechanistically, B. uniformis-derived HDA also inhibited fat absorption and transported, and entered the liver via the portal vein to suppress IRE1α-XBP1s-mediated flipogenesis and ferroptosis. B. uniformis and its potential putative metabolite HDA may contribute to MAFLD progression modulation, through regulation of the IRE1α-XBP1s axis. This study provides new insights into the gut-liver axis in MAFLD and offers promising therapeutic targets based on specific microbes and their metabolites.
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Affiliation(s)
- Da-Ya Zhang
- The Second School of Clinical Medicine, Hainan Medical University, Haikou, China
- Department of Gastroenterology, The Second Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Da Li
- The Second School of Clinical Medicine, Hainan Medical University, Haikou, China
- Department of Gastroenterology, The Second Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Shi-Ju Chen
- The Second School of Clinical Medicine, Hainan Medical University, Haikou, China
- Department of Gastroenterology, The Second Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Li-Jun Zhang
- Health Management Center, The Second Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Xu-Li Zhu
- Department of Gastroenterology, Otog Front Banner People's Hospital, Otog Front Banner, China
| | - Fa-Di Chen
- Wuzhishan Center for Disease Control and Prevention, Wuzhishan, China
| | - Chen Chen
- The Second School of Clinical Medicine, Hainan Medical University, Haikou, China
- Department of Gastroenterology, The Second Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Qi Wang
- The Second School of Clinical Medicine, Hainan Medical University, Haikou, China
- Department of Gastroenterology, The Second Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Yiping Du
- Cardiovascular Surgery, The Second Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Jian-Xin Xiong
- Department of Gastroenterology, Hainan Second People's Hospital, Wuzhishan, China
| | - Shi-Mei Huang
- The Second School of Clinical Medicine, Hainan Medical University, Haikou, China
- Department of Gastroenterology, The Second Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Xiao-Dong Zhang
- The Second School of Clinical Medicine, Hainan Medical University, Haikou, China
- Department of Gastroenterology, The Second Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Yan-Ting Lv
- The Second School of Clinical Medicine, Hainan Medical University, Haikou, China
- Department of Gastroenterology, The Second Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Fan Zeng
- The Second School of Clinical Medicine, Hainan Medical University, Haikou, China
- Department of Gastroenterology, The Second Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Run-Xiang Chen
- The Second School of Clinical Medicine, Hainan Medical University, Haikou, China
- Department of Gastroenterology, The Second Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Xianfeng Huang
- The Second School of Clinical Medicine, Hainan Medical University, Haikou, China
- Department of Gastroenterology, The Second Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Fengjiao Mao
- The Second School of Clinical Medicine, Hainan Medical University, Haikou, China
- Department of Gastroenterology, The Second Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Shuo Zhou
- The Second School of Clinical Medicine, Hainan Medical University, Haikou, China
- Department of Gastroenterology, The Second Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Qicen Yao
- Department of Rheumatology and Immunology, The Second Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Yuliang Huang
- The Second School of Clinical Medicine, Hainan Medical University, Haikou, China
- Department of Gastroenterology, The Second Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Runyu Chen
- The Second School of Clinical Medicine, Hainan Medical University, Haikou, China
- Department of Gastroenterology, The Second Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Ying Mo
- The Second School of Clinical Medicine, Hainan Medical University, Haikou, China
- Department of Gastroenterology, The Second Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Yunqian Xie
- Department of Gastroenterology, The Second Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Yue-Hong Jiang
- Department of Gastroenterology, The Second People's Hospital of Ledong Li Autonomous County, Ledong Li Autonomous County, China
| | - Zhai Chen
- Department of Gastroenterology, Dongfang People's Hospital, Dongfang, China
| | - Cui-Yi Mo
- Department of Gastroenterology, Qionghai People's Hospital, Qionghai, China
| | - Jia-Jia Chen
- Department of Gastroenterology, Qionghai People's Hospital, Qionghai, China
| | - Fei-Hu Bai
- Department of Gastroenterology, The Second Affiliated Hospital of Hainan Medical University, Haikou, China
- Department of Gastroenterology, The Gastroenterology Clinical Medical Center of Hainan Province, Haikou, China
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Zhang Y, Wang YP, Sun HL, Zhang XD, Guan SQ, Pan M. Mitochondrial viscosity, oxidative stress and autophagy responsive fluorescent Zn(II) complex for monitoring non-alcoholic fatty liver disease. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2025; 340:126319. [PMID: 40334578 DOI: 10.1016/j.saa.2025.126319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/19/2025] [Revised: 04/19/2025] [Accepted: 04/28/2025] [Indexed: 05/09/2025]
Abstract
Accumulating evidence highlights the critical role of dysfunctional mitochondrial quality control in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, there is limited information available regarding of viscosity-related cellular metabolic processes of NAFLD. To address this, we developed a novel viscosity-sensitive fluorescent metal Zn(II) complex, LIFM-ZY-1, for monitoring viscosity changes with one-photon (OP) and two-photon (TP) fluorescence. It could effectively track cellular oxidative stress induced by lipotoxicity with viscosity changes, as reflected by viscosity changes in the OP/TP channel. Besides, LIFM-ZY-1 was capable of detecting non-selective mitophagy triggered by starvation in real time and selective mitophagy induced by autophagy drug rapamycin. Moreover, LIFM-ZY-1 successfully monitored the deterioration and therapeutic outcome of NAFLD mice with changing viscosity induced by overeating and autophagy drug empagliflozin. Overall, our findings demonstrated the potential of LIFM-ZY-1 as a valuable tool for real time monitoring NAFLD treatment through viscosity, oxidative stress and autophagy changes, offering valuable insights into the underlying biological processes and potential therapeutic strategies for NAFLD.
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Affiliation(s)
- Yu Zhang
- MOE Laboratory of Bioinorganic and Synthetic Chemistry, Lehn Institute of Functional Materials, IGCME, GBRCE for Functional Molecular Engineering, School of Chemistry, Sun Yat-Sen University, Guangzhou 510006, China
| | - Ya-Ping Wang
- MOE Laboratory of Bioinorganic and Synthetic Chemistry, Lehn Institute of Functional Materials, IGCME, GBRCE for Functional Molecular Engineering, School of Chemistry, Sun Yat-Sen University, Guangzhou 510006, China; Department of Radiology, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510030, China
| | - Hui-Li Sun
- MOE Laboratory of Bioinorganic and Synthetic Chemistry, Lehn Institute of Functional Materials, IGCME, GBRCE for Functional Molecular Engineering, School of Chemistry, Sun Yat-Sen University, Guangzhou 510006, China
| | - Xiao-Dong Zhang
- MOE Laboratory of Bioinorganic and Synthetic Chemistry, Lehn Institute of Functional Materials, IGCME, GBRCE for Functional Molecular Engineering, School of Chemistry, Sun Yat-Sen University, Guangzhou 510006, China
| | - Shao-Qi Guan
- MOE Laboratory of Bioinorganic and Synthetic Chemistry, Lehn Institute of Functional Materials, IGCME, GBRCE for Functional Molecular Engineering, School of Chemistry, Sun Yat-Sen University, Guangzhou 510006, China
| | - Mei Pan
- MOE Laboratory of Bioinorganic and Synthetic Chemistry, Lehn Institute of Functional Materials, IGCME, GBRCE for Functional Molecular Engineering, School of Chemistry, Sun Yat-Sen University, Guangzhou 510006, China.
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Mekontso JG, Nnang JY, Tembi TB, Kortim AB, Nguefang GL, Wagner J, Bernstein M. Efficacy, Safety, and Tolerability of Farnesoid X Receptor Agonists in the Treatment of Metabolic Dysfunction-associated Steatotic Liver Disease: A Systematic Review and Meta-analysis. J Clin Exp Hepatol 2025; 15:102563. [PMID: 40337255 PMCID: PMC12053700 DOI: 10.1016/j.jceh.2025.102563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2025] [Accepted: 03/26/2025] [Indexed: 05/09/2025] Open
Abstract
Background/Aims Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of chronic liver disease. Farnesoid X receptor (FXR) agonists are emerging as promising therapies for fibrosis, steatosis, and metabolic dysfunctions. However, its efficacy and safety remain unclear. Methods A systematic search of PubMed, Embase, and Cochrane databases identified randomized controlled trials (RCTs) comparing FXR agonists with placebo in patients with MASLD. The main outcomes included improvement in fibrosis without worsening steatohepatitis, changes in liver chemistry and lipid profiles, and liver fat content (LFC). The safety outcomes assessed included side effects and treatment discontinuation rates. Heterogeneity was evaluated using I² statistics, with a random-effects model applied to the pooled analyses. Results Ten RCTs involving 3,779 patients were included, of which 2,527 (67%) were randomized to receive FXR agonists. FXR agonists significantly improved fibrosis by ≥ 1 stage (RR, 1.52; 95% CI: [1.23, 1.88]; P < 0.0001) and reduced LFC (mean difference: -4.9%; 95% CI: [-8.26, -1.55]; P < 0.001). A higher proportion of patients achieved a ≥30% reduction in LFC (42.8% vs. 18.4%; RR, 2.42; 95% CI: [1.69, 3.46]; P < 0.00001). Significant reductions in alanine aminotransferase and gamma glutamyltransferase levels were observed, whereas alkaline phosphatase levels were increased. FXR agonists were associated with a slight reduction in High-Density Lipoprotein (HDL) cholesterol levels and a higher incidence of pruritus (37.8% vs. 18.7%; RR, 2.67; 95% CI: [1.63, 4.38]; P < 0.00001), leading to higher treatment discontinuation rates. Conclusion FXR agonists have the potential to improve fibrosis and steatosis in MASLD patients. However, safety concerns still remain. Further research is required to determine the long-term efficacy and tolerability of these drugs.
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Affiliation(s)
- Joel G.K. Mekontso
- New York City Health and Hospitals, South Brooklyn Health, Brooklyn, NY, USA
| | - Joseph Y.B. Nnang
- Faculty of Medicine and Biomedical Sciences, University of Yaounde I, Yaounde, Cameroon
| | - Ticha B.T. Tembi
- Hubert Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA
| | | | - Guy L. Nguefang
- Texas Tech University Health Sciences Center, Odessa, TX, USA
| | - Justin Wagner
- New York City Health and Hospitals, South Brooklyn Health, Brooklyn, NY, USA
| | - Michael Bernstein
- New York City Health and Hospitals, South Brooklyn Health, Brooklyn, NY, USA
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Poudineh M, Mohammadyari F, Parsamanesh N, Jamialahmadi T, Kesharwani P, Sahebkar A. Cell and gene therapeutic approaches in non-alcoholic fatty liver disease. Gene 2025; 956:149466. [PMID: 40189164 DOI: 10.1016/j.gene.2025.149466] [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: 01/06/2025] [Revised: 03/14/2025] [Accepted: 03/31/2025] [Indexed: 04/11/2025]
Abstract
Non-Alcoholic Fatty Liver Disease (NAFLD) refers to a range of conditions marked by the buildup of triglycerides in liver cells, accompanied by inflammation, which contributes to liver damage, clinical symptoms, and histopathological alterations. Multiple molecular pathways contribute to NAFLD pathogenesis, including immune dysregulation, endoplasmic reticulum stress, and tissue injury. Both the innate and adaptive immune systems play crucial roles in disease progression, with intricate crosstalk between liver and immune cells driving NAFLD development. Among emerging therapeutic strategies, cell and gene-based therapies have shown promise. This study reviews the pathophysiological mechanisms of NAFLD and explores the therapeutic potential of cell-based interventions, highlighting their immunomodulatory effects, inhibition of hepatic stellate cells, promotion of hepatocyte regeneration, and potential for hepatocyte differentiation. Additionally, we examine gene delivery vectors designed to target NAFLD, focusing on their role in engineering hepatocytes through gene addition or editing to enhance therapeutic efficacy.
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Affiliation(s)
| | | | - Negin Parsamanesh
- Metabolic Diseases Research Center, Zanjan University of Medical Sciences, Zanjan, Iran; Department of Genetics and Molecular Medicine, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Tananz Jamialahmadi
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Medical Toxicology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Prashant Kesharwani
- Department of Pharmaceutical Sciences, Dr. Harisingh Gour Vishwavidyalaya, Sagar, Madhya Pradesh 470003, India.
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Centre for Research Impact and Outcome, Chitkara University, Rajpura 140417, Punjab, India; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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Liu Z, Shang Q, Cheng J, He Q, Liu Y, Li H, Fang D, Li X, Zhu Y, Chen J, Chen J. Mechanistic study of a triterpenoid-enriched fraction derived from Cynomorium songaricum against NAFLD: An integrative elucidation. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 142:156782. [PMID: 40318532 DOI: 10.1016/j.phymed.2025.156782] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/17/2025] [Revised: 03/28/2025] [Accepted: 04/17/2025] [Indexed: 05/07/2025]
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is a growing global health concern linked to metabolic dysfunction and inflammation. Traditional Chinese Medicine (TCM), with its emphasis on restoring balance and harmony within the body, is well-suited to address the heterogeneity of NAFLD. Effective strategies to manage NAFLD remain limited, emphasizing the need for novel bioactive compounds with therapeutic potential. PURPOSE This study aimed to investigate the protective effects of a triterpenoid-enriched fraction (CST) derived from Cynomorium songaricum and its active compounds on NAFLD and to elucidate their underlying mechanisms. METHODS CST composition was analyzed using UHPLC/ESI-LTQ-Orbitrap-MS. Anti-inflammatory and lipid-lowering effects were assessed through in vitro and in vivo experiments. Integration of RNA-seq and novel network pharmacology identified key molecular targets, while molecular docking confirmed interactions of oleanolic acid (OLA) and ursolic acid (UA) with IKBKB and TACE, crucial components of the NF-κB pathway. RESULTS CST, OLA and UA significantly reduced lipid accumulation and downregulated inflammatory markers, including TNF-α and lipogenesis-related genes in vitro. In vivo, these compounds reduced lipid accumulation and modulated NF-κB activation, demonstrating robust anti-inflammatory and lipid-regulating effects. CONCLUSION CST exhibits promising bioactive properties in managing NAFLD. IKBKB and TACE mediate CST's protective effects against NAFLD by suppressing NF-κB target genes, reducing TNF-α, and inhibiting lipogenesis. These findings provide a foundation for developing CST and its active components, OLA and UA, as potential therapeutic agents for NAFLD.
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Affiliation(s)
- Zhihao Liu
- Shenzhen Key Laboratory of Steroid Drug Discovery and Development, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, PR China; The Chinese University of Hong Kong, Shenzhen Futian Biomedical Innovation R&D Center, Shenzhen, Guangdong, PR China
| | - Qixiang Shang
- Shenzhen Key Laboratory of Steroid Drug Discovery and Development, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, PR China; The Chinese University of Hong Kong, Shenzhen Futian Biomedical Innovation R&D Center, Shenzhen, Guangdong, PR China
| | - Juanjuan Cheng
- The Chinese University of Hong Kong, Shenzhen Futian Biomedical Innovation R&D Center, Shenzhen, Guangdong, PR China; Shenzhen Traditional Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen Key Laboratory of Hospital Chinese Medicine Preparation, PR China
| | - Quanrun He
- Shenzhen Key Laboratory of Steroid Drug Discovery and Development, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, PR China; The Chinese University of Hong Kong, Shenzhen Futian Biomedical Innovation R&D Center, Shenzhen, Guangdong, PR China
| | - Yining Liu
- Shenzhen Key Laboratory of Steroid Drug Discovery and Development, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, PR China; The Chinese University of Hong Kong, Shenzhen Futian Biomedical Innovation R&D Center, Shenzhen, Guangdong, PR China
| | - Haimeng Li
- Shenzhen Key Laboratory of Steroid Drug Discovery and Development, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, PR China; The Chinese University of Hong Kong, Shenzhen Futian Biomedical Innovation R&D Center, Shenzhen, Guangdong, PR China
| | - Daozheng Fang
- Shenzhen Key Laboratory of Steroid Drug Discovery and Development, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, PR China; The Chinese University of Hong Kong, Shenzhen Futian Biomedical Innovation R&D Center, Shenzhen, Guangdong, PR China
| | - Xinyue Li
- Shenzhen Key Laboratory of Steroid Drug Discovery and Development, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, PR China; The Chinese University of Hong Kong, Shenzhen Futian Biomedical Innovation R&D Center, Shenzhen, Guangdong, PR China
| | - Yong Zhu
- Shenzhen Key Laboratory of Steroid Drug Discovery and Development, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, PR China; The Chinese University of Hong Kong, Shenzhen Futian Biomedical Innovation R&D Center, Shenzhen, Guangdong, PR China
| | - Jianping Chen
- Shenzhen Traditional Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen Key Laboratory of Hospital Chinese Medicine Preparation, PR China.
| | - Jihang Chen
- Shenzhen Key Laboratory of Steroid Drug Discovery and Development, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, PR China; The Chinese University of Hong Kong, Shenzhen Futian Biomedical Innovation R&D Center, Shenzhen, Guangdong, PR China.
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Dang M, Zhang J, Ren RX, Fu MM, Li KJ, Gao HQ, Zhang Q, Wang J, Sun J, Zhang XF, Wang CL, Zhang MM, Zhao CB. Platycodon grandiflorum Attenuates Non-Alcoholic Fatty Liver Disease in Rats Through Regulating Inflammatory Response via PPARγ and TLR4/NF-κB Signaling Pathway. Biomed Chromatogr 2025; 39:e70111. [PMID: 40395044 DOI: 10.1002/bmc.70111] [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: 04/02/2025] [Revised: 04/02/2025] [Accepted: 05/07/2025] [Indexed: 05/22/2025]
Abstract
Non-alcoholic fatty liver disease (NAFLD) has been considered a main health concern worldwide, and Platycodon grandiflorum (PG) has been traditionally employed in ethnopharmacology for managing hepatic metabolic disorders. This study aimed to elucidate the potential effect of PG on NAFLD in rats, and furthermore, the mechanism was explored. PG supplementation significantly increased body weight, serum total cholesterol, triglycerides, and LDL-cholesterol levels in HFD-induced obese rats (p < 0.05). In addition, HFD-induced lipid accumulation and inflammatory response in the liver were also suppressed. Then, the factors contributing to the regulating effect of PG on NAFLD were estimated by using network pharmacology and RNA sequencing. Moreover, western blotting and reverse transcription quantitative polymerase chain reaction (RT-qPCR) suggested that PG treatment obviously downregulated the expression levels of nuclear factor-κB (NF-κB), Toll-like receptor 4 (TLR4), myeloid differentiation primary response protein 88 (MyD88), and inhibitor I kappa B alpha (IκBα), whereas it upregulated the expression of peroxisome proliferator-activated receptor-gamma (PPARγ). Taken together, these findings corroborated the modulatory capacity of PG on NAFLD rats through regulating inflammatory response via PPARγ and TLR4/NF-κB pathway.
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Affiliation(s)
- Ming Dang
- College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, China
| | - Jie Zhang
- College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, China
| | - Run-Xin Ren
- College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, China
| | - Mao-Mao Fu
- College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, China
| | - Kang-Jie Li
- College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, China
| | - Huan-Qing Gao
- College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, China
| | - Qiao Zhang
- College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, China
| | - Jing Wang
- College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, China
| | - Jing Sun
- College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, China
- Shaanxi Traditional Chinese Medicine Processing Technology Heritage Base, Shaanxi University of Chinese Medicine, Xianyang, China
- Engineering Technology Research Center of Shaanxi Administration of Chinese Herbal Pieces, Shaanxi University of Chinese Medicine, Xianyang, China
| | - Xiao-Fei Zhang
- College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, China
| | - Chang-Li Wang
- College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, China
| | - Meng-Meng Zhang
- College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, China
| | - Chong-Bo Zhao
- College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, China
- Shaanxi Traditional Chinese Medicine Processing Technology Heritage Base, Shaanxi University of Chinese Medicine, Xianyang, China
- Engineering Technology Research Center of Shaanxi Administration of Chinese Herbal Pieces, Shaanxi University of Chinese Medicine, Xianyang, China
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Yang X, Guo C, Yang Y, Huang L, Luo L, Zhou Y, Xiao Y, Deng L, Li S. Targeting neutrophil extracellular traps: SERPINE1 and THBS1 as non-invasive biomarkers for early detection of liver fibrosis in metabolic dysfunction-associated Steatotic liver disease. Int Immunopharmacol 2025; 158:114828. [PMID: 40349409 DOI: 10.1016/j.intimp.2025.114828] [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: 02/17/2025] [Revised: 04/26/2025] [Accepted: 05/06/2025] [Indexed: 05/14/2025]
Abstract
Metabolic dysfunction - Associated Steatotic Liver Disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), poses a significant clinical burden due to its high prevalence and potential progression to fibrosis. While neutrophil extracellular traps (NETs) have been implicated in MASLD progression, their specific role in fibrosis remains unclear. This study integrates transcriptomic and single-cell data using weighted gene co-expression network analysis (WGCNA), causal WGCNA (CWGCNA), single-sample gene set enrichment analysis (ssGSEA), gene set variation analysis (GSVA), and linear models for microarray data (Limma) to identify key genes driving steatosis-to-fibrosis transition. Validation in human serum, mouse liver tissue, and mouse serum confirmed that SERPINE1 and THBS1 as robust non-invasive biomarkers with strong diagnostic performance. When combined with clinical features, these markers improved fibrosis prediction accuracy in MASLD patients. Additionally, SERPINE1 appears to mediate interactions between hepatic stellate cells and neutrophils, highlighting a novel therapeutic target. Overall, our findings reveal that NETs-related genes, particularly SERPINE1 and THBS1, hold strong diagnostic value for early-stage fibrosis in MASLD. Targeting SERPINE1 in hepatic stellate cells offers a promising strategy for therapeutic intervention. This study provides a novel framework for non-invasive MASLD fibrosis prediction and lays the foundation for targeted interventions to mitigate disease progression.
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Affiliation(s)
- Xiaofeng Yang
- Department of Gastroenterology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Chunhong Guo
- Department of Gastroenterology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yichun Yang
- Department of Gastroenterology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Lu Huang
- Department of Pediatric Research Institute, Chongqing, China; National Clinical Research Center for Child Health and Disorders, Chongqing, China; Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China; Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Ling Luo
- Department of Infectious Diseases, The First Affiliated Hospital of Chongqing Medical University, China
| | - Youping Zhou
- Department of Gastroenterology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yuliang Xiao
- Department of Gastroenterology, The Affiliated Hospital of Yunnan University, Kunming, China
| | - Liang Deng
- Department of Gastroenterology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
| | - Shan Li
- Department of Gastroenterology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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Taheri E, Ehtesham H, Safdari R, Hormati A. A scientometric analysis and visualization of research on fatty liver diseases in Iran from 2003 to 2023. J Diabetes Metab Disord 2025; 24:103. [PMID: 40224531 PMCID: PMC11992304 DOI: 10.1007/s40200-025-01606-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Accepted: 03/09/2025] [Indexed: 04/15/2025]
Abstract
Background Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide and is now a major global health threat. Due to the mechanistic links between these conditions, along with the rising prevalence of fatty liver disease, diabetes, and obesity, MAFLD (metabolic-associatedfatty liver diseases) was introduced as a new terminology and then updated to MASLD (Metabolic Dysfunction-associated Steatotic Liver Disease. These changes reflect a growing recognition of the importance of fatty liver and its associated health risks. Methods This scientometric study analyzed publications on "fatty liver diseases" (FLD) indexed in Scopus from 2003 to 2023 in Iran. Online Analysis Platforms and VOSviewer were used to assess publication trends and identify research hotspots. Results We retrieved 1,857 English articles on fatty liver diseases published between 2003 and 2023. The Journal of Hepatitis Monthly was notable for Iranian publications on fatty liver disease. Most publications were original articles and Dr. Sahebkar AH was the most prolific author. Iranian researchers primarily collaborated with scholars from the United States. The leading institution in terms of productivity was Tehran University of Medical Sciences. Conclusion This study reveals an increasing trend in both the number of Iranian publications and the citations of articles in the field of FLD. We believe this study can serve as a roadmap for future research and policy development on fatty liver diseases, which are a significant public health concern in Iran. Additionally, new strategies are needed to foster multi-disciplinary research and enhance international cooperation. Supplementary Information The online version contains supplementary material available at 10.1007/s40200-025-01606-8.
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Affiliation(s)
- Ehsaneh Taheri
- Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamideh Ehtesham
- Department of Health Information Technology, Birjand University of Medical Sciences, Birjand, Iran
| | - Reza Safdari
- Department of Health Information Management, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran
| | - Ahmad Hormati
- Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
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Wang J, Yang R, Miao Y, Zhang X, Paillard‐Borg S, Fang Z, Xu W. Metabolic Dysfunction-Associated Steatotic Liver Disease Is Associated With Accelerated Brain Ageing: A Population-Based Study. Liver Int 2025; 45:e70109. [PMID: 40296771 PMCID: PMC12038381 DOI: 10.1111/liv.70109] [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: 02/06/2025] [Revised: 04/09/2025] [Accepted: 04/12/2025] [Indexed: 04/30/2025]
Abstract
BACKGROUND Metabolic dysfunction-associated steatotic liver disease (MASLD) is linked to cognitive decline and dementia risk. We aimed to investigate the association between MASLD and brain ageing and explore the role of low-grade inflammation. METHODS Within the UK Biobank, 30 386 chronic neurological disorders-free participants who underwent brain magnetic resonance imaging (MRI) scans were included. Individuals were categorised into no MASLD/related SLD and MASLD/related SLD (including subtypes of MASLD, MASLD with increased alcohol intake [MetALD] and MASLD with other combined aetiology). Brain age was estimated using machine learning by 1079 brain MRI phenotypes. Brain age gap (BAG) was calculated as the difference between brain age and chronological age. Low-grade inflammation (INFLA) was calculated based on white blood cell count, platelet, neutrophil granulocyte to lymphocyte ratio and C-reactive protein. Data were analysed using linear regression and structural equation models. RESULTS At baseline, 7360 (24.2%) participants had MASLD/related SLD. Compared to participants with no MASLD/related SLD, those with MASLD/related SLD had significantly larger BAG (β = 0.86, 95% CI = 0.70, 1.02), as well as those with MASLD (β = 0.59, 95% CI = 0.41, 0.77) or MetALD (β = 1.57, 95% CI = 1.31, 1.83). The association between MASLD/related SLD and larger BAG was significant across middle-aged (< 60) and older (≥ 60) adults, males and females, and APOE ɛ4 carriers and non-carriers. INFLA mediated 13.53% of the association between MASLD/related SLD and larger BAG (p < 0.001). CONCLUSION MASLD/related SLD, as well as MASLD and MetALD, is associated with accelerated brain ageing, even among middle-aged adults and APOE ɛ4 non-carriers. Low-grade systemic inflammation may partially mediate this association.
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Affiliation(s)
- Jiao Wang
- Center of Gerontology and GeriatricsNational Clinical Research Center for GeriatricsWest China Hospital, Sichuan UniversityChengduChina
- Aging Research Center, Department of Neurobiology, Care Sciences and SocietyKarolinska InstitutetStockholmSweden
| | - Rongrong Yang
- Aging Research Center, Department of Neurobiology, Care Sciences and SocietyKarolinska InstitutetStockholmSweden
- Public Health Science and Engineering CollegeTianjin University of Traditional Chinese MedicineTianjinChina
| | - Yuyang Miao
- Tianjin Key Laboratory of Elderly Health, Department of Geriatrics, Tianjin Geriatrics InstituteTianjin Medical University General HospitalTianjinChina
| | - Xinjie Zhang
- Department of Pediatric Neurosurgery, West China Second University HospitalSichuan UniversityChengduChina
| | | | - Zhongze Fang
- Department of Toxicology and Health Inspection and Quarantine, School of Public HealthTianjin Medical UniversityTianjinChina
| | - Weili Xu
- Aging Research Center, Department of Neurobiology, Care Sciences and SocietyKarolinska InstitutetStockholmSweden
- Tianjin Key Laboratory of Elderly Health, Department of Geriatrics, Tianjin Geriatrics InstituteTianjin Medical University General HospitalTianjinChina
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14
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Chen M, Liu G, Fang Z, Gao W, Song Y, Lei L, Du X, Li X. Buddleoside alleviates nonalcoholic steatohepatitis by targeting the AMPK-TFEB signaling pathway. Autophagy 2025; 21:1316-1334. [PMID: 39936600 DOI: 10.1080/15548627.2025.2466145] [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: 07/04/2024] [Revised: 02/03/2025] [Accepted: 02/08/2025] [Indexed: 02/13/2025] Open
Abstract
Nonalcoholic steatohepatitis (NASH) is a combination of hepatic steatosis, inflammation, and fibrosis, and it often follows simple hepatic steatosis in nonalcoholic fatty liver disease (NAFLD). However, no pharmacological treatment is currently available for NASH. Given the important role of TFEB (transcription factor EB) in regulating the macroautophagy/autophagy-lysosomal pathway, TFEB is potentially a novel therapeutic target for treatment of NASH, which function can be regulated by AMP-activated protein kinase (AMPK) and MTOR (mechanistic target of rapamycin kinase) complex 1 (MTORC1). Buddleoside (Bud), a natural flavonoid compound, has recently emerged as a promising drug candidate for liver diseases. Here, we shown that Bud treatment alleviated hepatic steatosis, insulin resistance, inflammation, and fibrosis in mice fed a high-fat and high-cholesterol (HFHC) diet. Notably, Bud activated AMPK, inhibited MTORC1, and enhanced TFEB transcriptional activity as well as autophagic flux in vivo and in vitro. Inhibition of AMPK or knockout of hepatic Tfeb abrogated the alleviation effects of Bud on hepatic steatosis, insulin resistance, inflammation, and fibrosis. Mechanistic investigation revealed that Bud bound to the PRKAB1 subunit via Val81, Arg83, and Ser108 residues and activated AMPK, thereby eliciting phosphorylation of RPTOR (regulatory associated protein of MTOR complex 1) and inhibiting the kinase MTORC1, which activated the TFEB-mediated autophagy-lysosomal pathway and further ameliorated HFHC-induced NASH in mice. Altogether, our results indicate that Bud ameliorates NASH by activating hepatic the AMPK-TFEB axis, suggesting that Bud is a potential therapeutic strategy for NASH.Abbreviations: ACAC, acetyl-CoA carboxylase; ADaM, allosteric drug and metabolite; AICAR, 5-aminoimidazole-4-carboxamide1-β-D-ribofuranoside; AKT, AKT serine/threonine kinase; ALP, autophagy-lysosomal pathway; AMPK, AMP-activated protein kinase; Bud, buddleoside; CAMKK2, calcium/calmodulin dependent protein kinase kinase 2; CC, compound C; CETSA, cellular thermal shift assay; Cmax, maximum concentration; CQ, chloroquine; DARTS, drug affinity responsive target stability assay; EIF4EBP1, eukaryotic translation factor 4E binding protein 1; GOT1, glutamic-oxaloacetic transaminase 1; GPT, glutamic-pyruvic transaminase; GSK3B, glycogen synthase kinase 3 beta; GTT, glucose-tolerance test; HFD, high fat diet; HFHC, high-fat and high-cholesterol; HOMA-IR, homeostasis model assessment of insulin resistance; IKBKB, inhibitor of nuclear factor kappa B kinase subunit beta; INSR, insulin receptor; ITT, insulin-tolerance test; LDH, lactate dehydrogenase; STK11, serine/threonine kinase 11; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; MTORC1, MTOR complex 1; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; ND, normal diet; NFKB, nuclear factor kappa B; PA, palmitic acid; PSR, picrosirius red; RRAG, Ras related GTP binding; RPTOR, regulatory associated protein of MTOR complex 1; RPS6, ribosomal protein S6; RPS6KB, ribosomal protein S6 kinase B; SMAD2, SMAD family member 2; SMAD3, SMAD family member 3; SQSTM1, sequestosome 1; TFEB, transcription factor EB; tfeb-HKO, hepatocyte-specific tfeb knockout; TSC2, TSC complex subunit 2.
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Affiliation(s)
- Meng Chen
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun, China
| | - Guowen Liu
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun, China
| | - Zhiyuan Fang
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun, China
| | - Wenwen Gao
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun, China
| | - Yuxiang Song
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun, China
| | - Lin Lei
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun, China
| | - Xiliang Du
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun, China
| | - Xinwei Li
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun, China
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Jiang J, Liu Y, Yang H, Ma Z, Liu W, Zhao M, Peng X, Qin X, Xia Y. Dietary fiber intake, genetic predisposition of gut microbiota, and the risk of metabolic dysfunction-associated steatotic liver disease. Food Res Int 2025; 211:116497. [PMID: 40356189 DOI: 10.1016/j.foodres.2025.116497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 04/16/2025] [Accepted: 04/16/2025] [Indexed: 05/15/2025]
Abstract
This study aimed to explore the association between dietary fiber intake and the risk of metabolic dysfunction-associated steatotic liver disease (MASLD), as well as liver fat content, while considering genetic predispositions of MASLD, gut microbial abundance, and butyrate levels. This study analyzed data from 190,276 participants in the UK Biobank. Dietary fiber intake was assessed using 24-h dietary recall. MASLD cases were diagnosed through hospital admission records and death registries, and liver fat content was measured via magnetic resonance imaging. The genetic predispositions of MASLD, gut microbial abundance, and butyrate levels were evaluated using single nucleotide polymorphisms. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95 % confidence intervals (CIs). Over a median follow-up of 10.49 years, 1423 MASLD cases were recorded. Elevated dietary fiber intake was associated with a reduced risk of MASLD (HR: 0.72; 95 % CI: 0.58, 0.90) and a lower level of liver fat content (β: -0.97; 95 % CI: -1.21, -0.73) (all P for trend <0.05). Restricted cubic spline analyses further confirmed the linear inverse associations between fiber intake and the risk of MASLD. Notably, the negative associations between dietary fiber intake and both MASLD and liver fat content were consistent across different genetic predispositions of gut microbial abundance and butyrate levels. Moreover, the inverse association between dietary fiber intake and liver fat was strengthened by high genetic susceptibility of MASLD and elevated body mass index (both P for interaction <0.05). Overall, increased dietary fiber consumption was associated with a lower MASLD risk and decreased liver fat content regardless of genetic predispositions of gut microbial abundance and butyrate levels.
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Affiliation(s)
- Jinguo Jiang
- School of Public Health, Shenyang Medical College, Shenyang, China; Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, China Medical University, Shenyang, Liaoning, China.
| | - Yang Liu
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, 38# Xueyuan Road, Haidian District, Beijing 100191, China.
| | - Honghao Yang
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, China Medical University, Shenyang, Liaoning, China; Liaoning Key Laboratory of Precision Medical Research on Major Chronic Disease, Liaoning Province, Shenyang, China.
| | - Zheng Ma
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, China Medical University, Shenyang, Liaoning, China; Liaoning Key Laboratory of Precision Medical Research on Major Chronic Disease, Liaoning Province, Shenyang, China.
| | - Wenqi Liu
- School of Public Health, Shenyang Medical College, Shenyang, China; Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, China Medical University, Shenyang, Liaoning, China.
| | - Maoxiang Zhao
- Interventional Center of Valvular Heart Disease, Beijing Anzhen Hospital, Capital Medical University, Beijing 100011, China.
| | - Xinyi Peng
- Hypertension Center, Fuwai Hospital, State Key Laboratory of Cardiovascular Disease of China, National Center for Cardiovascular Diseases of China, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China.
| | - Xueying Qin
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, 38# Xueyuan Road, Haidian District, Beijing 100191, China; Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education, China.
| | - Yang Xia
- School of Public Health, Shenyang Medical College, Shenyang, China; Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, China Medical University, Shenyang, Liaoning, China.
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Abdollahi S, Lotfi AS, Saravani R, Taheri H. An association study of SERPINA1 gene polymorphisms with the risk of metabolic dysfunction-associated steatotic liver disease In an Iranian population: A preliminary case-control study. Biochem Biophys Rep 2025; 42:101974. [PMID: 40176953 PMCID: PMC11964567 DOI: 10.1016/j.bbrep.2025.101974] [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: 11/06/2024] [Revised: 03/02/2025] [Accepted: 03/06/2025] [Indexed: 04/05/2025] Open
Abstract
Background Metabolic dysfunction-associated steatotic liver disease (MASLD) is a type of fat accumulation in the liver that can lead to cirrhosis and chronic liver disease. MASLD is recognized as the most frequent of liver-associated deaths worldwide. The SERPINA1 gene encodes a serine protease protein that plays a pivotal role in the pathogenesis of liver deficiencies. In this study, we aimed to evaluate the genetic association between rs6647 (M1), rs709932 (M2), and rs1303 (M3) variants in the SERPINA1 gene and the risk of MASLD in an Iranian population. Methods In this case-control study, 120 patients affected by MASLD and 120 healthy subjects participated. The Nephelometry system measured serum levels of α1-antitrypsin (A1AT). Biochemical tests were conducted to assess serum levels of blood parameters using commercially available kits. DNA extraction was performed using the salting-out method, followed by the amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) method for genotyping. Statistical analysis was performed by SPSS v16.0. Results The findings showed that the rs6647 G allele significantly increased the risk of MASLD. The G allele in codominant, dominant, and over-dominant models caused an increase in the risk of MASLD. Additionally, the rs709932 T allele was more frequent among patients compared to healthy subjects and significantly enhanced the risk of MASLD. The T allele in the codominant and recessive models indicated a high risk for MASLD in our population. The G allele of rs1303 caused an enhancement in the mean serum levels of A1AT in the MASLD group. Conclusions Our results show an association between SERPINA1 gene variants and the risk of MASLD. The rs6647 (M1) and rs709932 (M2) variants of the SERPINA1 gene increased the risk of disorder in our population.
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Affiliation(s)
- Samira Abdollahi
- Department of Clinical Biochemistry, Faculty of Medical Science, Tarbiat Modares University, Tehran, Iran
- Cellular and Molecular Research Center, Research Institute of Cellular and Molecular Sciences in Infectious Diseases, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Abbas Sahebghadam Lotfi
- Department of Clinical Biochemistry, Faculty of Medical Science, Tarbiat Modares University, Tehran, Iran
| | - Ramin Saravani
- Cellular and Molecular Research Center, Research Institute of Cellular and Molecular Sciences in Infectious Diseases, Zahedan University of Medical Sciences, Zahedan, Iran
- Department of Clinical Biochemistry, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Hamed Taheri
- Cellular and Molecular Research Center, Research Institute of Cellular and Molecular Sciences in Infectious Diseases, Zahedan University of Medical Sciences, Zahedan, Iran
- Department of Internal Medicine, Ali-Ibn-Abitaleb Hospital, Zahedan University of Medical Sciences, Zahedan, Iran
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Cooper O, Kim S. Growth Hormone Replacement in Craniopharyngioma: Analysis of the Hypopituitary Control and Complications Study (HypoCCS). J Endocr Soc 2025; 9:bvaf072. [PMID: 40370679 PMCID: PMC12075769 DOI: 10.1210/jendso/bvaf072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Indexed: 05/16/2025] Open
Abstract
Context Patients with adult-onset craniopharyngioma (CP) show metabolic dysfunction and panhypopituitarism. Growth hormone (GH) deficiency is often left unaddressed despite the benefits of GH replacement on body composition and lipoprotein metabolism in the general population. Objective The aim was to analyze data from Hypopituitary Control and Complications Study (HypoCCS), a global prospective surveillance study of adult GH replacement, and assess the impact of GH replacement on metabolic outcomes in adult-onset CP. Methods Primary outcome was a composite endpoint of adverse hepatic outcomes including metabolic dysfunction-associated steatotic liver disease; secondary outcomes included body composition, lipids, blood pressure, glycemic measures, mortality, bone density, and cardiovascular endpoints. Results In total, 592 patients with adult-onset CP were identified; 544 received GH for a median of 4.03 years (IQR 2.28-7.82). The 3972 patients with pituitary adenoma (3346 receiving GH) were analyzed for context. GH replacement did not impact hepatic outcomes in either cohort. In adult-onset CP, bone mineral content was significantly lower with GH replacement (estimated mean [est]: 324.90 g; 95% CI -574.49, -75.31; P = .034); lower waist-hip ratio and less dyslipidemia medication use were also seen. In pituitary adenomas, fasting blood glucose (est 6.45; 95% CI 3.24, 9.66; P < .001), diastolic blood pressure (est 1.44; 95% CI 0.45, 2.43; P = .005), and mean arterial pressure (est 1.20; 95% CI 0.14, 2.26; P = .027) were significantly higher. Conclusion GH led to decreased waist-hip ratio and lipid medication use but adversely impacted bone mineral content in adult-onset CP. Prospective studies of GH replacement in adult-onset CP can further define the benefits on metabolic outcomes in these patients.
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Affiliation(s)
- Odelia Cooper
- Pituitary Center, Cedars-Sinai Medical Center, Los Angeles, CA, 90048 USA
| | - Sungjin Kim
- Biostatistics Research Center, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
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El-Kassas M, Villota-Rivas M, Alswat KA, AlNaamani KM, Yilmaz Y, Labidi A, Sanai FM, Awad A, Akroush MWI, Alqahtani SA, Elbadry M, Abdeen N, Henry L, Younossi ZM, Lazarus JV, Elzouki AN, Steatotic Liver Disease Study Foundation in Middle East and North Africa (SLMENA) Collaborators. Metabolic Dysfunction-Associated Steatotic Liver Disease in the MENA Region: Setting a Research and Action Priority Agenda. Liver Int 2025; 45:e70108. [PMID: 40411196 DOI: 10.1111/liv.70108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Collaborators] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2024] [Accepted: 04/11/2025] [Indexed: 05/26/2025]
Abstract
BACKGROUND & AIMS Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing health challenge, particularly in Middle East and North Africa (MENA) countries. This study aimed to establish a consensus-driven research and action agenda to address MASLD within the MENA region. METHODS Following a global MASLD research and action agenda setting study, over two Delphi rounds (Rs), MENA region experts (R1 n = 112, R2 n = 104) indicated their level of agreement with and provided feedback on MASLD research and action priorities via Qualtrics XM. In R2, panellists also ranked the priorities, which were categorised across six domains: (1) the human and economic burden, (2) defining and implementing care models, (3) disease management, (4) education and awareness, (5) patient and community perspectives, and (6) leadership and policies for the MASLD public health agenda. RESULTS The consensus-built MASLD research and action priority agenda for the MENA region comprises 52 priorities. Combined agreement (i.e., 'agree' + 'somewhat agree') increased from 97.6% and 98.1% in R1 to 98.2% and 98.5% in R2 with the research (n = 30) and action (n = 22) priorities, respectively. The highest ranked research priorities included developing regional MASLD databases and validating non-invasive diagnostic tools. The highest ranked action priorities included taking steps to enhance the adoption of lifestyle interventions among people living with MASLD and improving disease knowledge among healthcare providers. CONCLUSIONS This region-specific agenda can help to guide research and optimise clinical practice, thereby improving the understanding, prevention, and management of MASLD, enhancing health outcomes and reducing its burden within the MENA region.
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Affiliation(s)
- Mohamed El-Kassas
- Endemic Medicine Department, Faculty of Medicine, Helwan University, Cairo, Egypt
- Steatotic Liver Disease Study Foundation in Middle East and North Africa (SLMENA), Cairo, Egypt
- The Global NASH/MASH Council, Washington, DC, USA
| | | | - Khalid A Alswat
- Steatotic Liver Disease Study Foundation in Middle East and North Africa (SLMENA), Cairo, Egypt
- The Global NASH/MASH Council, Washington, DC, USA
- Liver Disease Research Center, Department of Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Khalid M AlNaamani
- Steatotic Liver Disease Study Foundation in Middle East and North Africa (SLMENA), Cairo, Egypt
- The Global NASH/MASH Council, Washington, DC, USA
- Division of Gastroenterology and Hepatology, Department of Medicine, The Medical City for Military and Security Services, Muscat, Oman
| | - Yusuf Yilmaz
- Steatotic Liver Disease Study Foundation in Middle East and North Africa (SLMENA), Cairo, Egypt
- The Global NASH/MASH Council, Washington, DC, USA
- Department of Gastroenterology, School of Medicine, Recep Tayyip Erdoğan University, Rize, Turkey
| | - Asma Labidi
- Steatotic Liver Disease Study Foundation in Middle East and North Africa (SLMENA), Cairo, Egypt
- Department of Gastroenterology "A", Rabta Hospital, Tunis, Tunisia
| | - Faisal M Sanai
- Steatotic Liver Disease Study Foundation in Middle East and North Africa (SLMENA), Cairo, Egypt
- Department of Medicine, Gastroenterology Section, King Abdulaziz Medical City, King Abdullah International Medical Research Center, Ministry of National Guard-Health Affairs, Jeddah, Saudi Arabia
| | - Abeer Awad
- Internal Medicine Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Maisam W I Akroush
- Steatotic Liver Disease Study Foundation in Middle East and North Africa (SLMENA), Cairo, Egypt
- Digestive and Liver Disease Clinic, Private Sector, Faculty of Medicine, Jordan University, Amman, Jordan
| | - Saleh A Alqahtani
- The Global NASH/MASH Council, Washington, DC, USA
- Liver, Digestive, and Lifestyle Health Research Section, and Organ Transplant Center of Excellence, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Mohamed Elbadry
- Endemic Medicine Department, Faculty of Medicine, Helwan University, Cairo, Egypt
- Steatotic Liver Disease Study Foundation in Middle East and North Africa (SLMENA), Cairo, Egypt
| | - Nermeen Abdeen
- Tropical Medicine Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Linda Henry
- The Global NASH/MASH Council, Washington, DC, USA
- Beatty Liver and Obesity Research Program, Inova Health System, Falls Church, Virginia, USA
| | - Zobair M Younossi
- The Global NASH/MASH Council, Washington, DC, USA
- Beatty Liver and Obesity Research Program, Inova Health System, Falls Church, Virginia, USA
| | - Jeffrey V Lazarus
- Barcelona Institute for Global Health (ISGlobal), Barcelona, Spain
- City University of New York Graduate School of Public Health and Health Policy (CUNY SPH), New York, New York, USA
- Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona (UB), Barcelona, Spain
| | - Abdel-Naser Elzouki
- Steatotic Liver Disease Study Foundation in Middle East and North Africa (SLMENA), Cairo, Egypt
- Department of Medicine, Hamad Medical Corporation and College of Medicine, Qatar University, Doha, Qatar
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Collaborators
Mohamed El-Kassas, Marcela Villota-Rivas, Khalid A Alswat, Khalid M AlNaamani, Yusuf Yilmaz, Asma Labidi, Faisal M Sanai, Abeer Awad, Maisam W I Akroush, Saleh A Alqahtani, Mohamed Elbadry, Nermeen Abdeen, Linda Henry, Zobair M Younossi, Jeffrey V Lazarus, Abdel-Naser Elzouki, Faisal A Abaalkhail, Haifa Abdesselem, Maheeba A Abdulla, Meral Akdogan Kayhan, Fatma E Akin, Said A Al-Busafi, Waleed K Al-Hamoudi, Abdulrahman A Al-Hussaini, Ahmad Al-Rifai, Khaldon K Al-Sarihin, Ali A Alali, Assaad Aldafter, Saad M Aldosari, Assim A Alfadda, Abdullah S Alghamdi, Mohammed Y Alghamdi, Ala K Ali, Mohammed Aljawad, Abdulrahman A Aljumah, Nasser M ALMasri, Maen AlMattooq, Dalal Alromaihi, Ashraf F Alsahafi, Ibrahim H Altraif, Nourdin Aqodad, Derya Ari, Cigdem Arikan, Zayed A Atef, Fehmi Ates, Ugur Avci, Mohamed M Awad, Myriam Ayari, Mohamed A Babatin, İbrahim H Bahçecioğlu, Yasemin H Balaban, Mustapha Benazzouz, Olfa Berriche, Sultan A Bin Tarif, Mona Boudabbous, Arif Mansur Cosar, Nabil Debzi, Coskun O Demirtas, Dinc Dincer, Suhail A Doi, Iman El Sherif, Hanaa M El-Karaksy, Mortada H F El-Shabrawi, Nour Elleuch, Medhat H Elsahhar, Nehal Hamdy Elsaid Awad, Aisha Elsharkawy, Reda Elwakil, Rym Ennaifer, Askin Erdogan, Gamal Esmat, Mamdouh A Gabr, Genco Gencdal, Lina J Haddad, Bilal H Hotayt, Mona H Ismail, Zahi Ismaili, Hani A Jawa, Saibe Merve Kazdal, Ayse Kefeli, Murat Kekilli, Caglayan Keklikkiran, Ashraf T Mahmoud, Mohammad Mawardi, Mohammed A Medhat, Engy A Mogahed, Mohsen S Mohamad, Heba Omar, Ashraf O Osman, Radia Osmane, Ozen Oz Gul, Tugce Ozlu Karahan, Yaser M Rayyan, Khadidja Saidani, İlker Şen, Abdelhamid A Serwah, Ala I Sharara, Mrabet Soumaya, Raja Tlili, Damla Tüfekçi, Ali Tumi, İnci Türkoğlu, Melin M Uygur, Imam Waked, Haythem Yacoub, Cesar G Yaghi, Suna Yapali, Yosra Zaimi, Doaa Z Zaky, Shahrazed Zemmouchi,
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Sun P, Song J, Liu Y, Li X, Zhang Y, Zhou Y, Gong W. Investigating the Mechanisms of Lycii fructus in Treating Nonalcoholic Fatty Liver Disease and Diabetes Comorbidity Through Network Pharmacology and Molecular Dynamics. Food Sci Nutr 2025; 13:e70256. [PMID: 40433113 PMCID: PMC12106045 DOI: 10.1002/fsn3.70256] [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: 09/22/2024] [Revised: 02/27/2025] [Accepted: 04/25/2025] [Indexed: 05/29/2025] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) and diabetes mellitus (DM) are prevalent metabolic disorders that frequently coexist, yet their shared molecular mechanisms remain poorly understood, and current therapies often yield suboptimal outcomes. Lycium barbarum L. (Lycii fructus, LF), a traditional medicinal herb, has demonstrated clinical efficacy in treating both conditions, but its mechanism of action in comorbidity management remains unclear. Active LF compounds were identified via the TCMSP database, with potential targets predicted using Swiss Target Prediction and PharmMapper. Disease-associated proteins for NAFLD and DM were curated from OMIM, GeneCards, DisGeNET, UniProt, DrugBank, and TTD. A protein-protein interaction (PPI) network was constructed from these targets, and GO and KEGG pathway analyses were performed using the DAVID platform. Key targets were further refined through network module analysis via Metascape. Drug-likeness of bioactive compounds was assessed using SwissADME and ADMETlab 2.0. Molecular docking and dynamics simulations validated interactions between core targets and LF compounds. Mendelian randomization (MR) analysis tested causal relationships between core genes and disease phenotypes. We identified 58 shared therapeutic targets for NAFLD-DM comorbidity, including HSP90AA1, ESR1, MMP9, EGFR, AKT1, and CASP3. GO analysis implicated LF in blood pressure regulation and glucose-stimulated insulin secretion. KEGG pathways highlighted modulation of MAPK, PI3K-Akt, FoxO, and mTOR signaling. 24-methylenelanost-8-enol and cryptoxanthin monoepoxide emerged as core bioactive compounds with favorable drug-likeness. Molecular docking confirmed strong binding of 24-methylenelanost-8-enol to HSP90AA1 and cryptoxanthin monoepoxide to MMP9, further supported by dynamics simulations. MR analysis revealed a significant causal role for CASP3 in both NAFLD and DM, aligning with network pharmacology predictions. LF's therapeutic effects on NAFLD-DM comorbidity likely arise from terpenoid and cryptoxanthin mediated modulation of apoptosis and inflammation pathway. This study identifies shared molecular networks, proposes candidate mechanisms for LF's efficacy, and provides a framework for targeting multifactorial metabolic diseases.
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Affiliation(s)
- Peng Sun
- Science and Technology CenterNingxia Medical UniversityYinchuanChina
- Ningxia Hui Autonomous Region Institute of Medical SciencesYinchuanChina
- Public Health SchoolNingxia Medical UniversityYinchuanChina
| | - Jiahui Song
- Science and Technology CenterNingxia Medical UniversityYinchuanChina
- Ningxia Hui Autonomous Region Institute of Medical SciencesYinchuanChina
| | - Yang Liu
- School of PharmacyNingxia Medical UniversityYinchuanChina
| | - Xiujing Li
- School of PharmacyNingxia Medical UniversityYinchuanChina
| | - Yiming Zhang
- School of PharmacyNingxia Medical UniversityYinchuanChina
| | - Yuxing Zhou
- School of PharmacyNingxia Medical UniversityYinchuanChina
| | - Wei Gong
- Public Health SchoolNingxia Medical UniversityYinchuanChina
- Key Laboratory of Environmental Factors and Chronic Disease ControlNingxia Medical UniversityYinchuanChina
- School of Medical Information and EngineeringNingxia Medical UniversityYinchuanChina
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20
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Li R, Wang T, Luo H, Fan Y, Guan Y, Tian Y. Causal effects and mediating pathways of metabolic dysfunction-associated fatty liver disease on novel subtypes of adult-onset diabetes: A two-step Mendelian randomization study. Nutr Metab Cardiovasc Dis 2025; 35:103976. [PMID: 40180825 DOI: 10.1016/j.numecd.2025.103976] [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: 01/07/2025] [Revised: 03/01/2025] [Accepted: 03/05/2025] [Indexed: 04/05/2025]
Abstract
BACKGROUND AND AIM Based on an in-depth understanding of diabetes heterogeneity, five novel subtypes of adult-onset diabetes have been identified. This study investigates the differential impact of metabolic dysfunction-associated fatty liver disease (MAFLD) on these subtypes using a Mendelian randomization (MR) approach, while also exploring modifiable mediating factors. METHODS AND RESULTS Genetic variants associated with MAFLD were selected at the genome-wide significance threshold (P < 5 × 10-8), with 16 variants used to assess causal associations with the risk of severe autoimmune diabetes (SAID), mild obesity-related diabetes (MOD), severe insulin-resistant diabetes (SIRD), severe insulin-deficient diabetes (SIDD), and mild age-related diabetes (MARD). Two-step MR was used to estimate total, direct, and mediated effects, analyzing 55 potential mediators across five domains. The primary method used was inverse variance weighting (IVW) along with a series of sensitivity analyses to ensure robustness of the results. Genetically predicted MAFLD was significantly associated with increased risk of MARD (OR = 1.171, 95 % CI 1.091-1.256), SIDD (OR = 1.158, 95 % CI 1.056-1.270), and SIRD (OR = 1.267, 95 % CI 1.119-1.434), with suggestive evidence for SAID (OR = 1.161, 95 % CI 1.016-1.327), but no association with MOD. Among all subtypes, waist-to-hip ratio adjusted for BMI (WHRadjBMI) was a common mediator, with liver fat, alanine aminotransferase (ALT), gamma-glutamyl transferase, fasting insulin (FI), and BMI mediating at least three subtypes. Liver fat accounted for the largest proportion of mediation (43.63 %-73.09 %), followed by ALT (8.99 %-17.93 %) and FI (6.81 %-13.04 %). CONCLUSION This study underscores the causal relationship between MAFLD and specific diabetes subtypes, highlighting the importance of integrated management of liver lipid metabolism, abdominal obesity, and blood glucose regulation. These findings support personalized intervention strategies.
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Affiliation(s)
- Rongrong Li
- Nursing Department, Tongii Hospital, Tongii Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China
| | - Ting Wang
- Nursing Department, Tongii Hospital, Tongii Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China
| | - Hongping Luo
- Nursing Department, Tongii Hospital, Tongii Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China
| | - Yawei Fan
- Nursing Department, Tongii Hospital, Tongii Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China
| | - Yan Guan
- Nursing Department, Tongii Hospital, Tongii Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China.
| | - Ye Tian
- Nursing Department, Tongii Hospital, Tongii Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China.
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India-Aldana S, Midya V, Betanzos-Robledo L, Yao M, Alcalá C, Andra SS, Arora M, Calafat AM, Chu J, Deierlein A, Estrada-Gutierrez G, Jagani R, Just AC, Kloog I, Landero J, Oulhote Y, Walker RW, Yelamanchili S, Baccarelli AA, Wright RO, Téllez Rojo MM, Colicino E, Cantoral A, Valvi D. Impact of metabolism-disrupting chemicals and folic acid supplementation on liver injury and steatosis in mother-child pairs. J Hepatol 2025; 82:956-966. [PMID: 39674324 DOI: 10.1016/j.jhep.2024.11.050] [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: 06/12/2024] [Revised: 11/20/2024] [Accepted: 11/26/2024] [Indexed: 12/16/2024]
Abstract
BACKGROUND & AIMS Scarce knowledge about the impact of metabolism-disrupting chemicals (MDCs) on steatotic liver disease limits opportunities for intervention. We evaluated pregnancy MDC-mixture associations with liver outcomes, and effect modification by folic acid (FA) supplementation in mother-child pairs. METHODS We studied ∼200 mother-child pairs from the Mexican PROGRESS cohort, with 43 MDCs measured during pregnancy (estimated air pollutants, blood/urine metals or metalloids, urine high- and low-molecular-weight phthalate [HMWPs, LMWPs] and organophosphate-pesticide metabolites), and serum liver enzymes (ALT, AST) at ∼9 years post-parturition. Outcomes included elevated liver enzymes in children and established clinical scores for steatosis and fibrosis in mothers (i.e. , AST ALT, FLI, HSI, FIB-4). Bayesian-weighted quantile sum regression assessed MDC-mixture associations with liver outcomes. We further examined chemical-chemical interactions and effect modification by self-reported FA supplementation. RESULTS In children, many MDC-mixtures were associated with liver injury. Per quartile HMWP-mixture increase, ALT increased by 10.1% (95% CI 1.67%, 19.4%) and AST by 5.27% (95% CI 0.80%, 10.1%). LMWP-mixtures and air pollutant-mixtures were associated with higher AST and ALT, respectively. Air pollutant and non-essential metal/element associations with liver enzymes were attenuated by maternal cobalt blood concentrations (p-interactions <0.05). In mothers, only the LMWP-mixture was associated with odds for steatosis (odds ratio = 1.53, 95% CI 1.01-2.28 for HSI >36, and odds ratio 1.62, 95% CI 1.05-2.49 for AST:ALT <1). In mothers and children, most associations were attenuated (null) at FA supplementation ≥600 μg/day (p-interactions <0.05). CONCLUSIONS Pregnancy MDC exposures may increase risk of liver injury and steatosis, particularly in children. Adequate FA supplementation and maternal cobalt levels may attenuate these associations. IMPACT AND IMPLICATIONS The effects of environmental chemical exposures on steatotic liver diseases are not well understood. In a parallel investigation of mothers and children, we found that pregnancy exposures to metabolism-disrupting chemicals may increase the risk of liver injury and steatosis, especially in the child, and that these associations could be attenuated by higher folic acid and/or cobalt levels. These findings can inform policies to decrease environmental chemical pollution and contribute to the design of clinical interventions addressing the metabolic dysfunction-associated steatotic liver disease epidemic.
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Affiliation(s)
- Sandra India-Aldana
- Department of Environmental Medicine and Climate Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Vishal Midya
- Department of Environmental Medicine and Climate Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Larissa Betanzos-Robledo
- Center for Nutrition and Health Research, National Institute of Public Health, Cuernavaca, Morelos, Mexico
| | - Meizhen Yao
- Department of Environmental Medicine and Climate Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Cecilia Alcalá
- Department of Environmental Medicine and Climate Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Syam S Andra
- Department of Environmental Medicine and Climate Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Manish Arora
- Department of Environmental Medicine and Climate Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Antonia M Calafat
- Division of Laboratory Sciences, National Center for Environmental Health, Centers for Disease Control and Prevention (CDC), Atlanta, GA, USA
| | - Jaime Chu
- Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Andrea Deierlein
- New York University School of Global Public Health, New York, NY, USA
| | | | - Ravikumar Jagani
- Department of Environmental Medicine and Climate Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Allan C Just
- Department of Epidemiology, School of Public Health, Brown University, Providence, RI, USA
| | - Itai Kloog
- Department of Environmental Medicine and Climate Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Julio Landero
- Department of Environmental Medicine and Climate Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Youssef Oulhote
- Department of Environmental Medicine and Climate Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Ryan W Walker
- Department of Environmental Medicine and Climate Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Shirisha Yelamanchili
- Department of Environmental Medicine and Climate Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | | | - Robert O Wright
- Department of Environmental Medicine and Climate Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Martha María Téllez Rojo
- Center for Nutrition and Health Research, National Institute of Public Health, Cuernavaca, Morelos, Mexico
| | - Elena Colicino
- Department of Environmental Medicine and Climate Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | | | - Damaskini Valvi
- Department of Environmental Medicine and Climate Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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22
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Xue Q, Chen H. Association of blood manganese levels with non-alcoholic fatty liver disease in NHANES 2017-2020: A retrospective cross-sectional study. Metabol Open 2025; 26:100358. [PMID: 40224537 PMCID: PMC11986999 DOI: 10.1016/j.metop.2025.100358] [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: 02/06/2025] [Revised: 03/16/2025] [Accepted: 03/17/2025] [Indexed: 04/15/2025] Open
Abstract
Objective This study investigates the link between blood manganese (Mn) levels and non-alcoholic fatty liver disease (NAFLD) in a U.S. adult population. Background The role of manganese in NAFLD remains poorly understood. However, the NHANES database offers valuable data on blood manganese levels and metabolic status for 6278 subjects in the United States, facilitating the study of this relationship. Methods To investigate the relationship between blood manganese (Mn) levels and NAFLD, we conducted a t-test to compare Mn levels between participants with and without NAFLD. Participants were categorized into quartiles based on their blood Mn levels. We then employed multiple logistic regression analysis and sensitivity analyses to further examine the Mn-NAFLD relationship. Results The NAFLD group had a significantly higher blood manganese level (10.0 ± 3.7 μg/L, P < 0.05) than the control group. Stratifying 6278 subjects by blood manganese quartiles showed increased NAFLD odds in higher quartiles (Q2-Q4) vs. Q1 (ORs: 1.49, 1.37, 1.49). The Mn-NAFLD relationship followed an inverted L-shaped curve, peaking at 8.52 μg/L. Conclusions Elevated levels of manganese in the blood have been shown to be associated with an increase in the risk of NAFLD, and blood manganese values can be utilized as a marker for assessing NAFLD.
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Affiliation(s)
- Qian Xue
- Department of Hepatobiliary Surgery, People's Hospital of Leshan, Sichuan, China
| | - Hongju Chen
- Department of Gynecology, Leshan Hospital of Traditional Chinese Medicine, Sichuan, China
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Wu Y, Dong P, Wu Q, Zhang Y, Xu G, Pan C, Tong H. Insights into Clinical Trials for Drugs Targeting MASLD: Progress, Challenges, and Future Directions. Clin Pharmacol Ther 2025; 117:1614-1626. [PMID: 39953659 DOI: 10.1002/cpt.3606] [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: 11/04/2024] [Accepted: 01/29/2025] [Indexed: 02/17/2025]
Abstract
The transition in terminology from fatty liver disease to metabolic dysfunction-associated steatotic liver disease (MASLD) marks a considerable evolution in diagnostic standards. This new definition focuses on liver fat accumulation in the context of overweight/obesity, type 2 diabetes, or metabolic dysfunction, without requiring the exclusion of other concurrent liver diseases. The new definition also provides clear guidelines for defining alcohol consumption in relation to the disease. MASLD is currently acknowledged as the most widespread liver disorder globally, affecting ~25% of the population. Despite the extensive array of clinical trials conducted in recent years, the number of approved treatments for metabolic dysfunction-associated fatty liver disease is very limited. In the review critically evaluates the results of clinical trials of related drugs and assesses the future directions for drug development trials. The renaming of MASLD presents new challenges and opportunities for the design of clinical trials and the selection of target populations for drug development.
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Affiliation(s)
- Yu Wu
- College of Life and Environmental Science, Wenzhou University, Wenzhou, China
| | - Pu Dong
- Department of Infectious Diseases, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Qifang Wu
- College of Life and Environmental Science, Wenzhou University, Wenzhou, China
| | - Ya Zhang
- Hepatology Diagnosis and Treatment Center & Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Gang Xu
- Department of Laboratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Chenwei Pan
- Department of Infectious Diseases, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
- Wenzhou Key Laboratory of Precision General Practice and Health Management, Wenzhou, China
| | - Haibin Tong
- College of Life and Environmental Science, Wenzhou University, Wenzhou, China
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24
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Garcia-Morena D, Fernandez-Cantos MV, Escalera SL, Lok J, Iannone V, Cancellieri P, Maathuis W, Panagiotou G, Aranzamendi C, Aidy SE, Kolehmainen M, El-Nezami H, Wellejus A, Kuipers OP. In Vitro Influence of Specific Bacteroidales Strains on Gut and Liver Health Related to Metabolic Dysfunction-Associated Fatty Liver Disease. Probiotics Antimicrob Proteins 2025; 17:1498-1512. [PMID: 38319537 PMCID: PMC12055940 DOI: 10.1007/s12602-024-10219-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/17/2024] [Indexed: 02/07/2024]
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) has become a major health risk and a serious worldwide issue. MAFLD typically arises from aberrant lipid metabolism, insulin resistance, oxidative stress, and inflammation. However, subjacent causes are multifactorial. The gut has been proposed as a major factor in health and disease, and over the last decade, bacterial strains with potentially beneficial effects on the host have been identified. In vitro cell models have been commonly used as an early step before in vivo drug assessment and can confer complementary advantages in gut and liver health research. In this study, several selected strains of the order Bacteroidales were used in a three-cell line in vitro analysis (HT-29, Caco-2, and HepG2 cell lines) to investigate their potential as new-generation probiotics and microbiota therapeutics. Antimicrobial activity, a potentially useful trait, was studied, and the results showed that Bacteroidales can be a source of either wide- or narrow-spectrum antimicrobials targeting other closely related strains. Moreover, Bacteroides sp. 4_1_36 induced a significant decrease in gut permeability, as evidenced by the high TEER values in the Caco-2 monolayer assay, as well as a reduction in free fatty acid accumulation and improved fatty acid clearance in a steatosis HepG2 model. These results suggest that Bacteroidales may spearhead the next generation of probiotics to prevent or diminish MAFLD.
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Affiliation(s)
- Diego Garcia-Morena
- Department of Molecular Genetics, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Nijenborgh 7, 9747 AG, Groningen, The Netherlands
| | - Maria Victoria Fernandez-Cantos
- Department of Molecular Genetics, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Nijenborgh 7, 9747 AG, Groningen, The Netherlands
| | - Silvia Lopez Escalera
- Chr. Hansen A/S, Bøge Allé 10-12, 2970, Hørsholm, Denmark
- Friedrich-Schiller Universität Jena, Fakultät für Biowissenschaften, 18K, 07743, Bachstraβe, Germany
| | - Johnson Lok
- School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70200, Kuopio, Finland
| | - Valeria Iannone
- School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70200, Kuopio, Finland
| | - Pierluca Cancellieri
- Department of Molecular Genetics, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Nijenborgh 7, 9747 AG, Groningen, The Netherlands
| | - Willem Maathuis
- Department of Molecular Genetics, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Nijenborgh 7, 9747 AG, Groningen, The Netherlands
| | - Gianni Panagiotou
- Department of Microbiome Dynamics, Leibniz Institute for Natural Product Research and Infection Biology (Leibniz-HKI), 07745, Jena, Germany
- Department of Medicine and State Key Laboratory of Pharmaceutical Biotechnology, University of Hong Kong, Hong Kong, China
- Faculty of Biological Sciences, Friedrich Schiller University, 07745, Jena, Germany
| | - Carmen Aranzamendi
- Groningen Biomolecular Sciences and Biotechnology Institute, Host-Microbe Metabolic Interactions, University of Groningen, Nijenborgh 7, 9747 AG, Groningen, the Netherlands
| | - Sahar El Aidy
- Groningen Biomolecular Sciences and Biotechnology Institute, Host-Microbe Metabolic Interactions, University of Groningen, Nijenborgh 7, 9747 AG, Groningen, the Netherlands
| | - Marjukka Kolehmainen
- School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70200, Kuopio, Finland
| | - Hani El-Nezami
- Molecular and Cell Biology Division, School of Biological Sciences, University of Hong Kong, Pok Fu Lam, Hong Kong SAR
| | - Anja Wellejus
- Chr. Hansen A/S, Bøge Allé 10-12, 2970, Hørsholm, Denmark
| | - Oscar P Kuipers
- Department of Molecular Genetics, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Nijenborgh 7, 9747 AG, Groningen, The Netherlands.
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25
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Cheng WT, Pei SY, Wu J, Wang YJ, Yang YW, Xiao MF, Chen J, Wang YY, Wu L, Huang ZB. Cannabinoid-2 receptor depletion promotes non-alcoholic fatty liver disease in mice via disturbing gut microbiota and tryptophan metabolism. Acta Pharmacol Sin 2025; 46:1676-1691. [PMID: 39979552 PMCID: PMC12098919 DOI: 10.1038/s41401-025-01495-w] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Accepted: 01/21/2025] [Indexed: 02/22/2025]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. NAFLD encompasses a spectrum of liver damage starting with liver steatosis and lipid disorders presented as the hallmark. Cannabinoid-2 receptor (CB2R) is the receptor of endocannabinoids mainly expressed in immune cells. Our preliminary study revealed the preventative role of CB2R in liver injury related to lipid metabolism. In this study, we aimed to explore the role of CB2R in NAFLD and the underlying mechanism related to microbial community. High-fat diet-induced NAFLD model was established in mice. We found that hepatic CB2R expression was significantly reduced in NAFLD mice and CB2R-/- mice fed with normal chow. Interestingly, cohousing with or transplanted with microbiota from WT mice, or treatment with an antibiotic cocktail ameliorated the NAFLD phenotype of CB2R-/- mice. The gut dysbiosis in CB2R-/- mice including increased Actinobacteriota and decreased Bacteroidota was similar to that of NAFLD patients and NAFLD mice. Microbial functional analysis and metabolomics profiling revealed obviously disturbed tryptophan metabolism in NAFLD patients and NAFLD mice, which were also seen in CB2R-/- mice. Correlation network showed that the disordered tryptophan metabolites such as indolelactic acid (ILA) and xanthurenic acid in CB2R-/- mice were mediated by gut dysbiosis and related to NAFLD severity indicators. In vitro and in vivo validation experiments showed that the enriched tryptophan metabolites ILA aggravated NAFLD phenotypes. These results demonstrate the involvement of CB2R in NAFLD, which is related to gut microbiota-mediated tryptophan metabolites. Our findings highlight CB2R and the associated microbes and tryptophan metabolites as promising targets for the treatment of NAFLD.
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MESH Headings
- Animals
- Non-alcoholic Fatty Liver Disease/metabolism
- Non-alcoholic Fatty Liver Disease/microbiology
- Non-alcoholic Fatty Liver Disease/pathology
- Gastrointestinal Microbiome/physiology
- Receptor, Cannabinoid, CB2/genetics
- Receptor, Cannabinoid, CB2/metabolism
- Receptor, Cannabinoid, CB2/deficiency
- Tryptophan/metabolism
- Mice, Inbred C57BL
- Male
- Mice
- Mice, Knockout
- Diet, High-Fat/adverse effects
- Humans
- Disease Models, Animal
- Dysbiosis/metabolism
- Liver/metabolism
- Liver/pathology
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Affiliation(s)
- Wei-Ting Cheng
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, 410008, China
- Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, 410008, China
- Nation Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Si-Ya Pei
- Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, 410008, China
- Nation Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
- Department of Blood Transfusion, Xiangya Hospital, Clinical Transfusion Research Center, Central South University, Changsha, 410007, China
| | - Jie Wu
- Shantou University Medical College, Shantou, 515041, China
| | - Yan-Jie Wang
- Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, 410008, China
- Nation Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
- Department of Blood Transfusion, Xiangya Hospital, Clinical Transfusion Research Center, Central South University, Changsha, 410007, China
| | - Yong-Wen Yang
- Department of Clinical Laboratory, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Mei-Fang Xiao
- Department of Health Management Center, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Jun Chen
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, 410008, China
- Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, 410008, China
- Nation Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Yuan-Yuan Wang
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Li Wu
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, 410008, China.
- Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, 410008, China.
- Nation Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China.
| | - Ze-Bing Huang
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, 410008, China.
- Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, 410008, China.
- Nation Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China.
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26
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Choullamy T, Kaadi L, Bezdikian A, Hachem S, Hachem K. Liver Fat Quantification With Ultrasound: The Influence of the Size of the Region of Interest on Attenuation Coefficient. Ultrasound Q 2025; 41:e00712. [PMID: 40173292 DOI: 10.1097/ruq.0000000000000712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/04/2025]
Abstract
ABSTRACT Noninvasive assessment of liver fat content is crucial due to the high global prevalence of nonalcoholic fatty liver disease. Algorithms based on ultrasound (US) attenuation coefficient (AC) for estimating liver fat content are commercially available, but a lack of consensus exists regarding the best estimation protocol. The aim of our study was to evaluate the influence of the size of the region of interest (ROI) on the US AC.A prospective study was conducted. An abdominal US was done for 86 outpatients. A sampling box was positioned within the liver parenchyma, approximately 2 cm beneath the liver capsule with a ROI, measuring about 2 × 4 cm and then 4 × 5 cm, precisely placed at the center of this sampling box. Five readings of the AC were captured, and the average of these measurements was employed to assess the severity of hepatic steatosisA statistically significant difference between AC with 2 different ROI sizes was shown (P < 0.001) with AC values with 2 × 4 cm ROI were higher than those obtained with 4 × 5 cm ROI (AC mean 0.668 VS 0.653). However, the agreement between AC values obtained with 2 different ROI sizes was excellent (correlation coefficient 0.941)An ROI size dependence is observed in the measurement of AC in the liver. A standardized acquisition protocol with a fixed size of the ROI needs to be developed to minimize differences in AC measurements and to assess changes in serial measurements reliably.
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Affiliation(s)
- Theresia Choullamy
- Medical Imaging Department, Hôtel-Dieu de France, Alfred Naccache Boulevard, Achrafieh, Beirut, Lebanon
| | - Lea Kaadi
- Medical Imaging Department, Hôtel-Dieu de France, Alfred Naccache Boulevard, Achrafieh, Beirut, Lebanon
| | - Aren Bezdikian
- Faculty of Medicine, University of Saint Joseph, Beirut, Lebanon
| | - Samir Hachem
- Faculty of Medicine, University of Saint Joseph, Beirut, Lebanon
| | - Kamal Hachem
- Medical Imaging Department, Hôtel-Dieu de France, Alfred Naccache Boulevard, Achrafieh, Beirut, Lebanon
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27
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Kushiro K, Hirono H, Ohkoshi S. Platelet-activating cytokines potentially associated with MASLD-induced liver injury significantly decreased following CPAP therapy: A translational study using a fatty liver mouse model. Sleep Med 2025; 130:15-24. [PMID: 40112616 DOI: 10.1016/j.sleep.2025.03.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 02/10/2025] [Accepted: 03/11/2025] [Indexed: 03/22/2025]
Abstract
BACKGROUND AND AIM Patients with obstructive sleep apnea (OSA) and metabolic dysfunction associated steatotic liver disease (MASLD) frequently overlap due to the high prevalence of obesity. This translational study aimed to identify cytokines linking these conditions, beginning with an analysis of fatty liver in mice. Serum cytokine levels upregulated in the fatty liver mice were subsequently examined in human OSA serum samples. METHODS Mice were fed a high-fat diet to induce fatty liver. Liver proteins were analyzed using cytokine arrays. Serum samples from seventy (70) OSA patients (with 20 non-MASLD and 50 MASLD, pre- and 6-month post-continuous positive airway pressure [CPAP] therapy) were analyzed for the cytokines identified in the mouse experiment using enzyme-linked immunosorbent assays. RESULTS Four platelet-activation chemokines/cytokines (CCL5/RANTES, P-selectin, CXCL4/PF4, and CXCL5/LIX) were upregulated in mice with fatty liver. While serum levels of these factors were not significantly higher in MASLD-OSA compared to non-MASLD-OSA patients, their levels significantly decreased 6 months after the initiation of CPAP therapy, along with a reduction in mean platelet volume. CPAP compliance was significantly associated with a reduction in CCL5 levels. Additionally, a decrease in ALT levels following 6 months of CPAP therapy was significantly associated with CPAP compliance in MASLD-OSA patients. CONCLUSIONS While platelet-activation cytokines were not directly implicated in liver injury in MASLD-OSA patients, they decreased with CPAP therapy. CPAP compliance may play a key role in ALT reduction in MASLD-OSA patients independently of body weight changes. CCL5/RANTES may be indirectly associated with liver injury in MASLD-OSA, potentially induced through intermittent hypoxia.
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Affiliation(s)
- Kosuke Kushiro
- Clinical Examination, Graduate School of Life Dentistry at Niigata, The Nippon Dental University, Niigata, Japan
| | - Haruka Hirono
- Clinical Examination, Graduate School of Life Dentistry at Niigata, The Nippon Dental University, Niigata, Japan
| | - Shogo Ohkoshi
- Clinical Examination, Graduate School of Life Dentistry at Niigata, The Nippon Dental University, Niigata, Japan.
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28
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Li L, Burgio MD, Fetzer DT, Ferraioli G, Lyshchik A, Meloni MF, Rafailidis V, Sidhu PS, Vilgrain V, Wilson SR, Zhou J. Contrast-Enhanced Ultrasound for Hepatocellular Carcinoma Diagnosis- AJR Expert Panel Narrative Review. AJR Am J Roentgenol 2025. [PMID: 40434167 DOI: 10.2214/ajr.25.32813] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/29/2025]
Abstract
Despite growing clinical use of contrast-enhanced ultrasound (CEUS), inconsistency remains in the modality's role in clinical pathways for hepatocellular carcinoma (HCC) diagnosis and management. This AJR Expert Panel Narrative Review provides practical insights on the use of CEUS for the diagnosis of HCC across populations, including individuals at high risk for HCC, individuals with metabolic dysfunction-associated steatotic liver disease, and remaining individuals not at high risk for HCC. Considerations addressed with respect to high-risk patients include CEUS diagnostic criteria for HCC, use of CEUS for differentiating HCC from non-HCC malignancy, use of CEUS for small (≤2 cm) lesions, use of CEUS for characterizing occult lesions on B-mode ultrasound, and use of CEUS for indeterminate lesions on CT or MRI. Representative literature addressing the use of CEUS for HCC diagnosis as well as gaps in knowledge requiring further investigation are highlighted. Throughout these discussions, the article distinguishes two broad types of ultrasound contrast agents used for liver imaging: pure blood-pool agents and a combined blood-pool and Kupffer-cell agent. Additional topics include the use of CEUS for treatment response assessment after nonradiation therapies and implications of artificial intelligence technologies. The article concludes with a series of consensus statements from the author panel.
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Affiliation(s)
- Lingling Li
- Department of Ultrasound, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong 510060, China
| | - Marco Dioguardi Burgio
- Université Paris Cité, Inserm, Centre de recherche sur l'inflammation, F-75018 Paris, France
- Department of Radiology, Hôpital Beaujon, AP-HP.Nord, 100 Boulevard du Général Leclerc, 92110 Clichy, France
| | - David T Fetzer
- Department of Radiology, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, E6-230-BF, Dallas, TX 75390-9316, USA
| | - Giovanna Ferraioli
- Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Campus della Salute c/o Policlinico San Matteo, Viale Golgi 19, Pavia, Italy
| | - Andrej Lyshchik
- Department of Radiology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Maria Franca Meloni
- Casa di Cura Villa Igea, Department of Interventional Ultrasound, Casa di Cura Igea, Milan, Italy
| | - Vasileios Rafailidis
- Department of Radiology, AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Paul S Sidhu
- Department of Imaging Sciences, School of Biomedical Engineering and Imaging Sciences, Faculty of Life Sciences and Medicine, King's College London, London UK; Department of Radiology, King's College Hospital NHS Foundation Trust, Denmark Hill, London UK
| | - Valerie Vilgrain
- Université Paris Cité, Inserm, Centre de recherche sur l'inflammation, F-75018 Paris, France
- Department of Radiology, Hôpital Beaujon, AP-HP.Nord, 100 Boulevard du Général Leclerc, 92110 Clichy, France
| | | | - Jianhua Zhou
- Department of Ultrasound, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong 510060, China
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29
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Chen JL, Duan SJ, Xie S, Yao SK. Diagnostic accuracy of noninvasive steatosis biomarkers with magnetic resonance imaging proton density fat fraction as gold standard. World J Radiol 2025; 17:104272. [DOI: 10.4329/wjr.v17.i5.104272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2024] [Revised: 03/16/2025] [Accepted: 04/11/2025] [Indexed: 05/26/2025] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. The accuracy of noninvasive biomarkers for detecting hepatic steatosis is still limited.
AIM To assess the diagnostic performance of noninvasive steatosis biomarkers in diagnosing NAFLD using magnetic resonance imaging proton density fat fraction (MRI-PDFF) as the gold standard.
METHODS A total of 131 suspected NAFLD patients (60% male, median age 36 years) undergoing MRI-PDFF were consecutively recruited from a tertiary hospital. Steatosis grades determined by MRI-PDFF were classified as none (< 5%), mild (5%-11%), moderate (11%-17%), and severe (≥ 17%). Six steatosis biomarkers were calculated according to clinical parameters and laboratory tests, including fatty liver index, hepatic steatosis index, ZJU index, Framingham steatosis index, triglycerides and glucose index, and visceral adiposity index. The accuracy of these biomarkers in detecting hepatic steatosis was evaluated using the area under the receiver operating characteristic curves (AUCs). The Youden index was used to determine the optimal cut-off for each biomarker. The linear trend analysis of each biomarker across the steatosis grades was conducted by Mantel-Haenszel χ2 test. Spearman's rank correlation assessed the relationship between steatosis biomarkers and MRI-PDFF.
RESULTS Steatosis grades based on MRI-PDFF prevalence were: None 27%, mild 40%, moderate 15% and severe 18%. Six steatosis biomarkers showed a linear trend across the steatosis grades and a significant positive correlation with MRI-PDFF. The six steatosis biomarkers demonstrated AUCs near 0.90 (range: 0.857-0.912, all P < 0.001) for diagnosing NAFLD by MRI-PDFF ≥ 5%. The optimal cut-offs showed sensitivity between 84.4%-91.7% and specificity between 71.4%-85.7%. The diagnostic performance of these biomarkers in detecting moderate-to-severe and severe steatosis was relatively weaker.
CONCLUSION These noninvasive steatosis biomarkers accurately diagnosed NAFLD and correlated well with MRI-PDFF for detecting NAFLD, but they did not effectively detect moderate or severe steatosis.
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Affiliation(s)
- Jia-Liang Chen
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Shao-Jie Duan
- Graduate School, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Sheng Xie
- Department of Radiology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Shu-Kun Yao
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
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30
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Xiao L, Zeng L, Wang J, Hong C, Zhang Z, Wu C, Cui H, Li Y, Li R, Liang S, Deng Q, Li W, Zou X, Ma P, Liu L. Development and Validation of Machine Learning-Based Marker for Early Detection and Prognosis Stratification of Nonalcoholic Fatty Liver Disease. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e10527. [PMID: 40432473 DOI: 10.1002/advs.202410527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 04/27/2025] [Indexed: 05/29/2025]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease and is considered the hepatic manifestation of metabolic syndrome, triggering out adverse outcomes. A stacked multimodal machine learning model is constructed and validated for early identification and prognosis stratification of NAFLD by integrating genetic and clinical data sourced from 36 490 UK Biobank and 9 007 Nanfang Hospital participants and extracted its probabilities as in-silico scores for NAFLD (ISNLD). The efficacy of ISNLD is evaluated for the early prediction of severe liver disease (SeLD) and analyzed its association with metabolism-related outcomes. The multimodal model performs satisfactorily in classifying individuals into low- and high-risk groups for NAFLD, achieving area under curves (AUCs) of 0.843, 0.840, and 0.872 within training, internal, and external test sets, respectively. Among high-risk group, ISNLD is significantly associated with intrahepatic and metabolism-related complications after lifestyle factors adjustment. Further, ISNLD demonstrates notable capability for early prediction of SeLD and further stratifies high-risk subjects into three risk subgroups of elevated risk for adverse outcomes. The findings emphasize the model's ability to integrate multimodal features to generate ISNLD, enabling early detection and prognostic prediction of NAFLD. This facilitates personalized stratification for NAFLD and metabolism-related outcomes based on digital non-invasive markers, enabling preventive interventions.
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Affiliation(s)
- Lushan Xiao
- Department of Health Management, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
- Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Lin Zeng
- Department of Health Management, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
- Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
- Department of Gastroenterology, Shenzhen Hospital, Southern Medical University, Shenzhen, 518133, China
| | - Jiaren Wang
- Department of Health Management, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
- Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Chang Hong
- Department of Health Management, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
- Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Ziyong Zhang
- Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Chengkai Wu
- School of Public Health, Southern Medical University, Guangzhou, 510515, China
- School of Health Management, Southern Medical University, Guangzhou, 510515, China
- Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Hao Cui
- Department of Health Management, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
- Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Yan Li
- Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Ruining Li
- Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Shengxing Liang
- School of Public Health, Southern Medical University, Guangzhou, 510515, China
- Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Qijie Deng
- Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Wenyuan Li
- Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Xuejing Zou
- Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Pengcheng Ma
- School of Public Health, Southern Medical University, Guangzhou, 510515, China
- School of Health Management, Southern Medical University, Guangzhou, 510515, China
- Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Li Liu
- Department of Health Management, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
- Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
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31
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Wang JP, Wang JY, Sun PQ, Wang XW, Yuan ZT, Cao Q, Pan SM, Jiang YY. Association between weight fluctuation and the risk of metabolic dysfunction-associated steatotic liver disease. World J Hepatol 2025; 17:103852. [DOI: 10.4254/wjh.v17.i5.103852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 03/24/2025] [Accepted: 04/24/2025] [Indexed: 05/27/2025] Open
Abstract
BACKGROUND The global incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) has increased in recent years. It has already been demonstrated that exercise and weight change are associated with the occurrence of MASLD; however, the association between weight fluctuation caused by different exercise intensities and the risk of MASLD remains to be studied.
AIM To investigate the impact of weight fluctuation and physical activity intensity on the risk of MASLD prevalence.
METHODS Data from the National Health and Nutrition Examination Survey database including five cycles from 2009 to 2018 were analyzed. The model included variables such as age, sex, and poverty income ratio. Weighted multivariate logistic regression was used to examine the influence of different weight fluctuation patterns within the two time intervals on the prevalence of MASLD. Nonparametric restricted cubic spline curves were used to analyze the non-linear relationship between net weight change and MASLD prevalence.
RESULTS Among 3183 MASLD cases, the risk of MASLD increased with age for individuals transitioning from non-obese to obese or maintaining obesity, with odds ratio (OR) changing from 8.91 (95%CI: 7.40–10.88) and 11.87 (95%CI: 9.65–14.60) at 10 years before baseline to 9.58 (95%CI: 8.08–11.37) and 12.51 (95%CI: 9.33-16.78) at 25 years. Stable obesity correlated with age-dependent MASLD prevalence escalation, whereas increased physical activity attenuated MASLD risk in this group, with an OR changing from 13.64 (95%CI: 10.59–17.57) to 6.42 (95%CI: 4.24–9.72). Further analysis of the net weight changes revealed a paradoxical risk elevation with intensified physical activity during different time periods.
CONCLUSION The risk of MASLD increases in individuals transitioning from non-obese to obese or maintaining obesity. High-intensity physical activity is beneficial for MASLD among individuals with stable obesity.
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Affiliation(s)
- Jin-Ping Wang
- Department of Gastroenterology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
| | - Jia-Yang Wang
- Department of Gastroenterology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
| | - Pei-Qi Sun
- Department of Gastroenterology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
| | - Xue-Wei Wang
- Department of Gastroenterology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
| | - Ze-Ting Yuan
- Department of Gastroenterology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
| | - Qin Cao
- Department of Gastroenterology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
| | - Shu-Ming Pan
- Department of Emergency, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
| | - Yuan-Ye Jiang
- Department of Gastroenterology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
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Wang J, He W, Cai X, Hu Z, Peng Y, Chen X, Yang P, Zeng X, Chen S, Wang D. Relative fat mass and risk of metabolic dysfunction associated steatotic liver disease and severe hepatic steatosis in U.S. adults: analysis of NHANES 2017-2020 data. BMC Gastroenterol 2025; 25:410. [PMID: 40426055 DOI: 10.1186/s12876-025-04006-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2025] [Accepted: 05/19/2025] [Indexed: 05/29/2025] Open
Abstract
BACKGROUND Relative fat mass (RFM) is a novel, easily calculated, and cost-effective index of fat content and distribution in the body, associated with the odds of developing various obesity-related diseases. However, its association with metabolic dysfunction associated steatotic liver disease (MASLD) and severe hepatic steatosis (SHS) is underexplored. This study aims to examine the relationship between RFM and the odds of having MASLD or SHS in the general adult population. METHODS This was a population-based cross-sectional study using data from the National Health and Nutrition Examination Survey (2017.01-2020.03). The aim of the statistical analysis was to examine the association between RFM and the prevalence of MASLD and SHS. Logistic regression was applied to explore this relationship. Nonlinear associations between RFM levels and MASLD or SHS prevalence were assessed using smoothed curve fitting and threshold effect models. Subgroup analyses were conducted to evaluate the consistency of this association across different population groups. RESULTS A total of 6699 participants were included in this study, of whom 2825 had MASLD and 1834 had SHS. After adjusting for confounders, significant positive associations were observed between RFM and the prevalence of MASLD and SHS (odds ratio [OR]: 1.22, 95% confidence interval [CI: ] 1.18-1.26 and OR: 1.26, 95% CI: 1.21-1.30). Smoothed curve fitting and threshold effect analysis showed a nonlinear relationship between RFM and the prevalence of MASLD and SHS, with thresholds of 41.96 for MASLD prevalence and 40.42 for SHS prevalence. When the subgroups were analyzed according to sex, age, race, education level, smoking status, household income, body mass index, hypertension, and diabetes, no significant interactions were found between RFM and most subgroups. CONCLUSIONS Our results demonstrated a positive nonlinear relationship between RFM and the prevalence of MASLD and SHS, with a threshold effect. Lower RFM levels are associated with lower odds of MASLD and SHS. These findings suggest that RFM may serve as a simple, cost-effective tool for identifying individuals at increased odds of NAFLD and SHS in the general population.
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Affiliation(s)
- Jianjun Wang
- Department of Hepatobiliary Surgery, School of Medicine, Mianyang Central Hospital, University of Electronic Science and Technology of China, Mianyang, 621000, China
- NHC Key Laboratory of Nuclear Technology Medical Transformation, School of Medicine, Mianyang Central Hospital, University of Electronic Science and Technology of China, Mianyang, 621000, China
| | - Wei He
- Department of Stomatology, School of Medicine, Mianyang Central Hospital, University of Electronic Science and Technology of China, Mianyang, 621000, China
| | - Xianfu Cai
- Department of Urology, School of Medicine, Mianyang Central Hospital, University of Electronic Science and Technology of China, Mianyang, 621000, China
| | - Zhaohui Hu
- Department of Hepatobiliary Surgery, School of Medicine, Mianyang Central Hospital, University of Electronic Science and Technology of China, Mianyang, 621000, China
| | - Yonghai Peng
- Department of Hepatobiliary Surgery, School of Medicine, Mianyang Central Hospital, University of Electronic Science and Technology of China, Mianyang, 621000, China
| | - Xi Chen
- Department of Hepatobiliary Surgery, School of Medicine, Mianyang Central Hospital, University of Electronic Science and Technology of China, Mianyang, 621000, China
| | - Pei Yang
- Department of Hepatobiliary Surgery, School of Medicine, Mianyang Central Hospital, University of Electronic Science and Technology of China, Mianyang, 621000, China
| | - Xintao Zeng
- Department of Hepatobiliary Surgery, School of Medicine, Mianyang Central Hospital, University of Electronic Science and Technology of China, Mianyang, 621000, China.
| | - Sirui Chen
- Department of Hepatobiliary Surgery, School of Medicine, Mianyang Central Hospital, University of Electronic Science and Technology of China, Mianyang, 621000, China.
| | - Decai Wang
- NHC Key Laboratory of Nuclear Technology Medical Transformation, School of Medicine, Mianyang Central Hospital, University of Electronic Science and Technology of China, Mianyang, 621000, China.
- Department of Urology, School of Medicine, Mianyang Central Hospital, University of Electronic Science and Technology of China, Mianyang, 621000, China.
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Shokri-Afra H, Yousefi Abdolmaleki E, Mousavi Sadr Jadidi ES, Oladi Z, Moradi-Sardareh H, Nabi Afjadi M, Ilbeigi D, Barmaki H. Nobiletin potentially reduce lipid accumulation by up-regulating the SIRT1-AMPK signaling pathway in HepG2 hepatocarcinoma cells. Mol Biol Rep 2025; 52:503. [PMID: 40413677 DOI: 10.1007/s11033-025-10587-z] [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: 11/09/2024] [Accepted: 05/09/2025] [Indexed: 05/27/2025]
Abstract
BACKGROUND The prevalence of nonalcoholic fatty liver disease (NAFLD) is rising at an alarming rate, making it a major global public health problem. The main pathophysiology of NAFLD is elevated de novo lipogenesis (DNL) in hepatocytes which leads to lipid accumulation. Because of their function in controlling DNL, sirtuin 1 (SIRT1) and AMP-activated protein kinase (AMPK) have been considered viable therapy targets for reduce lipid accumulation. METHODS AND RESULTS We examined the impact of the citrus flavonoid nobiletin (NOB) on the SIRT1-AMPK signaling pathway. This study involved incubating HepG2 cells with varying concentrations of NOB, measuring SIRT1 gene expression using qRT-PCR, assessing SIRT1 enzyme activity using a fluorometric assay, determining SIRT1 protein and AMPK phosphorylation levels by Western blotting, and measuring the lipid profile using semi- and quantitative assays. The results demonstrated that NOB significantly induced SIRT1 mRNA, protein expression, and activity similar to resveratrol (RSV) (as positive controls); additionally, NOB increased the phosphorylation of AMPK. EX-527 (negative control) significantly reversed the stimulatory effect of NOB on SIRT1 and AMPK. On the other hand, NOB decreased total lipid accumulation in cells exposed to oleic acid (OA) and reduced TG content to a normal level. However, the observed results on lipid profile were counteracted in the presence of EX-527. CONCLUSIONS NOB might be a new therapeutic approach for lipid accumulation management due to inducing the SIRT1-AMPK signaling pathway, however, it requires further investigations.
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Affiliation(s)
- Hajar Shokri-Afra
- Gut and Liver Research Center, Non-Communicable Diseases Institute, Mazandaran University of Medical Sciences, Sari, Iran
| | | | | | - Ziaeddin Oladi
- Gut and Liver Research Center, Non-Communicable Diseases Institute, Mazandaran University of Medical Sciences, Sari, Iran
| | - Hemen Moradi-Sardareh
- Director of Pasteur Medical Laboratory, Saqqez, Kurdistan, Iran
- BioMad As Company, Oslo, Norway
| | - Mohsen Nabi Afjadi
- Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Davod Ilbeigi
- Department of Clinical Biochemistry, School of Medicine, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran.
- Health Sciences Research Center, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran.
| | - Haleh Barmaki
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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Xiong KG, Lin TS, Lin QB, Kong JF, Ke KY. Impact of metabolic dysfunction-associated fatty liver disease on survival outcomes in patients undergoing radical resection for hepatitis B virus-related hepatocellular carcinoma. Sci Rep 2025; 15:18027. [PMID: 40410436 PMCID: PMC12102255 DOI: 10.1038/s41598-025-03244-9] [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] [Subscribe] [Scholar Register] [Received: 11/10/2024] [Accepted: 05/19/2025] [Indexed: 05/25/2025] Open
Abstract
The prevalence of concomitant metabolic dysfunction-associated fatty liver disease (MAFLD) in patients with hepatitis B virus-associated hepatocellular carcinoma (HBV-HCC) is increasing, though the relationship between MAFLD and HBV-HCC remains unclear. The aim of this study is to evaluate the clinical impact of MAFLD on survival outcomes in patients with HBV-HCC after radical resection. Patients with HBV-HCC who underwent radical resection consecutively from January 2015 to December 2020 were included. The retrospective analysis focused on the correlation between histologically confirmed concomitant MAFLD and clinical outcomes. Among the 843 patients with HBV-HCC who underwent radical resection, concomitant MAFLD was observed in 172 (20.4%) patients. In comparison to the non-MAFLD group, the MAFLD group did not have a significant impact on recurrence-free survival (RFS) or overall survival (OS) rates at 1-, 3-, and 5-years (all P > 0.05). However, subgroup analysis revealed significantly lower 1-, 3-, and 5-year rates of RFS and OS in the diabetic MAFLD group compared to the non-diabetic MAFLD group (all P < 0.05). Moreover, diabetic MAFLD was an independent risk factor associated with poorer OS after radical resection (HR, 1.444; 95% CI 1.082-2.331, P = 0.032). Concomitant diabetic MAFLD is associated with a poor prognosis after radical resection in patients with HBV-HCC.
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Affiliation(s)
- Ke-Gong Xiong
- Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, No. 312, Xihong Road, Gulou District, Fuzhou, 350025, China
| | - Tai-Shun Lin
- Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, No. 312, Xihong Road, Gulou District, Fuzhou, 350025, China
| | - Qing-Biao Lin
- Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, No. 312, Xihong Road, Gulou District, Fuzhou, 350025, China
| | - Jin-Feng Kong
- Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, No. 312, Xihong Road, Gulou District, Fuzhou, 350025, China.
| | - Kun-Yu Ke
- Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, No. 312, Xihong Road, Gulou District, Fuzhou, 350025, China.
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Zhang M, Yuan Y, Wang C, Huang Y, Fan M, Li X, Qin Z. Aggregate index of systemic inflammation tied to increased fatty liver disease risk: insights from NHANES data. BMC Gastroenterol 2025; 25:399. [PMID: 40410700 PMCID: PMC12101034 DOI: 10.1186/s12876-025-03998-6] [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: 02/26/2025] [Accepted: 05/15/2025] [Indexed: 05/25/2025] Open
Abstract
BACKGROUND Fatty liver disease (FLD), characterized by hepatic lipid accumulation, impairs quality of life and can progress to cirrhosis and hepatocellular carcinoma, imposing a healthcare burden. This study investigates the association between the aggregate index of systemic inflammation (AISI) and FLD prevalence, evaluating AISI's potential as an early biomarker for risk assessment. METHODS Data were obtained from the National Health and Nutrition Examination Survey (NHANES) database, which encompasses the years 2017 through 2020. Participants were chosen based on the availability of controlled attenuation parameter (CAP) scores derived from transient elastography (TE), a technique utilized for assessing liver steatosis. The formula employed to compute the AISI is as follows: AISI = N × P × M / L, where N, P, M, and L refer to neutrophils, platelets, monocytes, and lymphocytes, respectively. Additionally, demographic, socioeconomic, dietary, and health-related information was gathered. Logistic regression models were utilized to pinpoint risk factors associated with FLD, and a nomogram was created to forecast FLD risk. RESULTS Of the 3,961 participants, 2,377 (60.0%) were diagnosed with FLD based on a CAP score ≥ 248 dB/m. Elevated AISI was significantly associated with FLD (P = 0.021). Other significant risk factors included sex, age, BMI, race, marital status, hypertension, and diabetes. The nomogram demonstrated excellent discriminatory performance with an AUC of 0.814 (95% CI: 0.800, 0.827) and good calibration. CONCLUSION This study reveals a significant, independent association between elevated AISI and increased FLD risk in the U.S. population, even after adjusting for confounders. AISI demonstrated good discriminative performance for FLD, but its effect size suggests it should supplement, not replace, existing clinical risk assessment tools. AISI, a cost-effective biomarker, holds potential for enhancing FLD screening, particularly in resource-limited settings.
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Affiliation(s)
- Meng Zhang
- Guangxi International Zhuang Medicine Hospital (Affiliated International Zhuang Medicine Hospital, Guangxi University of Chinese Medicine), Nanning, 530200, China
| | - Yuan Yuan
- School of Public Health and Management, Guangxi University of Chinese Medicine, Nanning, 530200, China
| | - Chenglong Wang
- Guangxi International Zhuang Medicine Hospital (Affiliated International Zhuang Medicine Hospital, Guangxi University of Chinese Medicine), Nanning, 530200, China
| | - You Huang
- Institute of Chinese Medicine, Zhuang and Yao Medicine, Guangxi University of Chinese Medicine, Nanning, 530200, China
| | - Mingli Fan
- Institute of Chinese Medicine, Zhuang and Yao Medicine, Guangxi University of Chinese Medicine, Nanning, 530200, China
| | - Xiangling Li
- Institute of Chinese Medicine, Zhuang and Yao Medicine, Guangxi University of Chinese Medicine, Nanning, 530200, China.
| | - Zujie Qin
- Guangxi International Zhuang Medicine Hospital (Affiliated International Zhuang Medicine Hospital, Guangxi University of Chinese Medicine), Nanning, 530200, China.
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Salmanizadeh F, Sabzevari S, Shafieipour S, Zahedi MJ, Sarafinejad A. Challenges and needs in the management of non-alcoholic fatty liver disease from the perspective of gastroenterology and hepatology specialists: a qualitative study. BMC Gastroenterol 2025; 25:396. [PMID: 40405078 PMCID: PMC12096504 DOI: 10.1186/s12876-025-03921-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Accepted: 04/21/2025] [Indexed: 05/24/2025] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, and it poses a significant threat to public health. There is insufficient documented evidence about the problems and needs of patients and physicians in managing NAFLD. This study aimed to explore the challenges and needs in managing NAFLD from the perspective of gastroenterology and hepatology (GH) specialists. METHODS This qualitative study was conducted from January to September 2023. Fifteen Iranian GH specialists selected by purposive sampling. Data were collected through semi-structured interviews. The interviews were analyzed inductively using the Elo and Kyngas content analysis approach. The criteria proposed by Guba and Lincoln were used to ensure the study's validity. RESULTS The identified challenges were divided into thirteen main categories (34 subcategories and 117 primary codes), and the identified needs were divided into eight main categories (21 subcategories and 97 primary codes). The main categories of the challenges were chronic nature and time-consuming differential diagnosis, complex treatment process, defects in the patient management process, shortcomings of the healthcare system, the effect of unhealthy eating and cultural and social factors on the diet, incorrect attitude of patients, lack of knowledge and awareness of patients, lack of comprehensive treatment plans based on patients' conditions, defect in knowledge and awareness of physicians, inadequate cooperation of patients, defects in the process of recording and monitoring information and providing feedback, insufficient policies and plans in the prevention of NAFLD, and economic problems. The main categories of needs included developing a comprehensive treatment plan, updating physicians' knowledge and creating standard treatment protocols, changing attitudes and empowering patients, informing and educating patients, establishing multi-specialty clinics for NAFLD treatment, establishing peer support groups and facilitating communication, utilizing digital technology to track patient information and monitor their progress, and supportive, educational, prevention, and management policies in the treatment of NAFLD. CONCLUSIONS This study showed that managing NAFLD involves physical, psychological, nutritional, sports, economic, and social aspects and requires multidisciplinary clinical approaches, digital technologies, and supportive and educational policies. These findings have important implications that can help patients, physicians, and policymakers design better lifestyle prescriptions to manage NAFLD.
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Affiliation(s)
- Farzad Salmanizadeh
- Student Research Committee, Faculty of Management and Medical Information Science, Kerman University of Medical Sciences, Kerman, Iran
| | - Sakineh Sabzevari
- Nursing Research Center, Kerman University of Medical Sciences, Kerman, Iran
| | - Sara Shafieipour
- Gastroenterology and Hepatology Research Center, Institute of Basic and Clinical Physiology Science, Kerman University of medical Science, Kerman, Iran
| | - Mohammad Javad Zahedi
- Gastroenterology and Hepatology Research Center, Institute of Basic and Clinical Physiology Science, Kerman University of medical Science, Kerman, Iran
| | - Afshin Sarafinejad
- Clinical Informatics Research and Development Lab, Clinical Research Development Unit, Shafa Hospital, Kerman University of Medical Sciences, Kerman, Iran.
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Romualdo GR, Valente LC, Bacil GP, Riechelmann-Casarin L, da Fonseca ARB, Fornes MW, Barbisan LF. A diet-driven metabolic dysfunction-associated steatohepatitis (MASH) mouse model resembles the corresponding human disease. J Mol Histol 2025; 56:162. [PMID: 40392411 DOI: 10.1007/s10735-025-10449-9] [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: 02/28/2025] [Accepted: 05/03/2025] [Indexed: 05/22/2025]
Abstract
Most of the available preclinical Metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH) models fail to resemble metabolic comorbidities and liver fibrosis. To establish a standard MASLD/MASH model, we characterized some morphological, biochemical, and transcriptomic features in a Western diet-induced MASLD model in mice, depicting its similarities to the corresponding human disease. Male C57BL/6J mice received a hypercaloric diet containing sucrose, saturated fat, and cholesterol-rich chow, and high sugar solution for 24 weeks. This model featured a distinct MASH phenotype with obesity, impaired glucose metabolism, hypercholesterolemia, extensive macro and microvesicular, liver steatosis, and slight-to-moderate pericellular/perisinusoidal fibrosis, which was in keeping with the increased hepatic levels of IL-6 and TNF-α, and upregulation of 18 collagen subunit genes (as Col1a1, Col1a2, Col3a1, Col5a2, Col4a1, Col6a3, Col14a1, Col6a2, Col5a1), 34 cytokines or chemokines or related receptors-coding genes (as Il15, Cxcl9, Ccl22), 18 TNF-related genes (as Tnfaip8l3, Tnfrsf21, Tnfaip8, Tnfrfs12a) and 12 metalloproteinase/tissue inhibitors of metalloproteinases-related genes (as Mmp2, Mmp7). The downregulated genes were negative regulators of gluconeogenesis, insulin secretion, and lipid biosynthesis, most belonging to the major urinary protein (MUP) family. The computational analysis of human samples revealed a similarity between our bioassay and human steatohepatitis, with the upregulation of fibrosis- and inflammation-associated orthologs (COL1A1, COL1A2, COL3A1, COL5A2, COL4A1, COL6A3, COL14A1, COL6A2, COL5A1, TNFAIP8L3, TNFRSF21, TNFAIP8, TNFRFS12A, IL15, CXCL9, CCL22, MMP2, MMP7). Our mouse model may be applied as a standard MASH translational bioassay, providing valuable insights into the inflammatory/fibrosis axis of this chronic disease, from the pathogenesis to therapeutic intervention.
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Affiliation(s)
- Guilherme Ribeiro Romualdo
- Experimental Research Unit (UNIPEX), Botucatu Medical School, São Paulo State University (UNESP), Av. Prof. Mário Rubens Guimarães Montenegro, s/n -Rubião Jr, Botucatu, SP, 18618687, Brazil.
| | - Letícia C Valente
- Experimental Research Unit (UNIPEX), Botucatu Medical School, São Paulo State University (UNESP), Av. Prof. Mário Rubens Guimarães Montenegro, s/n -Rubião Jr, Botucatu, SP, 18618687, Brazil
- Department of Pathology, Botucatu Medical School, São Paulo State University (UNESP), Botucatu, SP, Brazil
| | - Gabriel P Bacil
- Department of Pathology, Botucatu Medical School, São Paulo State University (UNESP), Botucatu, SP, Brazil
| | - Luana Riechelmann-Casarin
- Experimental Research Unit (UNIPEX), Botucatu Medical School, São Paulo State University (UNESP), Av. Prof. Mário Rubens Guimarães Montenegro, s/n -Rubião Jr, Botucatu, SP, 18618687, Brazil
| | - Antônio R B da Fonseca
- Department of Pathology, Botucatu Medical School, São Paulo State University (UNESP), Botucatu, SP, Brazil
| | - Miguel W Fornes
- Institute of Histology and Embriology from Mendonza-IHEM, CONICET Mendonza, Universidad Nacional de Cuyo, Mendoza, Argentina
| | - Luís F Barbisan
- Department of Structural and Functional Biology, Biosciences Institute, São Paulo State University (UNESP), Botucatu, SP, Brazil.
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Shen H, Li H, Tang H. CCDC110 promotes the progression of hepatocellular carcinoma by activating the TGF-β/SMAD signaling pathway through targeted regulation of TGFBR1. Cancer Cell Int 2025; 25:183. [PMID: 40394630 PMCID: PMC12093845 DOI: 10.1186/s12935-025-03803-0] [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: 08/14/2024] [Accepted: 05/01/2025] [Indexed: 05/22/2025] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is recognized for its high growth rate, high degree of invasiveness, and tendency to spread, leading to a significant number of deaths. In the course of studying the transcriptome of HCC tissues, the protein coiled-coil domain-containing 110 (CCDC110) was identified. By employing tandem mass tag (TMT) quantitative proteomics, this research identified transforming growth factor beta receptor 1 (TGFBR1) as a potential target influenced by CCDC110. The purpose of this study was to examine the role of CCDC110 in the growth and invasion of HCC and to identify new potential targets for the treatment of HCC. METHODS In vitro and in vivo experiments were conducted to investigate the role and mechanism of CCDC110 in promoting the malignant behaviors of hepatocellular carcinoma through the regulation of TGFBR1. RESULTS We determined that the mRNA and protein levels of CCDC110 are elevated in hepatocellular carcinoma tissues and cell lines, which is correlated with a worse patient prognosis. CCDC110 enhances the proliferation of hepatocellular carcinoma cells, reduces their apoptosis, and increases their migration and invasion capabilities. In the cytoplasm, CCDC110 interacts with TGFBR1, enhancing stability of TGFBR1, promoting proliferation, and reducing the apoptosis, migration, and invasion of hepatocellular carcinoma cells through TGFBR1 both in vivo and in vitro. The CCDC110-TGFBR1 axis stimulates EMT, thereby enhancing the malignant biological behavior of hepatocellular carcinoma by activating the TGF-β/SMAD signaling pathway. The protein levels of CCDC110/TGFBR1 in hepatocellular carcinoma tissues are highly expressed and positively correlated. A combined analysis of CCDC110 and TGFBR1 provides improved guidance for the prognosis of patients with hepatocellular carcinoma. CONCLUSION CCDC110 is highly expressed in hepatocellular carcinoma tissues and cell lines, and the CCDC110-TGFBR1 axis facilitates EMT and the malignant biological behavior of hepatocellular carcinoma through the activation of the TGF-β/SMAD signaling pathway.
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Affiliation(s)
- Hao Shen
- Department of Thyroid Breast Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China.
| | - Haifeng Li
- Department of Hepatic-Biliary-Pancreatic Center, Zhongda Hospital, Medical School, Southeast University, Nanjing 210000, China
| | - Haodong Tang
- Department of Hepatic-Biliary-Pancreatic Center, Zhongda Hospital, Medical School, Southeast University, Nanjing 210000, China
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Ning M, Lu D, Teng B, Liang D, Ren PG. Comprehensive study of the murine MASH models' applicability by comparing human liver transcriptomes. Life Sci 2025; 376:123723. [PMID: 40404118 DOI: 10.1016/j.lfs.2025.123723] [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: 03/23/2025] [Revised: 04/29/2025] [Accepted: 05/15/2025] [Indexed: 05/24/2025]
Abstract
AIMS Multiple murine models, including high-fat diet (HFD), methionine-choline-deficient diet (MCD), choline-deficient, L-amino acid-defined high-fat diet (CDA-HFD), Western diet (WD), carbon tetrachloride (CCl₄) injection, and Gubra-Amylin diet (GAN), are widely used for mechanistic studies and therapeutic evaluation in MASH research. However, due to species-specific differences in metabolism, lifespan, and dietary composition, no single model could fully recapitulate the onset and progression of human MASH. Therefore, a detailed transcriptomic reference is urgently needed to better guide model selection and experimental design. METHODS We established three murine MASH models: HFD, MCD and CDA-HFD. Physiological and pathological features were systematically evaluated and compared across models. Bulk and single-cell RNA sequencing were performed, and the resulting data were integrated with transcriptomic profiles from CCl₄-induced models and human MASH datasets, with a focus on metabolism, inflammation, fibrosis, and cellular signaling pathways. KEY FINDINGS The CDA-HFD and CCl₄ models closely resembled human MASH in inflammation and fibrosis but disrupted key metabolic pathways. Conversely, the HFD model mirrored metabolic abnormalities but lacked severe inflammation and fibrosis. Immunoinfiltration and single-cell analyses revealed that macrophages dominate the inflammatory process, with activation of PPAR signaling, extracellular matrix remodeling, and phagocytosis. SIGNIFICANCE To balance metabolic and pathological fidelity without relying on genetic or toxin means, a combination of the CDA-HFD model with either HFD or WD is recommended as a robust and practical strategy for MASH research.
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Affiliation(s)
- Meng Ning
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518036, China; Center for Energy Metabolism and Reproduction, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; Department of Endocrinology, First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Donghui Lu
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen 518036, China
| | - Bin Teng
- Center for Energy Metabolism and Reproduction, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
| | - Dong Liang
- Center for Energy Metabolism and Reproduction, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
| | - Pei-Gen Ren
- Center for Cancer Immunology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; University of Chinese Academy of Sciences, Beijing, China.
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El-Sabawi B, Tanriverdi K, Gajjar P, Nayor M, Landman JM, Below JE, Haff M, Long M, Ezpeleta M, Freedman JE, Varady K, Shah R, Perry AS. Circulating Proteomics Identifies a Dynamic Profile of Hepatic Steatosis During Metabolic Intervention. J Am Heart Assoc 2025; 14:e037100. [PMID: 40371575 DOI: 10.1161/jaha.124.037100] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Accepted: 03/05/2025] [Indexed: 05/16/2025]
Abstract
BACKGROUND Weight reduction through lifestyle, activity, and dietary interventions are the mainstay of initial therapy for metabolic dysfunction associated steatotic liver disease. Data on the relative effectiveness and metabolic pathways linking weight loss and decreased hepatic steatosis are lacking. We sought to identify coordinated changes between the circulating proteome and hepatic steatosis within a randomized clinical trial of alternate day fasting and exercise and prioritize proteins relevant to hepatic steatosis within a broader context using a community cohort. METHODS AND RESULTS We quantified a broad cardiometabolic proteome (>300 proteins) in 67 individuals randomized in a 2×2 factorial design to alternate day fasting and exercise before and after the 3-month intervention to identify proteomic signatures of hepatic steatosis (measured by magnetic resonance imaging proton density fat fraction). Then, we analyzed the cross-sectional relationship of overlapping proteins (≈170) with hepatic attenuation (a computed tomographic technique linked to steatosis) in 707 participants from a community cohort. Principal component analysis demonstrated a proteomic signature associated with intrahepatic triglyceride content (Spearman rho=0.55, P<0.001) and insulin resistance (homeostatic model assessment for insulin resistance, Spearman rho=0.39, P=0.001). Changes in this proteomic signature were associated with changes in intrahepatic triglyceride content over the intervention period (beta=0.12, P<0.001). Moreover, cross-sectional analysis of overlapping proteins with hepatic attenuation in the community cohort showed generally, directionally consistent associations with hepatic steatosis. CONCLUSIONS These findings highlight the potential for broad proteomic profiling in small nutritional interventional studies with serial phenotyping alongside confirmatory large cohort epidemiology to prioritize targets of hepatic steatosis and cardiometabolic risk for mechanistic study.
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Affiliation(s)
- Bassim El-Sabawi
- Vanderbilt Translational and Clinical Cardiovascular Research Center Vanderbilt University School of Medicine Nashville TN USA
| | - Kahraman Tanriverdi
- Vanderbilt Translational and Clinical Cardiovascular Research Center Vanderbilt University School of Medicine Nashville TN USA
| | - Priya Gajjar
- Sections of Cardiovascular Medicine and Preventive Medicine and Epidemiology, Department of Medicine Boston University School of Medicine Boston MA USA
| | - Matthew Nayor
- Sections of Cardiovascular Medicine and Preventive Medicine and Epidemiology, Department of Medicine Boston University School of Medicine Boston MA USA
| | - Joshua M Landman
- Vanderbilt Genetics Institute Vanderbilt University Medical Center Nashville TN USA
| | - Jennifer E Below
- Vanderbilt Genetics Institute Vanderbilt University Medical Center Nashville TN USA
| | - Madeleine Haff
- Sections of Gastroenterology and Preventive Medicine and Epidemiology, Department of Medicine Boston University School of Medicine Boston MA USA
| | - Michelle Long
- Sections of Gastroenterology and Preventive Medicine and Epidemiology, Department of Medicine Boston University School of Medicine Boston MA USA
| | | | - Jane E Freedman
- Vanderbilt Translational and Clinical Cardiovascular Research Center Vanderbilt University School of Medicine Nashville TN USA
| | | | - Ravi Shah
- Vanderbilt Translational and Clinical Cardiovascular Research Center Vanderbilt University School of Medicine Nashville TN USA
| | - Andrew S Perry
- Vanderbilt Translational and Clinical Cardiovascular Research Center Vanderbilt University School of Medicine Nashville TN USA
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Sun M, Zhong M, Luo F, Lan M, Zhang X, Ma Z. Assessment of Liver Fibrosis with Multisample Point Shear Wave Elastography in Obese Patients with Metabolic Dysfunction-Associated Steatotic Liver Disease. Acad Radiol 2025:S1076-6332(25)00422-2. [PMID: 40393826 DOI: 10.1016/j.acra.2025.04.070] [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: 01/13/2025] [Revised: 04/26/2025] [Accepted: 04/29/2025] [Indexed: 05/22/2025]
Abstract
RATIONALE AND OBJECTIVES To evaluate the diagnostic performance of multisample point shear wave elastography (pSWE) for liver fibrosis in obese patients with metabolic dysfunction-associated steatotic liver disease (MASLD) using liver biopsy as the reference standard and to compare it with the FIB-4 index and aspartate to platelet ratio index (APRI). METHODS Patients with obesity who met the diagnostic criteria for MASLD between April 2023 and December 2024 were selected for this retrospective single-centre study. Liver stiffness measurements were reported as median values of measurements, and Auto-pSWVs (m/s) were measured using the multisample pSWE technique. The diagnostic performance of auto shear wave velocities (Auto-pSWVs), FIB-4 index and APRI for significant fibrosis (≥F2) and advanced fibrosis (≥F3) of the liver was evaluated and compared using receiver operating characteristic curves with liver biopsy as the criterion. The correlation between Auto-pSWVs and the clinical variables of the subjects was evaluated. RESULTS Data from 241 patients were analysed. Auto-pSWVs were positively correlated with the pathological diagnosis of liver fibrosis (r=0.34, p<0.001), and the liver fibrosis stage was an independent risk factor for Auto-pSWVs (beta coefficient: 0.42, p< 0.001). In addition, Auto-pSWVs was superior to FIB-4 index and APRI when comparing the diagnostic performance of significant liver fibrosis (≥F 2) and advanced fibrosis (≥F3) (p < 0.05). The AUC of Auto-pSWVs was 0.75 (95% CI 0.66-0.85) and 0.96 (95% CI 0.89-1.0) in the ≥ F2 and ≥ F3 groups, respectively. The cut-off value for Auto-pSWVs were determined as follows: grade F2 ≥ 1.02 m/s; and grade F3 ≥ 1.30 m/s. CONCLUSION Multisample pSWE appears to be a valuable tool for the diagnosis of liver fibrosis in obese patients with MASLD.
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Affiliation(s)
- Meng Sun
- Department of Medical Ultrasound, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, China (M.S., F.L., M.L., X.Z., Z.M.)
| | - Mingwei Zhong
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, China (M.Z.)
| | - Fangqiong Luo
- Department of Medical Ultrasound, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, China (M.S., F.L., M.L., X.Z., Z.M.)
| | - Meng Lan
- Department of Medical Ultrasound, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, China (M.S., F.L., M.L., X.Z., Z.M.)
| | - Xinru Zhang
- Department of Medical Ultrasound, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, China (M.S., F.L., M.L., X.Z., Z.M.)
| | - Zhe Ma
- Department of Medical Ultrasound, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, China (M.S., F.L., M.L., X.Z., Z.M.).
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Okada M, Hanayama M, Yamamoto Y, Miyake T, Yoshida O, Takeshita E, Ikeda Y, Hiasa Y. Effect of pemafibrate in reducing intestinal long-chain fatty acid absorption and hepatic fibrosis in metabolic dysfunction-associated steatohepatitis rats. BMC Gastroenterol 2025; 25:385. [PMID: 40389836 PMCID: PMC12090548 DOI: 10.1186/s12876-025-03967-z] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Accepted: 05/02/2025] [Indexed: 05/21/2025] Open
Abstract
BACKGROUND Pemafibrate helps regulate fatty acid dynamics in the liver, potentially preventing metabolic dysfunction-associated steatohepatitis (MASH). However, its effect on intestinal long-chain fatty acid (LCFA) metabolism in MASH remains unclear. Thus, we aimed to examine the influence of pemafibrate on intestinal LCFA metabolism and hepatic fibrosis in a MASH rat model. METHODS Sprague-Dawley rats were fed a high-fat and high-cholesterol diet to induce MASH and then divided into pemafibrate-treated (pemafibrate (+)) and untreated (pemafibrate (-)) groups. Triglyceride deposition in the small intestine and fibrosis, along with α-smooth muscle actin level in the liver, were evaluated. Furthermore, the mRNA expression levels of genes associated with lipid metabolism in the small intestine and markers of fibrosis and hepatic stellate cells activation in the liver were measured. RESULTS The pemafibrate-treated group had markedly lower triglyceride deposition and lipid absorption in the intestine, and significantly lower levels of molecules involved in intestinal lipid regulation than the pemafibrate-untreated group. Moreover, hepatic fibrosis significantly improved, and the mRNA levels of fibrosis-related molecules and hepatic stellate cell activation factors significantly decreased in the pemafibrate-treated compared with those in the pemafibrate-untreated group. CONCLUSIONS Pemafibrate reduced lipid droplet formation and LCFA absorption in the intestinal tract and alleviated hepatic fibrosis in MASH model rats.
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Affiliation(s)
- Masaya Okada
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
| | - Masakazu Hanayama
- Department of Gastroenterology, Matsuyama Shimin Hospital, Matsuyama, Ehime, Japan
| | - Yasunori Yamamoto
- Endoscopy Center, Ehime University Hospital, 454 Shitsukawa, Toon, Ehime, 791-0295, Japan.
| | - Teruki Miyake
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
| | - Osamu Yoshida
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
| | - Eiji Takeshita
- Department of Inflammatory Bowel Diseases and Therapeutics, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
| | - Yoshio Ikeda
- Endoscopy Center, Ehime University Hospital, 454 Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Yoichi Hiasa
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
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Chen K, Feng Q, Liu H. Bibliometric visualization of hepatocellular carcinoma and metabolic syndrome research: trends and emerging areas. Discov Oncol 2025; 16:809. [PMID: 40388038 PMCID: PMC12089568 DOI: 10.1007/s12672-025-02518-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Accepted: 04/28/2025] [Indexed: 05/20/2025] Open
Abstract
A growing body of research has highlighted the increasing relevance of hepatocellular carcinoma (HCC) and metabolic syndrome (MetS). However, a comprehensive bibliometric visualization analysis on this topic remains lacking. In this study, we retrieved 310 related articles from the Web of Science Core Collection, spanning from January 1, 2014, to December 31, 2023. Using VOS viewer and Cite Space software, we analyzed the relationships among authors, journals, institutions, countries, keywords, and citations. Between 2014 and 2023, there has been a steady increase in publications on HCC and MetS, with the United States and China being the leading contributors in terms of publication volume. The visualization analysis revealed that obesity, insulin resistance, MAFLD, and liver cirrhosis are emerging areas in the intersection of HCC and MetS. Additionally, the international community is increasingly adopting the disease diagnosis term MAFLD, which, compared to NAFLD, shows improved diagnostic performance for predicting both hepatic and extra-hepatic outcomes. Furthermore, hypertension and cardiovascular diseases are emerging as promising new research fields.
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Affiliation(s)
- Kang Chen
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou University, Chengguan District, Lanzhou, 730000, Gansu, China
| | - Qianye Feng
- Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.
| | - Haipeng Liu
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou University, Chengguan District, Lanzhou, 730000, Gansu, China.
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Vahrenbrink M, Coleman CD, Kuipers S, Lurje I, Hammerich L, Kunkel D, Keye J, Dittrich S, Schjeide BM, Hiß R, Müller J, Püschel GP, Henkel J. Dynamic changes in macrophage populations and resulting alterations in Prostaglandin E 2 sensitivity in mice with diet-induced MASH. Cell Commun Signal 2025; 23:227. [PMID: 40380177 DOI: 10.1186/s12964-025-02222-y] [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: 02/24/2025] [Accepted: 04/28/2025] [Indexed: 05/19/2025] Open
Abstract
BACKGROUND The transition from metabolic dysfunction-associated steatotic liver disease (MASLD) to steatohepatitis (MASH) is characterized by a chronic low-grade inflammation, involving activation of resident macrophages (Kupffer cells; KC) and recruitment of infiltrating macrophages. Macrophages produce cytokines and, after induction of Cyclooxygenase 2 (COX-2), the key enzyme of prostanoid synthesis, prostaglandin E2 (PGE2). PGE2 modulates cytokine production in an autocrine and paracrine manner, therefore playing a pivotal role in regulating inflammatory processes. Changes in the hepatic macrophage pool during MASLD progression to MASH could influence PGE2- and cytokine-mediated signaling processes. The aim of this study was to characterize these changes in mice with diet-induced MASH and further elucidate the role of COX-2-dependently formed PGE2 on the inflammatory response in different macrophage populations of mice with a macrophage-specific COX-2-deletion. METHODS Male, 6-7-week-old wildtype mice were fed either a Standard or high-fat, high-cholesterol MASH-inducing diet for 4, 12 and 20 weeks. Liver macrophages were isolated and analyzed by flow cytometry. For in vitro experiments primary KC, peritoneal macrophages (PM) and Bone-marrow-derived macrophages (BMDM) were isolated from macrophage-specific COX-2-deficient and wildtype mice and treated with lipopolysaccharide (LPS) and/or PGE2. RESULTS During MASH-development, the proportion of KC (Clec4F+Tim4+) decreased, while the proportion of monocyte-derived macrophages (Clec4F-Tim4-) and monocyte-derived cells exhibiting a phenotype similar to KC (Clec4F+Tim4-) significantly increased over time. In vitro experiments showed that exogenous PGE2 completely abrogated the LPS-induced mRNA expression and secretion of tumor necrosis factor-alpha (TNF-α) in primary KC, PM and BMDM from wildtype mice. PM and BMDM, as in vitro models for infiltrating macrophages, were more sensitive to PGE2 compared to KC. Deletion of COX-2 in all macrophage populations led to an impaired PGE2-dependent feedback inhibition of TNF-α production. LPSinduced TNF-α mRNA expression was higher compared to the respective wildtype macrophage population. CONCLUSION The current study, using a murine MASH model, indicates that PGE2 may have a protective, anti-inflammatory effect, especially by inhibiting the expression of pro-inflammatory cytokines such as TNFα in infiltrating monocyte-derived macrophages. An inhibition of endogenous PGE2 synthesis in macrophages by pharmacological inhibition of COX-2 could potentially increase inflammation and promote the progression of MASH.
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Affiliation(s)
- Madita Vahrenbrink
- Department of Nutritional Biochemistry, Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany.
- Max Rubner Center (MRC) for Cardiovascular Metabolic Renal Research, Institute of Pharmacology, Charité-Universitätsmedizin Berlin, Hessische Straße 3-4, 10115, Berlin, Germany.
| | - C D Coleman
- Department of Nutritional Biochemistry, Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany
| | - S Kuipers
- Department of Nutritional Biochemistry, Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany
| | - I Lurje
- Department of Hepatology and Gastroenterology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - L Hammerich
- Department of Hepatology and Gastroenterology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - D Kunkel
- Flow & Mass Cytometry Core Facility, Berlin Institute of Health at Charité- Universitätsmedizin Berlin, Berlin, Germany
| | - J Keye
- Flow & Mass Cytometry Core Facility, Berlin Institute of Health at Charité- Universitätsmedizin Berlin, Berlin, Germany
| | - S Dittrich
- Nutritional Biochemistry, Faculty of Life Sciences: Food, Nutrition and Health, University of Bayreuth, Kulmbach, Germany
| | - B M Schjeide
- Nutritional Biochemistry, Faculty of Life Sciences: Food, Nutrition and Health, University of Bayreuth, Kulmbach, Germany
| | - R Hiß
- Department of Nutritional Biochemistry, Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany
| | - J Müller
- Physics and Computer Sciences, Applied Computer Sciences VIII, Faculty of Mathematics, University of Bayreuth, Bayreuth, Germany
| | - G P Püschel
- Department of Nutritional Biochemistry, Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany
| | - J Henkel
- Department of Nutritional Biochemistry, Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany
- Nutritional Biochemistry, Faculty of Life Sciences: Food, Nutrition and Health, University of Bayreuth, Kulmbach, Germany
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Bugaichuk S, Wilkens V, Horvatits K, Huber S, Lohse AW, Kluwe J, Pischke S, Fründt T. Non-alcoholic fatty liver disease, in contrast to alcoholic liver disease, is associated with lower socio-economic status: results from a German referral center. Ann Hepatol 2025:101926. [PMID: 40383368 DOI: 10.1016/j.aohep.2025.101926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Revised: 04/16/2025] [Accepted: 04/26/2025] [Indexed: 05/20/2025]
Abstract
INTRODUCTION AND OBJECTIVES Elevated liver enzymes (ELE) are a common finding in the general population, often caused by undiagnosed chronic liver disease. But little is known to what extent socioeconomic status (SES) influences the occurrence of various liver diseases. MATERIAL AND METHODS Retrospective study of outpatients presenting with ELE. All patients received a structured work-up including abdominal ultrasound and serological testing. SES was assessed for patients from the Hamburg area using the social monitoring database of the Hamburg City Housing Department. SES was rated as high (SES-H), medium (SES-M), and low (SES-L). RESULTS Out of n=859 patients analysed, SES was assessable for n = 310 (53%) patients: SES-H/-M/-L [n; %]: 31 (10%), 223 (72%), 56 (18%). The most prevalent liver diseases were NAFLD (n=125; 40.3%), drug-induced liver injury (n=16; 5.2%) and alcoholic liver disease (ALD, n=13; 4.2%). Prevalence of NAFLD differed significantly between SES-subgroups (SES-H/-M/-L [n; %]: 6 (19%) vs. 88 (39%) vs. 32 (55%); p= .004), the distribution of ALD was similar between the SES subgroups (1(3.2%) vs. 11 (4.9%) vs. 1 (2%); p= .55). Median body mass index (BMI) increased from SES-H to SES-VL (SES-H/-M/-L [kg/m2]: 24.4 vs. 26.2 vs. 28.6; p= .001). CONCLUSIONS NAFLD is the most prevalent liver disease in patients presenting with unexplained ELE, with a significantly higher occurrence in individuals from lower SES groups. Furthermore, BMI increases among patients with lower SES, highlighting the potential role of socioeconomic factors in NAFLD development. These findings underscore the need for targeted public health interventions, particularly in socioeconomically disadvantaged population.
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Affiliation(s)
- Semjon Bugaichuk
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Germany
| | - Verena Wilkens
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Germany
| | | | - Samuel Huber
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Germany
| | - Ansgar W Lohse
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Germany
| | - Johannes Kluwe
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Germany; Department of Internal Medicine and Gastroenterology, Amalie Sieveking Hospital, Hamburg, Germany
| | - Sven Pischke
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Germany
| | - Thorben Fründt
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Germany.
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Pu Y, Ren W, Gan Z, Wang S, Peng M, Yue R, Huang R. Heshuxiaoji pill suppresses steatohepatitis and fibrosis by regulating the AngII-BACH1 mediated vasoconstriction. JOURNAL OF ETHNOPHARMACOLOGY 2025:119989. [PMID: 40383247 DOI: 10.1016/j.jep.2025.119989] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/26/2025] [Revised: 05/13/2025] [Accepted: 05/16/2025] [Indexed: 05/20/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Non-alcoholic steatohepatitis (NASH), a widespread hepatic affliction marked by hepatic fibrosis progression towards hepatocellular carcinoma, is significantly influenced by endothelial dysfunction and endothelial-to-mesenchymal transition (EndMT). Although Heshuxiaoji (HSXJ) Pill, an empirical prescription formulated by Prof. Tongjiao Sun has demonstrated significant efficacy in mitigating steatohepatitis and fibrosis, the precise mechanisms underlying its therapeutic effects remain to be fully elucidated. AIM OF THE STUDY To investigate the antifibrotic effect of HSXJ pill and to explore its mechanism in vivo and in vitro. MATERIALS AND METHODS To probe the antifibrotic impact of HSXJ pill and unravel its mechanisms, murine liver fibrosis and NASH models were induced in vivo via Western diet and CCl4 injection. In vitro, human umbilical vein endothelial cells were stimulated with AngII, followed by Western blot analysis. Additionally, liver biopsies from patients with mild-to-moderate fibrosis (S1-S2) were utilized to verify EndMT involvement in fibrosis. RESULTS In the hepatocyte sections exhibiting human liver fibrosis, we observed a significant upregulation of AngII and the transcription factor BTB and CNC homology 1 (BACH1). Genetic ablation of AngII significantly ameliorates hepatic fibrosis and EndMT, while attenuating pathological angiogenesis via decreased BACH1 expression. In contrast, AngII overexpression exacerbates these conditions. In vivo, the HSXJ pill effectively alleviates hepatic fibrosis, reduces alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, and suppresses BACH1 and AngII production, thereby inhibiting EndMT. In vitro, the pill mitigates EndMT-associated fibrosis by regulating BACH1 to inhibit AngII activation. CONCLUSION The study indicates that the HSXJ pill effectively diminishes hepatocyte injury markers and alleviates liver fibrosis, with optimal efficacy at medium/high doses. BACH1 serves as a key regulator of hepatic fibrosis via modulation of AngII expression.
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Affiliation(s)
- Yueheng Pu
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610032, China.
| | - Wei Ren
- National Traditional Chinese Medicine Clinical Research Base, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou 646000, China.
| | - Zhonghua Gan
- National Traditional Chinese Medicine Clinical Research Base, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou 646000, China.
| | - Shiyang Wang
- National Traditional Chinese Medicine Clinical Research Base, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou 646000, China.
| | - Mengyun Peng
- National Traditional Chinese Medicine Clinical Research Base, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou 646000, China.
| | - Rensong Yue
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610032, China.
| | - Rui Huang
- National Traditional Chinese Medicine Clinical Research Base, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou 646000, China; State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau SAR 999078, China.
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El-Kassas M, Al-Naamani K, Elbadry M, Awad A, Tharwat M, Debzi N, Zemmouchi S, Abdulla M, Zakaria D, Esmat G, El-Karaksy H, Waked I, Shaltout I, Medhat MA, El-Shabrawi M, Abdeen N, Al-Khairalla M, Akroush MW, Alali AA, Almattooq M, Yaghi C, Tumi A, Elmehdawi R, Benazzouz M, Attia MF, Sanai F, Idlbi S, Labidi A, Houni AE, Beshyah S, Lakhdar A, Atef Z, Abdel Rahman AG, Saleh R, Al-Rifai A, Alqahtani S, Elzouki AN, Alswat K. Establishing consensus on Arabic medical terminology for steatotic liver disease: a mixed-methods approach. Arab J Gastroenterol 2025:S1687-1979(25)00009-7. [PMID: 40379545 DOI: 10.1016/j.ajg.2025.01.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 09/03/2024] [Accepted: 01/11/2025] [Indexed: 05/19/2025]
Affiliation(s)
- Mohamed El-Kassas
- Endemic Medicine Department, Faculty of Medicine, Helwan University, Cairo, Egypt; Steatotic Liver Disease Study Foundation in the Middle East and North Africa (SLMENA), Cairo, Egypt.
| | - Khalid Al-Naamani
- Steatotic Liver Disease Study Foundation in the Middle East and North Africa (SLMENA), Cairo, Egypt; Department of Medicine, Division of Gastroenterology and Hepatology, The Medical City for Military and Security Services, Muscat, Oman
| | - Mohamed Elbadry
- Endemic Medicine Department, Faculty of Medicine, Helwan University, Cairo, Egypt; Steatotic Liver Disease Study Foundation in the Middle East and North Africa (SLMENA), Cairo, Egypt
| | - Abeer Awad
- Department of Internal Medicine, Hepatogastroenterology Unit, Kasr Al-Ainy School of Medicine, Cairo, Egypt
| | - Mina Tharwat
- Steatotic Liver Disease Study Foundation in the Middle East and North Africa (SLMENA), Cairo, Egypt; Department of Tropical Medicine and Gastroenterology, Aswan University, Aswan, Egypt
| | - Nabil Debzi
- Steatotic Liver Disease Study Foundation in the Middle East and North Africa (SLMENA), Cairo, Egypt; Hepatology Department, Mustapha Bacha University Hospital, Algeria, Algeria
| | | | - Maheeba Abdulla
- Internal Medicine Department, Ibn AlNafees Hospital, Manama, Bahrain
| | - Doaa Zakaria
- Tropical Medicine Department, Ain Shams University, Cairo, Egypt
| | - Gamal Esmat
- Steatotic Liver Disease Study Foundation in the Middle East and North Africa (SLMENA), Cairo, Egypt; Endemic Medicine Department, Cairo University, Cairo, Egypt; Badr University in Cairo Research Center, Badr University in Cairo, Badr City, Cairo, Egypt
| | - Hanaa El-Karaksy
- Pediatrics Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Imam Waked
- Steatotic Liver Disease Study Foundation in the Middle East and North Africa (SLMENA), Cairo, Egypt; Hepatology Department, National Liver Institute, Menoufia University, Shebeen ElKom, Egypt
| | - Inass Shaltout
- Internal Medicine and Diabetes Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Mohammed A Medhat
- Steatotic Liver Disease Study Foundation in the Middle East and North Africa (SLMENA), Cairo, Egypt; Tropical Medicine and Gastroenterology Department, Faculty of Medicine, Assiut University, Assiut, Egypt
| | | | - Nermeen Abdeen
- Tropical Medicine Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | | | - Maisam W Akroush
- Steatotic Liver Disease Study Foundation in the Middle East and North Africa (SLMENA), Cairo, Egypt; Digestive and Liver Disease Clinic, Private Sector, Faculty of Medicine, Jordan University, Amman, Jordan
| | - Ali A Alali
- Department of Medicine, Faculty of Medicine, Kuwait University, Jabriyah, Kuwait; Thunayan Alghanim Gastroenterology and Hepatology Center, Amiri Hospital, Sharq, Kuwait
| | - Maen Almattooq
- Steatotic Liver Disease Study Foundation in the Middle East and North Africa (SLMENA), Cairo, Egypt; Gastroenterology & Hepatology Department, Jaber Hospital, Kuwait
| | - Cesar Yaghi
- Gastroenterology and Hepatology Department, Hotel-Dieu de France University Hospital, Beirut, Lebanon
| | - Ali Tumi
- Steatotic Liver Disease Study Foundation in the Middle East and North Africa (SLMENA), Cairo, Egypt; Medical Department, Central Hospital, Tripoli, Libya
| | - Rafik Elmehdawi
- Internal Medicine Department, University of Benghazi, Benghazi, Libya
| | - Mustapha Benazzouz
- Steatotic Liver Disease Study Foundation in the Middle East and North Africa (SLMENA), Cairo, Egypt; Hepatogastroenterology Department, Rabat International University, Rabat, Morocco
| | - Mona F Attia
- Department of English Language and Literature, Helwan University, Cairo, Egypt
| | - Faisal Sanai
- Steatotic Liver Disease Study Foundation in the Middle East and North Africa (SLMENA), Cairo, Egypt; Gastroenterology Section, Department of Medicine, King Abdulaziz Medical City, King Abdullah International Medical Research Center, Ministry of National Guard - Health Affairs, Jeddah, Saudi Arabia
| | - Sahar Idlbi
- General Diseases Department, University's Children Hospital, Damascus, Syria
| | - Asma Labidi
- Steatotic Liver Disease Study Foundation in the Middle East and North Africa (SLMENA), Cairo, Egypt; Gastroenterology "A" Department, Rabta Hospital, Tunisia
| | - Ali El Houni
- Medicine Department, Dubai Medical University, Dubai, United Arab Emirates
| | - Salem Beshyah
- Endocrinology Department, Yas Clinic Khalifa City, Abu Dhabi, United Arab Emirates
| | - Abdul Lakhdar
- Endocrinology Department, Barts Health NHS Trust, London, UK
| | - Zayed Atef
- Internal Medicine Department, Faculty of Medicine, Sana'a University, Sana'a, Yemen
| | - Amira G Abdel Rahman
- Department of Public Health and Community, Environmental and Occupational Medicine, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Rasha Saleh
- Arabic Language and Literature Department, Helwan University, Cairo, Egypt
| | - Ahmad Al-Rifai
- Division of Gastroenterology, Sheikh Shakhbout Medical City, Abu Dhabi, United Arab Emirates
| | - Saleh Alqahtani
- Organ Transplant Center of Excellence, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Abdel-Naser Elzouki
- Steatotic Liver Disease Study Foundation in the Middle East and North Africa (SLMENA), Cairo, Egypt; Medicine Department, Hamad Medical Corporation and College of Medicine, Qatar University, Doha, Qatar
| | - Khalid Alswat
- Steatotic Liver Disease Study Foundation in the Middle East and North Africa (SLMENA), Cairo, Egypt; Liver Disease Research Center, College of Medicine, King Saud University, Riyadh, Saudi Arabia
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Chen HF, Chang YY, Chen P, Shen XH, Chang CH, Hsu WL. Risks of liver cirrhosis, hepatocellular carcinoma, hepatic-related complications, and mortality in patients with type 2 diabetes in Taiwan. World J Diabetes 2025; 16:104576. [DOI: 10.4239/wjd.v16.i5.104576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Revised: 02/25/2025] [Accepted: 03/21/2025] [Indexed: 04/25/2025] Open
Abstract
BACKGROUND Hepatitis B and C and alcoholic liver disease are the principal causes of hepatic-related morbidity and mortality. However, evidence of the associations between diabetes without the above risk factors and hepatic-related study endpoints is not well understood. In addition, the effects of associated metabolic dysfunction and exercise on hepatic outcomes are still not clear.
AIM To investigate the incidence and relative hazards of cirrhosis of the liver, hepatocellular carcinoma (HCC), hepatic-related complications and mortality in patients with type 2 diabetes (T2D) who were nonalcoholic and serologically negative for hepatitis B and C in Taiwan.
METHODS A total of 33184 T2D patients and 648746 nondiabetic subjects selected from Taiwan’s adult preventive health care service were linked to various National Health Insurance databases, cancer registry, and death registry to identify cirrhosis of the liver, HCC, hepatic-related complications, and mortality. The Poisson assumption and Cox proportional hazard regression model were used to estimate the incidences and relative hazards of all hepatic-related study endpoints, respectively. We also compared the risk of hepatic outcomes stratified by age, sex, associated metabolic dysfunctions, and regular exercise between T2D patients and nondiabetic subjects.
RESULTS Compared with nondiabetic subjects, T2D patients had a significantly greater incidence (6.32 vs 17.20 per 10000 person-years) and greater risk of cirrhosis of the liver [adjusted hazard ratio (aHR) 1.45; 95%CI: 1.30-1.62]. The aHRs for HCC, hepatic complications, and mortality were 1.81, 1.87, and 2.08, respectively. An older age, male sex, obesity, hypertension, and dyslipidemia further increased the risks of all hepatic-related study endpoints, and regular exercise decreased the risk, irrespective of diabetes status.
CONCLUSION Patients with T2D are at increased risk of cirrhosis of the liver, HCC, hepatic-related complications, and mortality, and associated metabolic dysfunctions provide additional hazard. Coordinated interprofessional care for high-risk T2D patients and diabetes education, with an emphasis on the importance of physical activity, are crucial for minimizing hepatic outcomes.
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Affiliation(s)
- Hua-Fen Chen
- Department of Endocrinology, Far Eastern Memorial Hospital, New Taipei City 220, Taiwan
- School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan
- Department of Public Health, College of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan
| | - Yung-Yueh Chang
- Department of Endocrinology, Far Eastern Memorial Hospital, New Taipei City 220, Taiwan
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei City 100, Taiwan
| | - Peter Chen
- Department of Gastroenterology, Choninn Hospital, Choninn Medical Group, New Taipei City 220, Taiwan
| | - Xiao-Han Shen
- Department of Endocrinology, Far Eastern Memorial Hospital, New Taipei City 220, Taiwan
- Master Program of Big Data in Medical Healthcare Industry, College of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan
- Data Science Center, Fu Jen Catholic University, New Taipei City 242, Taiwan
| | - Chin-Huan Chang
- Department of Endocrinology, Far Eastern Memorial Hospital, New Taipei City 220, Taiwan
| | - Wan-Lun Hsu
- Master Program of Big Data in Medical Healthcare Industry, College of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan
- Data Science Center, Fu Jen Catholic University, New Taipei City 242, Taiwan
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49
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Zheng Q, Deng S, Chen X, Wang Y, Yang Y. Macrophage inhibition in the alleviation of nonalcoholic steatohepatitis caused by bariatric surgery. Genes Immun 2025:10.1038/s41435-025-00334-6. [PMID: 40374920 DOI: 10.1038/s41435-025-00334-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 04/21/2025] [Accepted: 05/02/2025] [Indexed: 05/18/2025]
Abstract
The incidence of nonalcoholic steatohepatitis (NASH) is increasing worldwide, and effective treatment is urgently needed. To understand the molecular mechanisms behind the effectiveness of bariatric surgery in treating NASH, we integrated single-cell and bulk RNA sequencing data to identify the role of liver macrophage polarization in alleviating NASH and screen possible drugs for treatment. Analysis revealed that bariatric surgery alleviates NASH by inhibiting liver M1 macrophage polarization with 12 differentially expressed M1 macrophage-related genes. Additionally, 56 potentially effective drugs were predicted for NASH treatment. These findings shed light on the effectiveness of bariatric surgery in treating NASH and offer potential drug candidates for further exploration.
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Affiliation(s)
- Qianwen Zheng
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, The Fourth Military Medical University, Xi'an, 710032, China
| | - Shizhou Deng
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, The Fourth Military Medical University, Xi'an, 710032, China
| | - Xiyu Chen
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, The Fourth Military Medical University, Xi'an, 710032, China
| | - Yayun Wang
- Specific Lab for Mitochondrial Plasticity Underlying Nervous System Diseases, National Demonstration Center for Experimental Preclinical Medicine Education, The Fourth Military Medical University, Xi'an, 710032, China.
| | - Yanling Yang
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, The Fourth Military Medical University, Xi'an, 710032, China.
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50
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Barathon F, Graindorge PH, Bescher M, Gallais I, Burel A, Morel I, Schroeder H, Grova N, Lagadic-Gossmann D, Sergent O. Key role of extracellular vesicles in the induction of necroptosis and apoptosis by a mixture of polycyclic aromatic hydrocarbons in the context of a steatohepatitis-like state. Toxicology 2025; 516:154184. [PMID: 40378907 DOI: 10.1016/j.tox.2025.154184] [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: 03/17/2025] [Revised: 05/07/2025] [Accepted: 05/09/2025] [Indexed: 05/19/2025]
Abstract
A positive association between human exposure to environmental pollutants and progression from benign hepatic steatosis to advanced chronic liver diseases has been documented. Among chemicals found in air pollution, polycyclic aromatic hydrocarbons (PAHs) are of particular concern, due to their omnipresence in the environment. Ingestion of contaminated food is the primary route of exposure. Previous studies on the ability of PAHs to induce the pathological progression of liver steatosis have been limited to the analysis of individual PAHs. The aim of this study was therefore to examine the effects of a mixture of PAHs whose composition closely recapitulates that of contaminated food. The PAH mixture elicited both a steatohepatitis-like state in steatotic WIF-B9 hepatocytes (100 nM for 72 hours) and the progression of steatohepatitis in rats fed a lipid-enriched diet (0.8 mg/kg for 90 days). The PAH mixture induced transient necroptosis at 5 hours followed by a gradual increase in cellular apoptosis. PAH metabolism-dependent necroptosis appeared to be responsible for the development of the secondary apoptosis. Hepatocyte exposure induced a necroptosis-dependent release of extracellular vesicles (EVs), that appeared to be protective against necroptosis; however, those necroptotic EVs triggered apoptosis in recipient hepatocytes. Blocking of ASGR EV receptors with asialofetuin inhibited the interaction of EVs with hepatocytes and hence apoptosis. In conclusion, EV release seems to be crucial to avoid necroptosis, but inhibition of EV uptake can protect against apoptosis.
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Affiliation(s)
- Florian Barathon
- Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, Rennes F-35000, France.
| | | | - Maelle Bescher
- Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, Rennes F-35000, France.
| | - Isabelle Gallais
- Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, Rennes F-35000, France.
| | - Agnès Burel
- Univ Rennes, Biosit - UMS 3480, US_S 018, Rennes F-35000, France.
| | - Isabelle Morel
- Laboratoire de toxicologie biologique et Médico-légale, CHU Rennes, Rennes, France; INSERM, Univ Rennes, INRAE, Institut NUMECAN (Nutrition, Métabolismes et Cancer) UMR_A 1341, UMR_S 1317, F-35000, Rennes, France, CHU Rennes, Rennes, France.
| | - Henri Schroeder
- UMR Inserm 1256 NGERE - Lorraine University, Vandœuvre-lès-Nancy F-54500, France.
| | - Nathalie Grova
- UMR Inserm 1256 NGERE - Lorraine University, Vandœuvre-lès-Nancy F-54500, France; INRS (French National Research and Safety Institute for the Prevention of Occupational Accidents and Diseases) Department of Toxicology and Biomonitoring, France.
| | - Dominique Lagadic-Gossmann
- Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, Rennes F-35000, France.
| | - Odile Sergent
- Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, Rennes F-35000, France.
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