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1
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Choi MA, Rose S, Langouët S. Per- and polyfluoroalkyl substances as potentiators of hepatotoxicity in an exposome framework: Current challenges of environmental toxicology. Toxicology 2025; 515:154167. [PMID: 40300710 DOI: 10.1016/j.tox.2025.154167] [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: 02/05/2025] [Revised: 04/17/2025] [Accepted: 04/26/2025] [Indexed: 05/01/2025]
Abstract
Chronic liver diseases, including metabolic dysfunction-associated steatosic liver disease (MASLD) and hepatocellular carcinoma (HCC), are on the rise, potentially due to daily exposure to complex mixtures of chemical compounds forming part of the exposome. Understanding the mechanisms involved in hepatotoxicity of these mixtures is essential to identify common molecular targets that may highlight potential interactions at the molecular level. We illustrated this issue with two families of environmental contaminants, per- and polyfluoroalkyl substances (PFAS) and heterocyclic aromatic amines (HAAs), both of which could be involved in the progression of chronic liver diseases, and whose toxicity may be potentiated by interactions at the level of xenobiotic metabolism. In the study of exposome effects on chronic liver disease, New Approach Methodologies (NAMs) including omics analyses and data from various in vitro, in vivo and in silico approaches, are crucial for improving predictivity of toxicological studies in humans while reducing animal experimentation. Additionally, the development of complex in vitro human liver cell models, such as organoids, is essential to avoid interspecies differences that minimize the risk for humans. All together, these approaches will contribute to construct Adverse Outcome Pathways (AOPs) and could be applied not only to PFAS mixtures but also to other chemical families, providing valuable insights into mixture hepatotoxicity prediction in the study of the exposome. A better understanding of toxicological mechanisms will clarify the role of environmental contaminant mixtures in the development of MASLD and HCC, supporting risk assessment for better treatment, monitoring and prevention strategies.
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Affiliation(s)
- Minna A Choi
- Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, Rennes 35000, France
| | - Sophie Rose
- Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, Rennes 35000, France
| | - Sophie Langouët
- Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, Rennes 35000, France.
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2
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Zambrano-Vásquez OR, Cortés-Camacho F, Castañeda-Sánchez JI, Aréchaga-Ocampo E, Valle-Velázquez E, Cabrera-Angeles JC, Sánchez-Gloria JL, Sánchez-Muñoz F, Arellano-Buendia AS, Sánchez-Lozada LG, Osorio-Alonso H. Update in non-alcoholic fatty liver disease management: role of sodium-glucose cotransporter 2 inhibitors. Life Sci 2025; 372:123638. [PMID: 40246191 DOI: 10.1016/j.lfs.2025.123638] [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: 12/18/2024] [Revised: 03/28/2025] [Accepted: 04/09/2025] [Indexed: 04/19/2025]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation in hepatocytes without significant alcohol consumption. It is closely associated with sedentarism, hypercaloric diets, obesity, dyslipidemia, insulin resistance, type 2 diabetes mellitus, and genetic predisposition. NAFLD comprises a spectrum of liver disorders, from simple steatosis to non-alcoholic (NASH) and liver cirrhosis. The complex etiological mechanisms include oxidative stress, inflammation, apoptosis, and fibrosis; therefore, its management is challenging. Sodium-glucose cotransporter type 2 inhibitors (SGLT2i), a class of antidiabetic drugs, have emerged as promising therapeutic agents due to their ability to improve key metabolic parameters, including obesity, dyslipidemia, insulin resistance, and hyperglycemia. This review explores the cellular mechanisms by which SGLT2i, either as monotherapy or combined with other treatments, modulate signaling pathways involved in lipid and carbohydrate metabolism. Additionally, we examine their effects on oxidative stress, inflammation, fibrosis, and apoptosis, which are critical drivers of NAFLD progression. This review is intended to summarize the multiple benefits of SGLT2 inhibitors and to educate healthcare providers on the therapeutic potential of these drugs in order to foster their incorporation into effective NAFLD management plans.
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Affiliation(s)
- Oscar R Zambrano-Vásquez
- Doctorado en Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana, Ciudad de México 04960, Mexico; Departamento de Fisiopatología Cardio-Renal, Instituto Nacional de Cardiología Ignacio Chávez, México City 14080, Mexico
| | - Fernando Cortés-Camacho
- Doctorado en Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana, Ciudad de México 04960, Mexico; Departamento de Fisiopatología Cardio-Renal, Instituto Nacional de Cardiología Ignacio Chávez, México City 14080, Mexico
| | - Jorge I Castañeda-Sánchez
- Departamento de Sistemas Biológicos, Universidad Autónoma Metropolitana, Unidad Xochimilco, México City 04960, Mexico
| | - Elena Aréchaga-Ocampo
- Departamento de Ciencias Naturales, Universidad Autónoma Metropolitana, Unidad Cuajimalpa, México City 05348, Mexico
| | - Estefanía Valle-Velázquez
- Departamento de Fisiopatología Cardio-Renal, Instituto Nacional de Cardiología Ignacio Chávez, México City 14080, Mexico
| | - Juan C Cabrera-Angeles
- Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, México City, Mexico
| | - José L Sánchez-Gloria
- Department of Internal Medicine, Division of Nephrology, Rush University Medical Center, Chicago, IL 60612, USA
| | - Fausto Sánchez-Muñoz
- Departamento de Fisiología, Instituto Nacional de Cardiología Ignacio Chávez, México City 14080, Mexico
| | - Abraham S Arellano-Buendia
- Departamento de Fisiopatología Cardio-Renal, Instituto Nacional de Cardiología Ignacio Chávez, México City 14080, Mexico
| | - Laura G Sánchez-Lozada
- Departamento de Fisiopatología Cardio-Renal, Instituto Nacional de Cardiología Ignacio Chávez, México City 14080, Mexico
| | - Horacio Osorio-Alonso
- Departamento de Fisiopatología Cardio-Renal, Instituto Nacional de Cardiología Ignacio Chávez, México City 14080, Mexico.
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3
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Franzolin AML, Fioretto MN, Ribeiro IT, Maciel FA, Barata LA, Vitali PM, Magosso N, Fagundes FL, Emílio-Silva MT, Hiruma Lima CA, Scarano WR, Justulin LA. Maternal protein restriction compromises hepatic phenotype and antioxidant defense in postweaning male rats, while females exhibit resilience. Biochem Biophys Res Commun 2025; 766:151873. [PMID: 40300334 DOI: 10.1016/j.bbrc.2025.151873] [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: 01/29/2025] [Revised: 04/01/2025] [Accepted: 04/21/2025] [Indexed: 05/01/2025]
Abstract
The Developmental Origins of Health and Disease (DOHaD) concept postulates that maternal malnutrition can program offspring for dysfunction of multiple systems, including the liver. Maternal Protein Restriction (MPR) is a maternal malnutrition model that dysregulates catabolic hormones early in life, with long-term consequences on offspring such as hypertension and reproductive system cancers. Furthermore, studies evaluating sex-specific differences are scarce, especially considering the consequences of MPR on early life. Here, we investigated the impacts of MPR on hepatic phenotypic and molecular aspects of male and female rats at postnatal day (PND)21. The rats were divided into two groups: CTR, from dams that consumed a normal-protein diet (17 % protein), or GLLP, from dams that consumed a low-protein diet (6 % protein) throughout gestation and lactation. Our results demonstrated that MPR leads to an increase in collagen fibers, glycogen, and peroxiredoxin 1, in addition to a decrease in reticular fibers, mast cells, GSH, and MDA in the liver of male rats. In females, a reduction of reticular fibers and protein expression of hepatic peroxiredoxin 4 was observed. By contrasting these results with in silico analyses, we suggest that the main altered mechanisms in males are associated with oxidative stress, glycogen metabolism, and inflammatory responses. In females, a subtle dysregulation of antioxidant activity within the extracellular matrix was noted. Therefore, this work demonstrates sex-specific hepatic differences in post-weaning rats exposed to MPR, highlighting possible maternal modulations that lead males to be more affected, which may generate long-term effects on hepatic and systemic health.
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Affiliation(s)
| | - Matheus Naia Fioretto
- Department of Structural and Functional Biology, Institute of Biosciences, São Paulo State University, Botucatu, SP, Brazil
| | - Isabelle Tenori Ribeiro
- Department of Structural and Functional Biology, Institute of Biosciences, São Paulo State University, Botucatu, SP, Brazil
| | - Flávia Alessandra Maciel
- Department of Structural and Functional Biology, Institute of Biosciences, São Paulo State University, Botucatu, SP, Brazil
| | - Luisa Annibal Barata
- Department of Structural and Functional Biology, Institute of Biosciences, São Paulo State University, Botucatu, SP, Brazil
| | - Pedro Menchini Vitali
- Department of Structural and Functional Biology, Institute of Biosciences, São Paulo State University, Botucatu, SP, Brazil
| | - Natália Magosso
- Department of Structural and Functional Biology, Institute of Biosciences, São Paulo State University, Botucatu, SP, Brazil
| | - Felipe Leonardo Fagundes
- Department of Structural and Functional Biology, Institute of Biosciences, São Paulo State University, Botucatu, SP, Brazil
| | - Maycon Tavares Emílio-Silva
- Department of Structural and Functional Biology, Institute of Biosciences, São Paulo State University, Botucatu, SP, Brazil
| | - Clélia Akiko Hiruma Lima
- Department of Structural and Functional Biology, Institute of Biosciences, São Paulo State University, Botucatu, SP, Brazil
| | - Wellerson Rodrigo Scarano
- Department of Structural and Functional Biology, Institute of Biosciences, São Paulo State University, Botucatu, SP, Brazil
| | - Luis Antonio Justulin
- Department of Structural and Functional Biology, Institute of Biosciences, São Paulo State University, Botucatu, SP, Brazil.
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Ma X, Sun CY, Zhang Y, Li J, Zhao DS. The hepatoprotective effect of Lonicera japonica Flos on rats with high-fat diet-induced non-alcoholic fatty liver disease. Fitoterapia 2025; 183:106516. [PMID: 40188994 DOI: 10.1016/j.fitote.2025.106516] [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: 07/11/2024] [Revised: 03/18/2025] [Accepted: 03/30/2025] [Indexed: 04/11/2025]
Abstract
Lonicerae Japonica Flos (LJF) is an edible-medicinal herb, rich in phenolic acids, flavonoids, iridoids and other bioactive ingredients, that has anti-inflammatory, antioxidant, antilipemic, and hepatoprotective effects. However, its effect on non-alcoholic fatty liver disease (NAFLD) remains to be elucidated. The aim of this study was to determine the effect of LJF on liver injury in rats with high-fat diet (HFD)-induced NAFLD. The administration of LJF extract to rats with HFD-induced NAFLD significantly improved their body weight and daily food intake, liver tissue steatosis, lipid droplet vacuolization, and inflammatory cell infiltration. In addition, the LJF extract also improved to varying degrees the serum biochemical parameters, liver lipid content, levels of inflammatory factors, and oxidative stress markers. Among the treatment groups, the LJF high-dose group (LJF-H) showed the most significant improvement effect. Additionally, the correlation matrix heatmap visualization indicated that LJF may ameliorate NAFLD mainly by lowering liver lipid content and improving serum biochemical parameters.
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Affiliation(s)
- Xue Ma
- College of Pharmacy, Shandong University of Traditional Chinese Medicine, No. 4655 Daxue Road, Jinan 250355, China
| | - Chun-Yong Sun
- College of Pharmacy, Shandong University of Traditional Chinese Medicine, No. 4655 Daxue Road, Jinan 250355, China
| | - Yan Zhang
- College of Pharmacy, Shandong University of Traditional Chinese Medicine, No. 4655 Daxue Road, Jinan 250355, China
| | - Jia Li
- College of Pharmacy, Shandong University of Traditional Chinese Medicine, No. 4655 Daxue Road, Jinan 250355, China.
| | - Dong-Sheng Zhao
- College of Pharmacy, Shandong University of Traditional Chinese Medicine, No. 4655 Daxue Road, Jinan 250355, China.
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Liu G, Das SK. D-Xylose Ameliorates Non-Alcoholic Fatty Liver Disease by Targeting Macrophage-expressed LYZ Gene. Cell Biochem Biophys 2025; 83:1617-1629. [PMID: 39379786 DOI: 10.1007/s12013-024-01572-7] [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] [Accepted: 09/18/2024] [Indexed: 10/10/2024]
Abstract
This study investigates the therapeutic effects of D-Xylose, a natural sugar, on non-alcoholic fatty liver disease (NAFLD), focusing on the expression of the lysozyme gene (LYZ) in macrophages. Using the single-cell dataset GSE136103 for NAFLD, researchers analyzed macrophage populations and other groups utilizing the Seurat package in R, while a differential analysis was performed on the NAFLD dataset GSE61260 using the limma package. Both in vitro and in vivo models, including cell culture, mouse models, RT-qPCR, Western blot, ELISA, and histopathological analyses, were employed to examine the effect of D-Xylose on lipid accumulation, LYZ expression, blood lipid levels, and inflammatory responses. The study found a significant upregulation of LYZ in free fatty acid (FFA)-treated cells and mouse liver tissues, with a subsequent reduction after D-Xylose intervention. Treatment with D-Xylose and Amlodipine led to a notable decrease in lipid accumulation, as evidenced by reduced triglyceride and cholesterol levels. D-Xylose demonstrated a greater improvement in lipid metabolism than Amlodipine. Additionally, D-Xylose significantly mitigated inflammatory responses, reducing levels of inflammatory markers such as IL1R, IL6, MYS8, TNF, NF-κB, and IL-1. Furthermore, D-Xylose administration significantly reduced liver weight and liver index, with a positive impact on serum liver function and blood lipid levels. The findings suggest that D-Xylose could be a therapeutic intervention for NAFLD by targeting LYZ expression in macrophages, thereby modulating lipid metabolism and inflammatory responses.
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Affiliation(s)
- Guoxiang Liu
- Faculty of Pharmacy, Lincoln University College, Petaling Jaya, Selangor, Malaysia
| | - Sreemoy Kanti Das
- Faculty of Pharmacy, Lincoln University College, Petaling Jaya, Selangor, Malaysia.
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Thomas A, Thomas A. Managing Nonalcoholic Fatty Liver Disease Through Structured Lifestyle Modification Interventions. Am J Lifestyle Med 2025:15598276251346717. [PMID: 40438150 PMCID: PMC12106371 DOI: 10.1177/15598276251346717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Revised: 05/14/2025] [Accepted: 05/16/2025] [Indexed: 06/01/2025] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a significant global health burden. It comprises a broad pathological spectrum ranging from simple liver steatosis to steatohepatitis with variable degrees of fibrosis, and liver failure. Patients with NAFLD have an increased risk of liver-related and overall mortality. While the trials to assess the efficacy of the medications are ongoing, lifestyle modification is the first line of therapy recommended. The primary aim of this review paper is to synthesize literature related to current evidence-based lifestyle interventions for preventing and managing NAFLD. The review and synthesis of the literature reveal that personalized nutritional, exercise, and behavior change interventions are effective in managing NAFLD. Evidence suggests that there are several gaps in managing NAFLD. The gaps discussed in this paper include a lack of awareness of the disease, ineffective patient-provider communication, shortage of specialists, under-recognition of the disease, and liver health disparities. This paper highlights the evidence-based opportunities to overcome those gaps, such as utilizing comprehensive models of care, clinical care pathways, and clinical practice guidelines. Primary care physicians and endocrinologists, who are the first point of contact must utilize these opportunities for diagnosing and managing patients with NAFLD.
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Affiliation(s)
- Andrew Thomas
- Internal Medicine, Southern Illinois Healthcare, Carbondale, IL, USA (AT)
| | - Annie Thomas
- Marcella Niehoff School of Nursing, Loyola University Chicago, Maywood, IL, USA (AT)
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Lian K, Fan Q, Sheng S, Zhang K, Sun X, Kan C, Pan R, Guo Z. Metabolic Dysfunction-Associated Steatotic Liver Disease and Chronic Kidney Disease: Unraveling Connections and Advancing Therapies. BRATISL MED J 2025. [DOI: 10.1007/s44411-025-00189-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2025] [Revised: 05/07/2025] [Accepted: 05/09/2025] [Indexed: 06/02/2025]
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Ramírez-Gallegos I, Busquets-Cortes C, Paublini H, López-González ÁA, Martínez-Almoyna-Rifá E, Tárraga López PJ, Ramírez-Manent JI. Association Between Bioimpedance-Determined Metabolic Age and MASLD Risk Scores in Spanish Workers. Metabolites 2025; 15:343. [PMID: 40422919 DOI: 10.3390/metabo15050343] [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: 04/10/2025] [Revised: 05/11/2025] [Accepted: 05/19/2025] [Indexed: 05/28/2025] Open
Abstract
Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent liver disorder with significant metabolic implications. Metabolic age, determined through bioimpedance analysis, has emerged as a potential indicator of overall metabolic health. The objective of this study is to evaluate the association between metabolic age and MASLD risk scores in a cohort of Spanish workers. Methods: A cross-sectional study was conducted on 8590 Spanish workers who underwent annual occupational health examinations between 2019 and 2020. Metabolic age was determined using bioelectrical impedance analysis, and the Avoidable Lost Life Years (ALLY) index was calculated as the difference between their metabolic and chronological age. MASLD risk was assessed using various validated scales, including the Fatty Liver Index (FLI), Hepatic Steatosis Index (HSI), Zhejiang University Index (ZJU), Fatty Liver Disease Index (FLD), and Lipid Accumulation Product (LAP). A multinomial logistic regression analysis was performed to examine the association between metabolic age and MASLD risk scores, adjusting for sociodemographic and lifestyle variables. Results: Higher metabolic age values were observed in individuals with greater MASLD risk across all evaluated scales. The mean metabolic age was consistently lower in women compared to men, and these differences were statistically significant (p < 0.01). Multinomial logistic regression analysis revealed that the strongest associations with increased metabolic age were found for MASLD risk scores, physical inactivity, and poor adherence to the Mediterranean diet. ROC curve analysis demonstrated a high predictive capacity for the FLD (AUC: 0.935 in women and 0.917 in men) and FLI (AUC: 0.900 in women and 0.833 in men), with high Youden index values. Conclusions: Metabolic age is significantly associated with MASLD risk, suggesting its potential as a non-invasive biomarker for identifying individuals with a higher risk for metabolic liver disease. Lifestyle factors, including physical activity and dietary patterns, play a crucial role in modulating metabolic age, highlighting the importance of targeted interventions for MASLD prevention. Further research is warranted to validate metabolic age as a prognostic tool in MASLD risk assessment.
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Affiliation(s)
- Ignacio Ramírez-Gallegos
- ADEMA-Health Group, University Institute of Health Sciences Research (IUNICS), 07009 Palma, Balearic Islands, Spain
| | - Carla Busquets-Cortes
- ADEMA-Health Group, University Institute of Health Sciences Research (IUNICS), 07009 Palma, Balearic Islands, Spain
| | - Hernán Paublini
- ADEMA-Health Group, University Institute of Health Sciences Research (IUNICS), 07009 Palma, Balearic Islands, Spain
| | - Ángel Arturo López-González
- ADEMA-Health Group, University Institute of Health Sciences Research (IUNICS), 07009 Palma, Balearic Islands, Spain
- Faculty of Dentistry, University School ADEMA, 07009 Palma, Balearic Islands, Spain
- Balearic Islands Institute of Health Research (IDISBA), Balearic Islands Health Research Institute Foundation, 07010 Palma, Balearic Islands, Spain
- Balearic Islands Health Service, 07010 Palma, Balearic Islands, Spain
| | - Emilio Martínez-Almoyna-Rifá
- ADEMA-Health Group, University Institute of Health Sciences Research (IUNICS), 07009 Palma, Balearic Islands, Spain
| | - Pedro Juan Tárraga López
- ADEMA-Health Group, University Institute of Health Sciences Research (IUNICS), 07009 Palma, Balearic Islands, Spain
- Faculty of Medicine, University of Castilla la Mancha, 02008 Albacete, Castilla-La Mancha, Spain
| | - José Ignacio Ramírez-Manent
- ADEMA-Health Group, University Institute of Health Sciences Research (IUNICS), 07009 Palma, Balearic Islands, Spain
- Balearic Islands Institute of Health Research (IDISBA), Balearic Islands Health Research Institute Foundation, 07010 Palma, Balearic Islands, Spain
- Balearic Islands Health Service, 07010 Palma, Balearic Islands, Spain
- Faculty of Medicine, University of the Balearic Islands, 07010 Palma, Balearic Islands, Spain
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El-Naby SMA, Khedr NF, El-Ashmawy NE, Ibrahim AO. Proanthocyanidin and mitoglitazone suppress lipogenesis by targeting ferroptosis in metabolic dysfunction-associated steatohepatitis. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-04271-z. [PMID: 40387928 DOI: 10.1007/s00210-025-04271-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Accepted: 05/05/2025] [Indexed: 05/20/2025]
Abstract
Metabolic dysfunction-associated steatohepatitis (MASH) can progress to liver cirrhosis, increasing mortality risk. The study investigates the role of ferroptosis-an inflammatory cell death mechanism-in MASH and evaluates the therapeutic effects of mitoglitazone and proanthocyanidin in targeting ferroptosis to mitigate MASH progression. Forty male albino mice were divided into five groups (n = 8): normal control (NC) fed a standard chow diet and given 2% DMSO; MASH group was maintained on MASH protocol (high fructose-high fat diet); mitoglitazone (Mito) group was kept on MASH protocol and given Mito (10 mg/kg/day); proanthocyanidin (Pro) group was kept on MASH protocol and given Pro (150 mg/kg/day); Mito + Pro co-treated group was given Mito and Pro parallel with MASH protocol, all treatments for 12 weeks. MASH induction significantly (p < 0.001) increased liver weight, liver index, serum liver enzymes (ALT & AST), serum glucose, insulin, insulin resistance (HOMA-IR), lipid profile (total cholesterol, triglycerides, LDL-C), ferroptosis biomarkers (total iron, soluble transferrin receptor-1 (sTfR1), and expression of liver acyl-CoA synthetase long-chain family member 4 (ACSL4) with diffused macrovesicular severe steatosis, and inflammatory cells infiltration in liver tissues compared to NC. However, HDL-cholesterol, ferroptosis biomarkers (liver glutathione peroxidase X4 (GPX4), and total glutathione peroxidase (GPX) activities and glutathione (GSH) content) were reduced significantly (p < 0.001) in MASH group compared to NC. On the other hand, Mito, Pro, and their combination significantly improved ferroptotic biomarkers (GSH, GPX4, sTFR1, and total iron and ACSL-4 gene expression), glucose homeostasis, lipid profile, liver enzymes, and histology compared to MASH group. Combining the insulin-sensitizing properties with targeting of ferroptosis, by the co-treatment with mitoglitazone (MSDC-0160) and proanthocyanidin, could be beneficial in inhibition of lipogenesis with retardation of MASH development in mice.
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Affiliation(s)
- Sohair M Abd El-Naby
- Biochemistry Department, Faculty of Pharmacy, Medical Campus, Tanta University, Tanta, Postal Code: 31527, Egypt
| | - Naglaa F Khedr
- Biochemistry Department, Faculty of Pharmacy, Medical Campus, Tanta University, Tanta, Postal Code: 31527, Egypt.
| | - Nahla E El-Ashmawy
- Biochemistry Department, Faculty of Pharmacy, Medical Campus, Tanta University, Tanta, Postal Code: 31527, Egypt
- Department of Pharmacology and Biochemistry, Faculty of Pharmacy, The British University in Egypt, El Sherouk, Postal Code: 11837, Egypt
| | - Amera O Ibrahim
- Biochemistry Department, Faculty of Pharmacy, Medical Campus, Tanta University, Tanta, Postal Code: 31527, Egypt.
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10
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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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Alhazzani W, AlMuhaidib S, Alotaibi HF, Alomaim WS, Alqahtani R, Sanai FM, Abaalkhail F, Alqahtani SA. A bibliometric analysis of a decade's research on metabolic dysfunction-associated steatotic liver disease in the Arab world. Saudi J Gastroenterol 2025; 31:157-167. [PMID: 40025997 DOI: 10.4103/sjg.sjg_431_24] [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: 12/09/2024] [Accepted: 02/07/2025] [Indexed: 03/04/2025] Open
Abstract
BACKGROUND Metabolic dysfunction-associated steatotic liver disease (MASLD) presents a significant global health challenge, with the Arab region exhibiting a markedly higher prevalence. We aim to evaluate MASLD research output, collaboration patterns, and funding impact in the Arab region over the last decade. METHODS We conducted a bibliometric analysis of MASLD research in 22 Arab countries (2014-2023) using Clarivate Analytics' InCites. Data on MASLD prevalence were extracted from the Global Burden of Disease, while population and economic data from the World Bank. We assessed MASLD-related publications, prevalence, collaboration patterns, and citation and funding impact. RESULTS Between 2014 and 2023, Arab countries contributed 844 publications (3.3% of global MASLD research). We identified positive correlations between MASLD-related publications and gross domestic product (GDP) ( rs = 0.825, P < 0.001), age-standardized prevalence ( rs = 0.627, P = 0.002), and population size ( rs = 0.509, P = 0.016). International collaborations accounted for 48.7% of these publications, with a citation impact of 15.7 compared to the global average of 23.7. Arab-funded MASLD-related publications constituted 19.4% of MASLD publications in the Arab world versus 42.3% globally funded. Citation impacts were similar between Arab-funded (30.6) and globally funded publications (30.3). Of the top 10 countries globally with the highest GDP, 47.8% of the MASLD publications received funding, yielding a citation impact of 33.5. CONCLUSION Despite the high MASLD prevalence, Arab countries exhibit lower research output, impact, and funding compared to global levels. Increased regional collaboration and investment in MASLD research are critical to addressing this disparity.
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Affiliation(s)
- Waleed Alhazzani
- Health Research Center, Ministry of Defense Health Services, Riyadh, Saudi Arabia
- Department of Critical Care, College of Medicine, King Saud University, Riyadh, Saudi Arabia
- Critical Care and Internal Medicine Department, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Shadan AlMuhaidib
- Liver, Digestive, and Lifestyle Health Research Section, and Biostatistics, Epidemiology, and Scientific Computing Department, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Haifa F Alotaibi
- Health Research Center, Ministry of Defense Health Services, Riyadh, Saudi Arabia
| | - Waleed S Alomaim
- Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Rawan Alqahtani
- Department of Business Intelligence and Information Management, Rumah General Hospital, Riyadh Second Health Cluster, Ministry of Health, Riyadh, Saudi Arabia
| | - Faisal M Sanai
- Gastroenterology Section, Department of Medicine, King Abdulaziz Medical City, King Abdullah International Medical Research Center, Jeddah, Saudi Arabia
| | - Faisal Abaalkhail
- Department of Medicine, Gastroenterology Section, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Saleh A Alqahtani
- Liver, Digestive, and Lifestyle Health Research Section, and Organ Transplant Center of Excellence, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
- Division of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, NY, USA
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12
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Lucas MR, Pilling LC, Atkins JL, Melzer D. Incidence of liver complications with hemochromatosis-associated HFE p.C282Y homozygosity: The role of central adiposity. Hepatology 2025; 81:1522-1534. [PMID: 39178373 PMCID: PMC11999091 DOI: 10.1097/hep.0000000000001056] [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: 03/28/2024] [Accepted: 07/30/2024] [Indexed: 08/25/2024]
Abstract
BACKGROUND AND AIMS The HFE p.C282Y+/+ (homozygous) genotype and central adiposity both increase liver disease and diabetes risks, but the combined effects are unclear. We estimated waist-to-hip ratio (WHR) associations with incident clinical outcomes in routine care in p.C282Y+/+ participants in the UK Biobank community cohort. APPROACH AND RESULTS Baseline WHR data available in 1297 male and 1602 female p.C282Y+/+ with 13.3-year mean follow-up for diagnoses. Spline regressions and Cox proportional hazard models were adjusted for age and genetic principal components. Cumulative incidence was from age 40 to 80 years. In p.C282Y+/+ males, there were positive linear WHR relationships for hospital inpatient-diagnosed liver fibrosis/cirrhosis ( p = 2.4 × 10 -5 ), liver cancer ( p = 0.007), non-alcoholic fatty liver disease ( p = 7.7 × 10 -11 ), and type 2 diabetes ( p = 5.1 × 10 -16 ). The hazard ratio for high WHR in p.C282Y+/+ males (≥0.96; 33.9%) was 4.13 for liver fibrosis/cirrhosis (95% CI: 2.04-8.39, p = 8.4 × 10 -5 vs. normal WHR); cumulative age 80 incidence 15.0% (95% CI: 9.8%-22.6%) versus 3.9% (95% CI: 1.9%-7.6%); for liver cancer, cumulative incidence was 9.2% (95% CI: 5.7%-14.6%) versus 3.6% (95% CI: 1.9%-6.6%). Hemochromatosis was diagnosed in 23 (96%) of the 24 high WHR p.C282Y+/+ males with incident fibrosis/cirrhosis. High WHR (≥0.85; 30.0%) p.C282Y+/+ females had raised hazards for liver fibrosis/cirrhosis (hazard ratio = 9.17, 95% CI: 2.51-33.50, p = 3.8 × 10 -7 ) and Non-alcoholic fatty liver disease (hazard ratio = 5.17, 95% CI: 2.48-10.78, p = 1.2 × 10 -5 ). Fibrosis/cirrhosis associations were similar in the subset with additional primary care diagnoses. CONCLUSIONS In p.C282Y+/+ males and females, increasing WHR is associated with substantially higher risks of liver complications. Interventions to reduce central adiposity to improve these outcomes should be tested.
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13
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Chen Z, Zhu Y, Wang L, Cong R, Feng B, Cai W, Liang M, Li D, Wang S, Hu M, Mi Y, Wang S, Ma X, Zhao X. Virtual MR Elastography and Multi-b-value DWI Models for Predicting Microvascular Invasion in Solitary BCLC Stage A Hepatocellular Carcinoma. Acad Radiol 2025; 32:2569-2584. [PMID: 39643466 DOI: 10.1016/j.acra.2024.11.027] [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: 06/12/2024] [Revised: 11/07/2024] [Accepted: 11/11/2024] [Indexed: 12/09/2024]
Abstract
RATIONALE AND OBJECTIVES To evaluate the performance of virtual MR elastography (vMRE) for predicting microvascular invasion (MVI) in Barcelona Clinic Liver Cancer (BCLC) stage A (≤ 5.0 cm) hepatocellular carcinoma (HCC) and to construct a combined nomogram based on vMRE, multi-b-value DWI models, and clinical-radiological (CR) features. METHODS Consecutive patients with suspected HCC who underwent multi-b-value DWI examinations were prospectively collected. Quantitative parameters from vMRE, mono-exponential, intravoxel incoherent motion, and diffusion kurtosis imaging models were obtained. Multivariate logistic regression was used to identify independent MVI predictors and build prediction models. A combined MRI_Score was constructed using independent quantitative parameters. A visualized nomogram was built based on significant CR features and MRI_Score. The predictive performance of quantitative parameters and models was evaluated. RESULTS The study included 103 patients (median age: 56 years; range: 35-70 years; 87 males and 16 females). Diffusion-based shear modulus (μDiff) exhibited a predictive performance for MVI with area under the curve (AUC) of 0.735. The MRI_Score was developed employing true diffusion coefficient (D), mean kurtosis (MK), and μDiff. CR model and MRI_Score achieved AUCs of 0.787 and 0.840, respectively. The combined nomogram based on AFP, corona enhancement, tumor capsule, TTPVI, and MRI_Score significantly improved the predictive performance to an AUC of 0.931 (Delong test p < 0.05). CONCLUSION vMRE exhibited great potential for predicting MVI in BCLC stage A HCC. The combined nomogram integrating CR features, vMRE, and quantitative diffusion parameters significantly improved the predictive accuracy and could potentially assist clinicians in identifying appropriate treatment options.
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Affiliation(s)
- Zhaowei Chen
- Department of Diagnostic Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China (Z.C., Y.Z., L.W., R.C., B.F., W.C., M.L., D.L., S.W., M.H., Y.M., X.M., X.Z.).
| | - Yongjian Zhu
- Department of Diagnostic Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China (Z.C., Y.Z., L.W., R.C., B.F., W.C., M.L., D.L., S.W., M.H., Y.M., X.M., X.Z.).
| | - Leyao Wang
- Department of Diagnostic Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China (Z.C., Y.Z., L.W., R.C., B.F., W.C., M.L., D.L., S.W., M.H., Y.M., X.M., X.Z.).
| | - Rong Cong
- Department of Diagnostic Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China (Z.C., Y.Z., L.W., R.C., B.F., W.C., M.L., D.L., S.W., M.H., Y.M., X.M., X.Z.).
| | - Bing Feng
- Department of Diagnostic Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China (Z.C., Y.Z., L.W., R.C., B.F., W.C., M.L., D.L., S.W., M.H., Y.M., X.M., X.Z.).
| | - Wei Cai
- Department of Diagnostic Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China (Z.C., Y.Z., L.W., R.C., B.F., W.C., M.L., D.L., S.W., M.H., Y.M., X.M., X.Z.).
| | - Meng Liang
- Department of Diagnostic Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China (Z.C., Y.Z., L.W., R.C., B.F., W.C., M.L., D.L., S.W., M.H., Y.M., X.M., X.Z.).
| | - Dengfeng Li
- Department of Diagnostic Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China (Z.C., Y.Z., L.W., R.C., B.F., W.C., M.L., D.L., S.W., M.H., Y.M., X.M., X.Z.).
| | - Shuang Wang
- Department of Diagnostic Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China (Z.C., Y.Z., L.W., R.C., B.F., W.C., M.L., D.L., S.W., M.H., Y.M., X.M., X.Z.).
| | - Mancang Hu
- Department of Diagnostic Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China (Z.C., Y.Z., L.W., R.C., B.F., W.C., M.L., D.L., S.W., M.H., Y.M., X.M., X.Z.).
| | - Yongtao Mi
- Department of Diagnostic Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China (Z.C., Y.Z., L.W., R.C., B.F., W.C., M.L., D.L., S.W., M.H., Y.M., X.M., X.Z.).
| | - Sicong Wang
- Magnetic Resonance Imaging Research, General Electric Healthcare (China), Beijing 100176, China (S.W.).
| | - Xiaohong Ma
- Department of Diagnostic Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China (Z.C., Y.Z., L.W., R.C., B.F., W.C., M.L., D.L., S.W., M.H., Y.M., X.M., X.Z.).
| | - Xinming Zhao
- Department of Diagnostic Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China (Z.C., Y.Z., L.W., R.C., B.F., W.C., M.L., D.L., S.W., M.H., Y.M., X.M., X.Z.).
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14
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Figlioli G, Piovani D, Tsantes AG, Pugliese N, Nikolopoulos GK, Hassan C, Repici A, Lleo A, Aghemo A, Bonovas S. Burden of cancer attributable to high body mass index: A systematic analysis of the Global Burden of Disease Study 2021. Clin Nutr 2025; 48:144-152. [PMID: 40215883 DOI: 10.1016/j.clnu.2025.04.002] [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: 01/28/2025] [Revised: 03/12/2025] [Accepted: 04/01/2025] [Indexed: 04/20/2025]
Abstract
BACKGROUND High body mass index (BMI) is a well-established cancer risk factor. Reliable, updated data are essential for guiding public health policies and designing effective interventions to reduce the cancer burden associated with high BMI. METHODS Data from the Global Burden of Disease Study 2021 on cancer burden attributable to high BMI were analysed globally, stratified by sex, age, geographic region, cancer type, and socio-demographic index (SDI). Temporal trends in age-standardized rates from 1990 to 2021 were evaluated using estimated annual percentage changes. RESULTS In 2021, cancer attributable to high BMI resulted in 356.74 thousand deaths (95% uncertainty interval: 146.12-581.01) and 8.89 million (3.75-14.38) Disability-Adjusted Life Years (DALYs), with females bearing the largest burden. From 1990 to 2021, age-standardized rates of high BMI-related cancer deaths increased by 0.35% annually, while DALYs rose by 0.42% annually. In 2021, the burden of cancer deaths and DALYs attributable to high BMI varied considerably across geographical regions. Low-middle SDI regions experienced the largest increases in death and DALY rates attributable to high BMI, while these rates declined in high SDI regions. Colon and rectum cancers accounted for the greatest number of deaths and DALYs, while pancreatic cancer showed the most rapid growth in attributable burden. CONCLUSIONS High BMI is a major contributor to the global cancer burden, with significant variation by sex, cancer type, region, and SDI level. Targeted public health strategies are urgently needed to mitigate the growing impact of overweight and obesity on cancer.
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Affiliation(s)
- Gisella Figlioli
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy; IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Daniele Piovani
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy; IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Andreas G Tsantes
- Laboratory of Haematology and Blood Bank Unit, "Attiko" Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Nicola Pugliese
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy; Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | | | - Cesare Hassan
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy; Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Alessandro Repici
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy; Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Ana Lleo
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy; Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Alessio Aghemo
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy; Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Stefanos Bonovas
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy; IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.
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15
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Momeni S, Hajizadeh-Sharafabad F, Pashaei MR. Adherence to the Dietary Approaches to Stop Hypertension diet was associated with the risk of nonalcoholic fatty liver disease: A systematic review and meta-analysis of observational studies. Nutr Res 2025; 137:14-21. [PMID: 40188580 DOI: 10.1016/j.nutres.2025.03.005] [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: 11/22/2024] [Revised: 03/10/2025] [Accepted: 03/10/2025] [Indexed: 04/08/2025]
Abstract
The Dietary Approaches to Stop Hypertension (DASH) diet has long been recommended for the management of hypertension, while it may provide other metabolic benefits. This study aimed to analyze the association between the DASH diet and nonalcoholic fatty liver disease (NAFLD) risk through a systematic review and meta-analysis. We hypothesized that the adherence to DASH diet is inversely associated with NAFLD risk. PubMed, Web of Science, Scopus, and Google Scholar were searched to find relevant publications up to September 2024. We included observational studies evaluating the association between the DASH diet score and the risk of NAFLD. Pooling effect sizes was conducted using a random effects model to determine the odd ratio (OR) of incident NAFLD associated with the DASH diet. Eight studies with a total of 120937 participants were included in the meta-analysis. The pooled OR for NAFLD in the highest score of the DASH diet vs. lowest score was 0.78 (95% CI: 0.70-0.86, P < .001), indicating a significant inverse association between the DASH diet and NAFLD risk. The result was stable to sensitivity analysis. A significant heterogeneity was observed between studies (I2=62.7%, P = .009). Overall, this meta-analysis showed that individuals with the highest score of the DASH diet were 22% less likely to have NAFLD in comparison to those with the lowest score of the DASH diet, independent of body mass index. Further high-quality prospective studies are needed to confirm the protective effect of the DASH diet on NAFLD.
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Affiliation(s)
- Sadra Momeni
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran
| | | | - Mohammad Reza Pashaei
- Patient Safety Research Center, Clinical Research Institute, Urmia University of Medical Sciences, Urmia, Iran; Department of Internal Medicine, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran.
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16
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Cho W, Choi SW, Lim DS, Gwon HJ, Abd El-Aty AM, Ahmet Aydemir H, Hong SA, Jeong JH, Jung TW. Donepezil alleviates hepatic steatosis by mitigating ER stress via the AMPK/autophagy pathway. Mol Cell Endocrinol 2025; 601:112523. [PMID: 40118333 DOI: 10.1016/j.mce.2025.112523] [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: 12/30/2024] [Revised: 02/18/2025] [Accepted: 03/15/2025] [Indexed: 03/23/2025]
Abstract
Donepezil (Do), a drug known for its ability to reduce neuronal inflammation and for its use in the treatment of Alzheimer's disease, has shown promise in combating hepatic lipid accumulation in hyperlipidemic conditions and endoplasmic reticulum (ER) stress, a factor associated with alterations in hepatic lipid metabolism. However, the mechanisms by which these problems are alleviated have not been fully elucidated. In this study, we investigated the effects of Do on hepatic lipid metabolism through both in vitro and in vivo studies. We examined the expression of proteins associated with lipogenesis and ER stress via immunoblot analysis, and hepatic lipid accumulation was assessed via oil red O staining. In addition, autophagosome formation was analyzed by counting MDC-positive cells. Our results demonstrated that Do treatment improved hepatic lipid metabolism and reduced the expression of ER stress markers, resulting in decreased lipogenic lipid deposition and apoptosis in the hepatocytes and livers of hyperlipidemic mice. Mechanistically, knocking down AMPK or inhibiting autophagy with 3-methyladenine (3 MA) attenuated the effects of Do on palmitate-exposed hepatocytes. These results suggest that Do alleviates hepatic ER stress via the AMPK/autophagy pathway and AMPK-mediated fatty acid oxidation, resulting in improved hepatic lipid metabolism and reduced hepatic steatosis and apoptosis. Our study provides evidence that Do may be a promising therapeutic approach for Alzheimer's disease patients with metabolic dysfunction-associated steatotic liver disease (MASLD).
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Affiliation(s)
- Wonjun Cho
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
| | - Sung Woo Choi
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
| | - Do Su Lim
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea; Department of Global Innovative Drugs, Graduate School of Chung-Ang University, Seoul, Republic of Korea
| | - Hyeon Ji Gwon
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea; Department of Global Innovative Drugs, Graduate School of Chung-Ang University, Seoul, Republic of Korea
| | - A M Abd El-Aty
- Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, 12211, Giza, Egypt; Department of Medical Pharmacology, Medical Faculty, Ataturk University, Erzurum 25240, Turkey.
| | - Hacı Ahmet Aydemir
- Department of Family Medicine, Erzurum Regional Training and Research Hospital, Erzurum 25000, Turkey; Dr. Filiz Dolunay Family Health Center Unit Number:59, Yakutiye, Erzurum, Turkey
| | - Soon Auck Hong
- Department of Pathology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
| | - Ji Hoon Jeong
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea; Department of Global Innovative Drugs, Graduate School of Chung-Ang University, Seoul, Republic of Korea
| | - Tae Woo Jung
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea.
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17
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Chen TT, Shan S, Chen YN, Li MQ, Zhang HJ, Li L, Gao PP, Li N, Huang Y, Li XL, Wei W, Sun WY. Deficiency of β-arrestin2 ameliorates MASLD in mice by promoting the activation of TAK1/AMPK signaling. Arch Pharm Res 2025; 48:384-403. [PMID: 40341987 DOI: 10.1007/s12272-025-01544-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Accepted: 04/24/2025] [Indexed: 05/11/2025]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a liver manifestation of metabolic syndrome characterized by excessive hepatic lipid accumulation and lipid metabolism disorders. It has become the most common chronic liver disease worldwide. β-arrestin2 is a multifunctional scaffold protein that is among the most important regulatory molecules, and it exerts key roles in regulating various cellular processes, such as immune response, cellular collagen production, and inflammation. In the current study, we aimed to explore the function of β-arrestin2 in the development and progression of MASLD. Firstly, we observed that the expression of β-arrestin2 was upregulated in liver samples from patients with MASLD. Then, the western diet (WD) combined with CCl4 injection-induced MASLD was established in wild-type mice, and showed that liver β-arrestin2 expression was also gradually increased, and positively correlated with the degree of lipid metabolism disorder during MASLD progression. Ulteriorly, β-arrestin2 knockout (Arrb2 KO) mice were utilized to induce the MASLD model and found that β-arrestin2 deficiency significantly ameliorated lipid accumulation and inflammatory response in the liver of MASLD mice. Furthermore, the in vitro depletion and overexpression experiments showed that increased β-arrestin2 aggravated lipid accumulation via inhibiting the activation of the TAK1/AMPK pathway, which may be mediated by competitively binding to TAB1 with TAK1. These findings suggest that β-arrestin2 is essential to regulate intrahepatic lipid metabolism. Here, we provide a novel insight in understanding of the expression and function of β-arrestin2 in MASLD, demonstrating that it may be a potential therapeutic target for MASLD treatment.
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Affiliation(s)
- Ting-Ting Chen
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Anhui Medical University, Hefei, 230032, Anhui, China
| | - Shan Shan
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Anhui Medical University, Hefei, 230032, Anhui, China
| | - Ya-Ning Chen
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Anhui Medical University, Hefei, 230032, Anhui, China
| | - Meng-Qi Li
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Anhui Medical University, Hefei, 230032, Anhui, China
| | - Hui-Juan Zhang
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Anhui Medical University, Hefei, 230032, Anhui, China
| | - Ling Li
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Anhui Medical University, Hefei, 230032, Anhui, China
| | - Ping-Ping Gao
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Anhui Medical University, Hefei, 230032, Anhui, China
| | - Nan Li
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Anhui Medical University, Hefei, 230032, Anhui, China
| | - Yan Huang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, 230032, Anhui, China
| | - Xiao-Lei Li
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Anhui Medical University, Hefei, 230032, Anhui, China
| | - Wei Wei
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Anhui Medical University, Hefei, 230032, Anhui, China.
| | - Wu-Yi Sun
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Anhui Medical University, Hefei, 230032, Anhui, China.
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18
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Zhu Z, Liao Y, Mou Q, Liu H, Shen Y, Zhu L, Cong S. Thymosin β4 Regulates Tissue Inflammatory Response in Mouse Nonalcoholic Fatty Liver Disease by Promoting Macrophage M2-Type Polarization. J Inflamm Res 2025; 18:5791-5809. [PMID: 40322536 PMCID: PMC12049133 DOI: 10.2147/jir.s492814] [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: 09/14/2024] [Accepted: 12/15/2024] [Indexed: 05/08/2025] Open
Abstract
Introduction Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis, insulin resistance, and systemic pro-inflammatory response. Thymosin β4 (Tβ4) is a bioactive polypeptide that inhibits extracellular matrix (ECM) deposition and protects the liver. It can achieve immune homeostasis by regulating the polarization of liver macrophages and is a potential treatment for NAFLD. Methods A dataset was used to evaluate the expression of Tβ4 in fatty and non-fatty adjacent tissues of primary hepatocellular carcinoma. NAFLD was induced in C57 mice with methionine and choline-deficient diet (MCD), siRNATβ4 was injected into the tail vein to reduce liver Tβ4, and the therapeutic effect of Tβ4 was observed by phagocytosis of macrophages with clodronate liposomes. Hematoxylin and Eosin staining (HE) staining was used to observe the inflammation of mice in each group, and oil red O staining was used to determine the lipid accumulation. Macrophage polarization was detected by immunofluorescence assay. In the extrachromosomal experiment of oil red O, human myeloid leukemia mononuclear (THP-1) cells was co-cultured with human hepatic (LO2) constructed with oleic acid to detect the changes of aspartate transaminase (AST) and alanine transaminase (ALT) in supernatant and the apoptosis of LO2 under the intervention of different concentrations of Tβ4. Results Tβ4 allowed the mice to recover from NAFLD and reduce liver inflammation more effectively. Liver steatosis was more severe in sirnat4 mice. Macrophages are involved in Tβ4 treatment of NAFLD. The expression level of M1 phenotype in macrophages treated with Tβ4 decreased, and the apoptosis of hepatocytes decreased. At the same time, Tβ4 down-regulates signal transduction and activator of transcription1 (STAT1) phosphorylation and increases suppressor of cytokine signaling1/3 (SOCS1/3) expression in hepatocytes. Discussion This study revealed the molecular mechanism of the effective effect of Tβ4 on the polarization of liver macrophages, suggesting that Tβ4 may be a potential therapeutic measure for NAFLD.
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Affiliation(s)
- Zixin Zhu
- Department of Blood Transfusion, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, People’s Republic of China
| | - Yifan Liao
- School of Clinical Laboratory Science, Guizhou Medical University, Guiyang, 550004, People’s Republic of China
| | - Qiuju Mou
- Department of Blood Transfusion, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, People’s Republic of China
| | - Hongjie Liu
- School of Clinical Laboratory Science, Guizhou Medical University, Guiyang, 550004, People’s Republic of China
| | - Yuxue Shen
- School of Clinical Laboratory Science, Guizhou Medical University, Guiyang, 550004, People’s Republic of China
| | - Lili Zhu
- Department of Blood Transfusion, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, People’s Republic of China
| | - Shuo Cong
- Department of Blood Transfusion, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, People’s Republic of China
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19
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Zakaria AY, Badawi R, Osama H, Abdelrahman MA, El-Kalaawy AM. A Comparative Study of N-Acetyl Cysteine, Rosuvastatin, and Vitamin E in the Management of Patients with Non-Alcoholic Steatohepatitis: A Randomized Controlled Trial. Pharmaceuticals (Basel) 2025; 18:650. [PMID: 40430469 PMCID: PMC12114936 DOI: 10.3390/ph18050650] [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: 01/30/2025] [Revised: 04/03/2025] [Accepted: 04/10/2025] [Indexed: 05/29/2025] Open
Abstract
Background: Non-alcoholic steatohepatitis (NASH) is characterized by increased production of proinflammatory cytokines, fibrosis, and hepatocyte apoptosis. This study aimed to assess the efficacy of N-acetyl cysteine (NAC), rosuvastatin (RSV), and vitamin E (VE) in patients with NASH. Methods: A double-blinded, parallel, randomized, controlled study was conducted and registered on clinicaltrials.gov (Identifier: NCT06105060), involving 135 NASH participants, who were divided into three groups: the control group (group 1), consisting of patients receiving standard therapy VE at a dosage of 400 IU twice daily. In the treated group (group 2), patients were administered NAC at a dosage of 1200 mg twice daily, while treatment (group 3) received RSV at a dosage of 20 mg once daily. FibroScan® examination of liver tissue and fibrosis scores, along with tests for liver aminotransferases, lipid profile, glycemic parameters, and renal and hepatic functions, were assessed before and after six months of treatment. Results: The analyzed groups demonstrated a significant reduction in steatosis and lipid peroxidation (p < 0.05). The NAC group demonstrated greater anti-inflammatory and anti-apoptotic effects compared to the RSV group, although this difference was not significant in the control group. NAC is conceded as the only significant antifibrotic agent in liver stiffness measurement (LSM), biological marker findings, and non-invasive liver fibrosis scores (p < 0.05), in addition to its improvement of several metabolic parameters and health-related quality of life. Conclusions: Patients receiving NAC demonstrated safety and efficacy in enhancing steatosis, fibrosis, and metabolic parameters, representing a novel strategy in the management of NASH.
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Affiliation(s)
- Amr Y. Zakaria
- Pharmacy Practice (Clinical Pharmacy) Department, Faculty of Pharmacy, Horus University-Egypt, New Damietta 34517, Egypt;
| | - Rehab Badawi
- Tropical Medicine and Infectious Diseases Department, Faculty of Medicine, Tanta University, Tanta 31527, Egypt;
| | - Hasnaa Osama
- Clinical Pharmacy Department, Faculty of Pharmacy, Beni-Suef University, Beni Suef 62514, Egypt;
| | - Mona A. Abdelrahman
- Clinical Pharmacy Department, Faculty of Pharmacy, Beni-Suef University, Beni Suef 62514, Egypt;
| | - Asmaa M. El-Kalaawy
- Pharmacology Department, Faculty of Medicine, Beni-Suef University, Beni Suef 62511, Egypt;
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20
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Ramírez-Mejía MM, Martínez-Sánchez FD, Córdova-Gallardo J, Méndez-Sánchez N. Evaluating the RESET care program: Advancing towards scalable and effective healthcare solutions for metabolic dysfunction-associated liver disease. World J Hepatol 2025; 17:105254. [PMID: 40308819 PMCID: PMC12038424 DOI: 10.4254/wjh.v17.i4.105254] [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: 01/16/2025] [Revised: 02/26/2025] [Accepted: 03/08/2025] [Indexed: 04/25/2025] Open
Abstract
In this article, we discuss the recently published article by Soni et al. This study explores the effectiveness of a comprehensive digital health program, RESET care, which integrates personalized dietary plans, structured exercise, and cognitive behavioral therapy delivered through a mobile app equipped with Internet of Things devices such as body composition analyzers and smartwatches. Metabolic dysfunction-associated liver disease (MASLD), a global health burden affecting approximately 25% of the population, demands sustainable lifestyle modifications as its primary management strategy. The study reports that 100% of participants in the comprehensive intervention group (diet + exercise + cognitive behavioral therapy) achieved a weight reduction ≥ 7% (6.99 ± 2.98 kg, 7.00% ± 3.39%; P = 0.002), a clinically significant threshold for MASLD improvement. In addition, participants showed a mean weight reduction of 6.99 kg (101.10 ± 17.85 vs 94.11 ± 17.38, P < 0.001) and a body mass index reduction of 2.18 kg/m² (32.90 ± 3.02 vs 30.72 ± 3.41, P < 0.001). These results underscore the potential of digital health platforms to provide scalable, evidence-based solutions for the treatment of MASLD. While these results highlight the potential of digital platforms in the scalable and personalized management of MASLD, the small study sample size and short duration of follow-up limit the generalizability of the results. Future large-scale, long-term trials are needed to confirm sustained benefits, cost-effectiveness, and broader applicability. This letter contextualizes the study within the evolving landscape of MASLD management and emphasizes the clinical implications of integrating digital technologies into standard care.
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Affiliation(s)
- Mariana M Ramírez-Mejía
- Plan of Combined Studies in Medicine, Faculty of Medicine, National Autonomous University of Mexico, Mexico City 04360, Mexico
- Liver Research Unit, Medica Sur Clinic and Foundation, Mexico City 14050, Mexico
| | | | | | - Nahum Méndez-Sánchez
- Liver Research Unit, Medica Sur Clinic and Foundation, Mexico City 14050, Mexico
- Faculty of Medicine, National Autonomous University of Mexico, Mexico City 04360, Mexico.
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21
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Xia W, Xiao L, Cheng H, Feng Y. TRIB3 Is a Hub Gene in Steatohepatitis and Aggravates Lipid Deposition and Inflammation in Hepatocytes. Diabetes Metab Syndr Obes 2025; 18:1111-1124. [PMID: 40255971 PMCID: PMC12009121 DOI: 10.2147/dmso.s486377] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Accepted: 03/20/2025] [Indexed: 04/22/2025] Open
Abstract
Background Non-alcoholic fatty liver disease (NAFLD), also known as Metabolic dysfunction-associated fatty liver disease (MASLD), has become one of the most common chronic liver diseases worldwide, approximately 30% of adults and 70%~80% of patients with obesity and diabetes suffer from NAFLD. Objective We attempted to find a potential hub gene in NAFLD hepatocyte cell model induced by palmitic acid and oil acid (PAOA), and investigated the function of the hub-gene. Methods We searched and downloaded the GSE122660 dataset from GEO-DataSets, and differentially expressed genes (DEGs) were analyzed using R software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to identify the significantly activated signaling pathways in steatohepatitis. A protein-protein interaction (PPI) network was constructed to identify hub genes among the DEGs. qRT-PCR, Western blotting, and Oil Red O staining were used to explore the function of hub genes in PAOA-induced hepatocytes in vitro. Results A total of 255 DEGs were identified in the GSE122660 dataset and were primarily associated with inflammation-and lipid metabolism-related pathways. The tribbles pseudokinase 3 (TRIB3) was highlighted as a hub gene. We found that TRIB3 was upregulated in CDHFDinduced NAFLD mouse liver tissue and hepatocyte cell models. Furthermore, TRIB3 aggravated PAOA-induced lipid accumulation and inflammation in hepatocytes in vitro. Conclusion The present study identified TRIB3 as a hub gene for steatohepatitis and aggravated lipid accumulation and inflammation in vitro. Therefore, targeting TRIB3 could be a potential pharmacological strategy for NAFLD treatment.
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Affiliation(s)
- Wen Xia
- Department of Cardiovascular Medicine, Wuhan No.1 Hospital, Wuhan, Hubei, People’s Republic of China
| | - Li Xiao
- Department of Cardiovascular Medicine, Wuhan No.1 Hospital, Wuhan, Hubei, People’s Republic of China
| | - Huan Cheng
- Department of Cardiovascular Medicine, Wuhan No.1 Hospital, Wuhan, Hubei, People’s Republic of China
| | - Yuwei Feng
- Department of Hepatology with Integrated Traditional Chinese and Western Medicine, Hubei No.3 People’s Hospital of Jianghan University, Wuhan, Hubei, People’s Republic of China
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Sonaglioni A, Cerini F, Fagiani V, Nicolosi GL, Rumi MG, Lombardo M, Muti P. Effect of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) on Left Ventricular Mechanics in Patients Without Overt Cardiac Disease: A Systematic Review and Meta-Analysis. J Clin Med 2025; 14:2690. [PMID: 40283520 PMCID: PMC12028084 DOI: 10.3390/jcm14082690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2025] [Revised: 04/10/2025] [Accepted: 04/12/2025] [Indexed: 04/29/2025] Open
Abstract
Background: Over the last two decades, a fair number of echocardiographic studies have investigated the influence of metabolic dysfunction-associated steatotic liver disease (MASLD) on myocardial strain and strain rate parameters assessed by speckle tracking echocardiography (STE) in individuals without overt heart disease, reporting not univocal results. We aimed at analyzing the main findings of these studies. Methods: All studies examining conventional echoDoppler parameters by transthoracic echocardiography (TTE) and left ventricular (LV) mechanics [LV-global longitudinal strain (GLS), LV-global strain rate in systole (GSRs), in early diastole (GSRe) and late diastole (GSRl)] by STE in MASLD patients without known heart disease vs. healthy individuals, were searched on PubMed, Embase and Scopus databases. The primary endpoint was to quantify the effect of MASLD on LV-GLS in individuals without overt cardiac disease. Continuous data [LV-GLS, LV-GLSRs, LV-GLSRe, LV-GLSRl and left ventricular ejection fraction (LVEF)] were pooled as the standardized mean difference (SMD) comparing MASLD cohorts with healthy controls. Results: A total of 11 studies were included, totaling 1348 MASLD patients and 6098 healthy controls. Overall, MASLD showed a medium effect on LV-GLS (SMD -0.6894; 95%CI -0.895, -0.472, p < 0.001) and LV-GLSRs (SMD -0.753; 95%CI -1.501, -0.006, p = 0.048), a large effect on LV-GLSRe (SMD -0.837; 95%CI -1.662, -0.012, p = 0.047) and a small and not statistically significant effect on LV-GLSRl (SMD -0.375; 95%CI -1.113, 0.363, p = 0.319) and LVEF (SMD -0.134; 95%CI -0.285, 0.017, p = 0.083). The overall I2 statistic was 86.4%, 89.4%, 90.9%, 89.6% and 72.5% for LV-GLS, LV-GLSRs, LV-GLSRe, LV-GLSRl and LVEF studies, respectively, indicating high between-study heterogeneity. Egger's test for LV-GLS studies gave a p value of 0.11, 0.26, 0.40, 0.32 and 0.42 for LV-GLS, LV-GLSRs, LV-GLSRe, LV-GLSRl and LVEF studies, respectively, thus excluding publication bias. Meta-regression analysis excluded any correlation between potential confounders and LV-GLS in MASLD individuals (all p > 0.05). Sensitivity analysis confirmed the robustness of study results. Conclusions: MASLD has a medium effect on LV-GLS, independently of demographics, anthropometrics and the cardiovascular disease burden. STE analysis may allow early detection of subclinical LV systolic dysfunction in MASLD patients, potentially identifying those who may develop heart failure later in life.
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Affiliation(s)
| | - Federica Cerini
- Hepatology Unit, IRCCS MultiMedica, 20123 Milan, Italy; (F.C.); (M.G.R.)
- Department of Clinical Sciences and Community Health, Dipartimento di Eccellenza 2023–2027, University of Milan, 20122 Milan, Italy
| | - Valeria Fagiani
- Department of Emergency, Fondazione IRCSS Ca’ Granda, Ospedale Maggiore Policlinico, 20122 Milan, Italy;
| | | | - Maria Grazia Rumi
- Hepatology Unit, IRCCS MultiMedica, 20123 Milan, Italy; (F.C.); (M.G.R.)
- Department of Clinical Sciences and Community Health, Dipartimento di Eccellenza 2023–2027, University of Milan, 20122 Milan, Italy
| | | | - Paola Muti
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20122 Milan, Italy;
- IRCCS MultiMedica, 20138 Milan, Italy
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23
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Xu H, Wang X, Song S, Zhang L. Efficacy of sodium butyrate in improving nonalcoholic fatty liver disease: A meta-analysis of preclinical studies. Medicine (Baltimore) 2025; 104:e42101. [PMID: 40228267 PMCID: PMC11999427 DOI: 10.1097/md.0000000000042101] [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: 10/20/2023] [Accepted: 03/26/2025] [Indexed: 04/16/2025] Open
Abstract
BACKGROUND To evaluate the efficacy of sodium butyrate (NaB) in ameliorating nonalcoholic fatty liver disease (NAFLD) in animals. METHODS Chinese and English databases (including PubMed, Embase, Web of Science, Cochrane Library, CNKI, Wangfang Data, CQVIP, and SinoMed) were searched for literature related to NaB to improve the animal model of NAFLD from the establishment of each database to 2023-02. 2 researchers independently screened the literature and extracted the data. The SYRCLE tool was used to assess risk of bias. The extracted data were analyzed using Revman 5.3 and Stata 17.0. RESULTS A total of 1008 relevant references were reviewed, and 12 animal experiments involving 192 animals were included in the analysis: 96 in the NaB group and 96 in the model group. The results showed that animals in the NaB group had significantly lower levels of alanine aminotransferase (standardized mean difference (SMD) = -1.29, 95% confidence interval (CI) (-2.08, -0.49), P = .002], aspartate aminotransferase [SMD = -1.13, 95% CI (-1.75, -0.50), P = .0004], NAFLD activity scores [SMD = -3.19, 95%CI(-4.80, -1.58), P = .0001], triglyceride [SMD = -1.28, 95%CI(-1.66, -0.90), P < .00001] and total cholesterol levels [SMD = -1.39, 95%CI(-2.11, -0.67), P = .0002], interleukin-1β [SMD = -1.40, 95%CI (-1.87, -0.92), P < .00001], interleukin-6 [SMD = -1.38, 95%CI (-1.87, -0.90), P < .00001], tumor necrosis factor-alpha [SMD = -1.69, 95% CI (-2.10, -1.28), P < .00001], and other pro-inflammatory factors, and significantly higher tight junction protein-1 expression [SMD = 1.06, 95% CI (0.43,1.69), P = .0009]. CONCLUSION NaB treatment improves liver function in animals with NAFLD, protected the liver tissue, reduced triglyceride and total cholesterol levels, inhibited inflammation, and protected intestinal barrier function.
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Affiliation(s)
- Hongxin Xu
- Department of General Medicine, Ninth People’s Hospital of Zhengzhou, Zhengzhou, China
| | - Xia Wang
- Second Clinical Medical College, Binzhou Medical University, Yantai, China
| | - Shoujun Song
- Department of General Medicine, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, China
| | - Lingyun Zhang
- Department of General Medicine, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, China
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24
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Araszkiewicz AF, Jańczak K, Wójcik P, Białecki B, Kubiak S, Szczechowski M, Januszkiewicz-Lewandowska D. MTHFR Gene Polymorphisms: A Single Gene with Wide-Ranging Clinical Implications-A Review. Genes (Basel) 2025; 16:441. [PMID: 40282401 PMCID: PMC12027316 DOI: 10.3390/genes16040441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2025] [Revised: 04/03/2025] [Accepted: 04/05/2025] [Indexed: 04/29/2025] Open
Abstract
The enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a process essential for the methylation of homocysteine to methionine. Polymorphisms in the MTHFR gene can reduce enzyme activity, disrupting the folate cycle and leading to hyperhomocysteinemia. The two most common polymorphisms associated with this gene are 667C>T (rs1801133) and 1298A>C (rs1801131). Background: This review provides a comprehensive summary of the current knowledge regarding MTHFR polymorphisms, with a particular focus on their potential impact on disease susceptibility. We hope this review will serve as a valuable resource for understanding the significance of MTHFR polymorphisms and their complex relationships with various diseases. Methods: For this review, we prioritized recent evidence, focusing on reviews and meta-analyses published between 2015 and 2025, sourced from PubMed and Google Scholar. Results: We explore the connection between these polymorphisms and a broad spectrum of medical conditions, including cardiovascular diseases and oxidative stress pathology; neurological and psychiatric disorders, such as Autism Spectrum Disorder, Alzheimer's disease, Schizophrenia, and Major Depressive Disorder; fertility, pregnancy, and neonatal complications, including recurrent pregnancy loss, pre-eclampsia, preterm birth, low birth weight, and neural tube defects; metabolic disorders, such as diabetes mellitus, inflammatory bowel disease, and non-alcoholic fatty liver disease; and oncological conditions, including breast, prostate, and ovarian cancers; as well as leukemia, and autoimmune diseases, particularly rheumatoid arthritis. Conclusions: While some diseases have a well-established association with MTHFR polymorphisms, others require further investigation. Our analysis highlights the crucial role of environmental factors, such as ethnic background and dietary folate intake, in influencing study outcomes.
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Affiliation(s)
- Antoni F. Araszkiewicz
- Faculty of Medicine, Poznan University of Medical Sciences, ul. Fredry 10, 61-701 Poznan, Poland; (A.F.A.); (K.J.); (P.W.); (B.B.); (S.K.); (M.S.)
| | - Krzysztof Jańczak
- Faculty of Medicine, Poznan University of Medical Sciences, ul. Fredry 10, 61-701 Poznan, Poland; (A.F.A.); (K.J.); (P.W.); (B.B.); (S.K.); (M.S.)
| | - Paweł Wójcik
- Faculty of Medicine, Poznan University of Medical Sciences, ul. Fredry 10, 61-701 Poznan, Poland; (A.F.A.); (K.J.); (P.W.); (B.B.); (S.K.); (M.S.)
| | - Bartłomiej Białecki
- Faculty of Medicine, Poznan University of Medical Sciences, ul. Fredry 10, 61-701 Poznan, Poland; (A.F.A.); (K.J.); (P.W.); (B.B.); (S.K.); (M.S.)
| | - Szymon Kubiak
- Faculty of Medicine, Poznan University of Medical Sciences, ul. Fredry 10, 61-701 Poznan, Poland; (A.F.A.); (K.J.); (P.W.); (B.B.); (S.K.); (M.S.)
| | - Michał Szczechowski
- Faculty of Medicine, Poznan University of Medical Sciences, ul. Fredry 10, 61-701 Poznan, Poland; (A.F.A.); (K.J.); (P.W.); (B.B.); (S.K.); (M.S.)
| | - Danuta Januszkiewicz-Lewandowska
- Clinic of Oncology, Hematology and Pediatric Transplantology, Poznan University of Medical Sciences, ul. Fredry 10, 61-701 Poznan, Poland
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Arabzadeh E, Sarshin A, Feizolahi F, Mohabbat M, Soleiman-Fallah MA, Rahimi A, Petridou A, Emami Z, Tajik H, Bozorg Omid R, Maleki A, Ekrami Ogholbag H, Khademi A, Zargani M. Synergistic salvation: HIIT and herbal allies reverse NAFLD damage in rats. J Mol Histol 2025; 56:131. [PMID: 40186827 DOI: 10.1007/s10735-025-10413-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Accepted: 03/25/2025] [Indexed: 04/07/2025]
Abstract
Fatty liver disease is a build-up of fats in the liver that can damage the organ and lead to serious complications. This study aimed to investigate the effects of exercise training and supplementation (milk thistle, chicory and cumin) on liver metabolites related to its function and health in rats with non-alcoholic fatty liver disease (NAFLD). Forty adult male Wistar rats with an average weight of 215 ± 10 g were divided into a control group fed on the basal diet and four experimental groups fed with high-fat diet (HFD) for 6 weeks to induce non-alcoholic fatty liver disease (NAFLD). The 4 NAFLD groups were subdivided and treated with (a) plain HFD, (b) high-intensity interval training (HIIT), (c) supplement (milk thistle, chicory, and cumin), and (d) combined HIIT and supplementation for 4 weeks. The induction of NAFLD through HFD yielded dyslipidemia, liver tissue damage, increased malondialdehyde, uncoupling protein 2 (UCP2), and phosphatidylinositol-3 kinase (PI3K), as well as decreased superoxide dismutase (SOD) and peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC-1α) in liver tissue (p < 0.05). The 4 weeks intervention with either HIIT, supplement or especially the combined application of both, reversed these factors (p < 0.05) through changes in their concentrations in a direction indicative of enhanced liver health and function. HIIT beside supplementation (milk thistle, chicory, and cumin) improved indices related to oxidative stress, lipid profile, and the expression of PI3K, UCP2, PGC-1α genes expression and PGC-1α protein content, making it potentially promising in the treatment of liver damage caused by HFD.
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Affiliation(s)
- Ehsan Arabzadeh
- Exercise Physiology Research Center, Life Style Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Amir Sarshin
- Clinical Care and Health Promotion Research Center, Karaj Branch, Islamic Azad University, Karaj, Iran
| | - Foad Feizolahi
- Clinical Care and Health Promotion Research Center, Karaj Branch, Islamic Azad University, Karaj, Iran
| | - Majid Mohabbat
- Department of Exercise Physiology, Faculty of Sport Sciences, University of Guilan, Rasht, Iran
| | | | - Alireza Rahimi
- Department of Exercise Physiology, Karaj Branch, Islamic Azad University, Karaj, Iran
| | - Anatoli Petridou
- Laboratory of Evaluation of Human Biological Performance, School of Physical Education and Sport Science at Thessaloniki, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Zahra Emami
- Department of Exercise Physiology, Karaj Branch, Islamic Azad University, Karaj, Iran
| | - Helena Tajik
- Department of Exercise Physiology, Karaj Branch, Islamic Azad University, Karaj, Iran
| | - Reza Bozorg Omid
- Department of Exercise Physiology, Karaj Branch, Islamic Azad University, Karaj, Iran
| | - Amir Maleki
- Department of Exercise Physiology, Karaj Branch, Islamic Azad University, Karaj, Iran
| | | | - Ali Khademi
- PhD in Sport Management, Karaj Branch, Islamic Azad University, Karaj, Iran
| | - Mehdi Zargani
- Department of Exercise Physiology, Karaj Branch, Islamic Azad University, Karaj, Iran.
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Emanuele F, Biondo M, Tomasello L, Arnaldi G, Guarnotta V. Ketogenic Diet in Steatotic Liver Disease: A Metabolic Approach to Hepatic Health. Nutrients 2025; 17:1269. [PMID: 40219026 PMCID: PMC11990071 DOI: 10.3390/nu17071269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2025] [Revised: 03/28/2025] [Accepted: 03/31/2025] [Indexed: 04/14/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major cause of chronic liver dysfunction worldwide, characterized by hepatic steatosis that may progress to nonalcoholic steatohepatitis and cirrhosis. Owing to its strong association with metabolic disorders, current management focuses on weight reduction via lifestyle modifications. Recently, the very-low-calorie ketogenic diet (VLCKD) has emerged as a promising intervention due to its potential for rapid weight loss and reduction in liver fat. This review aims to evaluate the clinical evidence regarding the impact of ketogenic diets on hepatic steatosis. We conducted an extensive MEDLINE literature search in databases including PubMed, Scopus, and Web of Science up to December 2024. Studies assessing the effects of ketogenic or low-carbohydrate high-fat diets on liver fat, evaluated by imaging, histology, or biochemical markers, were included. The analysis indicates that ketogenic diets significantly reduce hepatic fat content and improve metabolic parameters, including insulin sensitivity and liver enzyme levels. Evidence further suggests that substituting saturated fats with unsaturated fats or replacing carbohydrates with proteins may enhance these benefits. However, considerable variability exists among studies and long-term data remain limited. Although short-term outcomes are encouraging, potential adverse effects such as dyslipidaemia, gastrointestinal disturbances, and transient 'keto flu' symptoms require careful clinical monitoring. Future research should focus on elucidating underlying mechanisms, optimizing dietary composition, and assessing long-term safety to establish ketogenic diets as a robust strategy for managing MASLD.
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Affiliation(s)
- Fabrizio Emanuele
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties “G. D’Alessandro” (PROMISE), Section of Endocrinology, University of Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy; (F.E.); (L.T.); (G.A.); (V.G.)
| | - Mattia Biondo
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Viale delle Scienze Ed. 16, 90128 Palermo, Italy;
| | - Laura Tomasello
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties “G. D’Alessandro” (PROMISE), Section of Endocrinology, University of Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy; (F.E.); (L.T.); (G.A.); (V.G.)
| | - Giorgio Arnaldi
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties “G. D’Alessandro” (PROMISE), Section of Endocrinology, University of Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy; (F.E.); (L.T.); (G.A.); (V.G.)
| | - Valentina Guarnotta
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties “G. D’Alessandro” (PROMISE), Section of Endocrinology, University of Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy; (F.E.); (L.T.); (G.A.); (V.G.)
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Mayengbam S, Raman M, Parnell JA, Eksteen B, Lambert JE, Eller LK, Nicolucci AC, Aktary ML, Reimer RA. Effects of combined prebiotic fiber supplementation and weight loss counseling in adults with metabolic dysfunction-associated steatotic liver disease: a randomized controlled trial. Eur J Nutr 2025; 64:144. [PMID: 40172664 DOI: 10.1007/s00394-025-03660-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Accepted: 03/22/2025] [Indexed: 04/04/2025]
Abstract
PURPOSE Our aim was to examine the effects of combined prebiotic fiber supplementation and weight loss counseling on liver fat, body composition, subjective appetite, serum metabolomics, and intestinal microbiota in adults with MASLD. METHODS In a double blind, placebo-controlled trial, adult participants aged 18-70 years old with MASLD were randomized to receive prebiotic (oligofructose-enriched inulin, 16 g/day; n = 22) or isocaloric placebo (maltodextrin; n = 20) for 24 weeks alongside weight loss counseling from a registered dietitian. Primary outcomes were change in intrahepatic fat % (IHF%) and hepatic injury from baseline to 24 weeks. Secondary outcomes included body composition, subjective appetite, serum lipids and cytokines, fecal microbiota, and serum metabolomics. RESULTS At baseline, participants had IHF of 14.4 ± 8.4%. The change in IHF from baseline to 24 weeks did not differ between prebiotic and placebo. Prebiotic participants had a greater decrease (p = 0.029) in percent trunk fat compared to placebo. Compared to placebo, prebiotic significantly decreased desire to eat and hunger ratings over the course of the intervention. Fecal microbiota analysis showed a significant increase in Bifidobacterium abundance with prebiotic. A pathway analysis based on untargeted serum metabolomics revealed a downregulation of taurine and hypotaurine metabolism in the placebo group which was conserved in the prebiotic group. CONCLUSION Adding prebiotic fiber supplementation to weight loss counseling for adults with MASLD enhanced reductions in trunk fat and had a beneficial effect on subjective appetite compared to placebo. Improvements in fecal microbial profile and taurine metabolism revealed specific beneficial effects of prebiotics in the management of MASLD. CLINICAL TRIAL REGISTRATION Clinicaltrials.gov/study/NCT02568605.
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Affiliation(s)
- Shyamchand Mayengbam
- Department of Biochemistry, Memorial University of Newfoundland, St. John's, NL, Canada
| | - Maitreyi Raman
- Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
- Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada
| | - Jill A Parnell
- Department of Health and Physical Education, Mount Royal University, Calgary, AB, Canada
| | | | - Jennifer E Lambert
- Faculty of Kinesiology, University of Calgary, 2500 University Drive NW, Calgary, AB, T2N 1N4, Canada
| | - Lindsay K Eller
- Faculty of Kinesiology, University of Calgary, 2500 University Drive NW, Calgary, AB, T2N 1N4, Canada
| | - Alissa C Nicolucci
- Faculty of Kinesiology, University of Calgary, 2500 University Drive NW, Calgary, AB, T2N 1N4, Canada
| | - Michelle L Aktary
- Faculty of Kinesiology, University of Calgary, 2500 University Drive NW, Calgary, AB, T2N 1N4, Canada
| | - Raylene A Reimer
- Faculty of Kinesiology, University of Calgary, 2500 University Drive NW, Calgary, AB, T2N 1N4, Canada.
- Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
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Oh Y, Song SJ. Association of Steatotic Liver Disease with Retinal Vascular Occlusion: The Influence of Obesity in a Large Health Screening Cohort. Endocrinol Metab (Seoul) 2025; 40:299-303. [PMID: 39962357 PMCID: PMC12061741 DOI: 10.3803/enm.2024.2181] [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: 09/21/2024] [Revised: 10/29/2024] [Accepted: 11/17/2024] [Indexed: 05/03/2025] Open
Abstract
In this cross-sectional study, we aimed to investigate the relationship between steatotic liver disease (SLD) and retinal abnormalities in a cohort undergoing health screening. Our study included 353,607 participants who underwent fundus photography and abdominal ultrasonography at least once at the Kangbuk Samsung Health Promotion Center from 2002 to 2022. After adjusting for age and sex, the risk of retinal vein occlusion (RVO) significantly increased with the presence of non-alcoholic fatty liver disease, metabolic dysfunction-associated fatty liver disease, and metabolic dysfunction-associated SLD, with odds ratios of 1.259 (95% confidence interval [CI], 1.050 to 1.510), 1.498 (95% CI, 1.249 to 1.796), and 1.342 (95% CI, 1.121 to 1.605), respectively. However, these associations weakened after adjusting for body mass index. No statistically significant associations were observed with other retinal disorders after adjusting for age, sex, and other confounding factors. Our findings suggest that obesity may mediate the relationship between SLD and RVO, while other retinal abnormalities may be more closely associated with known risk factors rather than SLD itself.
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Affiliation(s)
- Younjin Oh
- College of Nursing, Yonsei University, Seoul, Korea
| | - Su Jeong Song
- Department of Ophthalmology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
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Hou M, Wu L, Wei Z, Jiang S, Wang H, Chen W, Hu R, Guan B, Cheng L, Wang J, Hu S, Wang C, Zhang J, Dong Z, Yang J, Lin Q, Yang W. Elevated serum pepsinogen level predicts postoperative nausea and vomiting and pain in females with obesity following laparoscopic sleeve gastrectomy. Int J Obes (Lond) 2025; 49:665-672. [PMID: 39609600 DOI: 10.1038/s41366-024-01688-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 10/07/2024] [Accepted: 11/18/2024] [Indexed: 11/30/2024]
Abstract
BACKGROUND Postoperative nausea and vomiting (PONV) is the most common side effect after laparoscopic sleeve gastrectomy (LSG), affecting patients' postoperative recovery and increasing the medical and economic burden. This study aimed to analyze the relationship between serum pepsinogen and PONV. METHODS Patients with obesity who underwent LSG in our center between January 2021 and December 2022 were divided into PONV and NoPONV groups and analyzed retrospectively. Binary logistic regression analysis was used to determine the independent risk factors for PONV. RESULTS 219 female patients were enrolled, with an average BMI of 36.74 ± 8.34 kg/m2 and aged 32.61 ± 6.18 years. PONV occurred in 157 patients (71.7%). The influencing factors of PONV with different severity were analyzed, and the results showed that the severity of postoperative pain (χ2 = 13.169, p-values = 0.004), PGI (χ2 = 14.625, p-values = 0.002), PGII (χ2 = 25.916, p-values = 0.000), and PGR (χ2 = 17.697, p-values = 0.001) had statistical significance. Binary logistic regression showed that PGI was a risk factor for PONV with a OR (ng/mL) value of 1.013 (95% CI: 1.001-1.024, p-values = 0.037), while PGR was a protective factor for PONV with an OR(ng/mL) value of 0.952 (95% CI: 0.925-0.979, p-values = 0.001). CONCLUSIONS The incidence of PONV after LSG is high. Higher PGI may be a risk factor for promoting PONV after LSG. The higher the preoperative PGI, the later the onset of PONV; the longer the duration, the more serious the degree.
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Affiliation(s)
- Min Hou
- Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong Province, China
- School of Nursing; The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong Province, China
| | - Lina Wu
- Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong Province, China
| | - Zhuoqi Wei
- Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong Province, China
| | - Shuwen Jiang
- Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong Province, China
| | - Huaxi Wang
- Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong Province, China
| | - Wenhui Chen
- Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong Province, China
| | - Ruixiang Hu
- Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong Province, China
| | - Bingsheng Guan
- Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong Province, China
| | - Lyujia Cheng
- Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong Province, China
| | - Jianxue Wang
- Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong Province, China
| | - Songhao Hu
- Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong Province, China
| | - Cunchuan Wang
- Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong Province, China
| | - Junchang Zhang
- Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong Province, China
| | - Zhiyong Dong
- Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong Province, China.
| | - Jingge Yang
- Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong Province, China.
| | - Qingran Lin
- Department of Nursing, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong Province, China.
| | - Wah Yang
- Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong Province, China.
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Park JH, Kim SM, Lee DH. Comparison of Non-invasive Methods for Diagnosis of Non-alcoholic Fatty Liver Disease Before Bariatric Surgery and Postoperative Follow-up in Obese Patients. JOURNAL OF METABOLIC AND BARIATRIC SURGERY 2025; 14:53-64. [PMID: 40351816 PMCID: PMC12059311 DOI: 10.17476/jmbs.2025.14.1.53] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/02/2025] [Revised: 04/06/2025] [Accepted: 04/10/2025] [Indexed: 05/14/2025]
Abstract
Purpose This study aims to identify the most accurate and useful non-invasive method to replace liver biopsy for the diagnosis of non-alcoholic fatty liver disease (NAFLD) before bariatric surgery and postoperative follow-up in morbidly obese patients. Materials and Methods This single-center study is a retrospective analysis of prospectively collected data from 68 morbidly obese patients who underwent laparoscopic sleeve gastrectomy with intraoperative liver biopsy. Preoperative non-invasive diagnostic methods, including fatty liver index, NAFLD fibrosis score, enhanced liver fibrosis score, FibroScan, magnetic resonance imaging-proton density fat fraction (MRI-PDFF), magnetic resonance spectroscopy (MRS)-PDFF, and magnetic resonance elastography (MRE) were compared against liver biopsy results. Diagnostic performance was assessed using Spearman's correlation and receiver operating characteristic (ROC) curve analysis. Results Liver biopsy confirmed the presence of steatosis in 92.7% of patients, Nonalcoholic Steatohepatitis (NASH) in 64.7%, and liver fibrosis (≥F1) in 72.0%. MRI-PDFF and MRS-PDFF demonstrated the highest diagnostic accuracy for NASH, with the strongest correlation with histological findings. For liver fibrosis, MRE showed the strongest correlation with histological fibrosis stage, while FibroScan-Liver Stiffness Measurement (LSM) demonstrated better diagnostic performance in ROC analysis. However, the overall diagnostic quality of non-invasive methods for fibrosis assessment remained modest, with no method achieving a quality value above 0.6. Conclusion MRI-PDFF and MRS-PDFF were the most accurate noninvasive methods for diagnosing NASH in morbidly obese patients. For liver fibrosis, FibroScan-LSM may be more suitable for detection, while MRE may better reflect fibrosis severity. Further studies are needed to assess the cost-effectiveness and clinical applicability of these methods.
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Affiliation(s)
- Ji-Hyeon Park
- Department of Surgery, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon, Korea
| | - Seong Min Kim
- Department of Surgery, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon, Korea
| | - Dae Ho Lee
- Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon, Korea
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Yang Y, Jiao L, Huang Y, Shang H, Li E, Chang H, Cui H, Wan Y. Evaluation of FXR Activity in Pollutants Identified in Sewage Sludge and Subsequent in Vitro and in Vivo Characterization of Metabolic Effects of Triphenyl Phosphate. ENVIRONMENTAL HEALTH PERSPECTIVES 2025; 133:47005. [PMID: 40048564 PMCID: PMC12010937 DOI: 10.1289/ehp15435] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Revised: 01/03/2025] [Accepted: 01/27/2025] [Indexed: 04/15/2025]
Abstract
BACKGROUND Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common liver disease worldwide, and increasing evidence suggests that exposure to environmental pollutants is associated with the increased incidence of MASLD. The farnesoid X receptor (FXR) plays an important role in the development of MASLD by regulating bile acids (BAs) and lipid metabolism. However, whether FXR-active pollutants are the environmental drivers of MASLD remains unclear. OBJECTIVES This study aimed to determine whether FXR-active pollutants exist in the environment and evaluate their ability to trigger MASLD development in mice. METHODS An FXR protein affinity pull-down assay and nontargeted mass spectrometry (MS) analysis were used to identify environmental FXR ligands in sewage sludge. A homogeneous time-resolved fluorescence coactivator recruitment assay and cell-based dual-luciferase reporter assay were used to determine the FXR activities of the identified pollutants. Targeted analysis of BAs, MS imaging, lipidomic analysis, 16S rRNA sequencing, and quantitative polymerase chain reaction were conducted to assess the ability of FXR-active pollutants to induce metabolic disorders of BAs and lipids and to contribute to MASLD development in C57BL/6N mice. RESULTS We identified 19 compounds in the sewage sludge that had FXR-antagonistic activity, and triphenyl phosphate (TPHP) was the FXR antagonist with the highest efficacy. Mice exposed to either 10 or 50 mg / kg TPHP for 30 d had higher levels of conjugated primary BAs in enterohepatic circulation, and the BA pool showed FXR antagonistic activities. The exposed mice also had greater lipogenesis (more Oil Red O staining and high triglyceride levels) in liver. CONCLUSIONS Nineteen FXR-antagonistic pollutants were identified in sewage sludge. FXR inhibition by the strongest antagonist TPHP may have a role in promoting MASLD development in mice by inducing a positive feedback loop between the FXR and BAs. https://doi.org/10.1289/EHP15435.
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Affiliation(s)
- Yi Yang
- Laboratory for Earth Surface Processes, College of Urban and Environmental Sciences, Peking University, Beijing, China
| | - Ling Jiao
- Laboratory for Earth Surface Processes, College of Urban and Environmental Sciences, Peking University, Beijing, China
| | - Yixuan Huang
- Laboratory for Earth Surface Processes, College of Urban and Environmental Sciences, Peking University, Beijing, China
| | - Hailin Shang
- Laboratory for Earth Surface Processes, College of Urban and Environmental Sciences, Peking University, Beijing, China
| | - Enrui Li
- College of Environmental Science and Engineering, Beijing Forestry University, Beijing, China
| | - Hong Chang
- College of Environmental Science and Engineering, Beijing Forestry University, Beijing, China
| | - Hongyang Cui
- Laboratory for Earth Surface Processes, College of Urban and Environmental Sciences, Peking University, Beijing, China
| | - Yi Wan
- Laboratory for Earth Surface Processes, College of Urban and Environmental Sciences, Peking University, Beijing, China
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Wen Y, Li J, Mukama O, Huang R, Deng S, Li Z. New insights on mesenchymal stem cells therapy from the perspective of the pathogenesis of nonalcoholic fatty liver disease. Dig Liver Dis 2025:S1590-8658(25)00286-5. [PMID: 40158892 DOI: 10.1016/j.dld.2025.03.007] [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: 08/30/2024] [Revised: 03/09/2025] [Accepted: 03/10/2025] [Indexed: 04/02/2025]
Abstract
Nonalcoholic fatty liver disease (NAFLD) manifests as chronic hepatic steatosis, occurring variably across people due to racial and genetic diversity. It represents a stage in the development of chronic liver disease, marked by fat accumulation, inflammatory responses, oxidative stress in the endoplasmic reticulum, and fibrosis as primary concerns. Understanding its underlying mechanisms remains a challenging and pivotal area of study. In the past, acute liver injury-related diseases were commonly treated with methods such as liver transplantation. However, the emergence of artificial liver has shifted focus to stem cell therapies. Unlike conventional drugs, stem cell therapies are continuously evolving. Despite being classified as drugs, stem cells demonstrated significant efficacy after multiple injections. Mesenchymal stem cells, unlike other types of stem cells, do not have the risk of tumor formation and low immunogenicity, reducing the hypersensitivity reactions associated with liver transplantation. Increasingly, studies suggest that mesenchymal stem cells hold promise in the treatment of chronic liver injury diseases. This review focuses on investigating the role of mesenchymal stem cells in chronic metabolic liver diseases, such as non-alcoholic fatty liver disease, and delves into their specific functions.
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Affiliation(s)
- Yanxuan Wen
- Department of Anatomy and Neurobiology, Xiangya School of Medicine, Central South University, Changsha, 410013, China
| | - Jiaxing Li
- Department of Anatomy and Neurobiology, Xiangya School of Medicine, Central South University, Changsha, 410013, China
| | - Omar Mukama
- CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510663, China
| | - Rongqi Huang
- CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510663, China
| | - Sihao Deng
- Department of Anatomy and Neurobiology, Xiangya School of Medicine, Central South University, Changsha, 410013, China.
| | - Zhiyuan Li
- CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510663, China.
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Dai JJ, Deng Y, Wang GF, Lin KQ, He JR, Hu XG. Relationship of serum 25(OH)D3 and PTX3 with liver fat content in patients with non-alcoholic fatty liver disease: Diagnostic value for liver fibrosis. Shijie Huaren Xiaohua Zazhi 2025; 33:192-198. [DOI: 10.11569/wcjd.v33.i3.192] [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: 01/01/2025] [Revised: 02/15/2025] [Accepted: 03/16/2025] [Indexed: 03/28/2025] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in China. Vitamin D and pentraxin 3 (PTX3) participate in the occurrence and development of NAFLD by regulating calcium and phosphorus metabolism and inflammation. This study analyzed the relationship of serum 25-hydroxy vitamin D3 [25(OH)D3] and PTX3 levels with liver fat content and liver fibrosis in patients with NAFLD.
AIM To analyze the relationship of serum 25(OH)D3 and PTX3 with liver fat content in patients with NAFLD, as well as their diagnostic value for liver fibrosis.
METHODS A total of 120 NAFLD patients in our hospital from June 2022 to September 2023 were selected as a study group, and another 120 healthy individuals in the same period were selected as a control group. General information and serum levels of 25(OH)D3 and PTX3 were compared between and two groups, and the levels of 25(OH)D3 and PTX3 were compared in patients with different liver fat contents in the study group. The correlation between serum levels of 25(OH)D3 and PTX3 and liver fat content in NAFLD patients was analyzed. The levels of serum 25(OH)D3, PTX3, liver fibrosis, and liver function indicators [hyaluronic acid (HA), procollagen type Ⅲ (PCⅢ), procollagen type Ⅳ (PCIV), alanine aminotransferase (ALT), and aspartate aminotransferase (AST)] were compared among patients with different degrees of liver fibrosis in the study group. The correlation of serum 25(OH)D3 and PTX3 levels with liver fibrosis and liver function indicators was examined, and their value for diagnosing liver fibrosis was assessed.
RESULTS Serum 25(OH)D3 level in the study group was lower than that of the control group, while PTX3 level was higher than that of the control group (P < 0.05). There was a statistically significant difference in serum 25(OH)D3 and PTX3 levels among patients with different liver fat contents in the study group (P < 0.05). As the liver fat content increased, serum 25(OH)D3 levels significantly decreased, while PTX3 levels significantly increased. Serum 25(OH)D3 levels were negatively correlated with liver fat content in NAFLD patients, while PTX3 levels were positively correlated with liver fat content in NAFLD patients (P < 0.05). Serum 25(OH)D3 levels in patients at risk of liver fibrosis in the study group were lower than those in patients without liver fibrosis, while the levels of PTX3, HA, PC Ⅲ, PC Ⅳ, ALT, and AST were higher than those of patients without liver fibrosis (P < 0.05). Serum 25(OH)D3 levels in NAFLD patients were negatively correlated with HA, PC Ⅲ, PC Ⅳ, ALT, and AST levels, while PTX3 levels were positively correlated with HA, PC Ⅲ, PC Ⅳ, ALT, and AST levels (P < 0.05). The area under the curve (AUC) of serum 25(OH)D3 and PTX3 alone for diagnosing liver fibrosis in patients with NAFLD was 0.713 and 0.781, respectively, while the AUC of their combination was 0.908, which was greater than the AUC of either of them alone (P < 0.05).
CONCLUSION Serum 25(OH)D3 level in NAFLD patients is negatively correlated with liver fat content, while serum PTX3 level is positively correlated with liver fat content. The two have appreciated diagnostic value in liver fibrosis.
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Affiliation(s)
- Jian-Ji Dai
- Department of Oncology and Vascular Intervention, Jinhua Central Hospital, Jinhua 321000, Zhejiang Province, China
| | - Yi Deng
- Department of Oncology and Vascular Intervention, Jinhua Central Hospital, Jinhua 321000, Zhejiang Province, China
| | - Guo-Feng Wang
- Department of Oncology and Vascular Intervention, Jinhua Central Hospital, Jinhua 321000, Zhejiang Province, China
| | - Kai-Qin Lin
- Department of Oncology and Vascular Intervention, Jinhua Central Hospital, Jinhua 321000, Zhejiang Province, China
| | - Jian-Rong He
- Department of Oncology and Vascular Intervention, Jinhua Central Hospital, Jinhua 321000, Zhejiang Province, China
| | - Xiao-Gang Hu
- Department of Oncology and Vascular Intervention, Jinhua Central Hospital, Jinhua 321000, Zhejiang Province, China
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Martínez-Almoyna Rifá E, López González ÁA, Tárraga López PJ, Paublini H, Vallejos D, Ramírez Manent JI. [Relationship between diabesity and elevated values of metabolic-associated steatotic liver disease risk scales in Spanish workers using body mass index and the body adiposity estimator criteria of Clínica de Navarra]. NUTR HOSP 2025. [PMID: 40195779 DOI: 10.20960/nh.05441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/09/2025] Open
Abstract
INTRODUCTION diabesity (coexistence of diabetes and obesity) and metabolic associated steatotic liver disease (MASLD) are two very frequent pathologies whose prevalence is increasing every day. OBJECTIVE to find out how these two pathological entities are associated in a group of Spanish workers. METHODOLOGY a descriptive, cross-sectional study was carried out in 219477 workers to assess the association between diabesity (applying a double criterion, the body mass index BMI and the Clínica Universitaria de Navarra body adiposity estimator CUN BAE) and different risk scales for MASLD and liver fibrosis. RESULTS all MASH and liver fibrosis risk scales show higher values in people with diabesity applying the two criteria compared to people without diabesity. CONCLUSION diabesity and MASLD and liver fibrosis risk scales show a significant association in our study.
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Affiliation(s)
- Emilio Martínez-Almoyna Rifá
- Grupo ADEMA-SALUD. Institut Universitari d'Investigació en Ciències de la Salut (iUNICS). Facultad de Odontología. Escuela Universitaria-Universidad de las Islas Baleares - ADEMA-UIB
| | - Ángel Arturo López González
- Grupo ADEMA-SALUD. Institut Universitari d'Investigació en Ciències de la Salut (iUNICS). Facultad de Odontología. Escuela Universitaria-Universidad de las Islas Baleares - ADEMA-UIB
| | | | - Hernán Paublini
- Grupo ADEMA-SALUD. Institut Universitari d'Investigació en Ciències de la Salut (iUNICS). Facultad de Odontología. Escuela Universitaria-Universidad de las Islas Baleares - ADEMA-UIB
| | - Daniela Vallejos
- Grupo ADEMA-SALUD. Institut Universitari d'Investigació en Ciències de la Salut (iUNICS). Facultad de Odontología. Escuela Universitaria-Universidad de las Islas Baleares - ADEMA-UIB
| | - José Ignacio Ramírez Manent
- Grupo ADEMA-SALUD. Institut Universitari d'Investigació en Ciències de la Salut (iUNICS). Facultad de Odontología. Escuela Universitaria-Universidad de las Islas Baleares - ADEMA-UIB. Facultad de Medicina. Universidad de las Islas Baleares
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Wang J, Zhang C, Zhang Y, Guo J, Xie C, Liu Y, Chen L, Ma L. Circular RNA in liver cancer research: biogenesis, functions, and roles. Front Oncol 2025; 15:1523061. [PMID: 40224186 PMCID: PMC11985449 DOI: 10.3389/fonc.2025.1523061] [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: 11/07/2024] [Accepted: 03/11/2025] [Indexed: 04/15/2025] Open
Abstract
Liver cancer, characterized by its insidious nature, aggressive invasiveness, and propensity for metastasis, has witnessed a sustained increase in both incidence and mortality rates in recent years, underscoring the urgent need for innovative diagnostic and therapeutic approaches. Emerging research indicates that CircRNAs (circular RNAs) are abundantly and stably present within cells, with their expression levels closely associated with the progression of various malignancies, including hepatocellular carcinoma. In the context of liver cancer progression, circRNAs exhibit promising potential as highly sensitive diagnostic biomarkers, offering novel avenues for early detection, and also function as pivotal regulatory factors within the carcinogenic process. This study endeavors to elucidate the biogenesis, functional roles, and underlying mechanisms of circRNAs in hepatocellular carcinoma, thereby providing a fresh perspective on the pathogenesis of liver cancer and laying a robust foundation for the development of more precise and effective early diagnostic tools and therapeutic strategies.
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Affiliation(s)
- Jiayi Wang
- The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
- School of Rehabilitation Medicine, Henan University of Traditional Chinese Medicine, Zhengzhou, Henan, China
| | - Congcong Zhang
- The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
- School of Rehabilitation Medicine, Henan University of Traditional Chinese Medicine, Zhengzhou, Henan, China
| | - Yinghui Zhang
- The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Jiaojiao Guo
- School of Rehabilitation Medicine, Henan University of Traditional Chinese Medicine, Zhengzhou, Henan, China
| | - Chenyu Xie
- School of Rehabilitation Medicine, Henan University of Traditional Chinese Medicine, Zhengzhou, Henan, China
| | - Yulu Liu
- The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Lidian Chen
- School of Rehabilitation Medicine, Henan University of Traditional Chinese Medicine, Zhengzhou, Henan, China
| | - Liangliang Ma
- The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
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36
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Khanmohammadi S, Fallahtafti P, Habibzadeh A, Ezzatollahi Tanha A, Alamdari AA, Fallahtafti P, Shafi Kuchay M. Effectiveness of body roundness index for the prediction of nonalcoholic fatty liver disease: a systematic review and meta-analysis. Lipids Health Dis 2025; 24:117. [PMID: 40148946 PMCID: PMC11948846 DOI: 10.1186/s12944-025-02544-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2024] [Accepted: 03/20/2025] [Indexed: 03/29/2025] Open
Abstract
BACKGROUND Several anthropometric indices, such as body mass index and waist circumference, have been used as clinical screening tools for the prediction of nonalcoholic fatty liver disease (NAFLD). To further refine these clinical tools for NAFLD, the body roundness index (BRI) has recently been evaluated. In this systematic review and meta-analysis, the objective was to evaluate the relationship and predictive capability of the BRI in identifying NAFLD. METHODS A comprehensive search was conducted in PubMed, Embase, Web of Science, and Scopus up to December 31, 2024. Eligibility criteria included observational studies on adults (≥ 18 years old) with measured BRI and its association with NAFLD. The Joanna Briggs Institute tool was used for risk of bias assessment. Meta-analyses used random-effects models to pool data on mean difference, odds ratio, sensitivity, specificity, and the area under the curve (AUC), with heterogeneity and publication bias assessed. RESULTS Ten studies involving 59,466 participants were included. The pooled mean difference in BRI between the NAFLD and non-NAFLD groups was 1.73 (95% confidence interval [CI]: 1.31-2.15). The pooled sensitivity and specificity of BRI for diagnosing NAFLD were 0.806 and 0.692, respectively. The pooled AUC for BRI was 0.803 (95% CI: 0.775-0.830), indicating good diagnostic accuracy. Unlike subgroup analysis by country, subgroup analysis by sex showed no significant differences. Higher BRI values were associated with increased odds of NAFLD (pooled OR = 2.87, 95% CI: 1.39; 5.96). Studies provided mixed results on the predictive ability of BRI compared to other indices like body mass index, mostly favoring BRI over conventional indices. CONCLUSION BRI demonstrates a good diagnostic performance for NAFLD, suggesting it may be a valuable clinical tool for NAFLD assessment. Further research is necessary to validate these findings and strengthen the evidence base.
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Affiliation(s)
- Shaghayegh Khanmohammadi
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
- Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.
- Non-Communicable Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
| | - Parisa Fallahtafti
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Cardiovascular Diseases Research Institute, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
| | | | | | - Amir Ali Alamdari
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Parsa Fallahtafti
- School of Pharmacy and Pharmaceutical Sciences, Islamic Azad University, Tehran, Iran
| | - Mohammad Shafi Kuchay
- Divison of Endocrinology and Diabetes, Medanta the Medicity Hospital, Gurugram, Haryana, 122001, India
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El-Sehrawy AAMA, Rashid TA, Ullah MI, Uthirapathy S, Ganesan S, Singh A, Devi A, Joshi KK, Jasim AS, Kadhim AJ. Cutting edge: ferroptosis in metabolic dysfunction-associated steatotic liver disease (MASLD) pathogenesis and therapy. Funct Integr Genomics 2025; 25:71. [PMID: 40131513 DOI: 10.1007/s10142-025-01579-0] [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: 02/27/2025] [Accepted: 03/11/2025] [Indexed: 03/27/2025]
Abstract
Ferroptosis denotes a distinct form of controlled cell death marked by substantial iron buildup and significant lipid peroxidation, playing a crucial role in several disease processes linked to cell death. Given the liver's essential functions in iron and lipid metabolism and its vulnerability to oxidative damage, more research has investigated the correlation between ferroptosis and numerous hepatic diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD). NAFLD has arisen as a worldwide public health concern due to elevated morbidity and high death rates. The pathogenesis of MASLD remains incompletely elucidated. Recent data suggests that ferroptosis is crucial in the pathophysiology of MASLD; nevertheless, the specific processes by which ferroptosis influences MASLD remain unclear. The present review summarizes the molecular processes of ferroptosis and its intricate regulatory networks, outlines the differing impacts of ferroptosis at different stages of MASLD, and examines possible approaches targeting ferroptosis for the therapy of MASLD, suggesting a novel approach for its management.
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Affiliation(s)
| | - Teeba Ammar Rashid
- Medical Laboratory Techniques Department, College of Health and Medical Technology, University of Al-Maarif, Anbar, Iraq.
| | - Muhammad Ikram Ullah
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka, 72388, Aljouf, Saudi Arabia
| | - Subasini Uthirapathy
- Pharmacy Department, Tishk International University, Erbil, Kurdistan Region, Iraq
| | - Subbulakshmi Ganesan
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to Be University), Bangalore, Karnataka, India
| | - Abhayveer Singh
- Centre for Research Impact & Outcome, Chitkara University Institute of Engineering and Technology, Chitkara University, Rajpura, 140401, Punjab, India
| | - Anita Devi
- Department of Chemistry, Chandigarh Engineering College, Chandigarh Group of Colleges-Jhanjeri, Mohali, 140307, Punjab, India
| | - Kamal Kant Joshi
- Department of Allied Science, Graphic Era Hill University, Dehradun, 248002, Uttarakhand, India
- Graphic Era Deemed to Be University, Dehradun, Uttarakhand, India
| | - Ahmed Salman Jasim
- Radiology Techniques Department, College of Health and Medical Techniques, Al-Mustaqbal University, 5100, Babylon, Iraq
| | - Abed J Kadhim
- Department of Medical Engineering, Al-Nisour University College, Baghdad, Iraq
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38
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Sun M, Ma H, Miao Y, Zhang M. Quinoa bran polyphenol extract attenuates high-fat diet induced non-alcoholic fatty liver disease in mice. Food Funct 2025; 16:2291-2302. [PMID: 39981953 DOI: 10.1039/d4fo02647k] [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: 02/22/2025]
Abstract
Quinoa bran is a by-product of quinoa processing and is rich in polyphenolic bioactives. Previous studies have shown that polyphenol compounds can help alleviate metabolic diseases, but studies on quinoa bran polyphenols intervening in non-alcoholic fatty liver disease (NAFLD) have not yet been reported. In this study, a C57BL/6J mouse NAFLD model was established using a high-fat diet (HFD) to explore the interventional effects of quinoa bran polyphenol extract (QBP) on NAFLD in mice. The results showed that QBP was effective in attenuating abnormal lipid metabolism and hepatic fat accumulation and reducing inflammation in NAFLD mice. 16S rRNA sequencing analysis showed that QBP regulated the composition of the gut microbiota by increasing the abundance of beneficial bacteria Clostridium_innocuum_group, Clostridium_sensu_stricto_13, Ruminococcus_gnavus_group, Coriobacteriaceae_UCG_002 and UBA1819. Untargeted metabolomics identified 51 differential metabolites due to QBP supplementation. Functional predictions indicated that starch and sucrose metabolism and pentose and gluconate interconversion are key metabolic pathways for QBP to attenuate NAFLD, which may be influenced by the gut microbiota. These results demonstrated the potential application of QBP interventions for NAFLD.
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Affiliation(s)
- Minjun Sun
- College of Food Science and Engineering, Inner Mongolia Agriculture University, Hohhot 010018, China.
| | - Haoyuan Ma
- College of Food Science and Engineering, Inner Mongolia Agriculture University, Hohhot 010018, China.
| | - Ying Miao
- College of Food Science and Engineering, Inner Mongolia Agriculture University, Hohhot 010018, China.
| | - Meili Zhang
- College of Food Science and Engineering, Inner Mongolia Agriculture University, Hohhot 010018, China.
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Li Y, Li L, Zhang Y, Lu J, Tang X, Bi C, Qu Y, Chai J. Clinical and pathological characteristics of metabolic dysfunction-associated steatotic liver disease and the key role of epigenetic regulation: implications for molecular mechanism and treatment. Ther Adv Endocrinol Metab 2025; 16:20420188251321602. [PMID: 40098726 PMCID: PMC11912175 DOI: 10.1177/20420188251321602] [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: 05/20/2024] [Accepted: 01/31/2025] [Indexed: 03/19/2025] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), also called metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent syndrome marked by liver fat accumulation in the absence of significant alcohol consumption, encompassing simple fatty liver, nonalcoholic steatohepatitis (NASH), and advanced stages such as fibrosis and cirrhosis. Its incidence has surged globally, impacting up to 40% of the population, with a doubling of cases in China over a decade. NASH, a severe form, can progress to liver cirrhosis and cancer, posing a substantial health burden, especially among individuals with type 2 diabetes. Projections indicate a steep rise in NASH cases, necessitating urgent interventions beyond lifestyle modifications, such as innovative pharmaceuticals. Early diagnosis is crucial, yet current tools have limitations, highlighting the need for noninvasive, scalable diagnostic approaches. Advances in imaging and biomarker identification offer hope for early detection. Epigenetic factors play a significant role in MASLD pathogenesis, regulating key molecular mechanisms. Addressing MASLD requires a multifaceted approach, integrating lifestyle interventions, pharmacotherapy, and emerging therapeutics, against the backdrop of an evolving landscape in disease management.
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Affiliation(s)
- Yijing Li
- College of Basic Medical Sciences, Changchun University of Chinese Medicine, Changchun, Jilin, China
| | - Lijie Li
- Department of Pulmonology, Third Affiliated Clinical Hospital to Changchun University of Chinese Medicine, Changchun, Jilin, China
| | - Yishuo Zhang
- College of Pharmacy, Changchun University of Chinese Medicine, Changchun, Jilin, China
| | - Jing Lu
- Research Center of Traditional Chinese Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, Jilin, China
| | - Xiaolei Tang
- Research Center of Traditional Chinese Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, Jilin, China
| | - Chaoran Bi
- College of Traditional Chinese Medicine, Hainan Medical University, Haikou, Hainan, China
| | - Yanan Qu
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, Jilin, China
| | - Jingmei Chai
- Medical College, Yanbian University, 3 Gongyuan Road, Yanji, Jilin 133002, China
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40
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Leszczynska A, Alle T, Kaufmann B, Sung H, Stoess C, Reca A, Kim A, Kim S, Tran C, Oukoloff K, Monti L, Lucero B, Gertsman I, Momper JD, Hartmann P, Feldstein AE, Dohil R, Ballatore C. d 4-Cystamine: A Deuterated Cystamine Derivative with Improved Anti-Inflammatory and Anti-Fibrotic Activities in a Murine Model of Fibrosing Steatohepatitis. ACS Pharmacol Transl Sci 2025; 8:885-898. [PMID: 40109735 PMCID: PMC11915185 DOI: 10.1021/acsptsci.4c00738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Revised: 01/27/2025] [Accepted: 02/03/2025] [Indexed: 03/22/2025]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a multifactorial chronic disease that can progress to metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis, ultimately leading to liver cirrhosis and hepatocellular carcinoma. Oxidative stress is believed to play an important role in the development of MASH. Small aminothiol compounds such as cysteamine and its oxidized precursor, cystamine, are known pleiotropic compounds that exhibit relatively potent antioxidant and other effects. Herein, we evaluate the efficacy of cystamine, as well as two deuterated derivatives, in a choline-deficient, L-amino acid-defined, high-fat-diet (CDAA-HFD) mouse model of rapidly progressing liver fibrosis. Compared to control mice, daily oral administration of isotopically reinforced cystamine derivatives (200 mg/kg) led to a significant reduction of liver fibrosis and inflammation as well as oxidative stress. Moreover, the efficacy of treatment appeared to increase with the deuteration state of cystamine, with the tetradeuterated derivative, d 4 -cystamine, being the most effective. These results indicate that deuterated cystamine derivatives hold promise as potential candidates for the treatment of MASH.
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Affiliation(s)
- Aleksandra Leszczynska
- Department of Pediatrics, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
| | - Thibault Alle
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
| | - Benedikt Kaufmann
- Department of Pediatrics, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
| | - Hana Sung
- Department of Pediatrics, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
| | - Christian Stoess
- Department of Pediatrics, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
| | - Agustina Reca
- Department of Pediatrics, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
| | - Andrea Kim
- Department of Pediatrics, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
| | - Sun Kim
- Department of Pediatrics, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
| | - Chelsea Tran
- Department of Pediatrics, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
| | - Killian Oukoloff
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
| | - Ludovica Monti
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
| | - Bobby Lucero
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
| | - Ilya Gertsman
- Clarus Analytical LLC, 8545 Arjons Dr. Suite A, San Diego, California 92126, United States
| | - Jeremiah D Momper
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
| | - Phillipp Hartmann
- Department of Pediatrics, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
| | - Ariel E Feldstein
- Department of Pediatrics, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
- Global Drug Discovery, Novo Nordisk, Copenhagen DK-2880, Denmark
| | - Ranjan Dohil
- Department of Pediatrics, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
| | - Carlo Ballatore
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
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41
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Sharma J, Dey P. Differential modulation of the hepatocellular metabolome, cytoprotective and inflammatory responses due to endotoxemia and lipotoxicity. Mol Omics 2025; 21:152-163. [PMID: 39744997 DOI: 10.1039/d4mo00140k] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/11/2025]
Abstract
The present work aimed to examine the primary mechanisms of liver damage, namely the impact of gut-derived endotoxins along the gut-liver axis and adipose-derived free fatty acids along the adipose-liver axis. These processes are known to play a significant role in the development of hepatic inflammation and steatosis. Although possible overlapping in the pathogenesis was expected, these processes have unique pathophysiological consequences. Therefore, we used HepG2 cells as a model system to investigate the impact of lipopolysaccharides (LPS) and free fatty acid (FFA; albumin conjugated palmitic acid) on the intracellular metabolome. Although both LPS and FFA triggered the expression of nuclear factor κB (NFκB)-dependent inflammation, only LPS treatment was able to trigger a Toll-like receptor 4 (TLR4) dependent response. The intracellular cytoprotective enzymatic levels (catalase, peroxidase, glutathione) were increased due to FFA but lowered due to LPS. The free-radical neutralizing efficacies of cell-free metabolites of FFA-treated cells were better than those of the LPS-treated ones. The use of untargeted metabolomics allowed for the identification of distinct metabolic pathway enrichments, providing further insights into the differential effects of LPS and FFA on the metabolism of hepatocytes. Collectively, the current study highlights the distinct impacts of endotoxemia and lipotoxicity on the metabolome of hepatocytes, hence offering valuable insights into hepatocellular function.
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Affiliation(s)
- Jyoti Sharma
- Department of Biotechnology, Thapar Institute of Engineering and Technology, Patiala, Punjab, India.
| | - Priyankar Dey
- Department of Biotechnology, Thapar Institute of Engineering and Technology, Patiala, Punjab, India.
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42
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Yang Y, Luo Y, Shi J, Yin Y, Du X, Guo J, Zhuang H. The triglyceride glucose-waist circumference is the best indicator for screening non-alcoholic fatty liver disease in middle-aged and elderly people. NUTR HOSP 2025. [PMID: 40066565 DOI: 10.20960/nh.05367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/17/2025] Open
Abstract
BACKGROUND this investigation aimed to assess the correlation between the triglyceride glucose (TyG) index and its related indicators, as well as the ratio of triglyceride to high-density lipoprotein cholesterol (TG/HDL-c), with hepatic steatosis and liver fibrosis among middle-aged and elderly participants. METHODS based on data from the 2017-2020 National Health and Nutrition Examination Survey, the study included adults of ages 40 years and older in the United States. To explore the correlation between TyG and its related indicators, as well as TG/HDL-c with hepatic steatosis and liver fibrosis, multiple regression models were employed. In addition, the receiver operating characteristic curves were used to further explore the diagnostic efficacy of these indicators in non-alcoholic fatty liver disease (NAFLD) and liver fibrosis. RESULTS following the adjustment for various possible covariates, TyG, triglyceride glucose-body mass index (TyG-BMI), triglyceride glucose-waist circumference (TyG-WC), as well as TG/HDL-c were positively correlated with controlled attenuation parameter and NAFLD, with corresponding β coefficients of 17.90, 0.19, 0.20, and 1.57, alongside odds ratios of 2.10, 1.01, 1.01, and 1.15, respectively (all p < 0.05). The β coefficient for the association between TyG and liver stiffness measurement was -0.43 (p = 0.023). Notably, the area under the curve (AUC) of TyG-WC was the highest of all parameters, showing strong diagnostic potential for identifying NAFLD (AUC = 0.79) and liver fibrosis (AUC = 0.75). CONCLUSIONS this study reveals a significant positive correlation between TyG-WC and the prevalence of NAFLD in middle-aged and elderly people in the United States. These findings highlight that lowering TyG-WC levels may help reduce the incidence of NAFLD in middle-aged and older Americans.
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Affiliation(s)
- Yin Yang
- Department of Medical Ultrasound. West China Hospital. Sichuan University
| | - Yuan Luo
- Department of Medical Ultrasound. West China Tianfu Hospital. Sichuan University
| | - Jinchun Shi
- Affiliated Hospital of North Sichuan Medical College
| | - Yunyu Yin
- Affiliated Hospital of North Sichuan Medical College
| | - Xiangyu Du
- Department of Liver Surgery. West China Hospital. Sichuan University
| | - Jia Guo
- Department of Pancreatitis Center. West China Hospital. Sichuan University
| | - Hua Zhuang
- Department of Medical Ultrasound. West China Hospital. Sichuan University
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Kozłowska A. Clinical Insights into Non-Alcoholic Fatty Liver Disease and the Therapeutic Potential of Flavonoids: An Update. Nutrients 2025; 17:956. [PMID: 40289935 PMCID: PMC11944923 DOI: 10.3390/nu17060956] [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: 02/21/2025] [Revised: 03/04/2025] [Accepted: 03/06/2025] [Indexed: 04/30/2025] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is considered a significant global health issue related to serious metabolic disorders. However, effective pharmacological treatments are still limited. Flavonoids, a wide group of polyphenol substances, exert anti-inflammatory and lipid-lowering effects in preclinical data. Thus, implementing these research findings in clinical practice could significantly help manage NAFLD and its consequences. This narrative review assesses the therapeutic potential of flavonoids in managing NAFLD. The research collected randomized controlled trials (RCTs) and meta-analyses of RCTs from the past five years concerning the impact of flavonoids on NAFLD. A total of 20 studies were selected according to predetermined inclusion criteria, comprising thirteen randomized controlled trials (RCTs) and seven meta-analyses. The research underscores the beneficial effects of flavonoids in the management of NAFLD through the enhancement of lipid metabolism, the reduction in hepatic steatosis, and the provision of anti-inflammatory actions. Clinical trials demonstrate that interventions rich in flavonoids, including quercetin, epigallocatechin gallate, naringenin, and isoflavones, substantially reduce liver fat content and enhance liver enzyme profiles, with certain compounds exhibiting superior efficacy in particular subgroups, such as older adults and females. Nonetheless, whereas these therapies significantly diminish hepatic steatosis, their effect on fibrosis is constrained. To sum up, flavonoids exhibit significant potential as supplementary treatments for NAFLD by enhancing liver function, lipid metabolism, and inflammation. Additional extensive controlled clinical trials are necessary to create uniform treatment methods and ascertain their long-term therapeutic advantages.
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Affiliation(s)
- Aleksandra Kozłowska
- Department of Social Medicine and Public Health, Medical University of Warsaw, 02-106 Warsaw, Poland
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44
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Nguyen MT, Lian A, Guilford FT, Venketaraman V. A Literature Review of Glutathione Therapy in Ameliorating Hepatic Dysfunction in Non-Alcoholic Fatty Liver Disease. Biomedicines 2025; 13:644. [PMID: 40149620 PMCID: PMC11940638 DOI: 10.3390/biomedicines13030644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Revised: 03/01/2025] [Accepted: 03/04/2025] [Indexed: 03/29/2025] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a global cause of liver dysfunction. This spectrum of hepatic disorders can progress to severe conditions, such as non-alcoholic steatohepatitis (NASH) and cirrhosis, due to oxidative stress and sustained cellular injury. With limited pharmacological options, glutathione (GSH), a key antioxidant, has shown promising potential in reducing oxidative stress, maintaining redox balance, and improving liver function. This literature review examines studies from 2014-2024 exploring GSH therapy in NAFLD patients. Eligible studies assessed GSH as the primary intervention for NAFLD in human subjects, reporting outcomes such as liver function or oxidative stress markers. Randomized clinical trials (RCTs) were eligible, while combination therapy studies were included if GSH's effect could be isolated. Exclusions applied to non-NAFLD studies, animal/in vitro models, and non-GSH antioxidant interventions. Analysis of three studies (totaling 109 participants) demonstrated consistent improvements in alanine transaminase (ALT) levels and reductions in oxidative stress markers like 8-hydroxy-2-deoxyguanosine (8-OHdG). However, small sample sizes and inconsistent protocols limit generalizability. Further large-scale RCTs are required to confirm GSH's efficacy, determine optimal dosing, and assess long-term effects. This literature review highlights GSH's potential as a novel NAFLD therapeutic strategy while emphasizing the need for further studies to refine its clinical application.
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Affiliation(s)
- Michelle Thuy Nguyen
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA; (M.T.N.); (A.L.)
| | - Andrew Lian
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA; (M.T.N.); (A.L.)
| | | | - Vishwanath Venketaraman
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA; (M.T.N.); (A.L.)
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45
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Xu Y, He P, He B, Chen Z. Bioactive flavonoids metabolites in citrus species: their potential health benefits and medical potentials. Front Pharmacol 2025; 16:1552171. [PMID: 40098613 PMCID: PMC11911525 DOI: 10.3389/fphar.2025.1552171] [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: 12/27/2024] [Accepted: 02/03/2025] [Indexed: 03/19/2025] Open
Abstract
Citrus flavonoids are naturally occurring phytochemicals widely present in the peels and pulps of citrus fruits. They exhibit a wide range of biological activities, including antioxidant, anti-inflammatory, hypoglycemic, lipid-lowering, antimicrobial, and gut-protective effects. These metabolites show great potential in improving metabolic syndromes such as diabetes, non-alcoholic fatty liver disease (NAFLD), and cardiovascular diseases. Additionally, citrus flavonoids have demonstrated significant effects in inhibiting pancreatic lipase activity, regulating lipid metabolism, and enhancing intestinal barrier function. Advances in extraction and purification techniques have further promoted their applications in the fields of food, medicine, and functional materials. This review systematically summarizes the types, bioactivities, and mechanisms of action of citrus flavonoids, providing scientific evidence for their research and development.
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Affiliation(s)
- Yuqian Xu
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China
| | - Pan He
- Sichuan Provincial Women's and Children's Hospital, The Affiliated Women's and Children's Hospital of Chengdu Medical College, Chengdu, China
| | - Beihui He
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China
- School of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Zheng Chen
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China
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Shao J, Zhou M, Xie X, Lan S. Association between fatty liver disease and risk of microvascular complications in Type-2 diabetes mellitus: A systematic review and meta-analysis. Pak J Med Sci 2025; 41:902-909. [PMID: 40103889 PMCID: PMC11911733 DOI: 10.12669/pjms.41.3.11362] [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: 10/17/2024] [Revised: 11/13/2024] [Accepted: 02/15/2025] [Indexed: 03/20/2025] Open
Abstract
Objective To summarize the existing evidence on the association between non-alcoholic fatty liver disease (NAFLD) and the probability of microvascular complications in Type-2 diabetes mellitus (T2DM). Methods PubMed, EMBASE and Scopus databases search (from inception until October 31, 2023) was done for reports with cross-sectional, cohort or case-control design that included adult participants with T2DM and a documented NAFLD status. The selected studies were required to report on at least one microvascular outcome. Studies reporting adjusted associations were included. Random-effects models were used for all analysis. The pooled effect sizes for the associations were reported as odds ratio (OR) with 95% confidence intervals (CI). Results Sixteen studies were analysed. T2DM patients with associated NAFLD had similar risk of neuropathy (OR 1.08, 95% CI: 0.97, 1.21), compared to those without NALFD. NAFLD was associated with slightly lower risk of retinopathy (OR 0.86, 95% CI: 0.75, 0.98; N=10, I2=82.6%) an increased incidence of nephropathy (OR 1.21, 95% CI: 1.14, 1.29; N=12, I2=82.5%), compared to patients with T2DM but no NAFLD. Conclusion Diagnosis of NAFLD in patients with T2DM appears to increase the incidence of nephropathy and decrease the risk of retinopathy. Future studies are needed to confirm these observations.
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Affiliation(s)
- Jiawei Shao
- Jiawei Shao, Department of Hepatology, Affiliated Hospital of Shaoxing University, Shaoxing, Zhejiang Province 421002, P.R. China
| | - Mi Zhou
- Mi Zhou, Department of Dermatology, Affiliated Hospital of Shaoxing University, Shaoxing, Zhejiang Province 421002, P.R. China
| | - Xiaoqing Xie
- Xiaoqing Xie, Department of Hepatology, Affiliated Hospital of Shaoxing University, Shaoxing, Zhejiang Province 421002, P.R. China
| | - Shaobo Lan
- Shaobo Lan, Department of Hepatology, Affiliated Hospital of Shaoxing University, Shaoxing, Zhejiang Province 421002, P.R. China
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Yang J, Shrestha A, Ramalingam L. Fishing for Solutions: How Pre-Conceptional Fish Oil Supplementation in Obese Fathers Reduces Risk of Non-Alcoholic Fatty Liver Disease in Offspring Mice. Mol Nutr Food Res 2025; 69:e202400452. [PMID: 39910853 PMCID: PMC11874265 DOI: 10.1002/mnfr.202400452] [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: 08/12/2024] [Revised: 11/30/2024] [Accepted: 01/03/2025] [Indexed: 02/07/2025]
Abstract
Metabolic dysfunction associated fatty liver disease (MAFLD) is a chronic condition with hepatic fat accumulation. The intergenerational effect of obesity has predominantly focused on mothers, with limited studies on paternal obesity. Nutritional intervention with fish oil (FO) has beneficial effects in reducing markers of obesity. We hypothesized that supplementing obese fathers with FO before conception could enhance the metabolic health of their offspring liver. Male mice were assigned to low-fat (LF), high fat (HF), or HF supplemented with FO for 10 weeks. Subsequently, these males were mated with females on a chow diet. Offspring were sacrificed at 8 weeks, and liver tissues were analyzed for gene expression and histology. Offspring body weight was not significantly impacted by paternal diet. However, male offspring of HF fathers had higher levels of markers of inflammation and fatty acid synthesis compared to offspring of LF fed fathers. Paternal FO supplementation significantly reduced fatty acid synthesis and glucose metabolism, while increasing fatty acid oxidation in male offspring, with a less pronounced effect in female offspring. These findings suggest that FO supplementation in obese fathers prior to conception attenuates the development of MAFLD in male offspring. This data underscores the significance of paternal nutritional intervention in promoting offspring health.
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Affiliation(s)
- Junhui Yang
- Department of Nutrition and Food StudiesSyracuse UniversitySyracuseNew YorkUSA
| | - Akriti Shrestha
- Department of Nutrition and Food StudiesSyracuse UniversitySyracuseNew YorkUSA
| | - Latha Ramalingam
- Department of Nutrition and Food StudiesSyracuse UniversitySyracuseNew YorkUSA
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Yang Y, Jn-Simon N, He Y, Sun C, Zhang P, Hu W, Tian T, Zeng H, Basha S, Huerta AS, Sun LZ, Yin XM, Hromas R, Zheng G, Pi L, Zhou D. A BCL-xL/BCL-2 PROTAC effectively clears senescent cells in the liver and reduces MASH-driven hepatocellular carcinoma in mice. NATURE AGING 2025; 5:386-400. [PMID: 39890936 DOI: 10.1038/s43587-025-00811-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 12/05/2024] [Indexed: 02/03/2025]
Abstract
Accumulation of senescent cells (SnCs) plays a causative role in many age-related diseases and has also been implicated in the pathogenesis and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Senolytics that can selectively kill SnCs have the potential to be developed as therapeutics for these diseases. Here we report the finding that 753b, a dual BCL-xL/BCL-2 proteolysis-targeting chimera (PROTAC), acts as a potent and liver-tropic senolytic. We found that treatment with 753b selectively reduced SnCs in the liver in aged mice and STAM mice in part due to its sequestration in the liver. Moreover, 753b treatment could effectively reduce the progression of MASLD and the development of hepatocellular carcinoma (HCC) in STAM mice even after the mice developed substantial metabolic dysfunction-associated steatohepatitis (MASH) and hepatic fibrosis. These findings suggest that BCL-xL/BCL-2 PROTACs have the potential to be developed as therapeutics for MASLD to reduce MASH-driven HCC.
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Affiliation(s)
- Yang Yang
- Department of Biochemistry and Structural Biology, University of Texas Health Science Center, San Antonio, TX, USA
- Department of Pharmacology and Therapeutics, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Natacha Jn-Simon
- Department of Pathology, Tulane University, New Orleans, LA, USA
| | - Yonghan He
- Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, USA
| | - Chunbao Sun
- Department of Pathology, Tulane University, New Orleans, LA, USA
| | - Peiyi Zhang
- Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, USA
| | - Wanyi Hu
- Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, USA
| | - Tian Tian
- Department of Pathology, Tulane University, New Orleans, LA, USA
| | - Huadong Zeng
- Advanced Magnetic Resonance Imaging and Spectroscopy Facility, University of Florida, Gainesville, FL, USA
| | | | - Araceli S Huerta
- Department of Cell Systems and Anatomy, University of Texas Health Science Center, San Antonio, TX, USA
| | - Lu-Zhe Sun
- Department of Cell Systems and Anatomy, University of Texas Health Science Center, San Antonio, TX, USA
| | - Xian-Ming Yin
- Department of Pathology, Tulane University, New Orleans, LA, USA
| | - Robert Hromas
- Department of Medicine, University of Texas Health Science Center, San Antonio, TX, USA
| | - Guangrong Zheng
- Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, USA
| | - Liya Pi
- Department of Pathology, Tulane University, New Orleans, LA, USA.
| | - Daohong Zhou
- Department of Biochemistry and Structural Biology, University of Texas Health Science Center, San Antonio, TX, USA.
- Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, USA.
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Zuo R, Wang M, Wang YT, ShenTu Y, Moura AK, Zhou Y, Roudbari K, Hu JZ, Li PL, Hao J, Li X, Zhang Y. Ablation of Hepatic Asah1 Gene Disrupts Hepatic Lipid Homeostasis and Promotes Fibrotic Nonalcoholic Steatohepatitis in Mice. THE AMERICAN JOURNAL OF PATHOLOGY 2025; 195:542-560. [PMID: 39719015 PMCID: PMC11983695 DOI: 10.1016/j.ajpath.2024.11.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 10/14/2024] [Accepted: 11/06/2024] [Indexed: 12/26/2024]
Abstract
Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of chronic liver conditions, ranging from simple steatosis to nonalcoholic steatohepatitis, which may progress to fibrosis/cirrhosis. Here, the GSE163211 data set was analyzed, and Asah1 (encoding acid ceramidase) was identified as a crucial lysosomal gene that positively correlated with NAFLD stages in obese patients. To evaluate the role of Asah1 in the progression of NAFLD, Asah1fl/fl/Albcre mice (hepatocyte-specific deletion of Asah1) and Asah1 floxed (Asah1fl/fl/wild-type) mice were fed with either a normal diet or a high-fat, high-cholesterol paigen diet (PD) for 20 weeks. Hepatocyte-specific Asah1 ablation markedly aggravated PD-induced hepatic steatosis, hepatitis, and apoptosis, and resulted in marked fibrotic changes. In addition, Asah1 gene ablation exacerbated PD-induced portal venous hemodynamic abnormality. In cultured hepatocytes, Asah1 gene knockdown resulted in increased ceramide and cholesterol levels but did not affect triglyceride level. Knocking down Asah1 gene also exhibited broad impacts on lipid homeostasis pathways, including lipogenesis, fatty acid uptake, fatty acid oxidation, and lipid transport. Furthermore, Asah1 knockdown resulted in increased endoplasmic reticulum stress and lipid droplet biogenesis. Finally, Asah1 gene knockdown impaired chaperone-mediated autophagy. These results suggest that Asah1 functions as an important regulator of hepatic lipid homeostasis, and its deficiency exacerbates hepatocyte lipotoxicity and injury, and promotes the development of fibrotic nonalcoholic steatohepatitis.
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Affiliation(s)
- Rui Zuo
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas
| | - Mi Wang
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas; Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yun-Ting Wang
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas
| | - YangPing ShenTu
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas; Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Alexandra K Moura
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas
| | - Ying Zhou
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas; Department Nephrology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Kiana Roudbari
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas
| | - Jenny Z Hu
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas
| | - Pin-Lan Li
- Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, Virginia
| | - JiuKuan Hao
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas
| | - Xiang Li
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas
| | - Yang Zhang
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas.
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Abdel Monem MS, Adel A, Abbassi MM, Abdelaziz DH, Hassany M, Raziky ME, Sabry NA. Efficacy and safety of dapagliflozin compared to pioglitazone in diabetic and non-diabetic patients with non-alcoholic steatohepatitis: A randomized clinical trial. Clin Res Hepatol Gastroenterol 2025; 49:102543. [PMID: 39884573 DOI: 10.1016/j.clinre.2025.102543] [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: 12/08/2024] [Revised: 01/21/2025] [Accepted: 01/26/2025] [Indexed: 02/01/2025]
Abstract
BACKGROUND Non-alcoholic steatohepatitis (NASH) is a serious end-stage spectrum of non-alcoholic fatty liver disease (NAFLD) with associated high risk of hepatic and extrahepatic complications. Several studies showed the significant beneficial effect of dapagliflozin on body composition, hepatic and metabolic parameters on NAFLD/NASH patients. The study aimed to investigate the efficacy and safety of dapagliflozin in both diabetic and non-diabetic biopsy-proven NASH patients; compared to pioglitazone. METHODS This was a four-group, prospective, randomized, parallel, open label study in which 100 biopsy-proven NASH patients were selected, stratified to diabetics and non-diabetics and randomized with 1:1 allocation to either 30 mg pioglitazone or 10 mg dapagliflozin, once daily for 24 weeks. Histological evaluation, anthropometric measures, hepatic, metabolic biochemical markers, fibrosis non-invasive markers, quality of life (QOL) and medications adverse events were examined. RESULTS Dapagliflozin showed a comparable histological effect to pioglitazone in both diabetic and non-diabetic patients (P>0.05). As assessed by transient elastography, it also showed a comparable effect on liver fibrosis grade improvement from baseline in diabetics (P=0.287) versus a significant superiority in non-diabetics (P=0.018). Dapagliflozin showed a significant superiority in all anthropometric measures (P<0.001) and QOL (P<0.05) among both diabetics and non-diabetics. There was a significant interaction between interventions and diabetes status on change from baseline of hepatic and metabolic panel collectively (P=0.023) in favor to dapagliflozin among diabetics. CONCLUSION Compared to pioglitazone, dapagliflozin had a comparable effect histologically, superior effect biochemically among diabetics and superior effect on liver fibrosis, steatosis and insulin resistance among non-diabetics. TRIAL REGISTRATION The study was registered on clinicaltrials.gov, identifier number NCT05254626.
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Affiliation(s)
- Mona S Abdel Monem
- Department of Clinical Pharmacy, Faculty of Pharmacy, Cairo University, Egypt.
| | - Abdulmoneim Adel
- National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt.
| | - Maggie M Abbassi
- Department of Clinical Pharmacy, Faculty of Pharmacy, Cairo University, Egypt.
| | - Doaa H Abdelaziz
- Department of Clinical Pharmacy, Faculty of Pharmacy, Al-Baha University, Al-Baha, Saudi Arabia/Department of Clinical Pharmacy, National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt.
| | - Mohamed Hassany
- National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt.
| | - Maissa El Raziky
- Endemic Medicine and Hepatogastroenterology, Faculty of Medicine, Cairo University, Egypt.
| | - Nirmeen A Sabry
- Department of Clinical Pharmacy, Faculty of Pharmacy, Cairo University, Egypt.
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