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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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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] [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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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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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] [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] [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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7
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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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9
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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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10
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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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11
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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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12
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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] [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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13
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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 2025:00936815-990000000-00119. [PMID: 40025997 DOI: 10.4103/sjg.sjg_431_24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 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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14
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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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15
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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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16
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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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17
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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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18
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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 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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19
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Li H, Hou Y, Xin W, Ding L, Yang Y, Zhang Y, Wu W, Wang Z, Ding W. The efficacy of sodium-glucose transporter 2 inhibitors in patients with nonalcoholic fatty liver disease: A systematic review and meta-analysis. Pharmacol Res 2025; 213:107647. [PMID: 39929274 DOI: 10.1016/j.phrs.2025.107647] [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: 07/19/2024] [Revised: 02/05/2025] [Accepted: 02/05/2025] [Indexed: 02/13/2025]
Abstract
The efficacy of sodium-glucose transporter 2 (SGLT-2) inhibitors for nonalcoholic fatty liver disease (NAFLD) is unclear. Therefore, we conducted a systematic review and meta-analysis to evaluate SGLT-2 inhibitors efficacy for NAFLD treatment. We systematically searched major electronic databases (PubMed, Cochrane Library, Web of Science, Embase) from inception until 11/2023, identifying randomized controlled trials (RCTs) of SGLT-2 inhibitors treatment for patients with NAFLD. The mean differences (MD or SMD) and 95 % confidence intervals (CIs) were calculated via random-effects models. Eleven articles (n = 805 patients with NAFLD) were included in this study. Of these, 408 participants received SGLT-2 inhibitors, while 397 participants were in the control group. SGLT-2 inhibitors significantly reduced liver enzyme levels, including aspartate alanine aminotransferase (ALT) (MD [95 % CI]; -9.31 U/L [-13.41, -5.21], p < 0.00001), aspartate aminotransferase (AST) (MD [95 % CI]; -6.06 U/L [-10.98, -1.15], p = 0.02), and gamma-glutamyltransferase (GGT) (MD [95 % CI]; -11.72 U/L [-15.65, -7.80], p < 0.00001). SGLT-2 inhibitors intervention was also associated with significant reductions in body weight (MD [95 % CI]; -2.72 kg [-3.49, -1.95], p < 0.00001) and BMI (MD [95 % CI]; -1.11 kg/m2 [-1.39, -0.82], p < 0.00001) and improvements in glycaemic indices, triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C). However, no significant changes in total cholesterol (TC) or low-density lipoprotein cholesterol (LDL-C) were observed. The meta-analysis revealed a beneficial effect of SGLT-2 inhibitors on liver functions and body weight, BMI, TG, HDL-C, and glucose homeostasis in patients with NAFLD, indicating that SGLT-2 inhibitors might be a clinical therapeutic strategy for these patients, especially individuals with concurrent type 2 diabetes mellitus (T2DM).
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Affiliation(s)
- Hongsheng Li
- Endocrine and Metabolic Diseases Hospital of Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, 18877, Jingshi Rd, Jinan 250062, China; Jinan Key Laboratory of Translational Medicine on Metabolic Diseases, 18877, Jingshi Rd, Jinan 250062, China
| | - Yanli Hou
- Endocrine and Metabolic Diseases Hospital of Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, 18877, Jingshi Rd, Jinan 250062, China; Jinan Key Laboratory of Translational Medicine on Metabolic Diseases, 18877, Jingshi Rd, Jinan 250062, China; Shandong Institute of Endocrine and Metabolic Diseases, 18877, Jingshi Rd, Jinan 250062, China
| | - Wenyong Xin
- Department of Retirement Affairs, Shandong First Medical University & Shandong Academy of Medical Sciences, 18877, Jingshi Rd, Jinan 250062, China
| | - Lina Ding
- Endocrine and Metabolic Diseases Hospital of Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, 18877, Jingshi Rd, Jinan 250062, China; Jinan Key Laboratory of Translational Medicine on Metabolic Diseases, 18877, Jingshi Rd, Jinan 250062, China; Shandong Institute of Endocrine and Metabolic Diseases, 18877, Jingshi Rd, Jinan 250062, China
| | - Ying Yang
- Endocrine and Metabolic Diseases Hospital of Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, 18877, Jingshi Rd, Jinan 250062, China; Shandong Institute of Endocrine and Metabolic Diseases, 18877, Jingshi Rd, Jinan 250062, China
| | - Yikun Zhang
- Endocrine and Metabolic Diseases Hospital of Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, 18877, Jingshi Rd, Jinan 250062, China; Shandong Institute of Endocrine and Metabolic Diseases, 18877, Jingshi Rd, Jinan 250062, China
| | - Wenqi Wu
- Endocrine and Metabolic Diseases Hospital of Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, 18877, Jingshi Rd, Jinan 250062, China; Jinan Key Laboratory of Translational Medicine on Metabolic Diseases, 18877, Jingshi Rd, Jinan 250062, China
| | - Zhibin Wang
- Endocrine and Metabolic Diseases Hospital of Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, 18877, Jingshi Rd, Jinan 250062, China; Jinan Key Laboratory of Translational Medicine on Metabolic Diseases, 18877, Jingshi Rd, Jinan 250062, China; Shandong Institute of Endocrine and Metabolic Diseases, 18877, Jingshi Rd, Jinan 250062, China.
| | - Wenyu Ding
- Endocrine and Metabolic Diseases Hospital of Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, 18877, Jingshi Rd, Jinan 250062, China; Jinan Key Laboratory of Translational Medicine on Metabolic Diseases, 18877, Jingshi Rd, Jinan 250062, China; Shandong Institute of Endocrine and Metabolic Diseases, 18877, Jingshi Rd, Jinan 250062, China.
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20
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Cooper KM, Patel AK, Zammitti CA, Murchie E, Colletta A, Devuni D. Statin Therapy is Associated With Lower Risk of Mortality Among Liver Transplant Candidates With Metabolic Dysfunction-associated Steatohepatitis. J Clin Exp Hepatol 2025; 15:102427. [PMID: 39678071 PMCID: PMC11638578 DOI: 10.1016/j.jceh.2024.102427] [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: 08/10/2024] [Accepted: 10/09/2024] [Indexed: 12/17/2024] Open
Abstract
Background Statin therapy is historically underutilized in patients with chronic liver disease. There is increasing evidence to support the use of statins in patients with cirrhosis, though data in decompensated patients are limited. The primary aim of this study was to evaluate the association between statin use and mortality in patients with advanced liver disease, comparing MASH and non-MASH cirrhosis. Methods This single-center retrospective cohort study included patients undergoing liver transplant (LT) evaluation at a large quaternary care center. Patients were categorized by etiology as metabolic dysfunction-associated steatohepatitis (MASH) or non-MASH cirrhosis. Statin use was defined as having an active prescription at the time of LT evaluation. The association between statin use and mortality was evaluated using multivariable Cox proportional hazard regression. Results The study included 623 patients; 24% had MASH cirrhosis and 20% were prescribed a statin. Statin users were older, had a higher BMI, and were more likely to have coronary artery disease. At the end of the study, statin use was associated with lower mortality among MASH patients (16% vs. 35%, P = 0.010) and higher mortality among non-MASH patients (31% vs. 19%, P = 0.066). After controlling for age (HR 1.05, 95% CI: 1.00-1.10, P = 0.039), MELD-Na (HR: 1.07, 95% CI: 1.04-1.11, P < 0.001), BMI (HR: 1.09, 95% CI: 1.05-1.14, P < 0.001), and CAD (HR: 1.20, 95% CI: 0.54-2.69, P = 0.653), statin use conferred a 53% lower risk of death compared with no statin use in patients with MASH cirrhosis (HR: 0.47, 95% CI: 0.22-0.98, P = 0.043). Conclusions Statin use was associated with reduced mortality in patients with decompensated MASH cirrhosis undergoing LT evaluation, but increased mortality in those with non-MASH cirrhosis, particularly those with high-MELD-Na. These findings underscore the importance of reviewing individual patient characteristics and disease etiology when considering the benefits of statin therapy in patients with cirrhosis.
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Affiliation(s)
| | - Ami K. Patel
- UMass Chan Medical School, Department of Medicine, USA
| | | | - Ellen Murchie
- UMass Chan Medical School, Department of Medicine, USA
| | - Alessandro Colletta
- UMass Chan Medical School, Department of Medicine, USA
- UMass Chan Medical School, Division of Gastroenterology and Hepatology, USA
| | - Deepika Devuni
- UMass Chan Medical School, Department of Medicine, USA
- UMass Chan Medical School, Division of Gastroenterology and Hepatology, USA
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21
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Mohsenpoor MA, Parastouei K, Taghdir M, Akbarzadeh M, Abbaszadeh S, Abyazi Heris MA, Mansouri Rad MR, Jafari MA, Borzooei R. The effect of chitosan supplementation on liver function, hepatic steatosis predictors, and metabolic indicators in adults with non-alcoholic fatty liver disease: a randomized, double-blinded, placebo-controlled, clinical trial. JOURNAL OF HEALTH, POPULATION, AND NUTRITION 2025; 44:60. [PMID: 40025618 PMCID: PMC11872331 DOI: 10.1186/s41043-025-00797-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Accepted: 02/18/2025] [Indexed: 03/04/2025]
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is a disease with high complications. An increment in dietary fiber consumption is an approach to NAFLD management, and chitosan as dietary fiber can play a role in the management of NAFLD. Thus, the present study aimed to investigate the effect of chitosan supplementation on liver function, hepatic steatosis predictors, and metabolic indices in adults with NAFLD. METHODS Seventy-two adults with NAFLD were randomly assigned to consume either 1.5 g/day chitosan or placebo along with a low-calorie (- 500 kcal/day) diet for 8 weeks in a parallel, randomized, double-blinded, placebo-controlled, clinical trial. Participants were assessed for dietary intake, physical activity, and anthropometric indices. Blood samples were taken to measure fasting blood sugar (FBS), cholesterol, triglycerides, high- and low-density lipoprotein (HDL and LDL). Liver function indices including alanine aminotransferase (ALT), aspartate transaminase (AST), and gamma-glutamyltransferase (GGT) were evaluated using blood samples as the primary outcomes. Fatty liver index (FLI), hepatic steatosis index (HSI), and triglyceride-glucose index (TyG) were calculated as hepatic steatosis predictors' indices. RESULTS After 8 weeks of study, 66 participants finished the study. In comparison with placebo, chitosan supplementation reduced weight (P = 0.041), waist circumference (P = 0.049), AST (P = 0.040), ALT (P = 0.001), and GGT (P = 0.028). Although the reduction of FBS, triglycerides, cholesterol, LDL, FLI, HSI, and TyG, and increment in HDL was higher in the chitosan group, the results were not significant (P > 0.05). CONCLUSIONS Eight-week supplementation with 1.5 g/day chitosan along with a low-calorie diet could possibly reduce weight, waist circumference, AST, ALT, and GGT, and ameliorate NAFLD. Further investigations are recommended. Trial registration The trial was registered at IRCT.ir as IRCT20140502017522N4 (March 2023).
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Affiliation(s)
| | - Karim Parastouei
- Health Research Centre, Life Style Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Maryam Taghdir
- Health Research Centre, Life Style Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.
- Department of Nutrition and Food Hygiene, Faculty of Health, Baqiyatallah University of Medical Sciences, Tehran, Iran.
| | - Marzieh Akbarzadeh
- Nutrition Research Center, Department of Community Nutrition, School of Nutrition and Food Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Sepideh Abbaszadeh
- Health Research Centre, Life Style Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Mohammad Ali Abyazi Heris
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases (BRCGL), Baqiyatallah University of Medical Sciences, Tehran, Iran
| | | | | | - Ronak Borzooei
- Student Research Committee, Baqiyatallah University of Medical Sciences, Tehran, Iran
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22
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Huschet LA, Kliem FP, Wienand P, Wunderlich CM, Ribeiro A, Bustos-Martínez I, Barco Á, Wunderlich FT, Lech M, Robles MS. FrozONE: quick cell nucleus enrichment for comprehensive proteomics analysis of frozen tissues. Life Sci Alliance 2025; 8:e202403130. [PMID: 39667914 PMCID: PMC11638322 DOI: 10.26508/lsa.202403130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Revised: 12/02/2024] [Accepted: 12/03/2024] [Indexed: 12/14/2024] Open
Abstract
Subcellular fractionation allows for the investigation of compartmentalized processes in individual cellular organelles. Nuclear enrichment methods commonly employ the use of density gradients combined with ultracentrifugation for freshly isolated tissues. Although it is broadly used in combination with proteomics, this approach poses several challenges when it comes to scalability and applicability for frozen material. To overcome these limitations, we developed FrozONE (Frozen Organ Nucleus Enrichment), a nucleus enrichment and proteomics workflow for frozen tissues. By extensively benchmarking our workflow against alternative methods, we showed that FrozONE is a faster, simpler, and more scalable alternative to conventional ultracentrifugation methods. FrozONE allowed for the study, profiling, and classification of nuclear proteomes in different tissues with complex cellular heterogeneity, ensuring optimal nucleus enrichment from different cell types and quantitative resolution for low abundant proteins. In addition to its performance in healthy mouse tissues, FrozONE proved to be very efficient for the characterization of liver nuclear proteome alterations in a pathological condition, diet-induced nonalcoholic steatohepatitis.
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Affiliation(s)
- Lukas A Huschet
- Institute of Medical Psychology and Biomedical Center (BMC), Faculty of Medicine, LMU, Munich, Germany
| | - Fabian P Kliem
- Institute of Medical Psychology and Biomedical Center (BMC), Faculty of Medicine, LMU, Munich, Germany
| | - Peter Wienand
- Max Planck Institute for Metabolism Research, Center for Molecular Medicine Cologne (CMMC) and Policlinic for Endocrinology, Diabetes, and Preventive Medicine (PEDP), University Hospital Cologne, Cologne, Germany
| | - Claudia M Wunderlich
- Max Planck Institute for Metabolism Research, Center for Molecular Medicine Cologne (CMMC) and Policlinic for Endocrinology, Diabetes, and Preventive Medicine (PEDP), University Hospital Cologne, Cologne, Germany
| | - Andrea Ribeiro
- LMU Klinikum, Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Isabel Bustos-Martínez
- Instituto de Neurociencias (Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas), Alicante, Spain
| | - Ángel Barco
- Instituto de Neurociencias (Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas), Alicante, Spain
| | - F Thomas Wunderlich
- Max Planck Institute for Metabolism Research, Center for Molecular Medicine Cologne (CMMC) and Policlinic for Endocrinology, Diabetes, and Preventive Medicine (PEDP), University Hospital Cologne, Cologne, Germany
| | - Maciej Lech
- LMU Klinikum, Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Maria S Robles
- Institute of Medical Psychology and Biomedical Center (BMC), Faculty of Medicine, LMU, Munich, Germany
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23
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Zhang S, Wu J, Wang L, Zhang C, Zhang Y, Feng Y. Exploring the hepatic-ophthalmic axis through immune modulation and cellular dynamics in diabetic retinopathy and non-alcoholic fatty liver disease. Hum Genomics 2025; 19:19. [PMID: 40011971 DOI: 10.1186/s40246-025-00730-z] [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: 10/04/2024] [Accepted: 02/13/2025] [Indexed: 02/28/2025] Open
Abstract
BACKGROUND Dysfunctions within the liver system are intricately linked to the progression of diabetic retinopathy (DR) and non-alcoholic fatty liver disease (NAFLD). This study leverages systematic analysis to elucidate the complex cross-talk and communication pathways among diverse cell populations implicated in the pathogenesis of DR and NAFLD. METHODS Single-cell RNA sequencing data for proliferative diabetic retinopathy (PDR) and NAFLD were retrieved from the Gene Expression Omnibus (GEO) database. Differential gene expression analysis was conducted and followed by pseudo-time analysis to delineate dynamic changes in core cells and differentially expressed genes (DEGs). CellChat was employed to predict intercellular communication and signaling pathways. Additionally, gene set enrichment and variation analyses (GSEA and GSVA) were performed to uncover key functional enrichments. RESULTS Our comparative analysis of the two datasets focused on T cells, macrophages and endothelial cells, revealing SYNE2 as a notable DEG. Notably, common genes including PYHIN1, SLC38A1, ETS1 (T cells), PPFIBP1, LIFR, HSPG2 (endothelial cells), and MSR1 (macrophages), emerged among the top 50 DEGs across these cell types. The CD45 signaling pathway was pivotal for T cells and macrophages, exerting profound effects on other cells in both PDR and NAFLD. Moreover, GSEA and GSVA underscored their involvement in cellular communication, immune modulation, energy metabolism, mitotic processes. CONCLUSION The comprehensive investigation of T cells, macrophages, endothelial cells, and the CD45 signaling pathway advances our understanding of the intricate biological processes underpinning DR and NAFLD. This research underscores the imperative of exploring immune-related cell interactions, shedding light on novel therapeutic avenues in these disease contexts.
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Affiliation(s)
- Shuyan Zhang
- Department of Ophthalmology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Jiajun Wu
- Department of Ophthalmology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Leilei Wang
- Department of Ophthalmology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Eye Disease Prevention and Treatment Center, Shanghai, China
| | - Cheng Zhang
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Yinjian Zhang
- Department of Ophthalmology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| | - Yibin Feng
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
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24
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El-Kurjieh A, Al-Arab R, Hachem QA, Ibrahim JN, Kobeissy PH. ACSS2 and metabolic diseases: from lipid metabolism to therapeutic target. Lipids Health Dis 2025; 24:74. [PMID: 40001058 PMCID: PMC11853604 DOI: 10.1186/s12944-025-02491-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Accepted: 02/16/2025] [Indexed: 02/27/2025] Open
Abstract
Elevated incidence of metabolic disorders has been reported worldwide in the recent decade, highlighting the need for developing efficient therapies. These diseases result from a complex interplay of various factors that contribute to disease progression, complications, and resistance to current treatment options. Acetyl-CoA Synthetase Short Chain Family Member 2 (ACSS2) is a nucleo-cytosolic enzyme with both lipogenic and metabolic regulatory roles. Studies on ACSS2 have shown that it is involved in pathways commonly dysregulated in metabolic disorders, leading to fat deposition and disrupted cellular signaling. Although multiple studies have suggested a role of ACSS2 in the metabolic rewiring during tumorigenesis, few studies have examined its involvement in the pathophysiology of metabolic diseases. Recent evidence indicates that ACSS2 may contribute to the pathogenesis of various metabolic disorders making its examination of great interest and potentially aiding in the development of new therapeutic strategies. The objective of this review is to summarize the current understanding of ACSS2's role in metabolic disorders and its potential as a therapeutic target.
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Affiliation(s)
- Alaa El-Kurjieh
- Department of Biological Sciences, School of Arts and Sciences, Lebanese American University (LAU), Beirut, Lebanon
| | - Reem Al-Arab
- Department of Biological Sciences, School of Arts and Sciences, Lebanese American University (LAU), Beirut, Lebanon
| | - Qamar Abou Hachem
- Department of Biological Sciences, School of Arts and Sciences, Lebanese American University (LAU), Beirut, Lebanon
| | - José-Noel Ibrahim
- Department of Biological Sciences, School of Arts and Sciences, Lebanese American University (LAU), Beirut, Lebanon.
| | - Philippe Hussein Kobeissy
- Department of Biological Sciences, School of Arts and Sciences, Lebanese American University (LAU), Beirut, Lebanon.
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25
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Yang QL, Lu XW, Fang ZL, Gao YQ, He YN, Huang Y, Dai Y, Liang MY, Chan CHF, Jiang ZH. The association between Clonorchis sinensis seropositivity and hepatocellular carcinoma in an endemic area: a study in Guangxi, China. BMC Infect Dis 2025; 25:270. [PMID: 40000979 PMCID: PMC11852542 DOI: 10.1186/s12879-025-10675-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Accepted: 02/18/2025] [Indexed: 02/27/2025] Open
Abstract
BACKGROUND Chronic infection with Clonorchis sinensis (C.sinensis) has been associated swith the development of intrahepatic cholangiocarcinoma (ICC); however, the relationship between C.sinensis and hepatocellular carcinoma (HCC) remains uncertain. METHODS This study examined 120 patients with liver cancer in the clonorchiasis endemic area of Hengzhou, Guangxi, China. The type of cancer, the differentiation grade according to Edmondson Steiner's classification, and the pathological characteristics of HCC were determined through postoperative tissue biopsy. C.sinensis infection was detected by measuring serum specific IgG antibody, and hepatitis B virus (HBV) infection was determined by detecting serum HBsAg and HBV DNA in HCC tissues. The C.sinensis infection rates in control groups were drawn from the local general population based on previous surveys. The association between C.sinensis infection and HCC was analyzed by comparing the differences in C.sinensis infection rates between the two groups. RESULTS Of the patients evaluated, 98 (81.7%) had HCC, 21 (17.5%) had ICC, and 1 (0.8%) had comorbidity of HCC/ICC. Among the HCC patients, 24 (24.5%) were solely infected with HBV, 71 (72.4%) were C. sinensis seropositive, and 3 (3.1%) showed no evidence of infection. C. sinensis seropositive rates in HCC patients are much higher than in general outpatient and non-liver cancer inpatients (χ2 = 141.92, p < 0.001), as well as in the local residents (χ2 = 82.61/21.38, p < 0.001). There were no significant differences in the pathological type, differentiation grade, and lesion composition between the tumor associated with C.sinensis/HBV mono- and co-infection (p > 0.05). Among the patients with C.sinensis-related HCC, 8 (8.2%) were solely C.sinensis seropositive, while 63 (64.3%) were co-infected with HBV. Infection with C. sinensis and HBV has a significant impact on the pathological types of liver cancer (χ2 = 22.86, p < 0.001). CONCLUSIONS These findings indicate that HCC still accounts for the majority of liver cancer in this region. In addition to being most commonly related with HBV infection, HCC may also be related to C. sinensis infection. Co-infection of C. sinensis and HBV may enhance the development of HCC in this area. CLINICAL TRIAL Not applicable.
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Affiliation(s)
- Qing-Li Yang
- Guangxi University of Chinese Medicine, Guangxi Key Laboratory of Translational Medicine for Treating High-Incidence Infectious Diseases with Integrative Medicine, Nanning, Nanning, Guangxi, 530200, People's Republic of China
| | - Xi-Wei Lu
- People's Hospital of Hengzhou, Nanning, Guangxi, 530300, People's Republic of China
| | - Zhong-Liao Fang
- Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for Viral Hepatitis Prevention and Control, Nanning 530028, Guangxi, People's Republic of China, Nanning, Guangxi, People's Republic of China
| | - Yu-Qiu Gao
- Guangxi University of Chinese Medicine, Guangxi Key Laboratory of Translational Medicine for Treating High-Incidence Infectious Diseases with Integrative Medicine, Nanning, Nanning, Guangxi, 530200, People's Republic of China
| | - Yi-Ning He
- Guangxi University of Chinese Medicine, Guangxi Key Laboratory of Translational Medicine for Treating High-Incidence Infectious Diseases with Integrative Medicine, Nanning, Nanning, Guangxi, 530200, People's Republic of China
| | - Yan Huang
- Guangxi University of Chinese Medicine, Guangxi Key Laboratory of Translational Medicine for Treating High-Incidence Infectious Diseases with Integrative Medicine, Nanning, Nanning, Guangxi, 530200, People's Republic of China
| | - Yue Dai
- Guangxi University of Chinese Medicine, Guangxi Key Laboratory of Translational Medicine for Treating High-Incidence Infectious Diseases with Integrative Medicine, Nanning, Nanning, Guangxi, 530200, People's Republic of China
| | - Ming-Yong Liang
- Hengzshou Center for Disease Prevention and Control, Nanning, Guangxi, 530300, China
| | - Carlos H F Chan
- Department of Surgery, University of Iowa Health Care, Iowa City, IA 52242, USA.
| | - Zhi-Hua Jiang
- Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for Viral Hepatitis Prevention and Control, Nanning 530028, Guangxi, People's Republic of China, Nanning, Guangxi, People's Republic of China.
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26
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Li B, Liu Y, Ma X, Guo X. The association between non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio and hepatic steatosis and liver fibrosis among US adults based on NHANES. Sci Rep 2025; 15:6527. [PMID: 39988726 PMCID: PMC11847945 DOI: 10.1038/s41598-025-90773-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Accepted: 02/17/2025] [Indexed: 02/25/2025] Open
Abstract
Recently, the non-high-density to high-density lipoprotein cholesterol ratio (NHHR) has gained growing attention as an indicator for predicting diseases associated with lipid metabolism. Hepatic steatosis and fibrosis are tightly associated lipid metabolism. Our study aims to analyze the correlations among NHHR, hepatic steatosis, and fibrosis. This study analysed data from 14,578 adults in the US National Health and Nutrition Examination Survey (2005-2018). The degree of hepatic steatosis was measured through the Fatty Liver Index (FLI), while liver fibrosis severity was evaluated with the Fibrosis-4 (FIB-4) index. Multivariate linear regression assessed the association between NHHR and the FLI and FIB-4 score. Smooth curve describing the relationship between NHHR and FLI or FIB-4. Additionally, a two-part linear regression model adopted in order to more accurately account for the nonlinear relationship, with threshold effects estimated through its two components. To confirm the robustness of the findings, interaction tests and subgroup analyses were conducted. The multivariate logistic regression analysis demonstrated a significantly positive correlation of lnNHHR with FLI across all three models. In Model 3, the association was (β = 11.14, 95%CI:10.38,11.90). Curve fitting indicated a nonlinear relationship. The positive correlation between lnNHHR and FLI persists across gender, BMI, and physical activity groups. Nevertheless, a notable negative correlation between lnNHHR and FIB-4 was observed in all three models. In Model 3, the relationship between lnNHHR and FIB-4 was as follows: (β = -0.20; 95% CI: -0.22, -0.17). Curve fitting revealed a V-shaped relationship, with threshold effect analysis identifying a breakpoint at 1.51. Above this threshold, the relationship was found to be statistically insignificant (p-value = 0.424). Receiver operating characteristic (ROC) curve analysis demonstrated that NHHR exhibited better predictive performance for MASLD compared to non-HDL-C, HDL-C, and LDL-C/HDL-C. The current study's findings suggest that elevated levels of NHHR correlate with a greater risk of hepatic steatosis among adults in the U.S. Our findings imply that NHHR may be a valuable tool in improving MASLD prevention strategies in the general population.
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Affiliation(s)
- Baoyu Li
- Department of Gastroenterology, The Second Affiliated Hospital of Xi'an Jiaotong, University, Xi'an, Shaanxi, China
| | - Yuwei Liu
- Department of Gastroenterology, The Second Affiliated Hospital of Xi'an Jiaotong, University, Xi'an, Shaanxi, China
| | - Xiaorong Ma
- Department of Gastroenterology, The Second Affiliated Hospital of Xi'an Jiaotong, University, Xi'an, Shaanxi, China.
| | - Xiaoyan Guo
- Department of Gastroenterology, The Second Affiliated Hospital of Xi'an Jiaotong, University, Xi'an, Shaanxi, China.
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Zisis M, Chondrogianni ME, Androutsakos T, Rantos I, Oikonomou E, Chatzigeorgiou A, Kassi E. Linking Cardiovascular Disease and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): The Role of Cardiometabolic Drugs in MASLD Treatment. Biomolecules 2025; 15:324. [PMID: 40149860 PMCID: PMC11940321 DOI: 10.3390/biom15030324] [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: 12/27/2024] [Revised: 02/14/2025] [Accepted: 02/19/2025] [Indexed: 03/29/2025] Open
Abstract
The link between cardiovascular disease (CVD) and metabolic dysfunction-associated steatotic liver disease (MASLD) is well-established at both the epidemiological and pathophysiological levels. Among the common pathophysiological mechanisms involved in the development and progression of both diseases, oxidative stress and inflammation, insulin resistance, lipid metabolism deterioration, hepatokines, and gut dysbiosis along with genetic factors have been recognized to play a pivotal role. Pharmacologic interventions with drugs targeting common modifiable cardiometabolic risk factors, such as T2DM, dyslipidemia, and hypertension, are a reasonable strategy to prevent CVD development and progression of MASLD. Recently, a novel drug for metabolic dysfunction-associated steatohepatitis (MASH), resmetirom, has shown positive effects regarding CVD risk, opening new opportunities for the therapeutic approach of MASLD and CVD. This review provides current knowledge on the epidemiologic association of MASLD to CVD morbidity and mortality and enlightens the possible underlying pathophysiologic mechanisms linking MASLD with CVD. The role of cardiometabolic drugs such as anti-hypertensive drugs, hypolipidemic agents, glucose-lowering medications, acetylsalicylic acid, and the thyroid hormone receptor-beta agonist in the progression of MASLD is also discussed. Metformin failed to prove beneficial effects in MASLD progression. Studies on the administration of thiazolinediones in MASLD suggest effectiveness in improving steatosis, steatohepatitis, and fibrosis, while newer categories of glucose-lowering agents such as GLP-1Ra and SGLT-2i are currently being tested for their efficacy across the whole spectrum of MASLD. Statins alone or in combination with ezetimibe have yielded promising results. The conduction of long-duration, large, high-quality, randomized-controlled trials aiming to assess by biopsy the efficacy of cardiometabolic drugs to reverse MASLD progression is of great importance.
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Affiliation(s)
- Marios Zisis
- Medical School, National and Kapodistrian University of Athens, Mikras Asias 75, 11527 Athens, Greece; (M.Z.); (I.R.)
| | - Maria Eleni Chondrogianni
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
- Endocrine Unit, 1st Department of Propaedeutic and Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Theodoros Androutsakos
- Department of Pathophysiology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Str., 11527 Athens, Greece;
| | - Ilias Rantos
- Medical School, National and Kapodistrian University of Athens, Mikras Asias 75, 11527 Athens, Greece; (M.Z.); (I.R.)
| | - Evangelos Oikonomou
- 3rd Department of Cardiology, “Sotiria” Thoracic Diseases Hospital of Athens, University of Athens Medical School, 11527 Athens, Greece;
| | - Antonios Chatzigeorgiou
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Str., 11527 Athens, Greece;
| | - Eva Kassi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
- Endocrine Unit, 1st Department of Propaedeutic and Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece
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Li Q, Xiang J. METTL3 promotes the progression of non-alcoholic fatty liver disease by mediating m6A methylation of FAS. Sci Rep 2025; 15:6162. [PMID: 39979577 PMCID: PMC11842791 DOI: 10.1038/s41598-025-90419-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Accepted: 02/12/2025] [Indexed: 02/22/2025] Open
Abstract
N6-methyladenosine (m6A) is involved in the development of non-alcoholic fatty liver disease (NAFLD). Here, we aimed to investigate the effect of m6A methyltransferase METTL3 on liver damage in high-fat diet (HFD)-induced mouse model and hepatocyte damage treated with free fatty acid (FFA). Plasma lipid, lipogenesis, viability, and apoptosis were measured to assess injury. m6A methylation was evaluated using m6A dot blot, methylated RNA immunoprecipitation, dual-luciferase reporter assay, and RNA decay assay. The results indicated that METTL3 was highly expressed in the liver of HFD mice, which knockdown improved plasma lipid and reduced liver lipids. Additionally, silencing of METTL3 promoted cell viability, inhibited apoptosis, reduced lipid concentrations, and downregulated lipogenesis-related marker levels. Moreover, METTL3 promoted the m6A methylation of FAS and enhanced its stability. In conclusion, silencing of METTL3 attenuates the progression of NAFLD by FAS m6A methylation, suggesting that METTL3 may be a promising target for treating NAFLD.
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Affiliation(s)
- Qunhua Li
- Department of Gastroenterology, Affiliated Hospital of Chengdu University, 2nd N Section of 2nd Ring Rd, Chengdu, 610036, Sichuan, China
| | - Junying Xiang
- Department of Gastroenterology, Affiliated Hospital of Chengdu University, 2nd N Section of 2nd Ring Rd, Chengdu, 610036, Sichuan, China.
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Lajeunesse-Trempe F, Dugas S, Maltais-Payette I, Tremblay ÈJ, Piché ME, K. Dimitriadis G, Lafortune A, Marceau S, Biertho L, Tchernof A. Anthropometric Indices and Metabolic Dysfunction-Associated Fatty Liver Disease in Males and Females Living With Severe Obesity. Can J Gastroenterol Hepatol 2025; 2025:5545227. [PMID: 39989658 PMCID: PMC11847611 DOI: 10.1155/cjgh/5545227] [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: 10/23/2023] [Revised: 05/28/2024] [Accepted: 11/07/2024] [Indexed: 02/25/2025] Open
Abstract
Introduction: Metabolic dysfunction-associated fatty liver disease (MAFLD) is highly prevalent among people living with severe obesity (body mass index [BMI] ≥ 35 kg/m2). However, it remains unknown how sex and adipose tissue distribution are related to MAFLD onset and progression into metabolic dysfunction-associated steatohepatitis (MASH) or advanced stages of fibrosis. Methodology: We retrospectively studied patients with severe obesity who were eligible for bariatric surgery. Demographic characteristics, biomarkers, and cardiometabolic comorbidities were reported. Anthropometric indices such as BMI, waist circumference (WC), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), neck circumference (NC), lipid accumulation product (LAP), visceral adiposity index (VAI), body adiposity index (BAI), abdominal volume index (AVI), and body roundness index (BRI) were measured or calculated. MAFLD, MASH, and stages of fibrosis (F1-F4) were established from perioperative liver biopsies. Standardized univariate and multivariate logistic regression analyses were used to examine the association between demographic variables, anthropometric indices, cardiometabolic conditions, and the risk of MASH or severe fibrosis (F2-F4). Results: A total of 2091 participants with severe obesity were included in the analyses; BMI 47.9 ± 7.3 kg/m2, age 46.2 ± 11.2 years, and 68.4% females. Overall, MAFLD prevalence was 79.5%, with 44.5% having MASH and 24.4% having severe fibrosis (Stage 2 or higher). No anthropometric indices of adiposity were associated with MASH or fibrosis severity. In this population, female sex was a risk factor for severe fibrosis (OR: 1.27, 95% CI 1.01-1.59, p < 0.05). Conclusions: MAFLD and MASH are highly prevalent in individuals living with severe obesity, but no anthropometric indices or laboratory tests are good predictors of MAFLD or MASH in this population. When MAFLD is diagnosed, our results suggest that females with severe obesity might be at higher risk of advanced stages of fibrosis.
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Affiliation(s)
- Fannie Lajeunesse-Trempe
- Department of Specialized Medicine, Internal Medicine, Quebec Heart and Lung Institute, Laval University, Quebec City, Quebec, Canada
- Faculty of Agriculture and Food Sciences, School of Nutrition, Laval University, Quebec City, Quebec, Canada
- Faculty of Life Sciences and Medicine, School of Cardiovascular and Metabolic Medicine & Sciences, King's College London, London, UK
| | - Selena Dugas
- Faculty of Agriculture and Food Sciences, School of Nutrition, Laval University, Quebec City, Quebec, Canada
| | - Ina Maltais-Payette
- Faculty of Agriculture and Food Sciences, School of Nutrition, Laval University, Quebec City, Quebec, Canada
| | - Ève-Julie Tremblay
- Faculty of Agriculture and Food Sciences, School of Nutrition, Laval University, Quebec City, Quebec, Canada
| | - Marie-Eve Piché
- Department of Medicine, Laval University, Quebec City, Quebec, Canada
| | - Georgios K. Dimitriadis
- Faculty of Life Sciences and Medicine, School of Cardiovascular and Metabolic Medicine & Sciences, King's College London, London, UK
- Department of Endocrinology, King's College Hospital NHS Foundation Trust, London, UK
| | - Annie Lafortune
- Department of Surgery, Laval University, Quebec City, Quebec, Canada
| | - Simon Marceau
- Department of Surgery, Laval University, Quebec City, Quebec, Canada
| | - Laurent Biertho
- Department of Surgery, Laval University, Quebec City, Quebec, Canada
| | - André Tchernof
- Faculty of Agriculture and Food Sciences, School of Nutrition, Laval University, Quebec City, Quebec, Canada
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Shafiee M, Sadeghi A, Ghafouri-Taleghani F, Nilghaz M, Ghods M, Narimani B, Hekmatdoost A, Saidpour A. Effects of time restricted feeding combined with Lacto Ovo vegetarian diet on metabolic associated fatty liver disease management: a randomized clinical trial. Sci Rep 2025; 15:4463. [PMID: 39915600 PMCID: PMC11803106 DOI: 10.1038/s41598-025-88773-z] [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: 11/02/2024] [Accepted: 01/30/2025] [Indexed: 02/09/2025] Open
Abstract
Metabolic Associated Fatty Liver Disease (MAFLD) is becoming a major global health concern due to its links with obesity, insulin resistance, and cardiovascular risk. This randomized clinical trial assessed the effects of combining time-restricted feeding (TRF; 16/8) with a Lacto-Ovo-Vegetarian (LOV) diet on various factors in overweight and obese patients with MAFLD. Forty-six participants were randomly assigned to either the intervention group (TRF with LOV diet) or the control group, with 21 participants completing the 12-week study in each group. The intervention group showed significant reductions in weight (-8.07 ± 4.31 kg), BMI (-2.70 ± 1.32 kg/m2), waist circumference (-8.00 ± 4.06 cm), as well as ALT (-17.14 ± 14.33 U/L), GGT (-21.09 ± 24.06 U/L), Fatty Liver Index (-26.90 ± 15.81), insulin levels (-3.89 ± 4.69 mU/L), and TNF-α (-11.85 ± 12.52 pg/mL) compared to the control group (all P < 0.05). Lipid profiles also improved with a reduction in triglycerides (-46.85 ± 54.55 mg/dL) and an increase in HDL-C (3.91 ± 5.07 mg/dL) in the intervention group compared to the control group (P < 0.05). These findings imply that TRF combined with a LOV diet enhances metabolic markers, liver health, and weight loss, thus potentially offering a practical dietary approach for managing MAFLD. Further long-term studies are necessary to validate these results and investigate their clinical applications.
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Affiliation(s)
- Mahshad Shafiee
- Department of Clinical Nutrition & Dietetics, Faculty of Nutrition Sciences and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amir Sadeghi
- Gastroenterology and Liver Diseases Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fateme Ghafouri-Taleghani
- Micronutrient Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Nilghaz
- Department of Clinical Nutrition & Dietetics, Faculty of Nutrition Sciences and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Ghods
- Department of Clinical Nutrition & Dietetics, Faculty of Nutrition Sciences and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Behnaz Narimani
- Department of Clinical Nutrition & Dietetics, Faculty of Nutrition Sciences and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Azita Hekmatdoost
- Department of Clinical Nutrition & Dietetics, Faculty of Nutrition Sciences and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Atoosa Saidpour
- Department of Clinical Nutrition & Dietetics, Faculty of Nutrition Sciences and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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31
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Khalifa O, Ayoub S, Arredouani A. Exploring the Putative Involvement of MALAT1 in Mediating the Beneficial Effect of Exendin-4 on Oleic Acid-Induced Lipid Accumulation in HepG2 Cells. Biomedicines 2025; 13:370. [PMID: 40002783 PMCID: PMC11853215 DOI: 10.3390/biomedicines13020370] [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: 12/26/2024] [Revised: 01/27/2025] [Accepted: 02/01/2025] [Indexed: 02/27/2025] Open
Abstract
Background/Objectives: The reduction of oleic acid (OA)-induced steatosis in HepG2 cells observed upon treatment with the glucagon-like peptide-1 receptor agonist (GLP-1RA) Exendin-4 (Ex-4) is associated with the modulation of the expression of several microRNAs, long non-coding RNAs (lncRNAs), and mRNAs. Notably, MALAT1, an lncRNA, shows significant downregulation in the presence of Ex-4 as compared to OA alone. In this study, we aimed to explore the role of MALAT1 in the positive impact of Ex-4 on OA-induced lipid accumulation in HepG2 cells. Methods: Steatosis in HepG2 cells was induced by treating them with 400 µM OA. The effect of Ex-4 on steatosis was examined by treating the steatotic cells with 200 nM of EX-4 for 3 h. MALAT1 was silenced with siRNA, while gene expression was quantified using qRT-PCR. Results: In the presence of Ex-4, the silencing of MALAT1 did not exert any discernible influence on de novo lipogenesis genes such as PPARγ and SREBP1. However, MALAT1 silencing significantly affected, to varying degrees, the expression levels of several lipid metabolism genes such as FAS, ACADL, CPT1A, and MTTP. Conclusions: Further investigations are warranted to fully decipher the role of the Ex-4-MALAT1 in the positive impact of GLP-1RAs on steatosis.
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Affiliation(s)
- Olfa Khalifa
- Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation Doha, Doha P.O. Box 34110, Qatar;
| | - Sama Ayoub
- Weill Cornell Medicine Qatar, Qatar Foundation, Doha P.O. Box 24144, Qatar;
| | - Abdelilah Arredouani
- Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation Doha, Doha P.O. Box 34110, Qatar;
- College of Health and Life Sciences, Hamad Bin Khalifa University, Qatar Foundation, Doha P.O. Box 34110, Qatar
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Abu-Siniyeh A, Khataibeh M, Al-Zyoud W, Al Holi M. Zebrafish as a model for human epithelial pathology. Lab Anim Res 2025; 41:6. [PMID: 39901304 PMCID: PMC11789318 DOI: 10.1186/s42826-025-00238-6] [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: 08/10/2024] [Revised: 01/14/2025] [Accepted: 01/21/2025] [Indexed: 02/05/2025] Open
Abstract
Zebrafish (Danio rerio) have emerged as an influential model for studying human epithelial pathology, particularly because of their genetic similarity to humans and their unique physiological traits. This review explores the structural and functional homology between zebrafish and human epithelial tissues in organs, such as the gastrointestinal system, liver, and kidneys. Zebrafish possess significant cellular and functional homology with mammals, which facilitates the investigation of various diseases, including inflammatory bowel disease, nonalcoholic fatty liver disease, and polycystic kidney disease. The advantages of using zebrafish as a model organism include rapid external development, ease of genetic manipulation, and advanced imaging capabilities, allowing for the real-time observation of disease processes. However, limitations exist, particularly concerning the lack of organs in zebrafish and the potential for incomplete phenocopy of human conditions. Despite these challenges, ongoing research in adult zebrafish promises to enhance our understanding of the disease mechanisms and regenerative processes. By revealing the similarities and differences in epithelial cell function and disease pathways, this review highlights the value of zebrafish as a translational model for advancing our knowledge of human health and developing targeted therapies.
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Affiliation(s)
- Ahmed Abu-Siniyeh
- Department of Medical Laboratory Sciences, School of Science, The University of Jordan, Amman, Jordan.
| | - Moayad Khataibeh
- Department of Medical Laboratory Sciences, Faculty of Science, Al-Balqa Applied University, As Salt, Jordan
| | - Walid Al-Zyoud
- Department of Biomedical Engineering, School of Applied Medical Sciences, German Jordanian University, Amman, 11180, Jordan
| | - Majed Al Holi
- Cell Therapy Center, The University of Jordan, Amman, Jordan
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Wang J, Wang Z, Yu Y, Cheng S, Wu J. Advances in research on metabolic dysfunction-associated steatotic liver disease. Life Sci 2025; 362:123362. [PMID: 39761743 DOI: 10.1016/j.lfs.2024.123362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2024] [Revised: 12/13/2024] [Accepted: 12/31/2024] [Indexed: 01/12/2025]
Abstract
The global increase in obesity-related metabolic disorders has led to metabolic dysfunction-associated steatotic liver disease (MASLD) emerging as one of the most prevalent chronic liver disease worldwide. Despite growing concerns, the exact pathogenesis of MASLD remains unclear and no definitive treatments have been made available. Consequently, the need for comprehensive research on MASLD is more critical than ever. Gaining insight into the mechanisms of the disease can lay the groundwork for identifying new therapeutic targets and can facilitate the development of diagnostic tools that enable the early detection and intervention of MASLD. Research has discovered a multifactorial etiology for MASLD, suggesting that potential therapeutic strategies should be considered from a variety of perspectives. This review delves into the pathogenesis of MASLD, current diagnostic approaches, potential therapeutic targets, the status of clinical trials for emerging drugs, and the most promising treatment methods available today. With a focus on therapeutic targets, the aim is to offer fresh insights and guide for future research in the treatment of MASLD.
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Affiliation(s)
- Jiawang Wang
- Hubei Key Laboratory of Nanomedicine for Neurodegenerative Diseases, School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan 430070, China
| | - Zhongyu Wang
- School of Basic Medical Sciences, Guangxi Medical University, Nanning 530021, China
| | - Yao Yu
- Hubei Key Laboratory of Nanomedicine for Neurodegenerative Diseases, School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan 430070, China
| | - Si Cheng
- Beijing Tiantan Hospital, Capital Medical University, Beijing 10070, China; China National Clinical Research Center for Neurological Diseases, Beijing 10070, China; Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing 10070, China.
| | - Jianping Wu
- Hubei Key Laboratory of Nanomedicine for Neurodegenerative Diseases, School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan 430070, China; Department of Pharmacology, Hubei University of Medicine, Shiyan 440070, China; Beijing Tiantan Hospital, Capital Medical University, Beijing 10070, China; China National Clinical Research Center for Neurological Diseases, Beijing 10070, China; Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing 10070, China.
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Luo X, Fang Y, Wang W, Tong M, Qin B, Cao J, Yang Y. Yinchen lipid-lowering tea attenuates lipid deposition in a fatty liver model by regulating mitochondrial dysfunction through activation of AdipoR1/AMPK/SIRT1 signaling. 3 Biotech 2025; 15:39. [PMID: 39807243 PMCID: PMC11725549 DOI: 10.1007/s13205-024-04204-2] [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: 07/11/2024] [Accepted: 12/29/2024] [Indexed: 01/16/2025] Open
Abstract
This study investigated the ameliorative effects of Yinchen lipid-lowering tea (YCLLT) on Non-alcoholic fatty liver disease (NAFLD), the specific mechanism involved was also studied. We modeled hepatocellular steatosis with HepG2 cells and intervened with different concentrations of YCLLT-containing serum. Lipid deposition was assessed by oil red O staining and AdipoR1 expression was analyzed by Western blot. The hepatocyte steatosis model was further treated with YCLLT-containing serum and/or silencing AdipoR1. Lipid deposition was observed by oil red O staining. Flow cytometry was used to detect apoptosis and mitochondrial membrane potential. The levels of TNF-α, IL-6, MDA, 8-OHdG, and ATP were analyzed by ELISA or the corresponding kits. The mitochondrial structure was observed by transmission electron microscopy. The expression of AdipoR1/AMPK/SIRT1 signaling pathway factors was analyzed by Western blot, and co-localization of SIRT1 and immunofluorescence. The results revealed that YCLLT attenuated lipid deposition, inhibited the levels of inflammatory factors TNF-α and IL-6, reduced the levels of MDA and 8-OHdG, up-regulated the ATP content and mitochondrial membrane potential, and promoted the expression of AdipoR1, p-LKB1, p-AMPKα, SIRT1, and PGC-1a in a cellular model of NAFLD. Further, silencing of AdipoR1 inhibited the ameliorative effect of YCLLT in the NAFLD cell model. Altogether, Yinchen lipid-lowering tea attenuates lipid deposition in a fatty liver model by improving mitochondrial function via activating AdipoR1/AMPK/ SIRT1 signaling.
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Affiliation(s)
- Xilin Luo
- Department of Preventive Treatment of Disease Centre, Nanchong Chinese Medicine Hospital (Nanchong Traditional Chinese Medicine Hospital Affiliated to North Sichuan Medical College), 200 Jingyuling Zhengjie Road, Shunqing District, Nanchong City, Sichuan Province 637000 People’s Republic of China
| | - Yuanyuan Fang
- Department of Preventive Treatment of Disease Centre, Nanchong Chinese Medicine Hospital (Nanchong Traditional Chinese Medicine Hospital Affiliated to North Sichuan Medical College), 200 Jingyuling Zhengjie Road, Shunqing District, Nanchong City, Sichuan Province 637000 People’s Republic of China
| | - Wei Wang
- Department of Preventive Treatment of Disease Centre, Nanchong Chinese Medicine Hospital (Nanchong Traditional Chinese Medicine Hospital Affiliated to North Sichuan Medical College), 200 Jingyuling Zhengjie Road, Shunqing District, Nanchong City, Sichuan Province 637000 People’s Republic of China
| | - Meiling Tong
- Department of Preventive Treatment of Disease Centre, Nanchong Chinese Medicine Hospital (Nanchong Traditional Chinese Medicine Hospital Affiliated to North Sichuan Medical College), 200 Jingyuling Zhengjie Road, Shunqing District, Nanchong City, Sichuan Province 637000 People’s Republic of China
| | - Bin Qin
- Department of Preventive Treatment of Disease Centre, Nanchong Chinese Medicine Hospital (Nanchong Traditional Chinese Medicine Hospital Affiliated to North Sichuan Medical College), 200 Jingyuling Zhengjie Road, Shunqing District, Nanchong City, Sichuan Province 637000 People’s Republic of China
| | - Jinyu Cao
- Department of Preventive Treatment of Disease Centre, Nanchong Chinese Medicine Hospital (Nanchong Traditional Chinese Medicine Hospital Affiliated to North Sichuan Medical College), 200 Jingyuling Zhengjie Road, Shunqing District, Nanchong City, Sichuan Province 637000 People’s Republic of China
| | - Yinjie Yang
- Department of Preventive Treatment of Disease Centre, Nanchong Chinese Medicine Hospital (Nanchong Traditional Chinese Medicine Hospital Affiliated to North Sichuan Medical College), 200 Jingyuling Zhengjie Road, Shunqing District, Nanchong City, Sichuan Province 637000 People’s Republic of China
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de Melo Junior AF, Escouto L, Pimpão AB, Peixoto P, Brasil G, Ronchi SN, Pereira SA, Bissoli NS. Anabolic-androgen steroids: A possible independent risk factor to Cardiovascular, Kidney and Metabolic Syndrome. Toxicol Appl Pharmacol 2025; 495:117238. [PMID: 39855308 DOI: 10.1016/j.taap.2025.117238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 12/11/2024] [Accepted: 01/18/2025] [Indexed: 01/27/2025]
Abstract
Millions of individuals make illicit use of anabolic-androgenic steroids (AAS), remaining a public health issue. It often leads to detrimental effects, including cardiovascular and renal diseases, besides hormonal and metabolic imbalances. The objective of this review is to emphasize the contribution of oxidative stress and inflammation to these effects and connect the findings of experimental animal studies with the alterations found in clinical contexts, in AAS users. The study's results showed that AAS promotes a redox disruption and a pro-inflammatory state on organs that are involved in important physiologic processes. These drugs increase inflammatory high-sensitivity C-reactive protein (hs-CRP) and cytokines that contribute to the progression of atherosclerosis, cardiovascular disease risk or endpoints, including stroke, myocardial infarction and death. In the kidney, the AAS increase proteinuria and structural damage. Studies have linked AAS abuse with high BP, low HDL-C levels, high triglyceride levels and impaired fasting blood glucose that characterize Metabolic syndrome. Overall, the studies indicate that oxidative stress, apoptosis, and AAS-mediated inflammation play a significant role in tissue damage, regardless of the dose and duration of exposure, and we point it as a putative independent risk factor to Cardiovascular, Kidney and Metabolic syndrome.
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Affiliation(s)
- Antonio Ferreira de Melo Junior
- iNOVA4HEALTH, NOVA Medical School, Faculdade de Ciências Médicas (NMS/FCM), Universidade Nova de Lisboa, 1159-056 Lisboa, Portugal; Centro Clínico e Académico de Lisboa, 1156-056 Lisboa, Portugal.
| | - Leonardo Escouto
- Department of Physiological Sciences, Federal University of Espírito Santo, Vitória, Espírito Santo, Brazil
| | - António B Pimpão
- iNOVA4HEALTH, NOVA Medical School, Faculdade de Ciências Médicas (NMS/FCM), Universidade Nova de Lisboa, 1159-056 Lisboa, Portugal; Centro Clínico e Académico de Lisboa, 1156-056 Lisboa, Portugal.
| | - Pollyana Peixoto
- Department of Physiological Sciences, Federal University of Espírito Santo, Vitória, Espírito Santo, Brazil
| | | | - Silas Nascimento Ronchi
- Department of Physiological Sciences, Federal University of Espírito Santo, Vitória, Espírito Santo, Brazil
| | - Sofia Azeredo Pereira
- iNOVA4HEALTH, NOVA Medical School, Faculdade de Ciências Médicas (NMS/FCM), Universidade Nova de Lisboa, 1159-056 Lisboa, Portugal; Centro Clínico e Académico de Lisboa, 1156-056 Lisboa, Portugal.
| | - Nazaré Souza Bissoli
- iNOVA4HEALTH, NOVA Medical School, Faculdade de Ciências Médicas (NMS/FCM), Universidade Nova de Lisboa, 1159-056 Lisboa, Portugal; Department of Physiological Sciences, Federal University of Espírito Santo, Vitória, Espírito Santo, Brazil
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Rojo AI, Buttari B, Cadenas S, Carlos AR, Cuadrado A, Falcão AS, López MG, Georgiev MI, Grochot-Przeczek A, Gumeni S, Jimenez-Villegas J, Horbanczuk JO, Konu O, Lastres-Becker I, Levonen AL, Maksimova V, Michaeloudes C, Mihaylova LV, Mickael ME, Milisav I, Miova B, Rada P, Santos M, Seabra MC, Strac DS, Tenreiro S, Trougakos IP, Dinkova-Kostova AT. Model organisms for investigating the functional involvement of NRF2 in non-communicable diseases. Redox Biol 2025; 79:103464. [PMID: 39709790 PMCID: PMC11733061 DOI: 10.1016/j.redox.2024.103464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Revised: 11/26/2024] [Accepted: 12/08/2024] [Indexed: 12/24/2024] Open
Abstract
Non-communicable chronic diseases (NCDs) are most commonly characterized by age-related loss of homeostasis and/or by cumulative exposures to environmental factors, which lead to low-grade sustained generation of reactive oxygen species (ROS), chronic inflammation and metabolic imbalance. Nuclear factor erythroid 2-like 2 (NRF2) is a basic leucine-zipper transcription factor that regulates the cellular redox homeostasis. NRF2 controls the expression of more than 250 human genes that share in their regulatory regions a cis-acting enhancer termed the antioxidant response element (ARE). The products of these genes participate in numerous functions including biotransformation and redox homeostasis, lipid and iron metabolism, inflammation, proteostasis, as well as mitochondrial dynamics and energetics. Thus, it is possible that a single pharmacological NRF2 modulator might mitigate the effect of the main hallmarks of NCDs, including oxidative, proteostatic, inflammatory and/or metabolic stress. Research on model organisms has provided tremendous knowledge of the molecular mechanisms by which NRF2 affects NCDs pathogenesis. This review is a comprehensive summary of the most commonly used model organisms of NCDs in which NRF2 has been genetically or pharmacologically modulated, paving the way for drug development to combat NCDs. We discuss the validity and use of these models and identify future challenges.
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Affiliation(s)
- Ana I Rojo
- Department of Biochemistry, Medical College, Autonomous University of Madrid (UAM), Madrid, Spain; Instituto de Investigación Sanitaria La Paz (IdiPaz), Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Instituto de Investigaciones Biomédicas Sols-Morreale (CSIC-UAM), Madrid, Spain.
| | - Brigitta Buttari
- Department of Cardiovascular, Endocrine-Metabolic Diseases, and Aging, Italian National Institute of Health, 00161, Rome, Italy
| | - Susana Cadenas
- Centro de Biología Molecular Severo Ochoa (CSIC/UAM), Cantoblanco, Madrid, Spain
| | - Ana Rita Carlos
- CE3C-CHANGE, Department of Animal Biology, Faculty of Sciences, University of Lisbon, 1749-016, Lisbon, Portugal
| | - Antonio Cuadrado
- Department of Biochemistry, Medical College, Autonomous University of Madrid (UAM), Madrid, Spain; Instituto de Investigación Sanitaria La Paz (IdiPaz), Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Instituto de Investigaciones Biomédicas Sols-Morreale (CSIC-UAM), Madrid, Spain
| | - Ana Sofia Falcão
- iNOVA4Health, NOVA Medical School|Faculdade de Ciências Médicas, NMS|FCM, Universidade NOVA de Lisboa, Lisboa, Portugal
| | - Manuela G López
- Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain; Instituto de Investigación Sanitaria La Princesa, Hospital Universitario de la Princesa, Madrid, Spain
| | - Milen I Georgiev
- Department of Plant Cell Biotechnology, Center of Plant Systems Biology and Biotechnology, 4000, Plovdiv, Bulgaria; Laboratory of Metabolomics, Institute of Microbiology, Bulgarian Academy of Sciences, 139 Ruski Blvd., 4000, Plovdiv, Bulgaria
| | - Anna Grochot-Przeczek
- Department of Medical Biotechnology, Faculty of Biochemistry Biophysics and Biotechnology, Jagiellonian University, 30-387, Krakow, Poland
| | - Sentiljana Gumeni
- Department of Cell Biology and Biophysics, Faculty of Biology, National and Kapodistrian University of Athens, Athens, 15784, Greece
| | - José Jimenez-Villegas
- Department of Biochemistry, Medical College, Autonomous University of Madrid (UAM), Madrid, Spain; Instituto de Investigación Sanitaria La Paz (IdiPaz), Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Instituto de Investigaciones Biomédicas Sols-Morreale (CSIC-UAM), Madrid, Spain
| | - Jarosław Olav Horbanczuk
- Department of Experimental Genomics, Institute of Genetics and Animal Biotechnology, 36A Postępu, Jastrzębiec, 05-552, Poland
| | - Ozlen Konu
- Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey; Department of Neuroscience, Bilkent University, Ankara, Turkey; UNAM-Institute of Materials Science and Nanotechnology, Bilkent University, Ankara, Turkey
| | - Isabel Lastres-Becker
- Department of Biochemistry, Medical College, Autonomous University of Madrid (UAM), Madrid, Spain; Instituto de Investigación Sanitaria La Paz (IdiPaz), Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Institute Teófilo Hernando for Drug Discovery, Universidad Autónoma de Madrid, 28029, Madrid, Spain; Instituto de Investigaciones Biomédicas Sols-Morreale (CSIC-UAM), Madrid, Spain
| | - Anna-Liisa Levonen
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P.O. Box 1627, FI-70210, Kuopio, Finland
| | - Viktorija Maksimova
- Department of Applied Pharmacy, Division of Pharmacy, Faculty of Medical Sciences, Goce Delcev University, Stip, Krste Misirkov Str., No. 10-A, P.O. Box 201, 2000, Stip, Macedonia
| | | | - Liliya V Mihaylova
- Department of Plant Cell Biotechnology, Center of Plant Systems Biology and Biotechnology, 4000, Plovdiv, Bulgaria; Laboratory of Metabolomics, Institute of Microbiology, Bulgarian Academy of Sciences, 139 Ruski Blvd., 4000, Plovdiv, Bulgaria
| | - Michel Edwar Mickael
- Department of Experimental Genomics, Institute of Genetics and Animal Biotechnology, 36A Postępu, Jastrzębiec, 05-552, Poland
| | - Irina Milisav
- Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Zaloska 4, 1000, Ljubljana, Slovenia; Laboratory of oxidative stress research, Faculty of Health Sciences, University of Ljubljana, Zdravstvena pot 5, 1000, Ljubljana, Slovenia
| | - Biljana Miova
- Department of Experimental Physiology and Biochemistry, Institute of Biology, Faculty of Natural Sciences and Mathematics, University "St Cyril and Methodius", Skopje, Macedonia
| | - Patricia Rada
- Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
| | - Marlene Santos
- REQUIMTE/LAQV, Escola Superior de Saúde (E2S), Instituto Politécnico do Porto, Rua Dr. António Bernardino de Almeida 400, 4200-072, Porto, Portugal; Molecular Oncology & Viral Pathology, IPO-Porto Research Center (CI-IPOP), Portuguese Institute of Oncology, 4200-072, Porto, Portugal
| | - Miguel C Seabra
- iNOVA4Health, NOVA Medical School|Faculdade de Ciências Médicas, NMS|FCM, Universidade NOVA de Lisboa, Lisboa, Portugal
| | - Dubravka Svob Strac
- Laboratory for Molecular Neuropsychiatry, Division of Molecular Medicine, Ruder Boskovic Institute, 10 000, Zagreb, Croatia
| | - Sandra Tenreiro
- iNOVA4Health, NOVA Medical School|Faculdade de Ciências Médicas, NMS|FCM, Universidade NOVA de Lisboa, Lisboa, Portugal
| | - Ioannis P Trougakos
- Department of Cell Biology and Biophysics, Faculty of Biology, National and Kapodistrian University of Athens, Athens, 15784, Greece
| | - Albena T Dinkova-Kostova
- Jacqui Wood Cancer Centre, Division of Cancer Research, School of Medicine, University of Dundee, Dundee, UK; Department of Pharmacology and Molecular Sciences and Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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El‐Kassas M, Mostafa H, Abdellatif W, Shoman S, Esmat G, Brahmania M, Liu H, Lee SS. Lubiprostone Reduces Fat Content on MRI-PDFF in Patients With MASLD: A 48-Week Randomised Controlled Trial. Aliment Pharmacol Ther 2025; 61:628-635. [PMID: 39744921 PMCID: PMC11754939 DOI: 10.1111/apt.18478] [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: 05/08/2024] [Revised: 06/01/2024] [Accepted: 12/23/2024] [Indexed: 01/24/2025]
Abstract
BACKGROUND AND AIMS The laxative lubiprostone has been shown to decrease intestinal permeability. We aimed to assess the safety and efficacy of lubiprostone administered for 48 weeks in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). APPROACH AND RESULTS A randomised placebo-controlled trial was conducted in a specialised MASLD outpatient clinic at the National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt. The recruited patients had radiological evidence of MASLD along with other criteria for diagnosis. Eligible patients were randomly assigned to receive either placebo or lubiprostone 24 μg orally twice daily for 48 weeks. The liver fat content was quantified by magnetic resonance imaging estimated proton density fat fraction (MRI-PDFF). Between November 2020 and February 2023, 176 patients were screened, of whom 116 were eligible. Fifty-nine patients were randomised to receive placebo, while 57 patients were randomised to receive lubiprostone. Due mostly to patient dropout (i.e., loss to follow-up), complete data were available for 40 patients in each group. Compared with placebo group, 48-week lubiprostone treatment significantly reduced fat quantity (p = 0.04). Despite a significant reduction in body weight in the control group, no significant difference was found between both groups regarding fibrosis score by transient elastography or in serum ALT levels. One patient in the lubiprostone group developed severe diarrhoea requiring treatment stoppage. No other serious adverse events occurred. CONCLUSION Lubiprostone was well tolerated and reduced liver fat content as measured by MRI-PDFF in patients with MASLD over 48 weeks. Lubiprostone appears promising to treat MASLD and warrants more extensive studies to confirm such efficacy. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT05768334.
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Affiliation(s)
- Mohamed El‐Kassas
- Endemic Medicine Department, Faculty of MedicineHelwan UniversityCairoEgypt
- Liver Disease Research Center, College of MedicineKing Saud UniversityRiyadhSaudi Arabia
- Steatotic Liver Disease Study Foundation in Middle East and North Africa (SLMENA)CairoEgypt
| | - Hala Mostafa
- Endemic Medicine Department, Faculty of MedicineHelwan UniversityCairoEgypt
| | - Wessam Abdellatif
- Radiology DepartmentNational Hepatology & Tropical Medicine Research Institute (NHTMRI)CairoEgypt
| | - Sohier Shoman
- Gastroenterology and Hepatology DepartmentNational Hepatology & Tropical Medicine Research Institute (NHTMRI)CairoEgypt
| | - Gamal Esmat
- Hepatology and Endemic Medicine Department, Faculty of MedicineCairo UniversityCairoEgypt
| | - Mayur Brahmania
- Liver UnitUniversity of Calgary Cumming School of MedicineCalgaryAlbertaCanada
| | - Hongqun Liu
- Liver UnitUniversity of Calgary Cumming School of MedicineCalgaryAlbertaCanada
| | - Samuel S. Lee
- Liver UnitUniversity of Calgary Cumming School of MedicineCalgaryAlbertaCanada
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Wu X, Zhang T, Park S. Dietary quality, perceived health, and psychological status as key risk factors for newly developed metabolic dysfunction-associated steatotic liver disease in a longitudinal study. Nutrition 2025; 130:112604. [PMID: 39549647 DOI: 10.1016/j.nut.2024.112604] [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: 06/15/2024] [Revised: 09/30/2024] [Accepted: 10/13/2024] [Indexed: 11/18/2024]
Abstract
OBJECTIVES This study investigated biomarkers in individuals with newly developed metabolic dysfunction-associated steatotic liver disease (ND-MASLD) and examined the interplay between genetic predisposition and environmental factors using a machine learning approach in a large longitudinal study. METHODS Participants were classified into four groups based on metabolic dysfunction-associated steatotic liver disease (MASLD) status between the first and second measurements with an approximate 5-y gap. A model was developed to identify early-stage biomarkers of ND-MASLD (n = 1603). Nutrient intake, dietary patterns, genetic variants, and psychosocial factors were compared among the no MASLD (n = 60 081), recovered MASLD (n = 3181), persistent MASLD (n = 670), and ND-MASLD (n = 1603) groups. Their association with ND-MASLD was also predicted using a machine learning approach. RESULTS The model incorporating ND-MASLD status, age, sex, dietary inflammatory index, and metabolic syndrome (MetS), especially low high-density lipoprotein cholesterol and hypertriglyceridemia, at the second measurement demonstrated an optimal fit. High carbohydrate intake with a high glycemic index was associated with elevated ND-MADSLD risk. Fatty liver index was lower in persistent MASLD followed by ND-MASLD, recovered MASLD, and no MASLD. Participants in the ND-MASLD group had lower vitamin D and total isoflavonoid intake and a lower modified healthy eating index, indicating unhealthy diets. The XGBoost and deep neural network models identified age, sex, MetS components, dietary antioxidants, self-rated health, psychological well-being indexes, and serum liver enzyme levels at the second measurement as significant predictors of ND-MASLD. However, polygenic risk scores were not included. CONCLUSIONS Early-stage biomarkers of ND-MASLD were closely linked to MetS incidence. Dietary quality, perceived health status, and psychological stress emerged as potential targets for MASLD prevention strategies, with lifestyle modifications potentially overriding genetic predispositions. The results indicate that preventive strategies about lifestyle modification should be developed for MASLD.
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Affiliation(s)
- Xuangao Wu
- Korea Department of Bioconvergence, Hoseo University, Asan, South Korea.
| | - Ting Zhang
- Korea Department of Bioconvergence, Hoseo University, Asan, South Korea.
| | - Sunmin Park
- Korea Department of Bioconvergence, Hoseo University, Asan, South Korea; Department of Food and Nutrition, Obesity/Diabetes Research Center, Hoseo University, Asan, South Korea.
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Niu Y, Qin P, Lin P. Advances of deep Neural Networks (DNNs) in the development of peptide drugs. Future Med Chem 2025; 17:485-499. [PMID: 39935356 PMCID: PMC11834456 DOI: 10.1080/17568919.2025.2463319] [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: 11/24/2024] [Accepted: 01/27/2025] [Indexed: 02/13/2025] Open
Abstract
Peptides are able to bind to difficult disease targets with high potency and specificity, providing great opportunities to meet unmet medical requirements. Nevertheless, the unique features of peptides, such as their small size, high structural flexibility, and scarce data availability, bring extra challenges to the design process. Firstly, this review sums up the application of peptide drugs in treating diseases. Then, the review probes into the advantages of Deep Neural Networks (DNNs) in predicting and designing peptide structures. DNNs have demonstrated remarkable capabilities in structural prediction, enabling accurate three-dimensional modeling of peptide drugs through models like AlphaFold and its successors. Finally, the review deliberates on the challenges and coping strategies of DNNs in the development of peptide drugs, along with future research directions. Future research directions focus on further improving the accuracy and efficiency of DNN-based peptide drug design, exploring novel applications of peptide drugs, and accelerating their clinical translation. With continuous advancements in technology and data accumulation, DNNs are poised to play an increasingly crucial role in the field of peptide drug development.
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Affiliation(s)
- Yuzhen Niu
- College of Chemical Engineering and Environment, Weifang University of Science and Technology, Weifang, China
| | - Pingyang Qin
- College of Chemical Engineering and Environment, Weifang University of Science and Technology, Weifang, China
| | - Ping Lin
- College of Chemical Engineering and Environment, Weifang University of Science and Technology, Weifang, China
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Wang Z, Gao H, Ma X, Zhu D, Zhao L, Xiao W. Adrenic acid: A promising biomarker and therapeutic target (Review). Int J Mol Med 2025; 55:20. [PMID: 39575474 PMCID: PMC11611323 DOI: 10.3892/ijmm.2024.5461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Accepted: 11/06/2024] [Indexed: 01/05/2025] Open
Abstract
Adrenic acid is a 22‑carbon unsaturated fatty acid that is widely present in the adrenal gland, liver, brain, kidney and vascular system that plays a regulatory role in various pathophysiological processes, such as inflammatory reactions, lipid metabolism, oxidative stress, vascular function, and cell death. Adrenic acid is a potential biomarker for various ailments, including metabolic, neurodegenerative and cardiovascular diseases and cancer. In addition, adrenic acid is influenced by the pharmacological properties of several natural products, such as astragaloside IV, evodiamine, quercetin, kaempferol, Berberine‑baicalin and prebiotics, so it is a promising new target for clinical treatment and drug development. However, the molecular mechanisms by which adrenic acid exerts are unclear. The present study systematically reviewed the biosynthesis and metabolism of adrenic acid, focusing on intrinsic mechanisms that influence the progression of metabolic, cardiovascular and neurological disease. These mechanisms regulate several key processes, including immuno‑inflammatory response, oxidative stress, vascular function and cell death. In addition, the present study explored the potential clinical translational value of adrenic acid as a biomarker and therapeutic target. To the best of our knowledge, the present study is first systematic summary of the mechanisms of action of adrenic acid across a range of diseases. The present study provides understanding of the wide range of metabolic activities of adrenic acid and a basis for further exploring the pathogenesis and therapeutic targets of various diseases.
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Affiliation(s)
- Ze Wang
- Shanghai Key Laboratory of Human Performance, Shanghai University of Sport, Shanghai 200438, P.R. China
| | - Haoyang Gao
- Shanghai Key Laboratory of Human Performance, Shanghai University of Sport, Shanghai 200438, P.R. China
| | - Xiaotong Ma
- Shanghai Key Laboratory of Human Performance, Shanghai University of Sport, Shanghai 200438, P.R. China
| | - Danlin Zhu
- Shanghai Key Laboratory of Human Performance, Shanghai University of Sport, Shanghai 200438, P.R. China
| | - Linlin Zhao
- Shanghai Key Laboratory of Human Performance, Shanghai University of Sport, Shanghai 200438, P.R. China
- School of Physical Education, Shanghai Normal University, Shanghai 200234, P.R. China
| | - Weihua Xiao
- Shanghai Key Laboratory of Human Performance, Shanghai University of Sport, Shanghai 200438, P.R. China
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Ezhilarasan D. Thyromimetics and MASLD: Unveiling the Novel Molecules Beyond Resmetirom. J Gastroenterol Hepatol 2025; 40:367-378. [PMID: 39817461 DOI: 10.1111/jgh.16874] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2024] [Revised: 11/26/2024] [Accepted: 12/26/2024] [Indexed: 01/18/2025]
Abstract
BACKGROUND Resmetirom, the first FDA-approved drug for nonalcoholic steatohepatitis (NASH) with fibrosis in obese patients, when combined with lifestyle modifications, improves NASH resolution and reduces fibrosis by at least one stage. Low thyroid hormone (T3) levels are linked to a higher risk of developing metabolic dysfunction-associated steatotic liver disease (MASLD). Epidemiological studies have confirmed the positive correlation between hypothyroidism and MASLD. Unraveling the molecular mechanisms of T3 signaling pathways in MASLD will enhance the prospects of identifying effective and specific targets. Therefore, this review discusses the significant role of thyroid hormones in the homeostasis of fat metabolism and describes the possible molecular mechanisms of thyromimetics in the treatment of MASLD. METHODS A comprehensive search in PubMed and EMBASE was conducted using the keywords "thyromimetics and liver diseases," "thyroid hormone and liver diseases," "hypothyroidism and liver diseases," "T3, T4 and liver disease," and "resmetirom and liver disease." Relevant papers published before October 2024 were included. RESULTS T3 treatment enhances mitochondrial respiration, biogenesis, β-oxidation, and mitophagy, reducing liver lipid accumulation. However, T3 treatment causes cardiotoxicity through thyroid hormone receptor (THR)α agonistic activity. To address this, molecules with high THRβ agonistic but lower THRα activity have been developed. Besides resmetirom, other THRβ agonists like TG68, CS27109, MB07811, and KB-141 show promising results in experimental studies. These molecules upregulate THRβ target genes, activate genes for fatty acid β-oxidation in mitochondria and fatty acid breakdown in peroxisomes, downregulate the genes involved in de novo lipogenesis, reduce inflammation by downregulating NF-κB/JNK/STAT3 signaling pathways, and accelerate fibrosis resolution by downregulating the expressions of fibrosis marker genes in NASH liver tissue. CONCLUSION Future clinical studies should thoroughly investigate THRβ agonists, including TG68, CS27109, MB07811, and KB-141.
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Affiliation(s)
- Devaraj Ezhilarasan
- Department of Pharmacology, Hepatology and Molecular Medicine Lab, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences (SIMATS), Chennai, Tamil Nadu, India
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Wang YM, Ge MX, Ran SZ, Pan X, Chi CF, Wang B. Antioxidant Peptides from Miiuy Croaker Swim Bladders: Ameliorating Effect and Mechanism in NAFLD Cell Model through Regulation of Hypolipidemic and Antioxidant Capacity. Mar Drugs 2025; 23:63. [PMID: 39997187 PMCID: PMC11857530 DOI: 10.3390/md23020063] [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: 12/29/2024] [Revised: 01/13/2025] [Accepted: 01/30/2025] [Indexed: 02/26/2025] Open
Abstract
In this work, the hypolipidemic and antioxidative capacity of FSGLR (S7) and GIEWA (S10) from miiuy croaker swim bladders was explored systematically in an oleic acid (OA)-induced nonalcoholic fatty liver disease (NAFLD) model of HepG2 cells. Moreover, the hypolipidemic activity of S7 and S10 and their antioxidative abilities were preliminarily investigated in combination with molecular docking technology. The results indicated that S7 and S10 could decrease the amount of lipid accumulation and the content of triglycerides (TG) and total cholesterol (TC) in the OA-induced NAFLD cell model in a dose-dependent manner. In addition, S7 and S10 exhibited better bile salt binding, pancreatic lipase (PL) inhibition, and cholesterol esterase (CE) inhibition capacities. The hypolipidemic mechanisms of S7 and S10 were connected with the downregulation of the mRNA expression levels of adipogenic factors, including sterol-regulatory element-binding protein-1c (SREBP-1c), acetyl-CoA carboxylase (ACC), sterol-regulatory element-binding protein (SREBP)-2, hydroxymethylglutaryl-CoA reductase (HMGR), and fatty acid synthase (FAS) (p < 0.01), and the upregulation of the mRNA expression of β-oxidation-related factors, including carnitine palmitoyltransferase 1 (CPT-1), acyl-CoA oxidase 1 (ACOX-1), and peroxisome proliferator-activated receptor α (PPARα). Moreover, FSGLR (S7) and GIEWA (S10) could significantly protect HepG2 cells against OA-induced oxidative damage, and their antioxidant mechanisms were related to the increased activity of intracellular antioxidant proteases (superoxide dismutase, SOD; glutathione peroxidase, GSH-PX; catalase, CAT) to remove excess reactive oxygen species (ROS) and decrease the production of malondialdehyde (MDA). The presented findings indicate that the hypolipidemic and antioxidant functions and mechanisms of S7 and S10 could make them potential hypolipidemic and antioxidant candidates for the treatment of NAFLD.
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Affiliation(s)
- Yu-Mei Wang
- Zhejiang Provincial Engineering Technology Research Center of Marine Biomedical Products, School of Food and Pharmacy, Zhejiang Ocean University, Zhoushan 316022, China; (Y.-M.W.)
| | - Ming-Xue Ge
- Zhejiang Provincial Engineering Technology Research Center of Marine Biomedical Products, School of Food and Pharmacy, Zhejiang Ocean University, Zhoushan 316022, China; (Y.-M.W.)
| | - Su-Zhen Ran
- School of Foundation Studies, Zhejiang Pharmaceutical University, Ningbo 316022, China
| | - Xin Pan
- National and Provincial Joint Laboratory of Exploration, Utilization of Marine Aquatic Genetic Resources, National Engineering Research Center of Marine Facilities Aquaculture, School of Marine Science and Technology, Zhejiang Ocean University, Zhoushan 316022, China
| | - Chang-Feng Chi
- National and Provincial Joint Laboratory of Exploration, Utilization of Marine Aquatic Genetic Resources, National Engineering Research Center of Marine Facilities Aquaculture, School of Marine Science and Technology, Zhejiang Ocean University, Zhoushan 316022, China
| | - Bin Wang
- Zhejiang Provincial Engineering Technology Research Center of Marine Biomedical Products, School of Food and Pharmacy, Zhejiang Ocean University, Zhoushan 316022, China; (Y.-M.W.)
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Athar R, Shahsavan M, Shahabi S, Pazouki A, Husain FA, Kermansaravi M. Impact of Nonalcoholic Fatty Liver Disease on Weight Loss Outcomes After One Anastomosis Gastric Bypass. Surg Laparosc Endosc Percutan Tech 2025; 35:e1347. [PMID: 39588751 DOI: 10.1097/sle.0000000000001347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 10/10/2024] [Indexed: 11/27/2024]
Abstract
BACKGROUND Obesity-associated nonalcoholic fatty liver disease (NAFLD) is a significant cause of chronic liver disease. Our study sought to investigate preoperative NAFLD and the effect at 6 months and 2 years after surgery of one anastomosis gastric bypass (OAGB) and its development 6 months after surgery regarding weight loss outcomes. MATERIALS AND METHODS A retrospective cohort study was conducted on patients with severe obesity who underwent primary OAGB at Hazrat-e-Rasool Hospital between March 2020 and June 2021. Preoperative assessments included abdominal ultrasound (US) for NAFLD grading, weight, and biochemical blood tests. Follow-up examinations were performed at 10 days and 1, 3, 6, 9, 12, and 24 months postsurgery, with subsequent US examinations at the 6-month follow-up. RESULTS Two hundred thirty-one patients were included, with an average age of 40.3±10.5 years and a percentage of 78.4 women. Their mean weight and BMI were 131.2±26.8 and 48.8±8.5, respectively. Six-month grades of NAFLD showed that patients with grade 3 NAFLD had significantly lower TWL% compared with the lower grades. NAFLD grades improved in 72.3% of our patients, remained the same at 21.2%, and worsened at 6.5%. The 6-month TWL% was 28.4±4.3 in the no-change group, 28.4±5.3 for the improved group, and 25.2±14.6 in the worse group. CONCLUSION The severity and progression of NAFLD can significantly impact weight loss outcomes post-OAGB, highlighting the importance of monitoring and managing NAFLD in patients undergoing bariatric surgery.
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Affiliation(s)
- Rahmatullah Athar
- Minimally Invasive Surgery Research Center, Iran University of Medical Sciences
| | - Masoumeh Shahsavan
- Minimally Invasive Surgery Research Center, Iran University of Medical Sciences
| | - Shahab Shahabi
- Department of Surgery, Minimally Invasive Surgery Research Center, Division of Minimally Invasive and Bariatric Surgery, Hazrat-E Fatemeh Hospital, School of Medicine, Iran University of Medical Sciences
- Center of Excellence of European Branch of International Federation for Surgery of Obesity, Hazrat_e Rasool Hospital, Tehran, Iran
| | - Abdolreza Pazouki
- Department of Surgery, Minimally Invasive Surgery Research Center, Division of Minimally Invasive and Bariatric Surgery, Hazrat-E Fatemeh Hospital, School of Medicine, Iran University of Medical Sciences
- Center of Excellence of European Branch of International Federation for Surgery of Obesity, Hazrat_e Rasool Hospital, Tehran, Iran
| | - Farah A Husain
- Department of Surgery, University of Arizona College of Medicine, Phoenix, AZ
| | - Mohammad Kermansaravi
- Department of Surgery, Minimally Invasive Surgery Research Center, Division of Minimally Invasive and Bariatric Surgery, Hazrat-E Fatemeh Hospital, School of Medicine, Iran University of Medical Sciences
- Center of Excellence of European Branch of International Federation for Surgery of Obesity, Hazrat_e Rasool Hospital, Tehran, Iran
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Yang W, Yan X, Chen R, Xin X, Ge S, Zhao Y, Yan X, Zhang J. Smad4 deficiency in hepatocytes attenuates NAFLD progression via inhibition of lipogenesis and macrophage polarization. Cell Death Dis 2025; 16:58. [PMID: 39890803 PMCID: PMC11785999 DOI: 10.1038/s41419-025-07376-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 12/22/2024] [Accepted: 01/21/2025] [Indexed: 02/03/2025]
Abstract
Nonalcoholic fatty liver disease (NAFLD), a major cause of chronic liver disorders, has become a serious public health issue. Although the Smad4 signaling pathway has been implicated in the progression of NAFLD, the specific role of Smad4 in hepatocytes in NAFLD pathogenesis remains unclear. Hepatocyte-specific knockout Smad4 mice (AlbSmad4-/-) were first constructed using the Cre-Loxp recombinant system to establish a high-fat diet induced NAFLD model. The role of Smad4 in the occurrence and development of NAFLD was determined by monitoring the body weight of mice, detecting triglycerides and free fatty acids in serum and liver tissue homogenates, staining the tissue sections to observe the accumulation of liver fat, and RT-qPCR detecting the expression of genes related to lipogenesis, fatty acid intake, and fatty acid β oxidation. The molecular mechanism of Smad4 in hepatocytes affecting NAFLD was therefore investigated through combining in vitro and in vivo experiments. Smad4 deficiency in hepatocytes mitigated NAFLD progression and decreased inflammatory cell infiltration. Moreover, Smad4 deficiency inhibited CXCL1 secretion by suppressing the activation of the ASK1/P38/JNK signaling pathway. Furthermore, targeting CXCL1 using CXCR2 inhibitors diminished hepatocyte lipogenesis and inhibited the polarization of M1-type macrophages. Collectively, these results suggested that Smad4 plays a vital role in exacerbating NAFLD and may be a promising candidate for anti-NAFLD therapy.
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Affiliation(s)
- Wei Yang
- The College of Life Science and Bioengineering, Beijing Jiaotong University, Beijing, China
- National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-Targetubg Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-Targeting Theranostics, Guangxi Medical University, Nanning, China
| | - Xuanxuan Yan
- The College of Life Science and Bioengineering, Beijing Jiaotong University, Beijing, China
| | - Rui Chen
- The College of Life Science and Bioengineering, Beijing Jiaotong University, Beijing, China
| | - Xin Xin
- The College of Life Science and Bioengineering, Beijing Jiaotong University, Beijing, China
| | - Shuang Ge
- National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-Targetubg Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-Targeting Theranostics, Guangxi Medical University, Nanning, China
| | - Yongxiang Zhao
- National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-Targetubg Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-Targeting Theranostics, Guangxi Medical University, Nanning, China
| | - Xinlong Yan
- Faculty of Environmental and Life Sciences, Beijing University of Technology, Beijing, China.
| | - Jinhua Zhang
- The College of Life Science and Bioengineering, Beijing Jiaotong University, Beijing, China.
- National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-Targetubg Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-Targeting Theranostics, Guangxi Medical University, Nanning, China.
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Mansour RM, Abdel Mageed SS, Abulsoud AI, Sayed GA, Lutfy RH, Awad FA, Sadek MM, Shaker AAS, Mohammed OA, Abdel-Reheim MA, Elimam H, Doghish AS. From fatty liver to fibrosis: the impact of miRNAs on NAFLD and NASH. Funct Integr Genomics 2025; 25:30. [PMID: 39888504 DOI: 10.1007/s10142-025-01544-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 12/30/2024] [Accepted: 01/27/2025] [Indexed: 02/01/2025]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a disease with various levels varying from fatty liver steatosis to acute steatosis which is non-alcoholic steatohepatitis (NASH), which can develop into hepatic failure, as well as in some conditions it can develop into hepatocellular carcinoma (HCC). In the NAFLD and NASH context, aberrant microRNA (miRNA) expression has a thorough contribution to the incidence and development of these liver disorders by influencing key biological actions, involving lipid metabolism, inflammation, and fibrosis. Dysregulated miRNAs can disrupt the balance between lipid accumulation and clearance, exacerbate inflammatory responses, and promote fibrogenesis, thus advancing the severeness of the disorder from simple steatosis to more complex NASH. In the current review, the latest development concerned with the activity of complex regulatory networks of miRNA in the incidence as well as the evolution of NAFLD is to be discussed, also conferring about the miRNAs' role in the onset, pathogenesis as well as diagnosis of NAFLD and NASH discussing miRNAs' role as diagnostic biomarkers and their therapeutic effects on NAFLD/NASH.
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Affiliation(s)
- Reda M Mansour
- Zoology and Entomology Department, Faculty of Science, Helwan University, Helwan, 11795, Egypt
- Biology Department, School of Biotechnology, Badr University in Cairo, Badr City, 11829, Cairo, Egypt
| | - Sherif S Abdel Mageed
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Ahmed I Abulsoud
- Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo, 11785, Egypt
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11231, Cairo, Egypt
| | - Ghadir A Sayed
- Department of Biochemistry, Faculty of Pharmacy, Egyptian Russian University, Cairo, Egypt
| | - Radwa H Lutfy
- School of Biotechnology, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Farah A Awad
- School of Biotechnology, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Mohamed M Sadek
- School of Biotechnology, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Abanoub A S Shaker
- School of Biotechnology, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Osama A Mohammed
- Department of Pharmacology, College of Medicine, University of Bisha, Bisha, 61922, Saudi Arabia
| | | | - Hanan Elimam
- Department of Biochemistry, Faculty of Pharmacy, University of Sadat City, Sadat City, 32897, Egypt
| | - Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt.
- Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11231, Cairo, Egypt.
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Singh P, Singh R, Pasricha C, Kumari P. Navigating liver health with metabolomics: A comprehensive review. Clin Chim Acta 2025; 566:120038. [PMID: 39536895 DOI: 10.1016/j.cca.2024.120038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Revised: 11/06/2024] [Accepted: 11/10/2024] [Indexed: 11/16/2024]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the main cause of chronic liver disease worldwide, affecting one-fourth of the world's population. With more than half of the world's population, the Asia-Pacific region contributed 62.6 % of liver-related fatal incidents in 2015. Currently, liver imaging techniques such as computed tomography (CT), nuclear magnetic resonance (NMR) spectroscopy, and ultrasound are non-invasive imaging methods to diagnose the disease. A liver biopsy is the gold standard test for establishing the definite diagnosis of non-alcoholic steatohepatitis (NASH). However, there are still significant problems with sample variability and the procedure's invasiveness. Numerous studies have indicated various non-invasive biomarkers for both fibrosis and steatosis to counter the invasiveness of diagnostic procedures. Metabolomics could be a promising method for detecting early liver diseases, investigating pathophysiology, and developing drugs. Metabolomics, when utilized with other omics technologies, can result in a deeper understanding of biological systems. Metabolomics has emerged as a prominent research topic, offering extensive opportunities to investigate biomarkers for liver diseases that are both sensitive and specific. In this review, we have described the recent studies involving the use of a metabolomics approach in the diagnosis of liver diseases, which would be beneficial for the early detection and treatment of liver diseases.
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Affiliation(s)
- Preetpal Singh
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Ravinder Singh
- Chitkara College of Pharmacy, Chitkara University, Punjab, India.
| | - Chirag Pasricha
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Pratima Kumari
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
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La X, Zhang Z, Liang J, Li H, Pang Y, He X, Kang Y, Wu C, Li Z. Isolation and purification of flavonoids from quinoa whole grain and its inhibitory effect on lipid accumulation in nonalcoholic fatty liver disease by inhibiting the expression of CD36 and FASN. JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE 2025; 105:1330-1342. [PMID: 39305086 DOI: 10.1002/jsfa.13923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 09/03/2024] [Accepted: 09/10/2024] [Indexed: 12/12/2024]
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD), a chronic metabolic disorder marked by excessive lipid deposition, represents a considerable health burden with no established efficacious treatment strategy. Quinoa (Chenopodium quinoa Willd.), valued for its health benefits, is replete with flavonoid bioactives. The aims of this work are to isolate and purify flavonoids from quinoa whole grain that can intervene in NAFLD and to elucidate some of the underlying mechanisms. RESULTS Chenopodium quinoa Willd. flavonoids (CQWF) were obtained successfully through an optimized ultrasonic extraction methodology, followed by isolation and purification utilizing macroporous resin D101. The study then explored the therapeutic potential of CQWF and its eluted fractions in models emulating NAFLD conditions: an in vitro fatty liver cell model induced by oleic acid (OA) and palmitic acid (PA) in the HepG2 and BEL-7402 cell lines, and an in vivo high-fat diet (HFD)-induced NAFLD model in C57BL/6N mice. The findings revealed a comprehensive mitigating effect of CQWF30 on NAFLD, manifesting in reduced intracellular lipid accumulation in steatotic hepatocytes and a concerted downregulation of key lipid metabolism genes, CD36 and FASN. Administration of CQWF30 reduced triglyceride (TG) levels in both the cellular model and the livers of HFD-fed mice. It also reduced serum concentrations of TG, total cholesterol (T-CHO), low-density lipoprotein cholesterol (LDL-C), aspartate aminotransferase (AST), and alanine aminotransferase (ALT), while increasing high-density lipoprotein cholesterol (HDL-C) in the mice. CONCLUSION These results highlighted the promising therapeutic capacity of CQWF, particularly CQWF30. This research advances the exploration and utilization of flavonoids derived from quinoa whole grain, providing innovative dietary intervention strategies for NAFLD. © 2024 Society of Chemical Industry.
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Affiliation(s)
- Xiaoqin La
- Institutes of Biomedical Sciences, Shanxi University, Taiyuan, China
- Shanxi Provincial Key Laboratory of Medical Molecular Cell Biology, Shanxi University, Taiyuan, China
| | - Zhaoyan Zhang
- Institutes of Biomedical Sciences, Shanxi University, Taiyuan, China
| | - Jingyi Liang
- Institute of Biotechnology, Shanxi University, Taiyuan, China
| | - Hanqing Li
- School of Life Science, Shanxi University, Taiyuan, China
| | - Yan Pang
- School of Life Science, Shanxi University, Taiyuan, China
| | - Xiaoting He
- School of Life Science, Shanxi University, Taiyuan, China
| | - Yurui Kang
- School of Life Science, Shanxi University, Taiyuan, China
| | - Changxin Wu
- Institutes of Biomedical Sciences, Shanxi University, Taiyuan, China
| | - Zhuoyu Li
- Shanxi Provincial Key Laboratory of Medical Molecular Cell Biology, Shanxi University, Taiyuan, China
- Institute of Biotechnology, Shanxi University, Taiyuan, China
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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] [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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Jin LY, Wang K, Xu BT. High metabolic dysfunction-associated steatotic liver disease prevalence in type 2 diabetes: Urgent need for integrated screening and lifestyle intervention. World J Hepatol 2025; 17:103409. [PMID: 39871905 PMCID: PMC11736486 DOI: 10.4254/wjh.v17.i1.103409] [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: 11/18/2024] [Revised: 12/15/2024] [Accepted: 12/18/2024] [Indexed: 01/06/2025] Open
Abstract
This letter discusses the recent study by Mukherjee et al, which identifies a significant prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) among newly diagnosed type 2 diabetes mellitus (T2DM) patients in Bihar, India, and underscores the pressing need for integrated MASLD management within T2DM care. With 72.3% of the study cohort affected by MASLD, implementing routine liver function tests and ultrasound screenings is recommended as a standard practice in diabetes care, especially in regions with high prevalence rates. The study also advocates for dietary and lifestyle modifications, particularly the reduction of saturated fats, to slow MASLD progression. Patient education on monitoring body mass index and waist circumference, coupled with the integration of these metrics into digital health records, could enhance patient involvement and support proactive health management. Moreover, the letter emphasizes the advantages of developing a region-specific MASLD risk model that incorporates local dietary patterns and socioeconomic factors. Continued research into genetic and environmental determinants of MASLD remains essential for advancing our understanding of its etiology and informing targeted public health strategies.
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Affiliation(s)
- Lei-Yang Jin
- Department of Hepatobiliary Surgery, Zhuji People's Hospital, Zhuji 311800, Zhejiang Province, China.
| | - Kai Wang
- Department of Hepatobiliary Surgery, Zhuji People's Hospital, Zhuji 311800, Zhejiang Province, China
| | - Bo-Tao Xu
- Department of Cardiothoracic Surgery, Zhuji People's Hospital, Zhuji 311800, Zhejiang Province, China
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Soni J, Pathak N, Gharia M, Aswal D, Parikh J, Sharma P, Mishra A, Lalan D, Maheshwari T. Effectiveness of RESET care program: A real-world-evidence on managing non-alcoholic fatty liver disease through digital health interventions. World J Hepatol 2025; 17:101630. [PMID: 39871911 PMCID: PMC11736475 DOI: 10.4254/wjh.v17.i1.101630] [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: 09/23/2024] [Revised: 11/11/2024] [Accepted: 12/02/2024] [Indexed: 01/06/2025] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) management requires sustainable lifestyle modifications. This study aimed to evaluate the effectiveness of the RESET care plan, a comprehensive program that is an integrated personalized diet, exercise, and cognitive behavior therapy, delivered via MyTatva's digital health application enabled through a body composition analyzer (BCA) and smartwatch. AIM To evaluates the effectiveness of the comprehensive program delivered via MyTatva's digital health app enabled through internet of thing devices. METHODS This retrospective observational study analyzed deidentified data from 22 participants enrolled in the MyTatva RESET care program. Participants were divided into three groups: Group A, diet plan; Group B, diet + exercise plan; and Group C, diet + exercise + cognitive behavioral therapy plan. Participants were provided with a BCA and smartwatch for continuous monitoring of anthropometric parameters. Statistical analysis, including one-way ANOVA and post-hoc Tukey's Honest Significant Difference test, was conducted to compare mean changes in anthropometric parameters across the groups. RESULTS All intervention groups showed significant improvement across all anthropometric parameters. Group C showed the most significant improvements, with mean weight reduction of 7% or more (6.99 ± 2.98 kg, 7.00% ± 3.39%; P = 0.002) from baseline, a benchmark associated with improved NAFLD conditions. Post-hoc analysis revealed that Group C had significantly greater improvements than Groups A and B. Weight reduction was observed in 85.7% of Group A participants, 77.8% of Group B participants, and 100% of Group C participants. CONCLUSION The comprehensive RESET care plan achieved a 7% weight reduction in 12 weeks, demonstrating its effectiveness in managing NAFLD. These results support adopting digitally supported, patient-centric approaches for NAFLD treatment.
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Affiliation(s)
- Jayesh Soni
- Department of Gastroenterology, Digestive Disease Clinic, Mumbai 400092, Mahārāshtra, India
| | - Nikhilesh Pathak
- Department of Endocrinology, DPC Health and Diabetic Clinic, Delhi 110008, India
| | - Mihir Gharia
- Medical Affairs, Tatvacare, Ahmedabad 380058, Gujarāt, India.
| | - Devina Aswal
- Medical Affairs, Tatvacare, Ahmedabad 380058, Gujarāt, India
| | - Jaymin Parikh
- Medical Affairs, Tatvacare, Ahmedabad 380058, Gujarāt, India
| | - Prachi Sharma
- Medical Affairs, Tatvacare, Ahmedabad 380058, Gujarāt, India
| | - Astha Mishra
- Medical Affairs, Tatvacare, Ahmedabad 380058, Gujarāt, India
| | - Dhvni Lalan
- Medical Affairs, Tatvacare, Ahmedabad 380058, Gujarāt, India
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