Metabolism: clinical and experimental最新文献

{"title":"Exercise mitigates liver senescence but does not outmatch dietary restriction in obesity-related MASLD","authors":"Angeliki Katsarou ,&nbsp;Grigorios Papadopoulos ,&nbsp;Ioannis I. Moustakas ,&nbsp;Argyro Papadopetraki ,&nbsp;Athanasios Moustogiannis ,&nbsp;Aigli-Ioanna Legaki ,&nbsp;Eirini Giannousi ,&nbsp;George Agrogiannis ,&nbsp;Pavlos Pantelis ,&nbsp;Dimitris Veroutis ,&nbsp;Konstantinos Evangelou ,&nbsp;Athanassios Kotsinas ,&nbsp;Vassilis G. Gorgoulis ,&nbsp;Anastassios Philippou ,&nbsp;Michael Koutsilieris ,&nbsp;Antonios Chatzigeorgiou","doi":"10.1016/j.metabol.2025.156325","DOIUrl":"10.1016/j.metabol.2025.156325","url":null,"abstract":"<div><h3>Background</h3><div>The present study aims at deciphering the individual or combined benefits of aerobic exercise and dietary restriction on liver senescence, a state characterized by cell cycle arrest and simultaneous resistance to apoptosis, which is considered an established hallmark of metabolic dysfunction-associated steatotic liver disease (MASLD).</div></div><div><h3>Methods</h3><div>C57BL6 mice were subjected to a normal diet (ND) for 20 weeks or a high-fat diet (HFD) supplemented with 5 % High-fructose Corn Syrup (HFCS) for 12 weeks, followed by eight-week interventions, including dietary restriction (DR), aerobic exercise (EX), a combination of both (DREX) or continuation of a HFD-HFCS diet without intervention. Biomarkers of senescence were analyzed in terms of their liver mRNA expression levels, while GL13 and p21^WAF1/CIP1 immunohistochemical stainings were conducted to examine the levels of senescence-associated lipofuscin and p21^WAF1/CIP1 respectively, to finally investigate their relationship with the grade of hepatic steatosis and fibrosis observed in the studied mice.</div></div><div><h3>Results</h3><div>DR and DREX groups exhibited significantly reduced features of obesity and MASLD-related hepatic steatosis and fibrosis, to a greater extent than the respective amelioration driven by aerobic exercise only in HFDEX animals. A statistically significant increase of mRNA expression was detected for cyclin-dependent kinase p21^WAF1/CIP1 in HFD livers as compared to ND, which was also reversed upon DR-inclusive interventions. Immunohistochemical stainings for GL13 and p21^WAF1/CIP1, as well as for p16^INK4A confirmed the aforementioned alterations of p21^WAF1/CIP1 at the tissular level while also revealed a p16^INK4A elevation in HFD livers which was reversed only upon DR/DREX.</div></div><div><h3>Conclusion</h3><div>Liver senescence is responsive both to exercise and dietary restriction, but its amelioration in the context of MASLD is more robust upon DR-inclusive interventions.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"170 ","pages":"Article 156325"},"PeriodicalIF":10.8,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144272136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synergistic effects of C–C chemokine receptor 2 inhibitor and transforming growth factor-β type I receptor kinase inhibitor combination in metabolic dysfunction-associated steatohepatitis","authors":"Su Ho Jo ,&nbsp;Eun Soo Lee ,&nbsp;So Bin Lee ,&nbsp;Kyung Bong Ha ,&nbsp;Choon Hee Chung","doi":"10.1016/j.metabol.2025.156323","DOIUrl":"10.1016/j.metabol.2025.156323","url":null,"abstract":"<div><h3>Background</h3><div>Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive hepatic disorder characterized by its association with metabolic abnormalities, including obesity, hyperlipidemia, and type 2 diabetes mellitus. Characterized by hepatic steatosis, inflammation, and fibrosis, MASH presents a significant global health challenge, with limited pharmacological options available. There is a critical need for novel therapeutic strategies targeting key molecular pathways involved in MASH pathogenesis. Combination therapy with these two drugs is expected to provide complementary preventive and therapeutic effects against MASH.</div></div><div><h3>Methods</h3><div>This study examined the therapeutic efficacy of a C–C chemokine receptor 2 (CCR2) inhibitor (RS-102895) in combination with a TGF-β type I receptor kinase inhibitor (vactosertib) in preclinical MASH models. Histological analysis, serum biomarker quantification, and gene expression profiling were performed to assess hepatic lipid accumulation, inflammation, fibrosis, and metabolic regulatory pathways.</div></div><div><h3>Results</h3><div>Combination therapy significantly improved histological parameters and reduced liver inflammation and fibrosis markers compared with monotherapy. Notably, it led to reductions in lipid accumulation and inflammatory cytokines, alongside the restoration of AMP-activated protein kinase (AMPK) activation, a key regulator of metabolic regulator. The study also identified the Rho-associated protein kinase 1 (ROCK1)/AMPK axis as a central mediator of MASH progression.</div></div><div><h3>Conclusions</h3><div>These findings indicate that dual inhibition of CCR2 and TGF-β signaling pathways could serve as an effective therapeutic approach for MASH. By addressing lipid accumulation, inflammation, and fibrosis while promoting metabolic balance, this strategy holds promise for improved clinical applications in treating this complex disease.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"170 ","pages":"Article 156323"},"PeriodicalIF":10.8,"publicationDate":"2025-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144266724","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sedentary behaviour and cardiometabolic health: Integrating the potential underlying molecular health aspects","authors":"Wouter M.A. Franssen ,&nbsp;Ine Nieste ,&nbsp;Kenneth Verboven ,&nbsp;Bert O. Eijnde","doi":"10.1016/j.metabol.2025.156320","DOIUrl":"10.1016/j.metabol.2025.156320","url":null,"abstract":"<div><div>During the last decades, sedentary behaviour has been recognised as an interdependent risk factor for cardiometabolic health and premature mortality. Prolonged sedentary behaviour is associated with increased risks for chronic non-communicable diseases (NCDs) such as obesity, chronic respiratory diseases, type 2 diabetes mellitus, cardiovascular diseases and cancer due to disturbances in cardiometabolic health. However, despite the increased evidence supporting these associations, the underlying molecular mechanisms to the development of these NCDs remain largely unknown. In this review, we therefore discuss the existing evidence with regard to the potential underlying molecular mechanisms of sedentary behaviour-induced perturbations in cardiometabolic health. Here, various potential mechanisms related to carbohydrate metabolism, lipid metabolism, oxidative stress, inflammation and micro- and macro vascular function will be outlined. In addition, we summarise the current evidence on various strategies to interrupt sedentary behaviour and their effects on cardiometabolic health outcomes, including insulin sensitivity, blood lipid profiles, and cardiovascular health. Finally, we highlight key research gaps in the field of sedentary behaviour in relation to the underlying molecular mechanisms.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"170 ","pages":"Article 156320"},"PeriodicalIF":10.8,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144229905","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ganoderic acid T, a novel activator of pyruvate carboxylase, exhibits potent anti-liver cancer activity","authors":"Bo Lei ,&nbsp;Mengjie Zhang ,&nbsp;Xiangrui Shi ,&nbsp;Na Feng ,&nbsp;Jun Yin ,&nbsp;Rui Dong ,&nbsp;Chuanming Xie ,&nbsp;Yinan Zhu ,&nbsp;Jian-Jiang Zhong ,&nbsp;Bing Ni","doi":"10.1016/j.metabol.2025.156321","DOIUrl":"10.1016/j.metabol.2025.156321","url":null,"abstract":"<div><h3>Background</h3><div>Ganoderic acid T (GAT), a lanostane triterpenoid isolated from the methanol extract of <em>G. lucidum</em> mycelia, has demonstrated potent antitumor activity against various human cancer types. However, the specific molecular targets of GAT in cancer cells remain largely unknown. Therefore, this study systematically investigates these targets using the <em>in vitro</em> and <em>in vivo</em> hepatocellular carcinoma (HCC) model.</div></div><div><h3>Methods</h3><div>The anti-tumor activities of GAT were validated in HCC cells, xenograft tumor models in nude mice, and patient-derived organoid models. The specific molecular target of GAT was identified through targeted fishing techniques. Experimental approaches such as proteomics, metabolomics, biotin pull-down assays, molecular docking studies, molecular dynamics simulations, DARTS, CETSA, and biolayer interferometry (BLI) were employed to confirm the binding between GAT and its molecular target as well as elucidate the underlying mechanism.</div></div><div><h3>Results</h3><div>We have identified pyruvate carboxylase (PC) as a direct target of GAT. GAT, through its binding to the pocket composed of Arg453, Thr457, and Ile459 of PC, enhances the activity of PC, consequently disrupting the anaplerotic flux mediated by PC into the tricarboxylic acid (TCA) cycle. This disruption leads to impaired mitochondrial oxidative phosphorylation (OXPHOS) via the induction of reactive oxygen species (ROS)-mediated JNK/p38 MAPK signaling pathways, ultimately inhibiting HCC cell proliferation. Furthermore, molecular dynamics simulation suggests that GAT binds to and interacts with the biotin carboxylase (BC) domain of PC. This interaction potentially induces conformational changes in the protein structure of PC, leading to a tighter arrangement within the BC domain and stabilizing formation of a catalytically competent tetramer configuration for PC. The mutation of these key sites resulted in the destabilization of the BC domain and a reduction in the cytotoxic effect of GAT on HCC cells.</div></div><div><h3>Conclusion</h3><div>Overall, these findings demonstrate that GAT directly targets PC through an allosteric mechanism, providing valuable insights into the anti-HCC properties of GAT.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"170 ","pages":"Article 156321"},"PeriodicalIF":10.8,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144229907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MASLD may influence female-specific cancer risk indirectly through shared metabolic pathways rather than direct causation","authors":"Wenjie Li ,&nbsp;Ruxue Lv","doi":"10.1016/j.metabol.2025.156322","DOIUrl":"10.1016/j.metabol.2025.156322","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"171 ","pages":"Article 156322"},"PeriodicalIF":11.9,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Performance of Established and Novel Non-invasive Tests, Including New Clinical and Metabolomics-Based Machine Learning Models, for Detecting MASH with Fibrosis Stages F2-F3: A First-in-Class Approach in the post-Resmetirom approval era","authors":"Konstantinos Stefanakis ,&nbsp;Geltrude Mingrone ,&nbsp;Jacob George ,&nbsp;Christos S. Mantzoros","doi":"10.1016/j.metabol.2025.156206","DOIUrl":"10.1016/j.metabol.2025.156206","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"168 ","pages":"Article 156206"},"PeriodicalIF":10.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144184384","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inherited Stress Vulnerability Exacerbates Obesity-induced Metabolic Alterations Through Dysfunctional Adipose Tissue","authors":"Saumya Kishor Mehta,&nbsp;Michaella Ben-Shachar,&nbsp;Albert Pinhasov,&nbsp;Tovit Rosenzweig","doi":"10.1016/j.metabol.2025.156207","DOIUrl":"10.1016/j.metabol.2025.156207","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"168 ","pages":"Article 156207"},"PeriodicalIF":10.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144184385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correlation of Insulin Resistance, Type 2 Diabetes Mellitus, Obesity, and Colorectal Cancer Occurrence","authors":"Chong-Chi Chiu ,&nbsp;Chao-Ming Hung","doi":"10.1016/j.metabol.2025.156198","DOIUrl":"10.1016/j.metabol.2025.156198","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"168 ","pages":"Article 156198"},"PeriodicalIF":10.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144184938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparing Biomarkers of Metabolic Inflammation: The Predictive Accuracy of Plasma Water T2 Exceeds That of High-Sensitivity C-Reactive Protein and Erythrocyte Sedimentation Rate","authors":"David P. Cistola ,&nbsp;Alok K. Dwivedi","doi":"10.1016/j.metabol.2025.156210","DOIUrl":"10.1016/j.metabol.2025.156210","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"168 ","pages":"Article 156210"},"PeriodicalIF":10.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144185155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring Targeting Inflammasome Signaling: Ginsana-115 as Prime Driver in Insulin Resistance/ cardiovascular Risk (CVD) in Prototypal Brain Disorder: Schizophrenia","authors":"Autumn Carriere,&nbsp;Simon S. Chiu,&nbsp;Michel Woodbury,&nbsp;Mariwan Husni,&nbsp;John Copen,&nbsp;Allison Foskett,&nbsp;Ed Lui,&nbsp;Robbie Campbell","doi":"10.1016/j.metabol.2025.156216","DOIUrl":"10.1016/j.metabol.2025.156216","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"168 ","pages":"Article 156216"},"PeriodicalIF":10.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144185573","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}