{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T01:04:57Z","timestamp":1790730297150,"version":"4.1.0"},"reference-count":35,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2023,11,24]],"date-time":"2023-11-24T00:00:00Z","timestamp":1700784000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Key R&amp;D Program of China","award":["2019YFE0100700"],"award-info":[{"award-number":["2019YFE0100700"]}]},{"name":"National Key R&amp;D Program of China","award":["2022YFE0104000"],"award-info":[{"award-number":["2022YFE0104000"]}]},{"name":"National Key R&amp;D Program of China","award":["22177102"],"award-info":[{"award-number":["22177102"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["2019YFE0100700"],"award-info":[{"award-number":["2019YFE0100700"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["2022YFE0104000"],"award-info":[{"award-number":["2022YFE0104000"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["22177102"],"award-info":[{"award-number":["22177102"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Metabolic-dysfunction-associated steatotic liver disease (MASLD, formerly known as NAFLD) is a global chronic liver disease, and no licensed drugs are currently available for its treatment. The incidence of MASLD is increasing, which could lead to a huge clinical and economic burden. As a multifactorial disease, MASLD involves a complex set of metabolic changes, and many monotherapies for it are not clinically effective. Therefore, combination therapies using multiple drugs are emerging, with the advantages of improving drug efficacy and reducing side effects. Peanut skin extract (PSE), geniposide (GEN), and isoquercitrin (IQ) are three natural antiaging components or compounds. In this study, the preventive effects of individual PSE, GEN, and IQ in comparison with the effects of their mixture (MPGI) were examined in a mouse model of high-fat-feed-induced MASLD. The results showed that MPGI could significantly reduce the body and liver weights of mice and improve hepatic steatosis and liver function indicators. Further mechanistic studies showed that PSE, GEN, and IQ worked together by reducing inflammation, modulating the intestinal flora, and regulating the TLR4\/NF-\u03baB, AMPK\/ACC\/CPT1, and AMPK\/UKL1\/LC3B signaling pathways. It is a promising therapeutic method for preventing MASLD.<\/jats:p>","DOI":"10.3390\/ijms242316684","type":"journal-article","created":{"date-parts":[[2023,11,24]],"date-time":"2023-11-24T03:43:59Z","timestamp":1700797439000},"page":"16684","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Mixture of Peanut Skin Extract, Geniposide, and Isoquercitrin Improves the Hepatic Lipid Accumulation of Mice via Modification of Gut Microbiota Homeostasis and the TLR4 and AMPK Signaling Pathways"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-4924-2081","authenticated-orcid":false,"given":"Meijuan","family":"Yi","sequence":"first","affiliation":[{"name":"College of Pharmaceutical Science, Zhejiang University, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Opeyemi B.","family":"Fasina","sequence":"additional","affiliation":[{"name":"College of Pharmaceutical Science, Zhejiang University, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yajing","family":"Li","sequence":"additional","affiliation":[{"name":"College of Pharmaceutical Science, Zhejiang University, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6595-2836","authenticated-orcid":false,"given":"Lan","family":"Xiang","sequence":"additional","affiliation":[{"name":"College of Pharmaceutical Science, Zhejiang University, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianhua","family":"Qi","sequence":"additional","affiliation":[{"name":"College of Pharmaceutical Science, Zhejiang University, Hangzhou 310058, China"},{"name":"Jinhua Institute of Zhejiang University, Jinhua 321299, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2672","DOI":"10.1002\/hep.30251","article-title":"Global perspectives on nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: Hepatology","volume":"69","author":"Younossi","year":"2019","journal-title":"Hepatology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2537","DOI":"10.1016\/j.cell.2021.04.015","article-title":"Mechanisms and disease consequences of nonalcoholic fatty liver disease","volume":"184","author":"Loomba","year":"2021","journal-title":"Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"101133","DOI":"10.1016\/j.aohep.2023.101133","article-title":"A multisociety Delphi consensus statement on new fatty liver disease nomenclature","volume":"29","author":"Rinella","year":"2023","journal-title":"Ann. Hepatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1097\/TP.0000000000002480","article-title":"Nonalcoholic fatty liver disease: Basic pathogenetic mechanisms in the progression from NAFLD to NASH","volume":"103","author":"Pierantonelli","year":"2019","journal-title":"Transplantation"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1002\/hep.28431","article-title":"Global epidemiology of nonalcoholic fatty liver disease\u2014Meta-analytic assessment of prevalence, incidence, and outcomes","volume":"64","author":"Younossi","year":"2016","journal-title":"Hepatology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1404","DOI":"10.1002\/hep.32774","article-title":"Geographical similarity and differences in the burden and genetic predisposition of NAFLD","volume":"77","author":"Yip","year":"2023","journal-title":"Hepatology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1038\/s41574-021-00507-z","article-title":"Emerging therapeutic approaches for the treatment of NAFLD and type 2 diabetes mellitus","volume":"17","author":"Ferguson","year":"2021","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2249","DOI":"10.1111\/liv.15024","article-title":"Diet and exercise in NAFLD\/NASH: Beyond the obvious","volume":"41","author":"Semmler","year":"2021","journal-title":"Liver Int."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1016\/j.jhep.2018.05.036","article-title":"Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016\u20132030","volume":"69","author":"Estes","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"154170","DOI":"10.1016\/j.metabol.2020.154170","article-title":"Complications, morbidity and mortality of nonalcoholic fatty liver disease","volume":"111","author":"Mantovani","year":"2020","journal-title":"Metabolism"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1038\/s41591-018-0104-9","article-title":"Mechanisms of NAFLD development and therapeutic strategies","volume":"24","author":"Friedman","year":"2018","journal-title":"Nat. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"973366","DOI":"10.3389\/fphar.2022.973366","article-title":"Diagnostic and therapeutic strategies for non-alcoholic fatty liver disease","volume":"13","author":"Fu","year":"2022","journal-title":"Front. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1689","DOI":"10.1080\/10408398.2021.1966738","article-title":"Intestinal dysbiosis in nonalcoholic fatty liver disease (NAFLD): Focusing on the gut-liver axis","volume":"63","author":"Han","year":"2023","journal-title":"Crit. Rev. Food Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e9302","DOI":"10.15252\/emmm.201809302","article-title":"The role of the microbiome in NAFLD and NASH","volume":"11","author":"Kolodziejczyk","year":"2019","journal-title":"EMBO Mol. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1216","DOI":"10.1016\/j.jhep.2019.08.005","article-title":"Microbiota-driven gut vascular barrier disruption is a prerequisite for non-alcoholic steatohepatitis development","volume":"71","author":"Mouries","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"594150","DOI":"10.3389\/fimmu.2020.594150","article-title":"Role of metabolic endotoxemia in systemic inflammation and potential interventions","volume":"11","author":"Mohammad","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1021\/acs.jnatprod.5b01055","article-title":"Natural products as sources of new drugs from 1981 to 2014","volume":"79","author":"Newman","year":"2016","journal-title":"J. Nat. Prod."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2935315","DOI":"10.1155\/2019\/2935315","article-title":"Leptin and adiponectin signaling pathways are involved in the antiobesity effects of peanut skin extract","volume":"2019","author":"Xiang","year":"2019","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"13991","DOI":"10.18632\/aging.103521","article-title":"Peanut skin extract ameliorates the symptoms of type 2 diabetes mellitus in mice by alleviating inflammation and maintaining gut microbiota homeostasis","volume":"12","author":"Xiang","year":"2020","journal-title":"Aging"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4925682","DOI":"10.1155\/2019\/4925682","article-title":"Diverse pharmacological activities and potential medicinal benefits of geniposide","volume":"2019","author":"Zhou","year":"2019","journal-title":"Evid.-Based Complement. Altern. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"10923","DOI":"10.1039\/D2FO02438A","article-title":"Isoquercitrin from Apocynum venetum L. produces an anti-obesity effect on obese mice by targeting C-1-tetrahydrofolate synthase, carbonyl reductase, and glutathione S-transferase P and modification of the AMPK\/SREBP-1c\/FAS\/CD36 signaling pathway in mice in vivo","volume":"13","author":"Manzoor","year":"2022","journal-title":"Food Funct."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1038\/s41586-019-1365-2","article-title":"From discoveries in ageing research to therapeutics for healthy ageing","volume":"571","author":"Campisi","year":"2019","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e66","DOI":"10.1038\/emm.2013.97","article-title":"Recognition of lipopolysaccharide pattern by TLR4 complexes","volume":"45","author":"Park","year":"2013","journal-title":"Exp. Mol. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1016\/j.molcel.2017.05.032","article-title":"AMPK: Mechanisms of cellular energy sensing and restoration of metabolic balance","volume":"66","author":"Garcia","year":"2017","journal-title":"Mol. Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1210\/er.2019-00034","article-title":"The liver as an endocrine organ\u2014Linking NAFLD and insulin resistance","volume":"40","author":"Watt","year":"2019","journal-title":"Endocr. Rev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1424","DOI":"10.1007\/s12072-022-10387-8","article-title":"Effects of serum branched-chain amino acids on nonalcoholic fatty liver disease and subsequent cardiovascular disease","volume":"16","author":"Guo","year":"2022","journal-title":"Hepatol. Int."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1038\/s41467-023-36079-x","article-title":"Microbially produced vitamin B12 contributes to the lipid-lowering effect of silymarin","volume":"14","author":"Sun","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1038\/s41575-022-00631-9","article-title":"Akkermansia muciniphila: Paradigm for next-generation beneficial microorganisms","volume":"19","author":"Cani","year":"2022","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1038\/nature11450","article-title":"A metagenome-wide association study of gut microbiota in type 2 diabetes","volume":"490","author":"Qin","year":"2012","journal-title":"Nature"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1038\/s41591-018-0061-3","article-title":"Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women","volume":"24","author":"Hoyles","year":"2018","journal-title":"Nat. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"48","DOI":"10.3389\/fnut.2019.00048","article-title":"Metabolism of dietary and microbial vitamin B family in the regulation of host immunity","volume":"6","author":"Yoshii","year":"2019","journal-title":"Front. Nutr."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/j.tifs.2020.02.026","article-title":"Dynamic balancing of intestinal short-chain fatty acids: The crucial role of bacterial metabolism","volume":"100","author":"Xu","year":"2020","journal-title":"Trends Food Sci. Technol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1248\/cpb.38.888","article-title":"Tannins and related compounds. XCIII. Occurrence of enantiomeric proanthocyanidins in the leguminosae plants, Cassia fistula L. and C. javanica L.","volume":"38","author":"Kashiwada","year":"1990","journal-title":"Chem. Pharm. Bull."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/S0031-9422(98)00736-5","article-title":"A-type proanthocyanidins from peanut skins","volume":"51","author":"Lou","year":"1999","journal-title":"Phytochemistry"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"814271","DOI":"10.3389\/fphar.2022.814271","article-title":"Gastrodin from Gastrodia elata enhances cognitive function and neuroprotection of ad mice via the regulation of gut microbiota composition and inhibition of neuron inflammation","volume":"13","author":"Fasina","year":"2022","journal-title":"Front. Pharmacol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/23\/16684\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:28:59Z","timestamp":1760131739000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/23\/16684"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,24]]},"references-count":35,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["ijms242316684"],"URL":"https:\/\/doi.org\/10.3390\/ijms242316684","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,24]]}}}