{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T10:54:59Z","timestamp":1782989699253,"version":"3.54.5"},"reference-count":43,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T00:00:00Z","timestamp":1782950400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"China Green Food Development Center","award":["GFJY20240021"],"award-info":[{"award-number":["GFJY20240021"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background: Glucose and lipid metabolism disorders are characterized by hyperglycemia, dyslipidemia, hepatic oxidative stress, lipid accumulation, and gut microbiota dysbiosis, all of which contribute to progressive metabolic dysfunction and tissue injury. As a plant extract mixture derived from mulberry leaves, lotus leaves, and Eucommia leaves, MELHAC (Mulberry\u2013Eucommia\u2013Lotus Herbal Aqueous Complex) was developed as a medicinal and edible formula with potential multi-component metabolic regulatory activity. In the present study, we systematically evaluated the effects of MELHAC on glucose and lipid metabolic abnormalities in high-fat diet (HFD) plus alloxan-induced mice. Methods: The phytochemical profile of MELHAC was characterized using untargeted LC\u2013MS and network pharmacology. Its metabolic effects were evaluated in HFD plus alloxan-induced mice by measuring fasting blood glucose, serum lipid parameters, glucose tolerance, hepatic oxidative stress markers, histopathological changes, hepatic lipid accumulation, gut microbiota composition, and preliminary safety indices. Results: Chemical characterization revealed that MELHAC contains abundant bioactive constituents dominated by flavonoids, phenolic acids and alkaloids. In vivo experiments demonstrated that MELHAC lowered fasting blood glucose, total cholesterol and triglyceride levels, while ameliorating glucose intolerance and pathological damage in the liver, kidney and pancreas. MELHAC also improved liver-related biochemical abnormalities, increased hepatic superoxide dismutase, decreased malondialdehyde, and reduced hepatic lipid accumulation, indicating protective effects against oxidative stress and steatosis associated with metabolic dysfunction. In addition, MELHAC modulated gut microbial community structure and differential taxa linked to metabolic homeostasis. Short-term high-dose administration did not cause obvious abnormalities in serum biochemical, hematological, or histopathological indices. Conclusions: These findings suggest that MELHAC has potential as a plant-derived functional ingredient for improving glucose and lipid metabolic disorders and may provide an experimental basis for the future development of functional foods targeting metabolic health.<\/jats:p>","DOI":"10.3390\/nu18132145","type":"journal-article","created":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T10:04:44Z","timestamp":1782986684000},"page":"2145","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["MELHAC Improves Glucose and Lipid Metabolism in HFD + Alloxan-Induced Mice"],"prefix":"10.3390","volume":"18","author":[{"given":"Zihao","family":"Wang","sequence":"first","affiliation":[{"name":"Beijing Advanced Innovation Center for Food Nutrition and Human Health, Department of Nutrition and Health, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Yang","sequence":"additional","affiliation":[{"name":"Beijing Advanced Innovation Center for Food Nutrition and Human Health, Department of Nutrition and Health, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhixi","family":"Geng","sequence":"additional","affiliation":[{"name":"Institute of Environment and Sustainable Development in Agriculture, Chinese Academy of Agricuitural Sciences, Key Laboratory of Agricultural Environment, MARA, Beijing 100081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Senyang","family":"Hu","sequence":"additional","affiliation":[{"name":"Beijing Advanced Innovation Center for Food Nutrition and Human Health, Department of Nutrition and Health, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenhua","family":"Jin","sequence":"additional","affiliation":[{"name":"Beijing Advanced Innovation Center for Food Nutrition and Human Health, Department of Nutrition and Health, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hejing","family":"Tang","sequence":"additional","affiliation":[{"name":"Beijing Advanced Innovation Center for Food Nutrition and Human Health, Department of Nutrition and Health, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianmin","family":"Zou","sequence":"additional","affiliation":[{"name":"Beijing Advanced Innovation Center for Food Nutrition and Human Health, Department of Nutrition and Health, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang","family":"Liu","sequence":"additional","affiliation":[{"name":"Beijing Advanced Innovation Center for Food Nutrition and Human Health, Department of Nutrition and Health, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2803-3579","authenticated-orcid":false,"given":"Yinhua","family":"Zhu","sequence":"additional","affiliation":[{"name":"Beijing Advanced Innovation Center for Food Nutrition and Human Health, Department of Nutrition and Health, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,2]]},"reference":[{"key":"ref_1","unstructured":"NCD Risk Factor Collaboration (2024). Worldwide trends in underweight and obesity from 1990 to 2022: A pooled analysis of 3663 population-representative studies with 222 million children, adolescents, and adults. Lancet, 403, 1027\u20131050."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1038\/s41575-021-00523-4","article-title":"Advancing the global public health agenda for NAFLD: A consensus statement","volume":"19","author":"Lazarus","year":"2022","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1016\/j.jhep.2019.06.021","article-title":"The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: A systematic review and meta-analysis","volume":"71","author":"Younossi","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1097\/HEP.0000000000000004","article-title":"The global epidemiology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: A systematic review","volume":"77","author":"Younossi","year":"2023","journal-title":"Hepatology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1053\/jhep.2003.50161","article-title":"Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome","volume":"37","author":"Marchesini","year":"2003","journal-title":"Hepatology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1002\/hep.29367","article-title":"The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases","volume":"67","author":"Chalasani","year":"2018","journal-title":"Hepatology"},{"key":"ref_7","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_8","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1016\/j.cell.2012.02.017","article-title":"Mechanisms for insulin resistance: Common threads and missing links","volume":"148","author":"Samuel","year":"2012","journal-title":"Cell"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1836","DOI":"10.1002\/hep.24001","article-title":"Evolution of inflammation in nonalcoholic fatty liver disease: The multiple parallel hits hypothesis","volume":"52","author":"Tilg","year":"2010","journal-title":"Hepatology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.1016\/j.metabol.2015.12.012","article-title":"The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD)","volume":"65","author":"Buzzetti","year":"2016","journal-title":"Metabolism"},{"key":"ref_11","first-page":"824","article-title":"Mitochondrial adaptations and dysfunctions in nonalcoholic fatty liver disease","volume":"58","author":"Begriche","year":"2013","journal-title":"J. Hepatol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1016\/j.tem.2016.11.006","article-title":"Mitochondrial adaptation in nonalcoholic fatty liver disease: Novel mechanisms and treatment strategies","volume":"28","author":"Sunny","year":"2017","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"939","DOI":"10.14218\/JCTH.2022.00067","article-title":"Reactive oxygen species and oxidative stress in the pathogenesis of MAFLD","volume":"10","author":"Clare","year":"2022","journal-title":"J. Clin. Transl. Hepatol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/j.freeradbiomed.2022.06.226","article-title":"Nonalcoholic steatohepatitis and mechanisms by which it is ameliorated by activation of the CNC-bZIP transcription factor Nrf2","volume":"188","author":"Bathish","year":"2022","journal-title":"Free. Radic. Biol. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"299","DOI":"10.2174\/0929867328666210825111350","article-title":"Beneficial effects of dietary polyphenols in the prevention and treatment of NAFLD: Cell-signaling pathways underlying health effects","volume":"29","author":"Bustamante","year":"2022","journal-title":"Curr. Med. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1761","DOI":"10.2337\/db06-1491","article-title":"Metabolic endotoxemia initiates obesity and insulin resistance","volume":"56","author":"Cani","year":"2007","journal-title":"Diabetes"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1038\/nature05414","article-title":"An obesity-associated gut microbiome with increased capacity for energy harvest","volume":"444","author":"Turnbaugh","year":"2006","journal-title":"Nature"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1787","DOI":"10.1136\/gutjnl-2012-303816","article-title":"Intestinal microbiota determines development of non-alcoholic fatty liver disease in mice","volume":"62","author":"Llopis","year":"2013","journal-title":"Gut"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1038\/nrgastro.2016.85","article-title":"The role of the gut microbiota in NAFLD","volume":"13","author":"Leung","year":"2016","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"411","DOI":"10.3920\/BM2020.0057","article-title":"Short chain fatty acids in human gut and metabolic health","volume":"11","author":"Blaak","year":"2020","journal-title":"Benef. Microbes"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"He, J., Zhang, P., Shen, L., Niu, L., Tan, Y., Chen, L., Zhao, Y., Bai, L., Hao, X., and Li, X. (2020). Short-chain fatty acids and their association with signalling pathways in inflammation, glucose and lipid metabolism. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21176356"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"8848","DOI":"10.1038\/s41598-020-65051-8","article-title":"Gut metabolites and inflammation factors in non-alcoholic fatty liver disease: A systematic review and meta-analysis","volume":"10","author":"Pan","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Chuaypen, N., Asumpinawong, A., Sawangsri, P., Khamjerm, J., Iadsee, N., Jinato, T., Sutheeworapong, S., Udomsawaengsup, S., and Tangkijvanich, P. (2024). Gut microbiota in patients with non-alcoholic fatty liver disease. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25031807"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1080\/13880209.2018.1424210","article-title":"Mulberry leaves and their potential effects against cardiometabolic risks: A review of chemical compositions, biological properties and clinical efficacy","volume":"56","author":"Thaipitakwong","year":"2018","journal-title":"Pharm. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"155","DOI":"10.3164\/jcbn.10-53","article-title":"Effects of mulberry leaf extract rich in 1-deoxynojirimycin on blood lipid profiles in humans","volume":"47","author":"Kojima","year":"2010","journal-title":"J. Clin. Biochem. Nutr."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1111\/j.2040-1124.2011.00101.x","article-title":"Effect of mulberry leaf extract with enriched 1-deoxynojirimycin content on postprandial glycemic control in subjects with impaired glucose metabolism","volume":"2","author":"Asai","year":"2011","journal-title":"J. Diabetes Investig."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1016\/j.ijbiomac.2014.09.060","article-title":"A polysaccharide extract of mulberry leaf ameliorates hepatic glucose metabolism and insulin signaling in rats with type 2 diabetes induced by high-fat diet and streptozotocin","volume":"72","author":"Ren","year":"2015","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"7075","DOI":"10.1021\/jf101415v","article-title":"Improvement in high-fat diet-induced obesity and body fat accumulation by a Nelumbo nucifera leaf flavonoid-rich extract in mice","volume":"58","author":"Wu","year":"2010","journal-title":"J. Agric. Food Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1959","DOI":"10.1038\/s12276-020-00534-2","article-title":"Nuciferine modulates the gut microbiota and prevents obesity in high-fat diet-fed rats","volume":"52","author":"Wang","year":"2020","journal-title":"Exp. Mol. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4218","DOI":"10.1111\/bph.14482","article-title":"Nuciferine ameliorates hepatic steatosis in high-fat diet\/streptozocin-induced diabetic mice through a PPAR\u03b1\/PGC1\u03b1 pathway","volume":"175","author":"Zhang","year":"2018","journal-title":"Br. J. Pharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"251","DOI":"10.3109\/13880209.2015.1029054","article-title":"Chlorogenic acid-enriched extract from Eucommia ulmoides leaves inhibits hepatic lipid accumulation through regulation of cholesterol metabolism in HepG2 cells","volume":"54","author":"Hao","year":"2016","journal-title":"Pharm. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1186\/s13020-021-00482-7","article-title":"Traditional application and modern pharmacological research of Eucommia ulmoides Oliv","volume":"16","author":"Huang","year":"2021","journal-title":"Chin. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"801457","DOI":"10.1155\/2013\/801457","article-title":"Roles of chlorogenic acid on regulating glucose and lipids metabolism: A review","volume":"2013","author":"Meng","year":"2013","journal-title":"Evid.-Based Complement. Altern. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.1016\/j.bcp.2013.02.008","article-title":"Anti-diabetic and anti-lipidemic effects of chlorogenic acid are mediated by AMPK activation","volume":"85","author":"Ong","year":"2013","journal-title":"Biochem. Pharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"9340637","DOI":"10.1155\/2016\/9340637","article-title":"Therapeutic effects of quercetin on inflammation, obesity, and type 2 diabetes","volume":"2016","author":"Chen","year":"2016","journal-title":"Mediat. Inflamm."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4532482","DOI":"10.1155\/2020\/4532482","article-title":"Preventive effects of kaempferol on high-fat diet-induced obesity complications in C57BL\/6 mice","volume":"2020","author":"Wang","year":"2020","journal-title":"BioMed Res. Int."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1038\/nrm.2017.95","article-title":"AMPK: Guardian of metabolism and mitochondrial homeostasis","volume":"19","author":"Herzig","year":"2018","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e245","DOI":"10.1038\/emm.2016.81","article-title":"Regulation and function of AMPK in physiology and diseases","volume":"48","author":"Jeon","year":"2016","journal-title":"Exp. Mol. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1776","DOI":"10.1172\/JCI29044","article-title":"AMP-activated protein kinase signaling in metabolic regulation","volume":"116","author":"Long","year":"2006","journal-title":"J. Clin. Investig."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1007\/s00125-007-0886-7","article-title":"The mechanisms of alloxan- and streptozotocin-induced diabetes","volume":"51","author":"Lenzen","year":"2008","journal-title":"Diabetologia"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"S215","DOI":"10.2337\/diabetes.53.suppl_3.S215","article-title":"The high-fat diet-fed mouse: A model for studying mechanisms and treatment of impaired glucose tolerance and type 2 diabetes","volume":"53","author":"Winzell","year":"2004","journal-title":"Diabetes"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.cmet.2016.05.005","article-title":"Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism","volume":"24","author":"Sayin","year":"2016","journal-title":"Cell Metab."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1332","DOI":"10.1016\/j.cell.2016.05.041","article-title":"From dietary fiber to host physiology: Short-chain fatty acids as key bacterial metabolites","volume":"165","author":"Koh","year":"2016","journal-title":"Cell"}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/13\/2145\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T10:28:05Z","timestamp":1782988085000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/13\/2145"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,2]]},"references-count":43,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["nu18132145"],"URL":"https:\/\/doi.org\/10.3390\/nu18132145","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,2]]}}}