{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:09:17Z","timestamp":1792789757040,"version":"4.5.0"},"reference-count":55,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,2,16]],"date-time":"2023-02-16T00:00:00Z","timestamp":1676505600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Guangdong University Characteristic Innovation Project","award":["2019KTSCX023"],"award-info":[{"award-number":["2019KTSCX023"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Metabolic-associated fatty liver disease (MAFLD) is one of the most common chronic liver diseases, which in turn triggers mild inflammation, metabolic dysfunction, fibrosis, and even cancer. Accumulating evidence has suggested that Berberine (BBR) could significantly improve MAFLD progression. Clock and Bmal1 as heterodimer proteins highly participated in the development of MAFLD, but whether BBR targets Clock and Bmal1 in MAFLD remains poorly understood. The result suggested that the protein levels of Clock and Bmal1 were decreased in MAFLD mice, which was negatively correlated with elevated reactive oxygen species (ROS) accumulation, the H2O2 level, liver inflammation, metabolic dysfunction, and insulin resistance. The mRNA and protein levels of Clock and Bmal1 were also decreased in glucosamine-induced HepG2 cells, which were are negatively related to glucose uptake, the ROS level, and the H2O2 level. More importantly, Bmal1 siRNA could mimic the effect of glucosamine in HepG2 cells. Interestingly, Berberine (BBR) could rescue metabolism disorder and redox homeostasis through enhancing Clock and Bmal1 expression in vivo and in vitro. Therefore, BBR might be an effective natural compound for alleviating redox homeostasis, metabolism disorder, and liver pathological changes in MAFLD by activating Clock and Bmal1 expression.<\/jats:p>","DOI":"10.3390\/molecules28041874","type":"journal-article","created":{"date-parts":[[2023,2,16]],"date-time":"2023-02-16T04:01:52Z","timestamp":1676520112000},"page":"1874","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Berberine Ameliorates Metabolic-Associated Fatty Liver Disease Mediated Metabolism Disorder and Redox Homeostasis by Upregulating Clock Genes: Clock and Bmal1 Expressions"],"prefix":"10.3390","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6900-7217","authenticated-orcid":false,"given":"Cunsi","family":"Ye","sequence":"first","affiliation":[{"name":"School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yajing","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaomin","family":"Lin","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zimiao","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoyinghua","family":"Feng","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangqing","family":"Fang","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shijian","family":"Quan","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"329","DOI":"10.14218\/JCTH.2021.00178","article-title":"Metabolic-associated Fatty Liver Disease (MAFLD): A Multi-systemic Disease Beyond the Liver","volume":"10","author":"Kaya","year":"2022","journal-title":"J. Clin. Transl. Hepatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e573","DOI":"10.1016\/j.cgh.2021.02.030","article-title":"Estimating Global Prevalence of Metabolic Dysfunction-Associated Fatty Liver Disease in Overweight or Obese Adults","volume":"20","author":"Liu","year":"2022","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1999","DOI":"10.1053\/j.gastro.2019.11.312","article-title":"MAFLD: A Consensus-Driven Proposed Nomenclature for Metabolic Associated Fatty Liver Disease","volume":"158","author":"Eslam","year":"2020","journal-title":"Gastroenterology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1038\/ijo.2017.33","article-title":"Effects of topical capsaicin combined with moderate exercise on insulin resistance, body weight and oxidative stress in hypoestrogenic obese rats","volume":"41","author":"Carvajal","year":"2017","journal-title":"Int. J. Obes."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Zhong, Y., Li, Z., Jin, R., Yao, Y., He, S., Lei, M., Wang, X., Shi, C., Gao, L., and Peng, X. (2022). Diosgenin Ameliorated Type II Diabetes-Associated Nonalcoholic Fatty Liver Disease through Inhibiting De Novo Lipogenesis and Improving Fatty Acid Oxidation and Mitochondrial Function in Rats. Nutrients, 14.","DOI":"10.3390\/nu14234994"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"109158","DOI":"10.1016\/j.biopha.2019.109158","article-title":"Gender effect of hyperuricemia on the development of nonalcoholic fatty liver disease (NAFLD): A clinical analysis and mechanistic study","volume":"117","author":"Xu","year":"2019","journal-title":"Biomed. Pharm."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1038\/s41574-018-0122-1","article-title":"Circadian clocks and insulin resistance","volume":"15","author":"Stenvers","year":"2019","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e148282","DOI":"10.1172\/JCI148282","article-title":"Human circadian variations","volume":"131","author":"Gentry","year":"2021","journal-title":"J. Clin. Investig."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1016\/j.sleep.2010.09.007","article-title":"Association of onset of obesity with sleep duration and shift work among Japanese adults","volume":"12","author":"Itani","year":"2011","journal-title":"Sleep Med."},{"key":"ref_10","first-page":"E246","article-title":"Evidence for a circadian rhythm of insulin sensitivity in patients with NIDDM caused by cyclic changes in hepatic glucose production","volume":"271","author":"Boden","year":"1996","journal-title":"Am. J. Physiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1575","DOI":"10.1016\/j.bbadis.2017.04.009","article-title":"EGCG ameliorates diet-induced metabolic syndrome associating with the circadian clock","volume":"1863","author":"Mi","year":"2017","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1038\/s41467-020-20743-7","article-title":"Time-restricted feeding normalizes hyperinsulinemia to inhibit breast cancer in obese postmenopausal mouse models","volume":"12","author":"Das","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3164","DOI":"10.1002\/jcp.30772","article-title":"The Clock-NAD+-Sirtuin connection in nonalcoholic fatty liver disease","volume":"237","author":"Aggarwal","year":"2022","journal-title":"J. Cell. Physiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1700440","DOI":"10.1002\/mnfr.201700440","article-title":"(-)-Epigallocatechin-3-gallate Ameliorates Insulin Resistance and Mitochondrial Dysfunction in HepG2 Cells: Involvement of Bmal1","volume":"61","author":"Mi","year":"2017","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.neuchi.2015.03.002","article-title":"Melatonin: Physiological effects in humans","volume":"61","author":"Claustrat","year":"2015","journal-title":"Neurochirurgie"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1016\/j.biopha.2018.12.039","article-title":"Treating hyperuricemia related non-alcoholic fatty liver disease in rats with resveratrol","volume":"110","author":"Xu","year":"2019","journal-title":"Biomed. Pharmacother."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Li, J., Wei, L., Zhao, C., Li, J., Liu, Z., Zhang, M., and Wang, Y. (2019). Resveratrol Maintains Lipid Metabolism Homeostasis via One of the Mechanisms Associated with the Key Circadian Regulator Bmal1. Molecules, 24.","DOI":"10.3390\/molecules24162916"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1016\/j.cmet.2016.03.007","article-title":"The Small Molecule Nobiletin Targets the Molecular Oscillator to Enhance Circadian Rhythms and Protect against Metabolic Syndrome","volume":"23","author":"He","year":"2016","journal-title":"Cell Metab."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3122","DOI":"10.3390\/molecules23123122","article-title":"The Degradation Products of Ascorbic Acid Inhibit Amyloid Fibrillation of Insulin and Destabilize Preformed Fibrils","volume":"23","author":"Yang","year":"2018","journal-title":"Molecules"},{"key":"ref_20","first-page":"557","article-title":"A review of the effects of Berberis vulgaris and its major component, berberine, in metabolic syndrome","volume":"20","author":"Tabeshpour","year":"2017","journal-title":"Iran J. Basic. Med. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"591227","DOI":"10.3389\/fphar.2020.591227","article-title":"Adipose Tissue SIRT1 Regulates Insulin Sensitizing and Anti-Inflammatory Effects of Berberine","volume":"11","author":"Shan","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1682","DOI":"10.1016\/j.bbagen.2006.09.007","article-title":"Berberine-stimulated glucose uptake in L6 myotubes involves both AMPK and p38 MAPK","volume":"1760","author":"Cheng","year":"2006","journal-title":"Biochim. Biophys. Acta (BBA) Gen. Subj."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"722360","DOI":"10.3389\/fphar.2021.722360","article-title":"Berberine Alleviates Insulin Resistance and Inflammation via Inhibiting the LTB4-BLT1 Axis","volume":"12","author":"Gong","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.bcp.2019.04.017","article-title":"Berberine stimulates fibroblast growth factor 21 by modulating the molecular clock component brain and muscle Arnt-like 1 in brown adipose tissue","volume":"164","author":"Hirai","year":"2019","journal-title":"Biochem. Pharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1002\/hep.20701","article-title":"Design and validation of a histological scoring system for nonalcoholic fatty liver disease","volume":"41","author":"Kleiner","year":"2005","journal-title":"Hepatology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"10089","DOI":"10.1021\/acs.jafc.9b04016","article-title":"Capsaicin Ameliorates the Redox Imbalance and Glucose Metabolism Disorder in an Insulin-Resistance Model via Circadian Clock-Related Mechanisms","volume":"67","author":"Lu","year":"2019","journal-title":"J. Agric. Food Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1089\/ars.2012.4889","article-title":"Circadian rhythm connections to oxidative stress: Implications for human health","volume":"19","author":"Wilking","year":"2013","journal-title":"Antioxid. Redox Signal."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"E938","DOI":"10.1152\/ajpendo.00010.2021","article-title":"Genetically increasing flux through beta-oxidation in skeletal muscle increases mitochondrial reductive stress and glucose intolerance","volume":"320","author":"Smith","year":"2021","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"101964","DOI":"10.1016\/j.redox.2021.101964","article-title":"Redox regulation of the insulin signalling pathway","volume":"42","author":"Lennicke","year":"2021","journal-title":"Redox Biol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Chhunchha, B., Kubo, E., and Singh, D.P. (2020). Clock Protein Bmal1 and Nrf2 Cooperatively Control Aging or Oxidative Response and Redox Homeostasis by Regulating Rhythmic Expression of Prdx6. Cells, 9.","DOI":"10.3390\/cells9081861"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.fct.2018.10.031","article-title":"Tea polyphenols direct Bmal1-driven ameliorating of the redox imbalance and mitochondrial dysfunction in hepatocytes","volume":"122","author":"Qi","year":"2018","journal-title":"Food Chem. Toxicol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Zhang, W., Ho, C.T., and Lu, M. (2022). Piperine Improves Lipid Dysregulation by Modulating Circadian Genes Bmal1 and Clock in HepG2 Cells. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23105611"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.molmet.2019.09.012","article-title":"Circadian clock network desynchrony promotes weight gain and alters glucose homeostasis in mice","volume":"30","author":"Kolbe","year":"2019","journal-title":"Mol. Metab."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1038\/nrg.2016.150","article-title":"Transcriptional architecture of the mammalian circadian clock","volume":"18","author":"Takahashi","year":"2017","journal-title":"Nat. Rev. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.cell.2017.03.027","article-title":"Mutation of the Human Circadian Clock Gene CRY1 in Familial Delayed Sleep Phase Disorder","volume":"169","author":"Patke","year":"2017","journal-title":"Cell"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4614","DOI":"10.1038\/s41467-020-17978-9","article-title":"TRESK is a key regulator of nocturnal suprachiasmatic nucleus dynamics and light adaptive responses","volume":"11","author":"Lalic","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"6801","DOI":"10.1038\/s41598-021-86244-9","article-title":"Finding Nemo\u2019s clock reveals switch from nocturnal to diurnal activity","volume":"11","author":"Schalm","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.semcdb.2021.05.034","article-title":"Sleep timing and the circadian clock in mammals: Past, present and the road ahead","volume":"126","author":"Sanchez","year":"2022","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Hudec, M., Dankova, P., Solc, R., Bettazova, N., and Cerna, M. (2020). Epigenetic Regulation of Circadian Rhythm and Its Possible Role in Diabetes Mellitus. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21083005"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2388","DOI":"10.1038\/s41467-021-22571-9","article-title":"Circadian clock dysfunction in human omental fat links obesity to metabolic inflammation","volume":"12","author":"Maury","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1038\/nature09253","article-title":"Disruption of the clock components CLOCK and BMAL1 leads to hypoinsulinaemia and diabetes","volume":"466","author":"Marcheva","year":"2010","journal-title":"Nature"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.jhep.2019.03.020","article-title":"The circadian clock and liver function in health and disease","volume":"71","author":"Mukherji","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T))","volume":"25","author":"Livak","year":"2001","journal-title":"Method"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2196","DOI":"10.1002\/hep.26992","article-title":"CLOCK\/BMAL1 regulates circadian change of mouse hepatic insulin sensitivity by SIRT1","volume":"59","author":"Zhou","year":"2014","journal-title":"Hepatology"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1620","DOI":"10.1016\/j.drudis.2021.03.015","article-title":"Small-molecule modulators of the circadian clock: Pharmacological potentials in circadian-related diseases","volume":"26","author":"Ribeiro","year":"2021","journal-title":"Drug Discov. Today"},{"key":"ref_46","first-page":"4227","article-title":"Berberine protects against diabetic retinopathy by inhibiting cell apoptosis via deactivation of the NFkappaB signaling pathway","volume":"22","author":"Zhai","year":"2020","journal-title":"Mol. Med. Rep."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"7777","DOI":"10.3748\/wjg.v21.i25.7777","article-title":"Berberine inhibits hepatic gluconeogenesis via the LKB1-AMPK-TORC2 signaling pathway in streptozotocin-induced diabetic rats","volume":"21","author":"Jiang","year":"2015","journal-title":"World J. Gastroenterol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.lfs.2016.09.025","article-title":"Inhibition of M1 macrophage activation in adipose tissue by berberine improves insulin resistance","volume":"166","author":"Ye","year":"2016","journal-title":"Life Sci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1517\/13543784.10.3.439","article-title":"Glycogen phosphorylase inhibitors for treatment of type 2 diabetes mellitus","volume":"10","author":"Treadway","year":"2001","journal-title":"Expert. Opin. Investig. Drugs"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.freeradbiomed.2021.01.009","article-title":"Expanding the link between circadian rhythms and redox metabolism of epigenetic control","volume":"170","author":"Sato","year":"2021","journal-title":"Free Radic. Biol. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"456","DOI":"10.4239\/wjd.v6.i3.456","article-title":"Oxidative stress, insulin resistance, dyslipidemia and type 2 diabetes mellitus","volume":"6","author":"Tangvarasittichai","year":"2015","journal-title":"World J. Diabetes"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1717","DOI":"10.2147\/DMSO.S211188","article-title":"Effect of berberine on the HPA-axis pathway and skeletal muscle GLUT4 in type 2 diabetes mellitus rats","volume":"12","author":"Mi","year":"2019","journal-title":"Diabetes Metab. Syndr. Obes. Targets Ther."},{"key":"ref_53","first-page":"1717","article-title":"Insulin resistance index (HOMA-IR) in the differentiation of patients with non-alcoholic fatty liver disease and healthy individuals","volume":"12","author":"Salgado","year":"2019","journal-title":"Diabetes Metab. Syndr. Obes."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"10903","DOI":"10.1021\/acs.jafc.5b04533","article-title":"Cichoric Acid Reverses Insulin Resistance and Suppresses Inflammatory Responses in the Glucosamine-Induced HepG2 Cells","volume":"63","author":"Zhu","year":"2015","journal-title":"J. Agric. Food Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"101519","DOI":"10.1016\/j.redox.2020.101519","article-title":"Selenium deficiency-induced redox imbalance leads to metabolic reprogramming and inflammation in the liver","volume":"36","author":"Tang","year":"2020","journal-title":"Redox Biol."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/28\/4\/1874\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:37:57Z","timestamp":1760121477000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/28\/4\/1874"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,16]]},"references-count":55,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["molecules28041874"],"URL":"https:\/\/doi.org\/10.3390\/molecules28041874","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,16]]}}}