{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T14:20:39Z","timestamp":1789222839210,"version":"build-2803163510"},"reference-count":37,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,4,30]],"date-time":"2025-04-30T00:00:00Z","timestamp":1745971200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)","doi-asserted-by":"publisher","award":["1R15DK131507-01A1"],"award-info":[{"award-number":["1R15DK131507-01A1"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background and Aims: Metabolic dysfunction-associated steatohepatitis (MASH), a progressive form of metabolic dysfunction-associated steatotic liver disease (MASLD), involves inflammation, fibrosis, steatosis, and oxidative stress. Previous research from our lab shows that cannabigerol (CBG) reduces inflammation and fibrosis in male MASH mice, but its effects in females remain unknown. Given immune cell population changes in MASLD patients, this study examines CBG\u2019s impact on methionine-choline deficient (MCD) diet-induced MASH in female mice. Methods: MCD-fed female mice are supplemented with two different doses for three weeks. Liver fibrosis, steatosis, oxidative stress, ductular reaction, and inflammation are assessed via Sirius Red, Oil Red O, immunohistochemistry, and immunofluorescence staining. Immune cell changes in non-parenchymal cells (NPCs) are analyzed via flow cytometry. Results: CBG treatment improves liver health by reducing leukocyte infiltration. Both CBG doses significantly decrease fibrosis, oxidative stress, ductular proliferation, and inflammation in MCD-fed mice, including monocyte and T lymphocyte reductions. Additionally, CBG downregulates mast cell activation, inhibiting transforming growth factor (TGF)-\u03b21 release, thereby suppressing hepatic stellate cell activation. This reduces collagen deposition, fibrosis, and ductular proliferation. Conclusions: Our findings provide insights for pre-clinical and clinical research, highlighting CBG\u2019s potential therapeutic role and dosage considerations in mitigating liver fibrosis and inflammation in female patients.<\/jats:p>","DOI":"10.3390\/nu17091524","type":"journal-article","created":{"date-parts":[[2025,4,30]],"date-time":"2025-04-30T05:05:57Z","timestamp":1745989557000},"page":"1524","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Cannabigerol Alleviates Liver Damage in Metabolic Dysfunction-Associated Steatohepatitis Female Mice via Inhibition of Transforming Growth Factor Beta 1"],"prefix":"10.3390","volume":"17","author":[{"given":"Raznin","family":"Joly","sequence":"first","affiliation":[{"name":"College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fariha","family":"Tasnim","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Northern Colorado, Greeley, CO 80639, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9588-6144","authenticated-orcid":false,"given":"Kelsey","family":"Krutsinger","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Northern Colorado, Greeley, CO 80639, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuorui","family":"Li","sequence":"additional","affiliation":[{"name":"College of Biology, China Agricultural University, Beijing 100107, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4014-9278","authenticated-orcid":false,"given":"Nicholas","family":"Pullen","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Northern Colorado, Greeley, CO 80639, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9982-9286","authenticated-orcid":false,"given":"Yuyan","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Northern Colorado, Greeley, CO 80639, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,30]]},"reference":[{"key":"ref_1","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_2","doi-asserted-by":"crossref","first-page":"8263","DOI":"10.3748\/wjg.v23.i47.8263","article-title":"Clinical Epidemiology and Disease Burden of Nonalcoholic Fatty Liver Disease","volume":"23","author":"Perumpail","year":"2017","journal-title":"World J. Gastroenterol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"100727","DOI":"10.1016\/j.aohep.2022.100727","article-title":"The Epidemiology of Non-Alcoholic Steatohepatitis (NASH) in the United States between 2010\u20132020: A Population-Based Study","volume":"27","author":"Hamid","year":"2022","journal-title":"Ann. Hepatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1056\/NEJMoa2309000","article-title":"A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis","volume":"390","author":"Harrison","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1649","DOI":"10.1038\/s41395-018-0088-6","article-title":"NASH Leading Cause of Liver Transplant in Women: Updated Analysis of Indications for Liver Transplant and Ethnic and Gender Variances","volume":"113","author":"Noureddin","year":"2018","journal-title":"Off. J. Am. Coll. Gastroenterol. ACG"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1038\/nrg.2017.19","article-title":"Comparative Transcriptomics in Human and Mouse","volume":"18","author":"Breschi","year":"2017","journal-title":"Nat. Rev. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Diedrich, T., Kummer, S., Galante, A., Drolz, A., Schlicker, V., Lohse, A.W., Kluwe, J., Eberhard, J.M., and Schulze zur Wiesch, J. (2020). Characterization of the Immune Cell Landscape of Patients with NAFLD. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0230307"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1016\/j.immuni.2020.04.001","article-title":"Niche-Specific Reprogramming of Epigenetic Landscapes Drives Myeloid Cell Diversity in Nonalcoholic Steatohepatitis","volume":"52","author":"Seidman","year":"2020","journal-title":"Immunity"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1991","DOI":"10.1002\/hep.29079","article-title":"Bile Duct Ligation\u2013Induced Biliary Hyperplasia, Hepatic Injury, and Fibrosis Are Reduced in Mast Cell\u2013Deficient KitW-sh Mice","volume":"65","author":"Hargrove","year":"2017","journal-title":"Hepatology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.humpath.2018.11.029","article-title":"Hepatic Mast Cell Concentration Directly Correlates to Stage of Fibrosis in NASH","volume":"86","author":"Lombardo","year":"2019","journal-title":"Hum. Pathol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1016\/j.ajpath.2011.11.003","article-title":"The Endocannabinoid System and Plant-Derived Cannabinoids in Diabetes and Diabetic Complications","volume":"180","author":"Mukhopadhyay","year":"2012","journal-title":"Am. J. Pathol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/s40263-018-0589-2","article-title":"Long-Term Safety, Tolerability, and Efficacy of Cannabidiol in Children with Refractory Epilepsy: Results from an Expanded Access Program in the US","volume":"33","author":"Sands","year":"2019","journal-title":"CNS Drugs"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"on behalf of the GWCA1208 study group, Twelves, C., Sabel, M., Checketts, D., Miller, S., Tayo, B., Jove, M., Brazil, L., and Short, S.C. (2021). A Phase 1b Randomised, Placebo-Controlled Trial of Nabiximols Cannabinoid Oromucosal Spray with Temozolomide in Patients with Recurrent Glioblastoma. Br. J. Cancer, 124, 1379\u20131387.","DOI":"10.1038\/s41416-021-01259-3"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"di Giacomo, V., Chiavaroli, A., Recinella, L., Orlando, G., Cataldi, A., Rapino, M., Di Valerio, V., Ronci, M., Leone, S., and Brunetti, L. (2020). Antioxidant and Neuroprotective Effects Induced by Cannabidiol and Cannabigerol in Rat CTX-TNA2 Astrocytes and Isolated Cortexes. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21103575"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Gugliandolo, A., Pollastro, F., Grassi, G., Bramanti, P., and Mazzon, E. (2018). In Vitro Model of Neuroinflammation: Efficacy of Cannabigerol, a Non-Psychoactive Cannabinoid. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19071992"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Aljobaily, N., Krutsinger, K., Viereckl, M.J., Joly, R., Menlove, B., Cone, B., Suppes, A., and Han, Y. (2022). Low-Dose Administration of Cannabigerol Attenuates Inflammation and Fibrosis Associated with Methionine\/Choline Deficient Diet-Induced NASH Model via Modulation of Cannabinoid Receptor. Nutrients, 15.","DOI":"10.3390\/nu15010178"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1002\/ptr.4966","article-title":"Animal Studies on Medicinal Herbs: Predictability, Dose Conversion and Potential Value","volume":"28","author":"Wojcikowski","year":"2014","journal-title":"Phytother. Res."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Zagzoog, A., Mohamed, K.A., Kim, H.J.J., Kim, E.D., Frank, C.S., Black, T., Jadhav, P.D., Holbrook, L.A., and Laprairie, R.B. (2020). In Vitro and in Vivo Pharmacological Activity of Minor Cannabinoids Isolated from Cannabis Sativa. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-77175-y"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"100086","DOI":"10.1016\/j.xpro.2020.100086","article-title":"Protocol for Primary Mouse Hepatocyte Isolation","volume":"1","author":"Goldstein","year":"2020","journal-title":"STAR Protoc."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.freeradbiomed.2020.02.025","article-title":"Role of Oxidative Stress in the Pathogenesis of Nonalcoholic Fatty Liver Disease","volume":"152","author":"Chen","year":"2020","journal-title":"Free Radic. Biol. Med."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Ore, A., and Akinloye, O.A. (2019). Oxidative Stress and Antioxidant Biomarkers in Clinical and Experimental Models of Non-Alcoholic Fatty Liver Disease. Med. Kaunas. Lith., 55.","DOI":"10.3390\/medicina55020026"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2005","DOI":"10.1002\/hep.25762","article-title":"The Diagnosis and Management of Non-Alcoholic Fatty Liver Disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association","volume":"55","author":"Chalasani","year":"2012","journal-title":"Hepatology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1254\/fpj.154.203","article-title":"Mechanisms of Hepatic Stellate Cell Activation as a Therapeutic Target for the Treatment of Non-Alcoholic Steatohepatitis","volume":"154","author":"Tsuchida","year":"2019","journal-title":"Folia Pharmacol. Jpn."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Hoffmann, C., Djerir, N.E.H., Danckaert, A., Fernandes, J., Roux, P., Charrueau, C., Lachag\u00e8s, A.-M., Charlotte, F., Brocheriou, I., and Cl\u00e9ment, K. (2020). Hepatic Stellate Cell Hypertrophy Is Associated with Metabolic Liver Fibrosis. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-60615-0"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1038\/modpathol.2017.115","article-title":"Centrilobular Ductular Reaction Correlates with Fibrosis Stage and Fibrosis Progression in Non-Alcoholic Steatohepatitis","volume":"31","author":"Zhao","year":"2018","journal-title":"Mod. Pathol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1913","DOI":"10.1053\/j.gastro.2019.11.311","article-title":"Mechanisms of Fibrosis Development in Nonalcoholic Steatohepatitis","volume":"158","author":"Schwabe","year":"2020","journal-title":"Gastroenterology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4234061","DOI":"10.1155\/2016\/4234061","article-title":"Insights into the Role and Interdependence of Oxidative Stress and Inflammation in Liver Diseases","volume":"2016","author":"Li","year":"2016","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1002\/hep.31713","article-title":"Mast Cells Promote Nonalcoholic Fatty Liver Disease Phenotypes and Microvesicular Steatosis in Mice Fed a Western Diet","volume":"74","author":"Kennedy","year":"2021","journal-title":"Hepatology"},{"key":"ref_29","unstructured":"Terjung, R. (2013). Hepatic Stellate Cells and Liver Fibrosis. Comprehensive Physiology, Wiley."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Li, S., Li, X., Chen, F., Liu, M., Ning, L., Yan, Y., Zhang, S., Huang, S., and Tu, C. (2022). Nobiletin Mitigates Hepatocytes Death, Liver Inflammation, and Fibrosis in a Murine Model of NASH Through Modulating Hepatic Oxidative Stress and Mitochondrial Dysfunction. J. Nutr. Biochem., 100.","DOI":"10.1016\/j.jnutbio.2021.108888"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"153294","DOI":"10.1016\/j.phymed.2020.153294","article-title":"Physalin D Attenuates Hepatic Stellate Cell Activation and Liver Fibrosis by Blocking TGF-\u03b2\/Smad and YAP Signaling","volume":"78","author":"Xiang","year":"2020","journal-title":"Phytomedicine"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Lachowski, D., Cortes, E., Rice, A., Pinato, D., Rombouts, K., and del Rio Hernandez, A. (2019). Matrix Stiffness Modulates the Activity of MMP-9 and TIMP-1 in Hepatic Stellate Cells to Perpetuate Fibrosis. Sci. Rep., 9.","DOI":"10.1038\/s41598-019-43759-6"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Li, H., Zhou, Y., Wang, H., Zhang, M., Qiu, P., Zhang, M., Zhang, R., Zhao, Q., and Liu, J. (2020). Crosstalk between Liver Macrophages and Surrounding Cells in Nonalcoholic Steatohepatitis. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.01169"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Ortiz-Lopez, N., Fuenzalida, C., Dufeu, M.S., Pinto-Leon, A., Escobar, A., Poniachik, J., Roblero, J.P., Valenzuela-P\u00e9rez, L., and Beltran, C.J. (2022). The Immune Response as a Therapeutic Target in Non-Alcoholic Fatty Liver Disease. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.954869"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1406","DOI":"10.1038\/labinvest.2014.129","article-title":"Inhibition of Mast Cell-Derived Histamine Secretion by Cromolyn Sodium Treatment Decreases Biliary Hyperplasia in Cholestatic Rodents","volume":"94","author":"Kennedy","year":"2014","journal-title":"Lab. Investig."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1002\/hep.28704","article-title":"Inhibition of Mast Cell-secreted Histamine Decreases Biliary Proliferation and Fibrosis in Primary Sclerosing Cholangitis Mdr2\u2212\/\u2212 Mice","volume":"64","author":"Jones","year":"2016","journal-title":"Hepatology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1369\/0022155415627681","article-title":"TGF-\u03b2\/SMAD Pathway and Its Regulation in Hepatic Fibrosis","volume":"64","author":"Xu","year":"2016","journal-title":"J. Histochem. Cytochem."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/17\/9\/1524\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:24:48Z","timestamp":1760030688000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/17\/9\/1524"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,30]]},"references-count":37,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["nu17091524"],"URL":"https:\/\/doi.org\/10.3390\/nu17091524","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,30]]}}}