{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T16:05:19Z","timestamp":1789833919056,"version":"4.0.1"},"reference-count":47,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T00:00:00Z","timestamp":1774310400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81620108030"],"award-info":[{"award-number":["81620108030"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine","award":["LSLSKL20240130"],"award-info":[{"award-number":["LSLSKL20240130"]}]},{"name":"Postdoctoral Fellowship Program of CPSF","award":["GZB20250905"],"award-info":[{"award-number":["GZB20250905"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Objective: Based on previous findings on the Lingguizhugan (LGZG)-mediated gut\u2013liver axis, this study clarifies the therapeutic mechanisms of LGZG in metabolic dysfunction-associated steatotic liver disease (MASLD), with a focus on the gut microbiota\u2013bile acid\u2013TGR5 (GPBAR1) axis. Methods: C57BL\/6J mice were fed a high-fat diet (HFD) for 8 weeks to induce MASLD, followed by 4-week LGZG intervention (21.57 g\/kg\/day, oral gavage). Metabolic phenotypes, gut microbiota (16S rRNA sequencing), serum\/hepatic bile acids (targeted metabolomics), and molecular targets (qPCR\/Western blot) were analyzed. Results: LGZG significantly alleviated HFD-induced obesity, insulin resistance, and hepatic steatosis, while enhancing whole-body energy expenditure (increased oxygen consumption (VO2), and heat production (p &lt; 0.05). It also reduced serum ALT (p &lt; 0.001) and AST levels (p &lt; 0.01). Mechanistically, LGZG remodeled the gut microbiota, specifically increasing Akkermansia, Bifidobacterium and Lachnospiraceae_NK4A236_group while decreasing Lactobacillus. This shift inhibited the intestinal FXR-Fgf15 axis, concurrently activating the hepatic alternative bile acid synthesis pathway (upregulating CYP27A1 and CYP7B1 protein expression; p &lt; 0.001 and p &lt; 0.01, respectively). Consequently, systemic accumulation of non-12\u03b1-hydroxylated bile acids (non-12-OH BAs) such as hyocholic acid (HCA) and 7-ketolithocholic acid (7-ketoLCA) occurred\u2014known TGR5 agonists and intestinal FXR antagonists. These changes elevated serum GLP-1 levels (p &lt; 0.05) and activated adipose TGR5-cAMP\/PKA\/CREB signaling. The metabolic benefits primarily originated from non-12-OH BAs enrichment and TGR5-mediated adipose browning, not hepatic FXR activation. Conclusions: Our findings show that LGZG ameliorates MASLD by remodeling bile acid profiles via intestinal FXR-Fgf15 axis inhibition and hepatic alternative synthesis pathway activation. This study highlights the TGR5-targeting properties of LGZG, providing a mechanistic basis for its therapeutic use in metabolic disorders.<\/jats:p>","DOI":"10.3390\/ph19040523","type":"journal-article","created":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T10:07:13Z","timestamp":1774433233000},"page":"523","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Lingguizhugan Decoction Ameliorates MASLD by Modulating the Gut Microbiota and Enriching Non-12-OH Bile Acids to Activate TGR5-Mediated Thermogenesis"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-7050-8940","authenticated-orcid":false,"given":"Yun-Hong","family":"Sun","sequence":"first","affiliation":[{"name":"Institute of Digestive Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China"},{"name":"School of Public Health, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei-Lun","family":"Ding","sequence":"additional","affiliation":[{"name":"Institute of Digestive Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Digestive Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China"},{"name":"CAS Engineering Laboratory for Nutrition, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Shanghai 200031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Rong","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Digestive Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7238-6414","authenticated-orcid":false,"given":"Ming-Zhe","family":"Zhu","sequence":"additional","affiliation":[{"name":"School of Public Health, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Wang","sequence":"additional","affiliation":[{"name":"Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Dai","sequence":"additional","affiliation":[{"name":"Institute of Digestive Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China"},{"name":"School of Public Health, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China"},{"name":"State Key Laboratory of Integration and Innovation of Classical Formula and Modern Chinese Medicine, Shanghai 201203, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0316-7880","authenticated-orcid":false,"given":"Yan-Qi","family":"Dang","sequence":"additional","affiliation":[{"name":"Institute of Digestive Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China"},{"name":"State Key Laboratory of Integration and Innovation of Classical Formula and Modern Chinese Medicine, Shanghai 201203, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guang","family":"Ji","sequence":"additional","affiliation":[{"name":"Institute of Digestive Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China"},{"name":"State Key Laboratory of Integration and Innovation of Classical Formula and Modern Chinese Medicine, Shanghai 201203, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3602-3429","authenticated-orcid":false,"given":"Meng","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Digestive Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China"},{"name":"State Key Laboratory of Integration and Innovation of Classical Formula and Modern Chinese Medicine, Shanghai 201203, China"},{"name":"School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4167-0337","authenticated-orcid":false,"given":"Wen-Jun","family":"Zhou","sequence":"additional","affiliation":[{"name":"Institute of Digestive Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China"},{"name":"State Key Laboratory of Integration and Innovation of Classical Formula and Modern Chinese 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Hepatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1016\/S2468-1253(22)00165-0","article-title":"The prevalence and incidence of NAFLD worldwide: A systematic review and meta-analysis","volume":"7","author":"Riazi","year":"2022","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1016\/j.jhep.2020.03.039","article-title":"A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement","volume":"73","author":"Eslam","year":"2020","journal-title":"J. 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":"2184","DOI":"10.1016\/S0140-6736(19)33041-7","article-title":"Obeticholic acid for the treatment of non-alcoholic steatohepatitis: Interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial","volume":"394","author":"Younossi","year":"2019","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1038\/s41575-020-0269-9","article-title":"Gut microbiota and human NAFLD: Disentangling microbial signatures from metabolic disorders","volume":"17","author":"Vigliotti","year":"2020","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"100216","DOI":"10.1016\/j.mocell.2025.100216","article-title":"Intestinal bacteria-derived extracellular vesicles in metabolic dysfunction-associated steatotic liver disease: From mechanisms to therapeutics","volume":"48","author":"Qin","year":"2025","journal-title":"Mol. Cells"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"100271","DOI":"10.1016\/j.mocell.2025.100271","article-title":"Post ingestive systemic nutrient sensing for whole-body homeostasis","volume":"48","author":"Lee","year":"2025","journal-title":"Mol. Cells"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1007\/s11427-023-2353-0","article-title":"Bile acid signaling in the regulation of whole body metabolic and immunological homeostasis","volume":"67","author":"Jia","year":"2024","journal-title":"Sci. China Life Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1038\/nrgastro.2017.119","article-title":"Bile acid-microbiota crosstalk in gastrointestinal inflammation and carcinogenesis","volume":"15","author":"Jia","year":"2018","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1007\/s13238-020-00804-9","article-title":"Targeting the alternative bile acid synthetic pathway for metabolic diseases","volume":"12","author":"Jia","year":"2021","journal-title":"Protein Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1016\/j.cmet.2020.11.017","article-title":"Hyocholic acid species improve glucose homeostasis through a distinct TGR5 and FXR signaling mechanism","volume":"33","author":"Zheng","year":"2021","journal-title":"Cell Metab."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1574","DOI":"10.1002\/hep.29857","article-title":"Intestine farnesoid X receptor agonist and the gut microbiota activate G-protein bile acid receptor-1 signaling to improve metabolism","volume":"68","author":"Pathak","year":"2018","journal-title":"Hepatology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1831","DOI":"10.1021\/jm7015864","article-title":"Novel potent and selective bile acid derivatives as TGR5 agonists: Biological screening, structure-activity relationships, and molecular modeling studies","volume":"51","author":"Sato","year":"2008","journal-title":"J. Med. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1038\/nature04330","article-title":"Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation","volume":"439","author":"Watanabe","year":"2006","journal-title":"Nature"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"20235","DOI":"10.1021\/acs.jafc.5c06044","article-title":"Sargassum fusiforme Fucoidan Ameliorates Obesity-Associated Metabolic Dysfunction via a Tauroursodeoxycholic Acid-Mediated TGR5-cAMP-PKA Signaling Pathway","volume":"73","author":"Lin","year":"2025","journal-title":"J. Agric. Food Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1038\/s41467-017-02068-0","article-title":"TGR5 signalling promotes mitochondrial fission and beige remodelling of white adipose tissue","volume":"9","author":"Perino","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_18","first-page":"429738","article-title":"Chinese medicine formula lingguizhugan decoction improves Beta-oxidation and metabolism of Fatty Acid in high-fat-diet-induced rat model of Fatty liver disease","volume":"2013","author":"Liu","year":"2013","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Dang, Y., Hao, S., Zhou, W., Zhang, L., and Ji, G. (2019). The traditional Chinese formulae Ling-gui-zhu-gan decoction alleviated non-alcoholic fatty liver disease via inhibiting PPP1R3C mediated molecules. BMC Complement. Altern. Med., 19.","DOI":"10.1186\/s12906-018-2424-1"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e0197923","DOI":"10.1128\/spectrum.01979-23","article-title":"Ling-Gui-Zhu-Gan decoction ameliorates nonalcoholic fatty liver disease via modulating the gut microbiota","volume":"12","author":"Chen","year":"2024","journal-title":"Microbiol. Spectr."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Zhu, M., Wang, X., Wang, K., Zhao, Z., Dang, Y., Ji, G., Li, F., and Zhou, W. (2023). Lingguizhugan decoction improves non-alcoholic steatohepatitis partially by modulating gut microbiota and correlated metabolites. Front. Cell. Infect. Microbiol., 13.","DOI":"10.3389\/fcimb.2023.1066053"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"154208","DOI":"10.1016\/j.phymed.2022.154208","article-title":"The improvement of nonalcoholic steatohepatitis by Poria cocos polysaccharides associated with gut microbiota and NF-kappaB\/CCL3\/CCR1 axis","volume":"103","author":"Tan","year":"2022","journal-title":"Phytomedicine"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Hu, P.A., Chen, C.H., Guo, B.C., Kou, Y.R., and Lee, T.S. (2020). Bromelain Confers Protection against the Non-Alcoholic Fatty Liver Disease in Male C57bl\/6 Mice. Nutrients, 12.","DOI":"10.3390\/nu12051458"},{"key":"ref_24","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_25","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1016\/j.jhep.2023.07.034","article-title":"FXR agonists in NASH treatment","volume":"79","author":"Adorini","year":"2023","journal-title":"J. Hepatol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2293312","DOI":"10.1080\/19490976.2023.2293312","article-title":"Akkermansia muciniphila protects the intestine from irradiation-induced injury by secretion of propionic acid","volume":"15","author":"He","year":"2023","journal-title":"Gut Microbes"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1924","DOI":"10.1111\/1751-7915.14293","article-title":"Akkermansia muciniphila alleviates high-fat-diet-related metabolic-associated fatty liver disease by modulating gut microbiota and bile acids","volume":"16","author":"Wu","year":"2023","journal-title":"Microb. Biotechnol."},{"key":"ref_28","first-page":"BAD-0010-2016","article-title":"Bifidobacteria and Their Health-Promoting Effects","volume":"5","author":"Delgado","year":"2017","journal-title":"Microbiol. Spectr."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Xue, H., Ma, J., Wang, Y., Lu, M., Wang, F., and Tang, X. (2022). Shen-Ling-Bai-Zhu-San (SL) and SL Derived-Polysaccharide (PL) Ameliorate the Severity of Diarrhea-Induced by High Lactose via Modification of Colonic Fermentation. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.883355"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Amedei, A., and Morbidelli, L. (2019). Circulating Metabolites Originating from Gut Microbiota Control Endothelial Cell Function. Molecules, 24.","DOI":"10.3390\/molecules24213992"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1017\/S0029665118002719","article-title":"Gut microbiota and health: Connecting actors across the metabolic system","volume":"78","author":"Fava","year":"2019","journal-title":"Proc. Nutr. Soc."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Gasaly, N., Hermoso, M.A., and Gotteland, M. (2021). Butyrate and the Fine-Tuning of Colonic Homeostasis: Implication for Inflammatory Bowel Diseases. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22063061"},{"key":"ref_33","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_34","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1038\/nchembio.1864","article-title":"A biosynthetic pathway for a prominent class of microbiota-derived bile acids","volume":"11","author":"Devlin","year":"2015","journal-title":"Nat. Chem. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1016\/j.tips.2015.08.002","article-title":"TGR5 and Immunometabolism: Insights from Physiology and Pharmacology","volume":"36","author":"Perino","year":"2015","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1038\/s41579-022-00805-x","article-title":"Bile acids and the gut microbiota: Metabolic interactions and impacts on disease","volume":"21","author":"Collins","year":"2023","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/j.cgh.2018.07.012","article-title":"Environmental Factors, Gut Microbiota, and Colorectal Cancer Prevention","volume":"17","author":"Song","year":"2019","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Shi, Y., Su, W., Zhang, L., Shi, C., Zhou, J., Wang, P., Wang, H., Shi, X., Wei, S., and Wang, Q. (2020). TGR5 Regulates Macrophage Inflammation in Nonalcoholic Steatohepatitis by Modulating NLRP3 Inflammasome Activation. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.609060"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Li, M., Wang, Y.R., Wang, X., Xiao, X.L., Sun, Y.H., Zhang, S.A., Dang, Y.Q., Wang, K., and Zhou, W.J. (2025). Emodin Enhances Rosiglitazone\u2019s Therapeutic Profile by Dual Modulation of SREBP1-Mediated Adipogenesis and PPARgamma-Driven Thermogenesis. Pharmaceuticals, 18.","DOI":"10.3390\/ph18121810"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1313","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_41","doi-asserted-by":"crossref","unstructured":"Shu, X., Li, M., Cao, Y., Li, C., Zhou, W., Ji, G., and Zhang, L. (2021). Berberine Alleviates Non-alcoholic Steatohepatitis Through Modulating Gut Microbiota Mediated Intestinal FXR Activation. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.750826"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3583","DOI":"10.1096\/fj.13-231860","article-title":"Alteration of bile acid metabolism in the rat induced by chronic ethanol consumption","volume":"27","author":"Xie","year":"2013","journal-title":"FASEB J."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1021\/pr500920q","article-title":"Profiling of serum bile acids in a healthy Chinese population using UPLC-MS\/MS","volume":"14","author":"Xie","year":"2015","journal-title":"J. Proteome Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"5533","DOI":"10.1007\/s00216-017-0489-1","article-title":"Factors affecting separation and detection of bile acids by liquid chromatography coupled with mass spectrometry in negative mode","volume":"409","author":"Yin","year":"2017","journal-title":"Anal. Bioanal. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"5287","DOI":"10.1007\/s00216-018-1183-7","article-title":"Analysis of human C24 bile acids metabolome in serum and urine based on enzyme digestion of conjugated bile acids and LC-MS determination of unconjugated bile acids","volume":"410","author":"Zhu","year":"2018","journal-title":"Anal. Bioanal. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1016\/j.cmet.2023.12.027","article-title":"Statins aggravate insulin resistance through reduced blood glucagon-like peptide-1 levels in a microbiota-dependent manner","volume":"36","author":"She","year":"2024","journal-title":"Cell Metab."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1038\/s41564-023-01363-5","article-title":"Microbiota-derived tryptophan catabolites mediate the chemopreventive effects of statins on colorectal cancer","volume":"8","author":"Han","year":"2023","journal-title":"Nat. Microbiol."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/4\/523\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T10:24:45Z","timestamp":1774434285000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/4\/523"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,24]]},"references-count":47,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["ph19040523"],"URL":"https:\/\/doi.org\/10.3390\/ph19040523","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,24]]}}}