{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T18:52:14Z","timestamp":1792090334261,"version":"4.4.0"},"reference-count":119,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2023,9,28]],"date-time":"2023-09-28T00:00:00Z","timestamp":1695859200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Nuclear receptors (NRs) constitute a superfamily of ligand-activated transcription factors with a paramount role in ubiquitous physiological functions such as metabolism, growth, and reproduction. Owing to their physiological role and druggability, NRs are deemed attractive and valid targets for medicinal chemists. Pentacyclic triterpenes (PTs) represent one of the most important phytochemical classes present in higher plants, where oleanolic acid (OA) is the most studied PTs representative owing to its multitude of biological activities against cancer, inflammation, diabetes, and liver injury. PTs possess a lipophilic skeleton that imitates the NRs endogenous ligands. Herein, we report a literature overview on the modulation of metabolic NRs by OA and its semi-synthetic derivatives, highlighting their health benefits and potential therapeutic applications. Indeed, OA exhibited varying pharmacological effects on FXR, PPAR, LXR, RXR, PXR, and ROR in a tissue-specific manner. Owing to these NRs modulation, OA showed prominent hepatoprotective properties comparable to ursodeoxycholic acid (UDCA) in a bile duct ligation mice model and antiatherosclerosis effect as simvastatin in a model of New Zealand white (NZW) rabbits. It also demonstrated a great promise in alleviating non-alcoholic steatohepatitis (NASH) and liver fibrosis, attenuated alpha-naphthol isothiocyanate (ANIT)-induced cholestatic liver injury, and controlled blood glucose levels, making it a key player in the therapy of metabolic diseases. We also compiled OA semi-synthetic derivatives and explored their synthetic pathways and pharmacological effects on NRs, showcasing their structure-activity relationship (SAR). To the best of our knowledge, this is the first review article to highlight OA activity in terms of NRs modulation.<\/jats:p>","DOI":"10.3390\/biom13101465","type":"journal-article","created":{"date-parts":[[2023,9,28]],"date-time":"2023-09-28T08:24:44Z","timestamp":1695889484000},"page":"1465","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Harnessing Oleanolic Acid and Its Derivatives as Modulators of Metabolic Nuclear Receptors"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9220-2659","authenticated-orcid":false,"given":"Mohamed O.","family":"Radwan","sequence":"first","affiliation":[{"name":"Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto 862-0973, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8077-3668","authenticated-orcid":false,"given":"Sultan F.","family":"Kadasah","sequence":"additional","affiliation":[{"name":"Department of Biology, Faculty of Science, University of Bisha, Bisha 61922, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salha M.","family":"Aljubiri","sequence":"additional","affiliation":[{"name":"Department of Chemistry, College of Science, University of Bisha, Bisha 61922, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0804-2339","authenticated-orcid":false,"given":"Abdulmajeed F.","family":"Alrefaei","sequence":"additional","affiliation":[{"name":"Department of Biology, Umm Al-Qura University, Makkah 21955, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4661-6612","authenticated-orcid":false,"given":"Mahmoud H.","family":"El-Maghrabey","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9774-0587","authenticated-orcid":false,"given":"Mohamed A.","family":"El Hamd","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, Shaqra University, Shaqra 11961, Saudi Arabia"},{"name":"Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, South Valley University, Qena 83523, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1225-0720","authenticated-orcid":false,"given":"Hiroshi","family":"Tateishi","sequence":"additional","affiliation":[{"name":"Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto 862-0973, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masami","family":"Otsuka","sequence":"additional","affiliation":[{"name":"Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto 862-0973, Japan"},{"name":"Department of Drug Discovery, Science Farm Ltd., Kumamoto 862-0976, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6705-4052","authenticated-orcid":false,"given":"Mikako","family":"Fujita","sequence":"additional","affiliation":[{"name":"Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto 862-0973, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1016\/j.cbpa.2008.07.001","article-title":"Nuclear Receptor Drug Discovery","volume":"12","author":"Chen","year":"2008","journal-title":"Curr. Opin. Chem. Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1124\/pr.112.006833","article-title":"Nuclear Receptors and Their Selective Pharmacologic Modulators","volume":"65","author":"Burris","year":"2013","journal-title":"Pharmacol. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1016\/0092-8674(95)90199-X","article-title":"The Nuclear Receptor Superfamily: The Second Decade","volume":"83","author":"Mangelsdorf","year":"1995","journal-title":"Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1042\/EBC20210020","article-title":"Nuclear Receptors: From Molecular Mechanisms to Therapeutics","volume":"65","author":"Frigo","year":"2021","journal-title":"Essays Biochem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"17545","DOI":"10.1021\/acs.jmedchem.1c01017","article-title":"Recent Advances in the Medicinal Chemistry of Farnesoid X Receptor","volume":"64","author":"Fang","year":"2021","journal-title":"J. Med. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1042\/EBC20210004","article-title":"Nuclear Receptor Nur77: Its Role in Chronic Inflammatory Diseases","volume":"65","author":"Lith","year":"2021","journal-title":"Essays Biochem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2514","DOI":"10.1038\/s41467-019-10264-3","article-title":"Comprehensive Study of Nuclear Receptor DNA Binding Provides a Revised Framework for Understanding Receptor Specificity","volume":"10","author":"Penvose","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Pan, P., and Chen, X. (2020). Nuclear Receptors as Potential Therapeutic Targets for Myeloid Leukemia. Cells, 9.","DOI":"10.3390\/cells9091921"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"10588","DOI":"10.1073\/pnas.94.20.10588","article-title":"The Orphan Nuclear Receptor LXRalpha Is Positively and Negatively Regulated by Distinct Products of Mevalonate Metabolism","volume":"94","author":"Forman","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","first-page":"689","article-title":"Orphan Nuclear Receptors: From Gene to Function","volume":"20","year":"1999","journal-title":"Endocr. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1126\/science.284.5415.757","article-title":"Orphan Nuclear Receptors: Shifting Endocrinology into Reverse","volume":"284","author":"Kliewer","year":"1999","journal-title":"Science"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1124\/mol.109.060905","article-title":"The Benzenesulfoamide T0901317 [N-(2,2,2-Trifluoroethyl)-N-[4-[2,2,2-Trifluoro-1-Hydroxy-1-(Trifluoromethyl)Ethyl]Phenyl]-Benzenesulfonamide] Is a Novel Retinoic Acid Receptor-Related Orphan Receptor-Alpha\/Gamma Inverse Agonist","volume":"77","author":"Kumar","year":"2010","journal-title":"Mol. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1016\/0092-8674(95)90200-7","article-title":"The RXR Heterodimers and Orphan Receptors","volume":"83","author":"Mangelsdorf","year":"1995","journal-title":"Cell"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Sever, R., and Glass, C.K. (2013). Signaling by Nuclear Receptors. Cold Spring Harb. Perspect. Biol., 5.","DOI":"10.1101\/cshperspect.a016709"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.mce.2010.06.018","article-title":"What Are Nuclear Receptor Ligands?","volume":"334","author":"Sladek","year":"2011","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.1016\/j.bcp.2008.08.016","article-title":"Oleanolic Acid Derivative NPLC441 Potently Stimulates Glucose Transport in 3T3-L1 Adipocytes via a Multi-Target Mechanism","volume":"76","author":"Lin","year":"2008","journal-title":"Biochem. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1038\/aps.2014.120","article-title":"ROR Nuclear Receptors: Structures, Related Diseases, and Drug Discovery","volume":"36","author":"Zhang","year":"2015","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1657","DOI":"10.1016\/j.biotechadv.2018.03.003","article-title":"Natural Products as Modulators of the Nuclear Receptors and Metabolic Sensors LXR, FXR and RXR","volume":"36","author":"Hiebl","year":"2018","journal-title":"Biotechnol. Adv."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"601","DOI":"10.3390\/md12020601","article-title":"Targeting Nuclear Receptors with Marine Natural Products","volume":"12","author":"Yang","year":"2014","journal-title":"Mar. Drugs"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"772435","DOI":"10.3389\/fphar.2021.772435","article-title":"Natural Products Targeting Liver X Receptors or Farnesoid X Receptor","volume":"12","author":"She","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.mce.2010.06.016","article-title":"Evolution of Promiscuous Nuclear Hormone Receptors: LXR, FXR, VDR, PXR, and CAR","volume":"334","author":"Krasowski","year":"2011","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_22","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_23","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1038\/nrd1657","article-title":"The Evolving Role of Natural Products in Drug Discovery","volume":"4","author":"Koehn","year":"2005","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.ejmech.2017.07.013","article-title":"Oleanane-, Ursane-, and Quinone Methide Friedelane-Type Triterpenoid Derivatives: Recent Advances in Cancer Treatment","volume":"142","author":"Salvador","year":"2017","journal-title":"Eur. J. Med. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1016\/j.apjtm.2016.05.015","article-title":"Hepatoprotective Properties of Oleanolic and Ursolic Acids in Antitubercular Drug-Induced Liver Damage","volume":"9","year":"2016","journal-title":"Asian Pac. J. Trop. Med."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Ayeleso, T.B., Matumba, M.G., and Mukwevho, E. (2017). Oleanolic Acid and Its Derivatives: Biological Activities and Therapeutic Potential in Chronic Diseases. Molecules, 22.","DOI":"10.3390\/molecules22111915"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"H174","DOI":"10.1111\/j.1750-3841.2008.00864.x","article-title":"Antioxidative and Anti-Inflammatory Protection of Oleanolic Acid and Ursolic Acid in PC12 Cells","volume":"73","author":"Tsai","year":"2008","journal-title":"J. Food Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1016\/j.arabjc.2013.06.032","article-title":"Synthesis and Biological Activity of New 18\u03b2-Glycyrrhetinic Acid Derivatives","volume":"9","author":"Radwan","year":"2016","journal-title":"Arab. J. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.1055\/s-0029-1186102","article-title":"Pentacyclic Triterpenes of the Lupane, Oleanane and Ursane Group as Tools in Cancer Therapy","volume":"75","author":"Laszczyk","year":"2009","journal-title":"Planta Med."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Radwan, M.O., Abd-Alla, H.I., Alsaggaf, A.T., El-Mezayen, H., Abourehab, M.A.S., El-Beeh, M.E., Tateishi, H., Otsuka, M., and Fujita, M. (2023). Gypsogenin Battling for a Front Position in the Pentacyclic Triterpenes Game of Thrones on Anti-Cancer Therapy: A Critical Review\u2014Dedicated to the Memory of Professor Hanaa M. Rady. Molecules, 28.","DOI":"10.20944\/preprints202306.1671.v2"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"\u017diberna, L., \u0160amec, D., Mocan, A., Nabavi, S.F., Bishayee, A., Farooqi, A.A., Sureda, A., and Nabavi, S.M. (2017). Oleanolic Acid Alters Multiple Cell Signaling Pathways: Implication in Cancer Prevention and Therapy. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18030643"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.canlet.2015.04.018","article-title":"Smac Mimetic and Oleanolic Acid Synergize to Induce Cell Death in Human Hepatocellular Carcinoma Cells","volume":"365","author":"Liese","year":"2015","journal-title":"Cancer Lett."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1093\/carcin\/bgt058","article-title":"Inhibitory Effect of Oleanolic Acid on Hepatocellular Carcinoma via ERK-P53-Mediated Cell Cycle Arrest and Mitochondrial-Dependent Apoptosis","volume":"34","author":"Wang","year":"2013","journal-title":"Carcinogenesis"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s11010-014-2228-7","article-title":"Oleanolic Acid Suppresses the Proliferation of Lung Carcinoma Cells by miR-122\/Cyclin G1\/MEF2D Axis","volume":"400","author":"Zhao","year":"2015","journal-title":"Mol. Cell. Biochem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2151","DOI":"10.1007\/s11095-008-9582-7","article-title":"Chemoprevention of Colon Carcinogenesis by Oleanolic Acid and Its Analog in Male F344 Rats and Modulation of COX-2 and Apoptosis in Human Colon HT-29 Cancer Cells","volume":"25","author":"Janakiram","year":"2008","journal-title":"Pharm. Res."},{"key":"ref_36","first-page":"13864","article-title":"Oleanolic Acid Suppresses the Proliferation of Human Bladder Cancer by Akt\/mTOR\/S6K and ERK1\/2 Signaling","volume":"8","author":"Mu","year":"2015","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.jep.2012.04.015","article-title":"In Vitro Anti-Breast Cancer Activity of Ethanolic Extract of Wrightia Tomentosa: Role of pro-Apoptotic Effects of Oleanolic Acid and Urosolic Acid","volume":"142","author":"Chakravarti","year":"2012","journal-title":"J. Ethnopharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Ciftci, H.I., Radwan, M.O., Ozturk, S.E., Ulusoy, N.G., Sozer, E., Ellakwa, D.E., Ocak, Z., Can, M., Ali, T.F.S., and Abd-Alla, H.I. (2019). Design, Synthesis and Biological Evaluation of Pentacyclic Triterpene Derivatives: Optimization of Anti-ABL Kinase Activity. Molecules, 24.","DOI":"10.3390\/molecules24193535"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Tang, Z.-Y., Li, Y., Tang, Y.-T., Ma, X.-D., and Tang, Z.-Y. (2022). Anticancer Activity of Oleanolic Acid and Its Derivatives: Recent Advances in Evidence, Target Profiling and Mechanisms of Action. Biomed. Pharmacother., 145.","DOI":"10.1016\/j.biopha.2021.112397"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1248\/cpb.47.290","article-title":"Hepatoprotective and Hepatotoxic Actions of Oleanolic Acid-Type Triterpenoidal Glucuronides on Rat Primary Hepatocyte Cultures","volume":"47","author":"Kinjo","year":"1999","journal-title":"Chem. Pharm. Bull."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1111\/liv.13940","article-title":"Oleanolic Acid Reprograms the Liver to Protect against Hepatotoxicants, but Is Hepatotoxic at High Doses","volume":"39","author":"Liu","year":"2019","journal-title":"Liver Int."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1016\/j.toxlet.2014.09.027","article-title":"Protection against Phalloidin-Induced Liver Injury by Oleanolic Acid Involves Nrf2 Activation and Suppression of Oatp1b2","volume":"232","author":"Lu","year":"2015","journal-title":"Toxicol. Lett."},{"key":"ref_43","first-page":"1691","article-title":"Oral Administration of Oleanolic Acid, Isolated from Swertia Mussotii Franch, Attenuates Liver Injury, Inflammation, and Cholestasis in Bile Duct-Ligated Rats","volume":"8","author":"Chai","year":"2015","journal-title":"Int. J. Clin. Exp. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1124\/dmd.113.056549","article-title":"Low Dose of Oleanolic Acid Protects against Lithocholic Acid\u2013Induced Cholestasis in Mice: Potential Involvement of Nuclear Factor-E2-Related Factor 2-Mediated Upregulation of Multidrug Resistance-Associated Proteins","volume":"42","author":"Chen","year":"2014","journal-title":"Drug Metab. Dispos."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1038\/bjp.2008.289","article-title":"Oleanolic Acid Induces Relaxation and Calcium-Independent Release of Endothelium-Derived Nitric Oxide","volume":"155","author":"Stankevicius","year":"2008","journal-title":"Br. J. Pharmacol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1016\/j.ejphar.2011.09.037","article-title":"Antiatherogenic Effects of Oleanolic Acid in Apolipoprotein E Knockout Mice","volume":"670","author":"Buus","year":"2011","journal-title":"Eur. J. Pharmacol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1080\/10286020310001596033","article-title":"PTP1B Inhibitors from Ardisia Japonica","volume":"7","author":"Li","year":"2005","journal-title":"J. Asian Nat. Prod. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1016\/j.bbrc.2007.06.130","article-title":"Anti-Hyperglycemic Activity of a TGR5 Agonist Isolated from Olea Europaea","volume":"362","author":"Sato","year":"2007","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Guo, F., Gao, Y., Li, X., and Lei, X. (2022). Natural Product 2-Oxokolavenol Is a Novel FXR Agonist. Molecules, 27.","DOI":"10.3390\/molecules27248968"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1007\/978-3-319-41342-6_15","article-title":"Guggulsterone and Its Role in Chronic Diseases","volume":"929","author":"Yamada","year":"2016","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1937","DOI":"10.1038\/ncomms2924","article-title":"The Antiparasitic Drug Ivermectin Is a Novel FXR Ligand That Regulates Metabolism","volume":"4","author":"Jin","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"6779","DOI":"10.1016\/j.bmc.2011.09.039","article-title":"Pharmacophore-Based Discovery of FXR-Agonists. Part II: Identification of Bioactive Triterpenes from Ganoderma Lucidum","volume":"19","author":"Grienke","year":"2011","journal-title":"Bioorganic Med. Chem."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Renga, B., Mencarelli, A., D\u2019Amore, C., Cipriani, S., D\u2019Auria, M.V., Sepe, V., Chini, M.G., Monti, M.C., Bifulco, G., and Zampella, A. (2012). Discovery That Theonellasterol a Marine Sponge Sterol Is a Highly Selective FXR Antagonist That Protects against Liver Injury in Cholestasis. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0030443"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"22707","DOI":"10.1074\/jbc.C111.250407","article-title":"Ursolic Acid Suppresses Interleukin-17 (IL-17) Production by Selectively Antagonizing the Function of ROR\u03b3t Protein*","volume":"286","author":"Xu","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"11647","DOI":"10.1021\/acs.jafc.8b04116","article-title":"Ursolic Acid, a Novel Liver X Receptor \u03b1 (LXR\u03b1) Antagonist Inhibiting Ligand-Induced Non-alcoholic Fatty Liver and Drug-Induced Lipogenesis","volume":"66","author":"Lin","year":"2018","journal-title":"J. Agric. Food Chem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1111\/bph.14570","article-title":"Betulinic Acid Alleviates Endoplasmic Reticulum Stress-Mediated Non-alcoholic Fatty Liver Disease through Activation of Farnesoid X Receptors in Mice","volume":"176","author":"Gu","year":"2019","journal-title":"Br. J. Pharmacol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1124\/mol.117.109900","article-title":"Identification of an Oleanane-Type Triterpene Hedragonic Acid as a Novel Farnesoid X Receptor Ligand with Liver Protective Effects and Anti-Inflammatory Activity","volume":"93","author":"Lu","year":"2018","journal-title":"Mol. Pharmacol."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Fallon, C.M., Smyth, J.S., Quach, A., Lajczak-McGinley, N., O\u2019Toole, A., Barrett, K.E., Sheridan, H., and Keely, S.J. (2022). Pentacyclic Triterpenes Modulate Farnesoid X Receptor Expression in Colonic Epithelial Cells: Implications for Colonic Secretory Function. J. Biol. Chem., 298.","DOI":"10.1016\/j.jbc.2022.102569"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"9589","DOI":"10.1158\/0008-5472.CAN-08-1791","article-title":"Nuclear Bile Acid Receptor FXR Protects against Intestinal Tumorigenesis","volume":"68","author":"Modica","year":"2008","journal-title":"Cancer Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.molcel.2017.03.008","article-title":"Celastrol-Induced Nur77 Interaction with TRAF2 Alleviates Inflammation by Promoting Mitochondrial Ubiquitination and Autophagy","volume":"66","author":"Hu","year":"2017","journal-title":"Mol. Cell"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/j.canlet.2014.01.016","article-title":"Oleanolic Acid and Its Synthetic Derivatives for the Prevention and Therapy of Cancer: Preclinical and Clinical Evidence","volume":"346","author":"Shanmugam","year":"2014","journal-title":"Cancer Lett."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2188","DOI":"10.2174\/1568026614666141112103516","article-title":"Medicinal Chemistry and Pharmacological Effects of Farnesoid X Receptor (FXR) Antagonists","volume":"14","author":"Lamers","year":"2014","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1038\/s41575-020-00404-2","article-title":"The Role of Farnesoid X Receptor in Metabolic Diseases, and Gastrointestinal and Liver Cancer","volume":"18","author":"Sun","year":"2021","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2148","DOI":"10.1016\/j.csbj.2021.04.029","article-title":"Farnesoid X Receptor (FXR): Structures and Ligands","volume":"19","author":"Jiang","year":"2021","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1362","DOI":"10.1126\/science.284.5418.1362","article-title":"Identification of a Nuclear Receptor for Bile Acids","volume":"284","author":"Makishima","year":"1999","journal-title":"Science"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1126\/science.284.5418.1365","article-title":"Bile Acids: Natural Ligands for an Orphan Nuclear Receptor","volume":"284","author":"Parks","year":"1999","journal-title":"Science"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1073\/pnas.0506982103","article-title":"Activation of the Nuclear Receptor FXR Improves Hyperglycemia and Hyperlipidemia in Diabetic Mice","volume":"103","author":"Zhang","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"5383","DOI":"10.1021\/jm0582221","article-title":"Farnesoid X Receptor: From Structure to Potential Clinical Applications","volume":"48","author":"Pellicciari","year":"2005","journal-title":"J. Med. Chem."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.metabol.2018.03.016","article-title":"HS218 as an FXR Antagonist Suppresses Gluconeogenesis by Inhibiting FXR Binding to PGC-1\u03b1 Promoter","volume":"85","author":"Xu","year":"2018","journal-title":"Metabolism"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1021\/acsmedchemlett.8b00534","article-title":"Investigation around the Oxadiazole Core in the Discovery of a New Chemotype of Potent and Selective FXR Antagonists","volume":"10","author":"Festa","year":"2019","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"294","DOI":"10.2174\/1381612822666151112153117","article-title":"Guggulsterone for Chemoprevention of Cancer","volume":"22","author":"Shishodia","year":"2016","journal-title":"Curr. Pharm. Des."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1053\/j.gastro.2013.05.042","article-title":"Efficacy and Safety of the Farnesoid X Receptor Agonist Obeticholic Acid in Patients with Type 2 Diabetes and Non-alcoholic Fatty Liver Disease","volume":"145","author":"Mudaliar","year":"2013","journal-title":"Gastroenterology"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Kainuma, M., Takada, I., Makishima, M., and Sano, K. (2018). Farnesoid X Receptor Activation Enhances Transforming Growth Factor \u03b2-Induced Epithelial-Mesenchymal Transition in Hepatocellular Carcinoma Cells. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19071898"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1002\/ptr.2948","article-title":"Oleanolic Acid Is a Selective Farnesoid X Receptor Modulator","volume":"24","author":"Liu","year":"2010","journal-title":"Phytother. Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"309","DOI":"10.2131\/jts.38.309","article-title":"TO901317, a Potent LXR Agonist, Is an Inverse Agonist of CAR","volume":"38","author":"Kanno","year":"2013","journal-title":"J. Toxicol. Sci."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.ejphar.2015.08.029","article-title":"Oleanolic Acid Attenuates Obstructive Cholestasis in Bile Duct-Ligated Mice, Possibly via Activation of NRF2-MRPs and FXR Antagonism","volume":"765","author":"Chen","year":"2015","journal-title":"Eur. J. Pharmacol."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Wang, S.-R., Xu, T., Deng, K., Wong, C.-W., Liu, J., and Fang, W.-S. (2017). Discovery of Farnesoid X Receptor Antagonists Based on a Library of Oleanolic Acid 3-O-Esters through Diverse Substituent Design and Molecular Docking Methods. Molecules, 22.","DOI":"10.3390\/molecules22050690"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1694","DOI":"10.1016\/j.biopha.2017.11.151","article-title":"Oleanolic Acid Protects against Pathogenesis of Atherosclerosis, Possibly via FXR-Mediated Angiotensin (Ang)-(1\u20137) Upregulation","volume":"97","author":"Pan","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.2174\/1389557521666210105110848","article-title":"Structure and Activity of Pentacyclic Triterpenes Codrugs. A Review","volume":"21","author":"Olender","year":"2021","journal-title":"Mini-Rev. Med. Chem."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.1016\/j.bbadis.2017.06.027","article-title":"Animal Models of Biliary Injury and Altered Bile Acid Metabolism","volume":"1864","author":"Mariotti","year":"2018","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"154173","DOI":"10.1016\/j.phymed.2022.154173","article-title":"Oleanolic Acid Alleviates ANIT-Induced Cholestatic Liver Injury by Activating Fxr and Nrf2 Pathways to Ameliorate Disordered Bile Acids Homeostasis","volume":"102","author":"Liu","year":"2022","journal-title":"Phytomedicine"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"154529","DOI":"10.1016\/j.phymed.2022.154529","article-title":"NRF2 and FXR Dual Signaling Pathways Cooperatively Regulate the Effects of Oleanolic Acid on Cholestatic Liver Injury","volume":"108","author":"Liu","year":"2023","journal-title":"Phytomedicine"},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Wang, S., Huan, Y., Niu, S., Cao, H., Yang, M., Zhou, X., Gao, X., Wang, X., Shen, Z., and Fang, W.-S. (2022). Discovery of 12\u03b2-Oxygenated Oleanolic Acid Alkyl Esters as Potent and Selective FXR Modulators Exhibiting Hyperglycemia Amelioration in Vivo. Bioorganic Chem., 129.","DOI":"10.1016\/j.bioorg.2022.106203"},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Ma, H., Bao, Y., Niu, S., Wang, S., Li, Y., He, H., Zhang, N., and Fang, W. (2023). Structure Optimization of 12\u03b2-O-\u03b3-Glutamyl Oleanolic Acid Derivatives Resulting in Potent FXR Antagonist\/Modulator for NASH Therapy. Pharmaceuticals, 16.","DOI":"10.3390\/ph16050758"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"154771","DOI":"10.1016\/j.metabol.2021.154771","article-title":"Mebhydrolin Ameliorates Glucose Homeostasis in Type 2 Diabetic Mice by Functioning as a Selective FXR Antagonist","volume":"119","author":"Zhao","year":"2021","journal-title":"Metabolism"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1002\/jat.4298","article-title":"Farnesoid X Receptor Contributes to Oleanolic Acid-Induced Cholestatic Liver Injury in Mice","volume":"42","author":"Feng","year":"2022","journal-title":"J. Appl. Toxicol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"3060","DOI":"10.3390\/molecules18033060","article-title":"Repeated Oral Administration of Oleanolic Acid Produces Cholestatic Liver Injury in Mice","volume":"18","author":"Lu","year":"2013","journal-title":"Molecules"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.jep.2005.05.024","article-title":"Oleanolic Acid and Ursolic Acid: Research Perspectives","volume":"100","author":"Liu","year":"2005","journal-title":"J. Ethnopharmacol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1146\/annurev.med.53.082901.104018","article-title":"The Mechanisms of Action of PPARs","volume":"53","author":"Berger","year":"2002","journal-title":"Annu. Rev. Med."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"32696","DOI":"10.1155\/2007\/32696","article-title":"Selective Modulators of PPAR-Gamma Activity: Molecular Aspects Related to Obesity and Side-Effects","volume":"2007","author":"Zhang","year":"2007","journal-title":"PPAR Res."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"2523","DOI":"10.2337\/db06-0618","article-title":"Halofenate Is a Selective Peroxisome Proliferator-Activated Receptor Gamma Modulator with Antidiabetic Activity","volume":"55","author":"Allen","year":"2006","journal-title":"Diabetes"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1007\/s00125-012-2777-9","article-title":"Identification of the Antibiotic Ionomycin as an Unexpected Peroxisome Proliferator-Activated Receptor \u03b3 (PPAR\u03b3) Ligand with a Unique Binding Mode and Effective Glucose-Lowering Activity in a Mouse Model of Diabetes","volume":"56","author":"Zheng","year":"2013","journal-title":"Diabetologia"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"6257","DOI":"10.1128\/MCB.00370-09","article-title":"Peroxisome Proliferator-Activated Receptor Beta\/Delta (PPARbeta\/Delta) but Not PPARalpha Serves as a Plasma Free Fatty Acid Sensor in Liver","volume":"29","author":"Sanderson","year":"2009","journal-title":"Mol. Cell Biol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"18779","DOI":"10.1074\/jbc.272.30.18779","article-title":"The Organization, Promoter Analysis, and Expression of the Human PPAR\u03b3 Gene*","volume":"272","author":"Fajas","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1016\/j.jacc.2008.04.055","article-title":"The PPAR\u03b3 Agonist Pioglitazone Represses Inflammation In A PPAR\u03b1-Dependent Manner In Vitro and In Vivo In Mice","volume":"52","author":"Orasanu","year":"2008","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1038\/sj.bjp.0706245","article-title":"Pomegranate Flower Improves Cardiac Lipid Metabolism in a Diabetic Rat Model: Role of Lowering Circulating Lipids","volume":"145","author":"Huang","year":"2005","journal-title":"Br. J. Pharmacol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.jep.2010.07.054","article-title":"Activation of the Nuclear Receptor PPAR\u03b3 by Metabolites Isolated from Sage (Salvia officinalis L.)","volume":"132","author":"Christensen","year":"2010","journal-title":"J. Ethnopharmacol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1055\/s-2006-946680","article-title":"Carnosic Acid and Carnosol, Phenolic Diterpene Compounds of the Labiate Herbs Rosemary and Sage, Are Activators of the Human Peroxisome Proliferator-Activated Receptor Gamma","volume":"72","author":"Rau","year":"2006","journal-title":"Planta Med."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1007\/s10822-010-9398-5","article-title":"Pharmacophore-Driven Identification of PPAR\u03b3 Agonists from Natural Sources","volume":"25","author":"Petersen","year":"2011","journal-title":"J. Comput. Aided Mol. Des."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1089\/jmf.2014.0021","article-title":"Beneficial Health Effects of Chios Gum Mastic and Peroxisome Proliferator-Activated Receptors: Indications of Common Mechanisms","volume":"18","author":"Georgiadis","year":"2015","journal-title":"J. Med. Food"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1007\/s10068-018-0307-3","article-title":"Effects of Chios Mastic Gum and Exercise on Physical Characteristics, Blood Lipid Markers, Insulin Resistance, and Hepatic Function in Healthy Japanese Men","volume":"27","author":"Fukazawa","year":"2018","journal-title":"Food Sci. Biotechnol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"e47","DOI":"10.1016\/j.atherosclerosis.2020.10.148","article-title":"Chios Mastic Gum Inhibits Diet-Induced Non-Alcoholic Steatohepatitis in Mice via Activation of PPAR-\u03b1","volume":"315","author":"Tzani","year":"2020","journal-title":"Atherosclerosis"},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Soulaidopoulos, S., Tsiogka, A., Chrysohoou, C., Lazarou, E., Aznaouridis, K., Doundoulakis, I., Tyrovola, D., Tousoulis, D., Tsioufis, K., and Vlachopoulos, C. (2022). Overview of Chios Mastic Gum (Pistacia lentiscus) Effects on Human Health. Nutrients, 14.","DOI":"10.3390\/nu14030590"},{"key":"ref_104","first-page":"1550","article-title":"A Synthetic Triterpenoid, 2-Cyano-3,12-Dioxooleana-1,9-Dien-28-Oic Acid (CDDO), Is a Ligand for the Peroxisome Proliferator-Activated Receptor Gamma","volume":"14","author":"Wang","year":"2000","journal-title":"Mol. Endocrinol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/S1537-1891(02)00175-1","article-title":"LXRs; Oxysterol-Activated Nuclear Receptors That Regulate Genes Controlling Lipid Homeostasis","volume":"38","author":"Edwards","year":"2002","journal-title":"Vascul. Pharmacol."},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Dixon, E.D., Nardo, A.D., Claudel, T., and Trauner, M. (2021). The Role of Lipid Sensing Nuclear Receptors (PPARs and LXR) and Metabolic Lipases in Obesity, Diabetes and NAFLD. Genes, 12.","DOI":"10.3390\/genes12050645"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.1111\/j.1872-034X.2008.00382.x","article-title":"Liver X Receptor in Cooperation with SREBP-1c Is a Major Lipid Synthesis Regulator in Non-alcoholic Fatty Liver Disease","volume":"38","author":"Higuchi","year":"2008","journal-title":"Hepatol. Res."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1102469","DOI":"10.3389\/fmed.2023.1102469","article-title":"Development of LXR Inverse Agonists to Treat MAFLD, NASH, and Other Metabolic Diseases","volume":"10","author":"Griffett","year":"2023","journal-title":"Front. Med."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"10964","DOI":"10.1021\/acs.jafc.8b03372","article-title":"Oleanolic Acid Inhibits Liver X Receptor Alpha and Pregnane X Receptor to Attenuate Ligand-Induced Lipogenesis","volume":"66","author":"Lin","year":"2018","journal-title":"J. Agric. Food Chem."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/bs.apha.2021.01.004","article-title":"Chapter Four\u2014Potential Therapeutic Uses of Rexinoids","volume":"Volume 91","author":"Copple","year":"2021","journal-title":"Advances in Pharmacology"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1038\/nrc2129","article-title":"Triterpenoids and Rexinoids as Multifunctional Agents for the Prevention and Treatment of Cancer","volume":"7","author":"Liby","year":"2007","journal-title":"Nat. Rev. Cancer"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"4147","DOI":"10.1242\/jcs.097063","article-title":"GLUT4 Exocytosis","volume":"124","author":"Fazakerley","year":"2011","journal-title":"J. Cell Sci."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/j.tem.2009.03.003","article-title":"PXR and CAR in Energy Metabolism","volume":"20","author":"Wada","year":"2009","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1210\/er.2001-0038","article-title":"The Nuclear Pregnane X Receptor: A Key Regulator of Xenobiotic Metabolism","volume":"23","author":"Kliewer","year":"2002","journal-title":"Endocr. Rev."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1021\/mp700103m","article-title":"Xenoreceptors CAR and PXR Activation and Consequences on Lipid Metabolism, Glucose Homeostasis, and Inflammatory Response","volume":"5","author":"Moreau","year":"2008","journal-title":"Mol. Pharm."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"614","DOI":"10.2174\/138920008785821666","article-title":"New Insights on the Xenobiotic-Sensing Nuclear Receptors in Liver Diseases\u2014CAR and PXR-","volume":"9","author":"Kakizaki","year":"2008","journal-title":"Curr. Drug Metab."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1124\/mol.107.038398","article-title":"Human Pregnane X Receptor Antagonists and Agonists Define Molecular Requirements for Different Binding Sites","volume":"72","author":"Ekins","year":"2007","journal-title":"Mol. Pharmacol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"8606","DOI":"10.1021\/acs.jafc.7b02696","article-title":"Oleanolic Acid-Mediated Inhibition of Pregnane X Receptor and Constitutive Androstane Receptor Attenuates Rifampin-Isoniazid Cytotoxicity","volume":"65","author":"Lin","year":"2017","journal-title":"J. Agric. Food Chem."},{"key":"ref_119","doi-asserted-by":"crossref","unstructured":"Pastwi\u0144ska, J., Kara\u015b, K., Sa\u0142kowska, A., Karwaciak, I., Cha\u0142a\u015bkiewicz, K., Wojtczak, B.A., Bachorz, R.A., and Ratajewski, M. (2022). Identification of Corosolic and Oleanolic Acids as Molecules Antagonizing the Human ROR\u03b3T Nuclear Receptor Using the Calculated Fingerprints of the Molecular Similarity. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031906"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/13\/10\/1465\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:01:05Z","timestamp":1760130065000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/13\/10\/1465"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,28]]},"references-count":119,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2023,10]]}},"alternative-id":["biom13101465"],"URL":"https:\/\/doi.org\/10.3390\/biom13101465","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,28]]}}}