{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T11:43:54Z","timestamp":1781091834434,"version":"3.54.1"},"reference-count":161,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,24]],"date-time":"2025-12-24T00:00:00Z","timestamp":1766534400000},"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>Due to their complexity, both genotypic and phenotypic, neurodegenerative diseases are one of the main causes of death globally nowadays. Among phytochemicals of high scientific interest, based on experimental studies, pentacyclic triterpenoids (TTs), including mainly betulin, betulinic, and ursolic acid, became targets of scientific research in recent years, especially in terms of their biological activity and pharmacological potential. Due to their anti-inflammatory and antioxidant properties, as well as their involvement in cellular signal transductions, they have been observed to act as anticancer, chemopreventive, and neuroprotective agents. The aim of this review is to update the reader on the diversity, bioavailability, pharmacological properties, and neuroprotective effects of TTs, as biomolecules that can interfere with metabolic mechanisms related to neurodegeneration and restoring of neuronal integrity. Recent data were analyzed, with a particular focus on mechanistic insights related to their neuroprotective effects. Starting with their biosynthetic pathways, bioavailability, and involvement in specific metabolic pathways, their impact on neurological pathology and benefits as natural neuroprotection agents through specific signaling pathways are presented. Furthermore, emphasis will also be put on current challenges and future strategies that could develop TTs into effective compounds for neuroprotection and personalized medicine.<\/jats:p>","DOI":"10.3390\/biom16010025","type":"journal-article","created":{"date-parts":[[2025,12,24]],"date-time":"2025-12-24T09:58:34Z","timestamp":1766570314000},"page":"25","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Mechanistic Insights into the Metabolic Pathways and Neuroprotective Potential of Pentacyclic Triterpenoids: In-Depth Analysis of Betulin, Betulinic, and Ursolic Acids"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5835-3755","authenticated-orcid":false,"given":"Mihai Adrian","family":"Socaciu","sequence":"first","affiliation":[{"name":"Department of Radiology and Medical Imaging, Faculty of Medicine, University of Medicine and Pharmacy \u201cIuliu Hatieganu\u201d, 400347 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5325-3859","authenticated-orcid":false,"given":"Zorita","family":"Diaconeasa","sequence":"additional","affiliation":[{"name":"Faculty of Food Science and Technology, University of Agricultural Sciences and Veterinary Medicine, 400372 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4881-3273","authenticated-orcid":false,"given":"Dumitrita","family":"Rugina","sequence":"additional","affiliation":[{"name":"Faculty of Veterinary Medicine, University of Agricultural Sciences and Veterinary Medicine, 400372 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7352-5057","authenticated-orcid":false,"given":"Carmen","family":"Socaciu","sequence":"additional","affiliation":[{"name":"Faculty of Food Science and Technology, University of Agricultural Sciences and Veterinary Medicine, 400372 Cluj-Napoca, Romania"},{"name":"Department of Biotechnology, Research Centre for Applied Biotechnology in Diagnosis and Molecular Therapy, Biodiatech-Proplanta SRL, 400478 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Remus","family":"Moldovan","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, University of Medicine and Pharmacy \u201cIuliu Hatieganu\u201d, 400347 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0046-0803","authenticated-orcid":false,"given":"Simona","family":"Clichici","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, University of Medicine and Pharmacy \u201cIuliu Hatieganu\u201d, 400347 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Vijayakumar, R., and Sudalaimuthu Raja, S.S. (2022). Secondary Metabolites\u2014Trends and Reviews (Chapter 4). Secondary Metabolites from Natural Products, Intech Open.","DOI":"10.5772\/intechopen.98129"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1039\/D2NP00063F","article-title":"Natural products of pentacyclic triterpenoids: From discovery to heterologous biosynthesis","volume":"40","author":"Li","year":"2023","journal-title":"Nat. Prod. Rep."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Bergman, M.E., Davis, B., and Phillips, M.A. (2019). Medically Useful Plant Terpenoids: Biosynthesis, Occurrence, and Mechanism of Action. Molecules, 24.","DOI":"10.3390\/molecules24213961"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"5203","DOI":"10.1080\/10408398.2022.2153238","article-title":"Edible pentacyclic triterpenes: A review of their sources, bioactivities, bioavailability, self-assembly behavior, and emerging applications as functional delivery vehicles","volume":"64","author":"Liu","year":"2022","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"ref_5","first-page":"354","article-title":"Neuropharmacological effects of triterpenoids","volume":"4","author":"Parmar","year":"2013","journal-title":"Phytopharmacology"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Xu, B., Bai, L., Chen, L., Tong, R., Feng, Y., and Shi, J. (2022). Terpenoid natural products exert neuroprotection via the PI3K\/Akt pathway. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.1036506"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"231","DOI":"10.37349\/en.2024.00047","article-title":"Neuroprotective prospectives of triterpenoids","volume":"3","author":"Bankar","year":"2024","journal-title":"Explor. Neurosci."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Lee, Y.-S., Kwon, R.J., Lee, H.S., Chung, J.H., Kim, Y.S., Jeong, H.-S., Park, S.-J., Lee, S.Y., Kim, T., and Yoon, S.H. (2025). The Role of Pentacyclic Triterpenoids in Non-Small Cell Lung Cancer: The Mechanisms of Action and Therapeutic Potential. Pharmaceutics, 17.","DOI":"10.3390\/pharmaceutics17010022"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Wimmer, Z. (2025). Selected Pentacyclic Triterpenoids and Their Derivatives as Biologically Active Compounds. Molecules, 30.","DOI":"10.3390\/molecules30153106"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Sawai, S., and Saito, K. (2011). Triterpenoid biosynthesis and engineering in plants. Front. Plant Sci., 2.","DOI":"10.3389\/fpls.2011.00025"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"108214","DOI":"10.1016\/j.biotechadv.2023.108214","article-title":"Recent advances in triterpenoid pathway elucidation and engineering","volume":"68","author":"Dinday","year":"2023","journal-title":"Biotech. Adv."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Fanani, M., Fukushima, E.O., Sawai, S., Tang, J., Ishimori, M., Sudo, H., Ohyama, K., Seki, H., Saito, K., and Muranaka, T. (2019). Molecular Basis of C-30 Product Regioselectivity of Legume Oxidases Involved in High-Value Triterpenoid Biosynthesis. Front. Plant Sci., 10.","DOI":"10.3389\/fpls.2019.01520"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"C\u00e1rdenas, P.D., Almeida, A., and Bak, S. (2019). Evolution of Structural Diversity of Triterpenoids. Front. Plant Sci., 10.","DOI":"10.3389\/fpls.2019.01523"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1146\/annurev-arplant-050312-120229","article-title":"Triterpene biosynthesis in plants","volume":"65","author":"Thimmappa","year":"2014","journal-title":"Annu. Rev. Plant Biol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Karunanithi, P.S., and Zerbe, P. (2019). Terpene Synthases as Metabolic Gatekeepers in the Evolution of Plant Terpenoid Chemical Diversity. Front. Plant Sci., 10.","DOI":"10.3389\/fpls.2019.01166"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Cunha, A.B., Batista, R., Castro, M.\u00c1., and David, J.M. (2021). Chemical strategies towards the synthesis of betulinic acid and its more potent antiprotozoal analogues. Molecules, 26.","DOI":"10.3390\/molecules26041081"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"235","DOI":"10.4196\/kjpp.2018.22.3.235","article-title":"Ursolic acid in health and disease","volume":"22","author":"Seo","year":"2018","journal-title":"Korean J. Physiol. Pharmacol."},{"key":"ref_18","unstructured":"Duke, J. (1994). Dr. Duke\u2019s Phytochemical and Ethnobotanical Databases, United States Department of Agriculture, Agricultural Research Service."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Shinbo, Y., Nakamura, Y., Altaf-Ul-Amin, M., Asahi, H., Kurokawa, K., Arita, M., Saito, K., Ohta, D., Shibata, D., and Kanaya, S. (2006). KNApSAcK: A comprehensive species-metabolite relationship database. Plant Metabolomics, Springer.","DOI":"10.1007\/3-540-29782-0_13"},{"key":"ref_20","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_21","doi-asserted-by":"crossref","first-page":"237","DOI":"10.22270\/jddt.v11i2.4588","article-title":"Medicinal Uses of Maslinic Acid: A Review","volume":"11","author":"Choudhary","year":"2021","journal-title":"J. Drug Deliv. Ther."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"79","DOI":"10.2174\/1389557520666200722134208","article-title":"Advances in research on the preparation and biological activity of maslinic acid","volume":"21","author":"Deng","year":"2021","journal-title":"Mini Rev. Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e202301327","DOI":"10.1002\/cbdv.202301327","article-title":"Bioactivities and structure-activity relationships of maslinic acid derivatives: A review","volume":"21","author":"Yan","year":"2024","journal-title":"Chem. Biodivers."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1244","DOI":"10.1080\/10942912.2023.2209702","article-title":"Asiatic acid: A review on its polypharmacological properties and therapeutic potential against various Maladies","volume":"26","author":"Mushtaq","year":"2023","journal-title":"Int. J. Food Prop."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/B978-0-444-64179-3.00010-4","article-title":"Natural Products for the Management of Diabetes","volume":"Volume 59","year":"2018","journal-title":"Studies in Natural Products Chemistry"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.ejmech.2017.11.046","article-title":"Platanic acid: A new scaffold for the synthesis of cytotoxic agents","volume":"143","author":"Kahnt","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Teng, W., Zhou, Z., Cao, J., and Guo, Q. (2024). Recent Advances of Natural Pentacyclic Triterpenoids as Bioactive Delivery System for Synergetic Biological Applications. Foods, 13.","DOI":"10.3390\/foods13142226"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1002\/tcr.201600123","article-title":"Self-assembly of Renewable Nano-sized Triterpenoids","volume":"17","author":"Bag","year":"2017","journal-title":"Chem. Rec."},{"key":"ref_29","unstructured":"Socaciu, C., and Socaciu, M.A. Microscopy of betulins\u2019 nanoformulations: Solubility and sizes. Biodiatech RTD, Cluj-Napoca, Romania, 2025 (manuscript in preparation)."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Adepoju, F.O., Duru, K.C., Li, E., Kovaleva, E.G., and Tsurkan, M.V. (2023). Pharmacological Potential of Betulin as a Multitarget Compound. Biomolecules, 13.","DOI":"10.3390\/biom13071105"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"\u0160iman, P., Bezrouk, A., Tich\u00e1, A., Koz\u00e1kov\u00e1, H., Hudcovic, T., Ku\u010dera, O., and Niang, M. (2025). Promising Protocol for In Vivo Experiments with Betulin. Pharmaceutics, 17.","DOI":"10.1101\/2025.05.12.653392"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Furtado, N.A.J.C., Pirson, L., Edelberg, H., Miranda, L.M., Loira-Pastoriza, C., Preat, V., Larondelle, Y., and Andr\u00e9, C.M. (2017). Pentacyclic Triterpene Bioavailability: An Overview of In Vitro and In Vivo Studies. Molecules, 22.","DOI":"10.3390\/molecules22030400"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Jaroszewski, B., Jelonek, K., and Kasperczyk, J. (2024). Drug Delivery Systems of Betulin and Its Derivatives: An Overview. Biomedicines, 12.","DOI":"10.3390\/biomedicines12061168"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Socaciu, C., Fetea, F., and Socaciu, M.A. (2024). Synthesis and Characterization of PEGylated Liposomes and Nanostructured Lipid Carriers with Entrapped Bioactive Triterpenoids: Comparative Fingerprints and Quantification by UHPLC-QTOF-ESI+-MS, ATR-FTIR Spectroscopy, and HPLC-DAD. Pharmaceuticals, 18.","DOI":"10.20944\/preprints202412.0108.v1"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Rugin\u0103, D., Socaciu, M.A., Nistor, M., Diaconeasa, Z., Cenariu, M., Tabaran, F.A., and Socaciu, C. (2024). Liposomal and Nanostructured Lipid Nanoformulations of a Pentacyclic Triterpenoid Birch Bark Extract: Structural Characterization and In Vitro Effects on Melanoma B16-F10 and Walker 256 Tumor Cells Apoptosis. Pharmaceuticals, 17.","DOI":"10.3390\/ph17121630"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Nistor, M., Rugin\u0103, D., Diaconeasa, Z., Socaciu, C., and Socaciu, M.A. (2023). Pentacyclic Triterpenoid Phytochemicals with Anticancer Activity: Updated Studies on Mechanisms and Targeted Delivery. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241612923"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1007\/s11240-025-03031-4","article-title":"Nanoliposomal encapsulation approach for enhancing the anticancer biological compounds produced in birch callus cell extracts","volume":"161","author":"Payamnoor","year":"2025","journal-title":"Plant Cell Tissue Organ Cult."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Markowski, A., Jaromin, A., Migda\u0142, P., Olczak, E., Zygmunt, A., Zaremba-Czogalla, M., Pawlik, K., and Gubernator, J. (2022). Design and Development of a New Type of Hybrid PLGA\/Lipid Nanoparticle as an Ursolic Acid Delivery System against Pancreatic Ductal Adenocarcinoma Cells. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23105536"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4791","DOI":"10.1007\/s11101-024-10056-8","article-title":"Pentacyclic triterpenoids: Diversity, distribution and their propitious pharmacological potential","volume":"24","author":"Malik","year":"2024","journal-title":"Phytochem. Rev."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Dalimunthe, A., Gunawan, M.C., Utari, Z.D., Dinata, M.R., Halim, P., Pakpahan, N.E.S., Sitohang, A.I., Sukarno, M.A., Harahap, Y., and Setyowati, E.P. (2024). In-depth analysis of lupeol: Delving into the diverse pharmacological profile. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1461478"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"154012","DOI":"10.1016\/j.phymed.2022.154012","article-title":"Molecular pharmacology and therapeutic advances of the pentacyclic triterpene lupeol","volume":"99","author":"Sohag","year":"2022","journal-title":"Phytomedicine"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1007\/s11101-019-09623-1","article-title":"Betulin and betulinic acid: Triterpenoids derivatives with a powerful biological potential","volume":"18","author":"Hordyjewska","year":"2019","journal-title":"Phytochem. Rev."},{"key":"ref_43","first-page":"1","article-title":"Betulin and Its Derivatives. Chemistry and Biological Activity","volume":"13","author":"Tolstikov","year":"2005","journal-title":"Chem. Sustain. Dev."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3224","DOI":"10.3390\/molecules13123224","article-title":"A Preliminary Pharmacokinetic Study of Betulin, the Main Pentacyclic Triterpene from Extract of Outer Bark of Birch (Betulae alba cortex)","volume":"13","author":"Laszczyk","year":"2008","journal-title":"Molecules"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"119","DOI":"10.4236\/pp.2012.32018","article-title":"Biological activity of betulinic acid: A review","volume":"3","author":"Moghaddam","year":"2012","journal-title":"Pharmacol. Pharm."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Liu, G., Qin, P., Cheng, X., Wu, L., Wang, R., and Gao, W. (2023). Ursolic acid: Biological functions and application in animal husbandry. Front. Vet. Sci., 10.","DOI":"10.3389\/fvets.2023.1251248"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Mlala, S., Oyedeji, A.O., Gondwe, M., and Oyedeji, O.O. (2019). Ursolic acid and its derivatives as bioactive agents. Molecules, 24.","DOI":"10.3390\/molecules24152751"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Liu, Y., Yang, L., Wang, H., and Xiong, Y. (2022). Recent Advances in Antiviral Activities of Triterpenoids. Pharmaceuticals, 15.","DOI":"10.3390\/ph15101169"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1610","DOI":"10.3390\/molecules20011610","article-title":"Triterpenes as Potentially Cytotoxic Compounds","volume":"20","author":"Chudzik","year":"2015","journal-title":"Molecules"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"499","DOI":"10.4062\/biomolther.2012.20.6.499","article-title":"Targeting Nrf2-mediated gene transcription by triterpenoids and their derivatives","volume":"20","author":"Loboda","year":"2012","journal-title":"Biomol. Ther."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1002\/ijc.25059","article-title":"Betulinic acid suppresses STAT3 activation pathway through induction of protein tyrosine phosphatase SHP1 in human multiple myeloma cells","volume":"127","author":"Pandey","year":"2010","journal-title":"Int. J. Cancer"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1038\/s41401-020-00534-y","article-title":"Ursolic acid reduces hepatocellular apoptosis and alleviates alcohol-induced liver injury via irreversible inhibition of CASP3 in vivo","volume":"42","author":"Ma","year":"2021","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.joim.2019.03.003","article-title":"Ursolic Acid: An Overview on Its Cytotoxic Activities Against Breast and Colorectal Cancer Cells","volume":"17","author":"Chan","year":"2019","journal-title":"J. Integr. Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"11","DOI":"10.3892\/mmr.2022.12898","article-title":"Inhibition of colorectal cancer tumorigenesis by ursolic acid and doxorubicin is mediated by targeting the Akt signaling pathway and activating the Hippo signaling pathway","volume":"27","author":"Hu","year":"2023","journal-title":"Mol. Med. Rep."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1016\/j.bbadis.2016.11.005","article-title":"Nrf2 signaling pathway: Pivotal roles in inflammation","volume":"1863","author":"Ahmed","year":"2017","journal-title":"Biochim. Biophys. Acta-Mol. Basis Dis."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2857","DOI":"10.1007\/s10787-023-01366-y","article-title":"Therapeutic potential of natural products in inflammation: Underlying molecular mechanisms, clinical outcomes, technological advances, and future perspectives","volume":"31","author":"Gouda","year":"2023","journal-title":"Inflammopharmacology"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1055\/s-2006-957748","article-title":"Antinflammatory actions of pentacyclic triterpenes","volume":"63","author":"Safayhi","year":"1997","journal-title":"Planta Med."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Mantiniotou, M., Athanasiadis, V., Kalompatsios, D., Bozinou, E., and Lalas, S.I. (2025). Therapeutic Capabilities of Triterpenes and Triterpenoids in Immune and Inflammatory Processes: A Review. Compounds, 5.","DOI":"10.3390\/compounds5010002"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1134\/S1068162010020147","article-title":"The immunotropic activity of lupane and oleanane 2,3-seco-triterpenoids","volume":"36","author":"Anikina","year":"2010","journal-title":"Russ. J. Bioorganic Chem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"10059","DOI":"10.1002\/fsn3.4639","article-title":"Chemopreventive and Chemotherapeutic Potential of Betulin and Betulinic Acid: Mechanistic Insights From In Vitro, In Vivo and Clinical Studies","volume":"12","author":"Nemli","year":"2024","journal-title":"Food Sci. Nutr."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Tuli, H.S., Sak, K., Gupta, D.S., Kaur, G., Aggarwal, D., Parashar, N.C., Choudhary, R., Yerer, M.B., Kaur, J., and Kumar, M. (2021). Anti-Inflammatory and Anticancer Properties of Birch Bark-Derived Betulin: Recent Developments. Plants, 10.","DOI":"10.3390\/plants10122663"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1021\/acs.jnatprod.5b00709","article-title":"Betulin Derivatives Effectively Suppress Inflammation In Vitro and In Vivo","volume":"79","author":"Laavola","year":"2016","journal-title":"J. Nat. Prod."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Ren, C., Jin, J., Hu, W., Chen, Q., Yang, J., Wu, Y., Zhou, Y., Sun, L., Gao, W., and Zhang, X. (2021). Betulin Alleviates the Inflammatory Response in Mouse Chondrocytes and Ameliorates Osteoarthritis via AKT\/Nrf2\/HO-1\/NF-B Axis. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.754038"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"112539","DOI":"10.1016\/j.fct.2021.112539","article-title":"Antinflammatory action of betulin and its potential as a dissociated glucocorticoid receptor modulator","volume":"157","author":"Ren","year":"2021","journal-title":"Food Chem. Toxicol."},{"key":"ref_65","first-page":"455","article-title":"Betulin inhibits pro-inflammatory cytokines expression through activation STAT3 signaling pathway in human cardiac cells","volume":"19","author":"Zhang","year":"2015","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"627","DOI":"10.2174\/0115672018329544240922151617","article-title":"Betulin-NLC-hydrogel for the Treatment of Psoriasis like Skin Inflammation: Optimization, Characterisation, and In Vitro and In Vivo Evaluation","volume":"22","author":"Prakash","year":"2025","journal-title":"Curr. Drug Deliv."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"303","DOI":"10.4314\/tjpr.v18i2.12","article-title":"Antoxidant, antinflammatory and antacetylcholinesterase activity of betulinic acid and 3\u03b2-acetoxybetulinic acid from Melaleuca bracteata Revolution Gold","volume":"18","author":"Osunsanmi","year":"2019","journal-title":"Trop. J. Pharm. Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1573","DOI":"10.1016\/j.bmc.2005.10.063","article-title":"Activity of lupane triterpenoids from Maytenus species as inhibitors of nitric oxide and prostaglandin E2","volume":"14","author":"Reyes","year":"2006","journal-title":"Bioorganic Med. Chem."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Seca, A.M.L., and Pinto, D.C.G.A. (2018). Plant Secondary Metabolites as Anticancer Agents: Successes in Clinical Trials and Therapeutic Application. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19010263"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.2174\/0929867324666170112115313","article-title":"Modulation of Tumour-Related Signaling Pathways By Natural Pentacyclic Triterpenoids and Their Semisynthetic Derivatives","volume":"24","author":"Markov","year":"2017","journal-title":"Curr. Med. Chem."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Saeidnia, S. (2015). Anticancer Terpenoids. New Approaches to Natural Anticancer Drugs, Springer.","DOI":"10.1007\/978-3-319-14027-8"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"820","DOI":"10.2174\/1389203724666230418123409","article-title":"Bioactive Pentacyclic Triterpenes Trigger Multiple Signalling Pathways for Selective Apoptosis Leading to Anticancer Efficacy: Recent Updates and Future Perspectives","volume":"24","author":"Jhimli","year":"2023","journal-title":"Curr. Protein Pept. Sci."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"55","DOI":"10.3831\/KPI.201.22.007","article-title":"Role of Pentacyclic Triterpenoids in Chemoprevention and Anticancer Treatment: An Overview on Targets and Underling Mechanisms","volume":"22","author":"Ghante","year":"2019","journal-title":"J. Pharmacopunct."},{"key":"ref_74","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_75","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.canlet.2012.02.037","article-title":"Targeted inhibition of tumor proliferation, survival, and metastasis by pentacyclic triterpenoids: Potential role in prevention and therapy of cancer","volume":"320","author":"Shanmugam","year":"2012","journal-title":"Cancer Lett."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Similie, D., Minda, D., Bora, L., Kro\u0161kins, V., Lugi\u0146ina, J., Turks, M., Dehelean, C.A., and Danciu, C. (2024). An Update on Pentacyclic Triterpenoids Ursolic and Oleanolic Acids and Related Derivatives as Anticancer Candidates. Antioxidants, 13.","DOI":"10.3390\/antiox13080952"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1080\/02648725.2022.2162257","article-title":"Ursolic acid: A pentacyclic triterpenoid that exhibits anticancer therapeutic potential by modulating multiple oncogenic targets","volume":"39","author":"Sandhu","year":"2023","journal-title":"Biotechnol. Genet. Eng. Rev."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"112228","DOI":"10.1016\/j.phytochem.2019.112228","article-title":"Triterpenoids from Liquidambar Fructus induced cell apoptosis via a PI3K-AKT related signal pathway in SMMC7721 cancer cells","volume":"171","author":"Zhang","year":"2020","journal-title":"Phytochemistry"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"e23206","DOI":"10.1002\/jbt.23206","article-title":"Betulinic acid: A natural promising anticancer drug, current situation, and future perspectives","volume":"36","author":"Aswathy","year":"2022","journal-title":"J. Biochem. Mol. Toxicol."},{"key":"ref_80","first-page":"641","article-title":"Recent progress on betulinic acid and its derivatives as antitumor agents: A mini review","volume":"19","author":"Zhong","year":"2021","journal-title":"Chin. J. Nat. Med."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"105441","DOI":"10.1016\/j.jff.2023.105441","article-title":"Betulinic acid inhibits growth of hepatoma cells through activating the NCOA4-mediated ferritinophagy pathway","volume":"102","author":"Xiu","year":"2023","journal-title":"J. Funct. Foods"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"3260","DOI":"10.1080\/14786419.2024.2412838","article-title":"Recent advancements of betulinic acid-based drug delivery systems for cancer therapy (2002\u20132023)","volume":"39","author":"Morparia","year":"2024","journal-title":"Nat. Prod. Res."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Switalska, M., Chrobak, E., Kadela-Tomanek, M., Wietrzyk, J., and Bebenek, E. (2025). Betulin Hippuric Acid Conjugates: Chemistry, Antiproliferative Activity and Mechanism of Action. Appl. Sci., 15.","DOI":"10.3390\/app15179824"},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"K\u0142os, P., and Chlubek, D. (2022). Plant-Derived Terpenoids: A Promising Tool in the Fight Against Melanoma. Cancers, 14.","DOI":"10.3390\/cancers14030502"},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Grudzinska, M., Stachnik, B., Galanty, A., So\u0142tys, A., and Podolak, I. (2023). Progress in Antimelanoma Research of Natural Triterpenoids and Their Derivatives: Mechanisms of Action, Bioavailability Enhancement and Structure Modifications. Molecules, 28.","DOI":"10.3390\/molecules28237763"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"5571","DOI":"10.1007\/s00210-024-03054-2","article-title":"Unveiling the pharmacological potential of plant triterpenoids in breast cancer management: An updated review","volume":"397","author":"Aly","year":"2024","journal-title":"NaunySchmiedeberg\u2019s Arch. Pharmacol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"120511","DOI":"10.1016\/j.ijpharm.2021.120511","article-title":"Innovative Betulin Nanosuspension exhibits enhanced anticancer activity in a Triple Negative Breast Cancer Cell line and Zebrafish angiogenesis model","volume":"600","author":"John","year":"2021","journal-title":"Int. J. Pharm."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1432","DOI":"10.1080\/1061186X.2025.2500036","article-title":"Breast cancer cell targeting of L-leuciPLGA conjugated hybrid solid lipid nanoparticles of betulin via L-amino acid transport system-1","volume":"33","author":"Gajbhiye","year":"2025","journal-title":"J. Drug Target."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.3892\/or.2015.4045","article-title":"Induction of apoptotic cell death by betulin in multidrug-resistant human renal carcinoma cells","volume":"34","author":"Yim","year":"2015","journal-title":"Oncol. Rep."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.3390\/molecules14041639","article-title":"Comparision of the cytotoxic effects of birch bark extract, betulin and betulinic acid towards human gastric carcinoma and pancreatic carcinoma drug-sensitive and drug-resistant cell lines","volume":"14","author":"Drag","year":"2009","journal-title":"Molecules"},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Madej, M., Gola, J., and Chrobak, E. (2023). Synthesis, Pharmacological Properties, and Potential Molecular Mechanisms of Antitumor Activity of Betulin and Its Derivatives in Gastrointestinal Cancers. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15122768"},{"key":"ref_92","first-page":"298","article-title":"Betulin: A natural product with promising anticancer activity against colorectal cancer cells","volume":"36","author":"Chrobak","year":"2020","journal-title":"Stud. Med."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"173588","DOI":"10.1016\/j.ejphar.2020.173588","article-title":"Phytochemical compounds targeting on Nrf2 for chemoprevention in colorectal cancer","volume":"887","author":"Zhu","year":"2020","journal-title":"Eur. J. Pharmacol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1007\/s12032-022-01707-x","article-title":"Pentacyclic triterpenoid ursolic acid induces apoptosis with mitochondrial dysfunction in adult T-cell leukemia MT-4 cells to promote surrounding cell growth","volume":"39","author":"Shen","year":"2022","journal-title":"Med. Oncol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"6353","DOI":"10.1021\/acs.jmedchem.7b00679","article-title":"Mitochondria-Targeted Lupane Triterpenoid Derivatives and Their Selective Apoptosis Inducing Anticancer Mechanisms","volume":"60","author":"Ye","year":"2017","journal-title":"J. Med. Chem."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"183383","DOI":"10.1016\/j.bbamem.2020.183383","article-title":"Effect of betulin and betulonic acid on isolated rat liver mitochondria and liposomes","volume":"1862","author":"Dubinin","year":"2020","journal-title":"Biochim. Et Biophys. Acta (BBA)-Biomembr."},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Dubinin, M.V., Semenova, A.A., Nedopekina, D.A., Davletshin, E.V., Spivak, A.Y., and Belosludtsev, K.N. (2021). Effect of F16-Betulin Conjugate on Mitochondrial Membranes and Its Role in Cell Death Initiation. Membranes, 11.","DOI":"10.3390\/membranes11050352"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1939","DOI":"10.1021\/acs.jnatprod.3c00304","article-title":"Bifunctionalized Betulinic Acid Conjugates with C-3-Monodesmoside and C-28-Triphenylphosphonium Moieties with Increased Cancer Cell Targetability","volume":"86","author":"Tsepaeva","year":"2023","journal-title":"J. Nat. Prod."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1411","DOI":"10.1055\/s-0031-1282806","article-title":"Evaluation of acute toxicity of betulin","volume":"77","author":"Makarova","year":"2011","journal-title":"Planta Medica"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/s43094-020-00173-4","article-title":"Toxicological evaluations of betulinic acid and ursolic acid; common constituents of Houttuynia cordata used as an anthelmintic by the Naga tribes in North-east India","volume":"7","author":"Mishra","year":"2021","journal-title":"Futur. J. Pharm. Sci."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"3129","DOI":"10.1016\/j.bbagen.2016.10.018","article-title":"Membrane damage by betulinic acid provides insights into cellular aging","volume":"1861","author":"Martins","year":"2017","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1242\/dmm.030205","article-title":"Neurodegenerative disease: Models, mechanisms, and A new hope","volume":"10","author":"Gitler","year":"2017","journal-title":"Dis. Model. Mech."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1038\/nrneurol.2018.23","article-title":"Physiological changes in neurodegeneration\u2014Mechanistic insights and clinical utility","volume":"14","author":"Ahmed","year":"2018","journal-title":"Nat. Rev. Neurol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1042\/BST20220830","article-title":"The role of the blood\u2013brain barrier during neurological disease and infection","volume":"51","author":"Patabendige","year":"2023","journal-title":"Biochem. Soc. Trans."},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Gullotta, G.S., Costantino, G., Sortino, M.A., and Spampinato, S.F. (2023). Microglia and the Blood\u2013Brain Barrier: An External Player in Acute and Chronic Neuroinflammatory Conditions. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24119144"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1016\/S1474-4422(24)00038-3","article-title":"Global, regional, and national burden of disorders affecting the nervous system, 1990\u20132021: A systematic analysis for the Global Burden of Disease Study 2021","volume":"23","author":"Steinmetz","year":"2024","journal-title":"Lancet Neurol."},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Abdolmaleky, H.M., and Zhou, J.R. (2023). Underlying Mechanisms of Brain Aging and Neurodegenerative Diseases as Potential Targets for Preventive or Therapeutic Strategies Using Phytochemicals. Nutrients, 15.","DOI":"10.3390\/nu15153456"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"307","DOI":"10.2174\/1570193X1103140915111559","article-title":"Natural Triterpenoids and their Derivatives with Pharmacological Activity Against Neurodegenerative Disorders","volume":"11","author":"Ruszkowski","year":"2014","journal-title":"MiniRev. Org. Chem."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1007\/978-3-319-62817-2_2","article-title":"CREB at the crossroads of activity dependent regulation of nervous system development and function","volume":"1015","author":"Belgacem","year":"2017","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_110","doi-asserted-by":"crossref","unstructured":"Dominiak, A., Gawinek, E., Banaszek, A.A., and Wilkaniec, A. (2025). Mitochondrial Quality Control in Neurodegeneration and Cancer: A Common Denominator, Distinct Therapeutic Challenges. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26178693"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"S189","DOI":"10.1016\/S1353-8020(09)70812-0","article-title":"Therapeutic approaches to mitochondrial dysfunction in Parkinson\u2019s disease","volume":"15","author":"Beal","year":"2009","journal-title":"Park. Relat. Disord."},{"key":"ref_112","doi-asserted-by":"crossref","unstructured":"Kurowska, A., Ziemich\u00f3d, W., Herbet, M., and Pi\u0105tkowska-Chmiel, I. (2023). The Role of Diet as a Modulator of the Inflammatory Process in Neurological Diseases. Nutrients, 15.","DOI":"10.3390\/nu15061436"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/s13244-022-01358-6","article-title":"Multimodality imaging of neurodegenerative disorders with a focus on multiparametric magnetic resonance and molecular imaging","volume":"14","author":"Loftus","year":"2023","journal-title":"Insights Imaging"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1186\/s13195-020-00612-7","article-title":"Imaging biomarkers in neurodegeneration: Current and future practices","volume":"12","author":"Young","year":"2020","journal-title":"Alzheimer\u2019s Res. Ther."},{"key":"ref_115","doi-asserted-by":"crossref","unstructured":"Song, J., Cho, E., Lee, H., Lee, S., Kim, S., and Kim, J. (2025). Development of Neurodegenerative Disease Diagnosis and Monitoring from Traditional to Digital Biomarkers. Biosensors, 15.","DOI":"10.3390\/bios15020102"},{"key":"ref_116","doi-asserted-by":"crossref","unstructured":"Sharifi-Rad, M., Lankatillake, C., Dias, D.A., Docea, A.D., Fawzi, M., Lobine, D., Chazot, P.L., Beg\u00fcm, K., Tugba, T., and Moreira, A. (2020). Impact of Natural Compounds on Neurodegenerative Disorders: From Preclinical to Pharmacotherapeutics. J. Clin. Med., 9.","DOI":"10.3390\/jcm9041061"},{"key":"ref_117","doi-asserted-by":"crossref","unstructured":"Lim, D.W., Lee, J.-E., Lee, C., and Kim, Y.T. (2024). Natural Products and Their Neuroprotective Effects in Degenerative Brain Diseases: A Comprehensive Review. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms252011223"},{"key":"ref_118","first-page":"1934578X20903555","article-title":"Advances in Pharmacological Activities of Terpenoids","volume":"15","author":"Yang","year":"2020","journal-title":"Nat. Prod. Commun."},{"key":"ref_119","doi-asserted-by":"crossref","unstructured":"de Lima, E.P., Laurindo, L.F., Catharin, V.C.S., Direito, R., Tanaka, M., German, I.J.S., Lamas, C.B., Guiguer, E.L., Ara\u00fajo, A.C., and Fiorini, A.M.R. (2025). Polyphenols, Alkaloids, and Terpenoids Against Neurodegeneration: Evaluating the Neuroprotective Effects of Phytocompounds Through a Comprehensive Review of the Current Evidence. Metabolites, 15.","DOI":"10.3390\/metabo15020124"},{"key":"ref_120","unstructured":"Khan, H., Aschner, M., and Mirzaei, H. (2023). Neuroprotective effect of terpenoids, Chapter 8. Phytonutrients and Neurological Disorders, Academic Press."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"153664","DOI":"10.1016\/j.phymed.2021.153664","article-title":"Natural products attenuate PI3k\/AKT\/mtor signaling pathway: A promising strategy in regulating neurodegeneration","volume":"91","author":"Fakhri","year":"2021","journal-title":"Phytomedicine"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"6873874","DOI":"10.1155\/2022\/6873874","article-title":"Therapeutic Potential of Different Natural Products for the Treatment of Alzheimer\u2019s Disease","volume":"2022","author":"Chakraborty","year":"2022","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_123","doi-asserted-by":"crossref","unstructured":"Chen, X., Drew, J., Berney, W., and Lei, W.J.C. (2021). Neuroprotective natural products for Alzheimer\u2019s disease. Cells, 10.","DOI":"10.3390\/cells10061309"},{"key":"ref_124","doi-asserted-by":"crossref","unstructured":"Zhang, R., Zeng, M., Zhang, X., Zheng, Y., Lv, N., Wang, L., Gan, J., Li, Y., Jiang, X., and Yang, L. (2023). Therapeutic Candidates for Alzheimer\u2019s Disease: Saponins. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241310505"},{"key":"ref_125","doi-asserted-by":"crossref","unstructured":"Park, J.S., Rehman, I.U., Choe, K., Ahmad, R., Lee, H.J., and Kim, M.O. (2023). A Triterpenoid Lupeol as an Antioxidant and AntNeuroinflammatory Agent: Impacts on Oxidative Stress in Alzheimer\u2019s Disease. Nutrients, 15.","DOI":"10.3390\/nu15133059"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1080\/1028415X.2023.2180865","article-title":"Neuroprotective properties of Betulin, Betulinic acid, and Ursolic acid as triterpenoids derivatives: A comprehensive review of mechanistic studies","volume":"27","author":"Farzan","year":"2024","journal-title":"Nutr. Neurosci."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"512048","DOI":"10.1155\/2019\/8512048","article-title":"Antioxidant and Antinflammatory Mechanisms of Neuroprotection by Ursolic Acid: Addressing brain injury, cerebral ischemia, cognition deficit, anxiety, and depression","volume":"2019","author":"Habtemariam","year":"2019","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1089\/ars.2011.4491","article-title":"Targeting Nrf2-mediated gene transcription by extremely potent synthetic triterpenoids attenuate dopaminergic neurotoxicity in the MPTP mouse model of Parkinson\u2019s disease","volume":"18","author":"Kaidery","year":"2013","journal-title":"Antioxid. Redox Signal."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"232","DOI":"10.3892\/mmr.2024.13356","article-title":"Exploring the protective effect and molecular mechanism of betulin in Alzheimer\u2019s disease based on network pharmacology, molecular docking and experimental validation","volume":"30","author":"Wang","year":"2024","journal-title":"Mol. Med. Rep."},{"key":"ref_130","doi-asserted-by":"crossref","unstructured":"Gudoityte, E., Arandarcikaite, O., Mazeikiene, I., Bendokas, V., and Liobikas, J. (2021). Ursolic and oleanolic acids: Plant metabolites with neuroprotective potential. Int. J. Mol. Sci., 22.","DOI":"10.20944\/preprints202103.0783.v1"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1080\/1028415X.2022.2051957","article-title":"Oleanolic acid and ursolic acid: Therapeutic potential in neurodegenerative diseases, neuropsychiatric diseases and other brain disorders","volume":"26","author":"Chen","year":"2022","journal-title":"Nutr. Neurosci."},{"key":"ref_132","doi-asserted-by":"crossref","unstructured":"Subedi, L., Gaire, B.P., Kim, S.-Y., and Parveen, A. (2021). Nitric Oxide as a Target for Phytochemicals in Anti-Neuroinflammatory Prevention Therapy. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22094771"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"104142","DOI":"10.1016\/j.jff.2020.104142","article-title":"Terpenoids of Ganoderma lucidum reverse cognitive impairment through attenuating neurodegeneration via suppression of PI3K\/AKT\/mTOR expression in vivo model","volume":"73","author":"Wang","year":"2020","journal-title":"J. Funct. Foods"},{"key":"ref_134","doi-asserted-by":"crossref","unstructured":"Valotto Neto, L.J., Reverete de Araujo, M., Moretti Junior, R.C., Mendes Machado, N., Joshi, R.K., dos Santos Buglio, D., Barbalho Lamas, C., Direito, R., Fornari Laurindo, L., and Tanaka, M. (2024). Investigating the Neuroprotective and Cognitive-Enhancing Effects of Bacopa monnieri: A Systematic Review Focused on Inflammation, Oxidative Stress, Mitochondrial Dysfunction, and Apoptosis. Antioxidants, 13.","DOI":"10.3390\/antiox13040393"},{"key":"ref_135","first-page":"1934578X19896684","article-title":"Betulin Protects HT-22 Hippocampal Cells against ER Stress through Induction of Heme Oxygenase-1 and Inhibition of ROS Production","volume":"14","author":"Lee","year":"2019","journal-title":"Nat. Prod. Commun."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"127193","DOI":"10.1016\/j.bmcl.2020.127193","article-title":"Betulin isolated from Pyrola incarnata Fisch. inhibited lipopolysaccharide (LPS)-induced neuroinflammation with the guidance of computer-aided drug design","volume":"30","author":"Liu","year":"2020","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_137","doi-asserted-by":"crossref","unstructured":"Zakrzeska, A., Ko\u0142odziejczyk, A., Komorowski, P., Soko\u0142owska, P., Rokita, B., Wach, R.A., and Siatkowska, M. (2025). Neuroprotective Potential of Betulin and Its Drug Formulation with Cyclodextri In Vitro Assessment. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26125605"},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"2007","DOI":"10.1016\/S0959-8049(97)00294-3","article-title":"Betulinic acid induces apoptosis in human neuroblastoma cell lines","volume":"33","author":"Schmidt","year":"1997","journal-title":"Eur. J. Cancer"},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1002\/1096-911X(20001201)35:6<616::AID-MPO27>3.0.CO;2-N","article-title":"Betulinic acid induces apoptosis through a direct effect on mitochondria in neuroectodermal tumors","volume":"35","author":"Fulda","year":"2000","journal-title":"Med. Pediatr. Oncol."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1007\/s43450-022-00349-4","article-title":"Betulinic Acid Modulates Redox Imbalance and Dysregulated Metabolisms, While Ameliorating Purinergic and Cholinergic Activities in Iron-Induced Neurotoxicity","volume":"33","author":"Salau","year":"2023","journal-title":"Rev. Bras. Farmacogn."},{"key":"ref_141","doi-asserted-by":"crossref","unstructured":"Li, C., Zhang, C., Zhou, H., Feng, Y., Tang, F., Hoi, M.P.M., He, C., Ma, D., Zhao, C., and Lee, S.M.Y. (2018). Inhibitory Effects of Betulinic Acid on LP-Induced Neuroinflammation Involve M2 Microglial Polarization via CaMKK\u03b2-Dependent AMPK Activation. Front. Mol. Neurosci., 11.","DOI":"10.3389\/fnmol.2018.00098"},{"key":"ref_142","doi-asserted-by":"crossref","unstructured":"Cavalcante, B.R.R., Arag\u00e3o-Fran\u00e7a, L.S., Sampaio, G.L.A., Nonaka, C.K.V., Oliveira, M.S., Campos, G.S., Sardi, S.I., Dias, B.R.S., Menezes, J.P.B., and Rocha, V.P.C. (2020). Betulinic Acid Exerts Cytoprotective Activity on Zika Virus Infected Neural Progenitor Cells. Front. Cell Infect. Microbiol., 10.","DOI":"10.3389\/fcimb.2020.558324"},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"1849","DOI":"10.1007\/s13311-021-01089-4","article-title":"Betulinic Acid Hydroxamate is Neuroprotective and Induces Protein Phosphatase 2A-Dependent HIF-1\u03b1 Stabilization and Post-transcriptional Dephosphorylation of Prolyl Hydrolase 2","volume":"18","author":"Prados","year":"2021","journal-title":"Neurotherapeutics"},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"4911","DOI":"10.1021\/jf501314g","article-title":"p-Coumaric acid and ursolic acid from Corni fructus attenuated \u03b2-amyloid(25\u201335)-induced toxicity through regulation of the NF-\u03baB signaling pathway in PC12 cells","volume":"62","author":"Yoon","year":"2014","journal-title":"J. Agric. Food Chem."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"10831","DOI":"10.3390\/molecules170910831","article-title":"Protective Effects of the Key Compounds Isolated from Corni fructus against \u03b2-Amyloid-Induced Neurotoxicity in PC12 Cells","volume":"17","author":"Hong","year":"2012","journal-title":"Molecules"},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"1903","DOI":"10.1177\/0963689717738785","article-title":"Neuroprotective Effects of Betulin in Pharmacological and Transgenic Caenorhabditis elegans Models of Parkinson\u2019s Disease","volume":"26","author":"Tsai","year":"2018","journal-title":"Cell Transplant."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.3233\/JAD-230940","article-title":"Ferroptotic Potency of ISM1 Expression in the Drug-Induced Alzheimer\u2019s Disease-Like Phenotype Under the Influence of Betulin","volume":"96","author":"Bozkurt","year":"2023","journal-title":"J. Alzheimers Dis."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.neuro.2016.09.009","article-title":"Protective effect of betulin on cognitive decline in streptozotocin (STZ)-induced diabetic rats","volume":"57","author":"Ma","year":"2016","journal-title":"Neurotoxicology"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.bbr.2017.10.002","article-title":"The effects of betulinic acid on neurobe-havioral activity, electrophysiology and histological changes in an animal model of Alzheimer\u2019s disease","volume":"337","author":"Navabi","year":"2018","journal-title":"Behav. Brain Res."},{"key":"ref_150","first-page":"57","article-title":"Brain targeting, acid-responsive antioxidant nanoparticles for stroke treatment and drug delivery","volume":"16","author":"Zhang","year":"2022","journal-title":"Bioact. Mater."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.1016\/j.biopha.2016.11.028","article-title":"Betulinic acid protects against cerebral ischemia\/reperfusion injury by activating the PI3K\/Akt signaling pathway","volume":"84","author":"Jiao","year":"2016","journal-title":"Biomed. Pharmacother."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1016\/j.freeradbiomed.2025.04.013","article-title":"Betulinic acid protects against lipopolysaccharide and ferrous sul-fate-induced oxidative stress, ferroptosis, apoptosis, and neuroinflammation signaling relevant to Parkinson\u2019s Disease","volume":"233","author":"Pandey","year":"2025","journal-title":"Free Radic. Biol. Med."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.ejphar.2018.05.015","article-title":"Betulinic acid, a natural PDE inhibitor restores hippocampal cAMP\/cGMP and BDNF, improve cerebral blood flow and recover memory deficits in permanent BCCAO induced vascular dementia in rats","volume":"832","author":"Kaundal","year":"2018","journal-title":"Eur. J. Pharmacol."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/s12951-022-01238-7","article-title":"Betulinic acid self-assembled nanoparticles for effective treatment of glioblastoma","volume":"20","author":"Li","year":"2022","journal-title":"J. Nanobiotechnology"},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1007\/s11064-016-2077-8","article-title":"Ursolic Acid Ameliorates Early Brain Injury After Experimental Traumatic Brain Injury in Mice by Activating the Nrf2 Pathway","volume":"42","author":"Ding","year":"2017","journal-title":"Neurochem. Res."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1016\/j.intimp.2014.10.009","article-title":"Ursolic acid alleviates early brain injury after experimental subarachnoid hemorrhage by suppressing TLR4-mediated inflammatory pathway","volume":"23","author":"Zhang","year":"2014","journal-title":"Int. Immunopharmacol."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.neulet.2014.07.005","article-title":"Ursolic acid reduces oxidative stress to alleviate early brain injury following experimental subarachnoid hemorrhage","volume":"579","author":"Zhang","year":"2014","journal-title":"Neurosci. Lett."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.jnutbio.2018.01.016","article-title":"The human natural killer-1 (HNK-1) glycan mimetic ursolic acid promotes functional recovery after spinal cord injury in mouse","volume":"55","author":"Sahu","year":"2018","journal-title":"J. Nutr. Biochem."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.brainres.2012.12.032","article-title":"Ursolic acid promotes the neuroprotection by activating Nrf2 pathway after cerebral ischemia in mice","volume":"1497","author":"Li","year":"2013","journal-title":"Brain Res."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.brainresbull.2020.03.003","article-title":"Mechanistic evaluation of ursolic acid against rotenone induced Parkinson\u2019s disease\u2014Emphasizing the role of mitochondrial biogenesis","volume":"160","author":"Peshattiwara","year":"2020","journal-title":"Brain Res. Bull."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1007\/s12640-019-00038-6","article-title":"Antiinflammatory activity of ursolic acid in MPTP-induced parkinsonian mouse model","volume":"36","author":"Rai","year":"2019","journal-title":"Neurotox. Res."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/1\/25\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,24]],"date-time":"2025-12-24T10:21:00Z","timestamp":1766571660000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/1\/25"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,24]]},"references-count":161,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["biom16010025"],"URL":"https:\/\/doi.org\/10.3390\/biom16010025","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,24]]}}}