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Nutritional Neuroscience
An International Journal on Nutrition, Diet and Nervous System
Volume 26, 2023 - Issue 5
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Review

Oleanolic acid and ursolic acid: therapeutic potential in neurodegenerative diseases, neuropsychiatric diseases and other brain disorders

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References

  • Petrovic S, Arsic A, Ristic-Medic D, Cvetkovic Z, Vucic V. Lipid peroxidation and antioxidant supplementation in neurodegenerative diseases: A review of human studies. Antioxidants (Basel). 2020;9(11).
  • Ludea-Huaman MA, Ramos-Inquiltupa DA. Determination of the content of ursolic and oleanolic acid in the cuticular wax of fruits of different species of rosaceae. Rev Colomb Quim. 2019;48(2):15–20.
  • Janicsák G, Veres K, Kakasy AZ, Máthé I. Study of the oleanolic and ursolic acid contents of some species of the Lamiaceae. Biochem System Ecol. 2006;34(5):392–6.
  • Yamaguchi H, Noshita T, Kidachi Y, Umetsu H, Hayashi M, Komiyama K, et al. Isolation of ursolic acid from apple peels and Its specific efficacy as a potent antitumor agent. J Health Sci. 2008;54(6):654–60.
  • Waller GR, Jurzysta M, Karns T, Geno PW. Isolation and identification of ursolic acid from Coffea arabica L. (coffee) leaves. 1992.
  • Jayaprakasam B, Olson LK, Schutzki RE, Tai MH, Nair MG. Amelioration of obesity and glucose intolerance in high-fat-fed C57BL/6 mice by anthocyanins and ursolic acid in cornelian cherry (Cornus mas). J Agric Food Chem. 2006;54(1):243–8.
  • Lin Y, Vermeer MA, Trautwein EA. Triterpenic acids present in hawthorn lower plasma cholesterol by inhibiting intestinal ACAT activity in hamsters. Evid Based Complement Alternat Med. 2011: 801272.
  • Jäger S, Trojan H, Kopp T, Laszczyk MN, Scheffler A. Pentacyclic triterpene distribution in various plants – Rich sources for a new group of multi-potent plant extracts. Molecules. 2009;14(6):2016–31.
  • Furtado NAJC, Pirson L, Edelberg H, Miranda LM, Loira-Pastoriza C, Preat V, et al. Pentacyclic triterpene bioavailability: An overview of In vitro and In vivo studies. Molecules. 2017;22(3).
  • Pironi AM, de Araújo PR, Fernandes MA, Salgado HRN, Chorilli M. Characteristics, biological properties and analytical methods of ursolic acid: A review. Crit Rev Anal Chem. 2018;48(1):86–93.
  • Tong HH, Du Z, Wang GN, Chan HM, Chang Q, Lai LC, et al. Spray freeze drying with polyvinylpyrrolidone and sodium caprate for improved dissolution and oral bioavailability of oleanolic acid, a BCS class IV compound. Int J Pharm. 2011;404(1-2):148–58.
  • Jeong DW, Kim YH, Kim HH, Ji HY, Yoo SD, Choi WR, et al. Dose-linear pharmacokinetics of oleanolic acid after intravenous and oral administration in rats. Biopharm Drug Dispos. 2007;28(2):51–7.
  • Chen Q, Luo S, Zhang Y, Chen Z. Development of a liquid chromatography-mass spectrometry method for the determination of ursolic acid in rat plasma and tissue: application to the pharmacokinetic and tissue distribution study. Anal Bioanal Chem. 2011;399(8):2877–84.
  • Ramos-Hryb AB, Pazini FL, Kaster MP, Rodrigues ALS. Therapeutic potential of ursolic acid to manage neurodegenerative and psychiatric diseases. CNS Drugs. 2017;31(12):1029–41.
  • Gudoityte E, Arandarcikaite O, Mazeikiene I, Bendokas V, Liobikas J. Ursolic and oleanolic acids: plant metabolites with neuroprotective potential. Int J Mol Sci. 2021;22(9).
  • Hou Y, Dan X, Babbar M, Wei Y, Hasselbalch SG, Croteau DL, Bohr VA. Ageing as a risk factor for neurodegenerative disease. Nat Rev Neurol. 2019;15(10):565–81.
  • Wang K, Sun W, Zhang L, Guo W, Xu J, Liu S, et al. Oleanolic acid ameliorates Aβ25-35 injection-induced memory deficit in Alzheimer's disease model rats by maintaining synaptic plasticity. CNS Neurol Disord Drug Targets. 2018;17(5):389–99.
  • Lin K, Sze SC, Liu B, Zhang Z, Zhang Z, Zhu P, et al. 20(S)-protopanaxadiol and oleanolic acid ameliorate cognitive deficits in APP/PS1 transgenic mice by enhancing hippocampal neurogenesis. J Ginseng Res. 2021;45(2):325–33.
  • Guo Q, He J, Zhang H, Yao L, Li H. Oleanolic acid alleviates oxidative stress in Alzheimer's disease by regulating stanniocalcin-1 and uncoupling protein-2 signalling. Clin Exp Pharmacol Physiol. 2020;47(7):1263–71.
  • Zhang L, Xia R, Jia J, Wang L, Li K, Li Y, Zhang J. Oleanolic acid protects against cognitive decline and neuroinflammation-mediated neurotoxicity by blocking secretory phospholipase A2 IIA-activated calcium signals. Mol Immunol. 2018;99:95–103.
  • Castellano JM, Garcia-Rodriguez S, Espinosa JM, Millan-Linares MC, Rada M, Perona JS. Oleanolic acid exerts a neuroprotective effect against microglial cell activation by modulating cytokine release and antioxidant defense systems. Biomolecules. 2019;9(11).
  • Li G, Hernandez-Ono A, Crooke RM, Graham MJ, Ginsberg HN. Effects of antisense-mediated inhibition of 11β-hydroxysteroid dehydrogenase type 1 on hepatic lipid metabolism. J Lipid Res. 2011;52(5):971–81.
  • Rollinger JM, Kratschmar DV, Schuster D, Pfisterer PH, Gumy C, Aubry EM, et al. 11beta-Hydroxysteroid dehydrogenase 1 inhibiting constituents from Eriobotrya japonica revealed by bioactivity-guided isolation and computational approaches. Bioorg Med Chem. 2010;18(4):1507–15.
  • Ramírez-Espinosa JJ, García-Jiménez S, Rios MY, Medina-Franco JL, López-Vallejo F, Webster SP, et al. Antihyperglycemic and sub-chronic antidiabetic actions of morolic and moronic acids, in vitro and in silico inhibition of 11β-HSD 1. Phytomedicine. 2013;20(7):571–6.
  • Mirza FJ, Amber S, Sumera DH, Ahmed T, Zahid S. Rosmarinic acid and ursolic acid alleviate deficits in cognition, synaptic regulation and adult hippocampal neurogenesis in an Aβ(1-42)-induced mouse model of Alzheimer's disease. Phytomedicine. 2021;83(153490).
  • Yoon JH, Youn K, Ho CT, Karwe MV, Jeong WS, Jun M. p-Coumaric acid and ursolic acid from Corni fructus attenuated β-amyloid(25-35)-induced toxicity through regulation of the NF-κB signaling pathway in PC12 cells. J Agric Food Chem. 2014;62(21):4911–6.
  • Hong SY, Jeong WS, Jun M. Protective effects of the key compounds isolated from Corni fructus against β-amyloid-induced neurotoxicity in PC12 cells. Molecules. 2012;17(9):10831–45.
  • Liang W, Zhao X, Feng J, Song F, Pan Y. Ursolic acid attenuates beta-amyloid-induced memory impairment in mice. Arq Neuropsiquiatr. 2016;74(6):482–8.
  • Stewart CR, Stuart LM, Wilkinson K, van Gils JM, Deng J, Halle A, et al. CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nat Immunol. 2010;11(2):155–61.
  • Wilkinson K, Boyd JD, Glicksman M, Moore KJ, El Khoury J. A high content drug screen identifies ursolic acid as an inhibitor of amyloid beta protein interactions with its receptor CD36. J Biol Chem. 2011;286(40):34914–22.
  • Youn K, Jun M. Inhibitory effects of key compounds isolated from Corni fructus on BACE1 activity. Phytother Res. 2012;26(11):1714–8.
  • Chung YK, Heo HJ, Kim EK, Kim HK, Huh TL, Lim Y, et al. Inhibitory effect of ursolic acid purified from Origanum majorana L on the acetylcholinesterase. Mol Cells. 2001;11(2):137–43.
  • Ndlovu BC, Daniels WM, Mabandla MV. Oleanolic acid enhances the beneficial effects of preconditioning on PC12 cells. Parkinsons Dis. 2014: 929854.
  • Mabandla MV, Nyoka M, Daniels WM. Early use of oleanolic acid provides protection against 6-hydroxydopamine induced dopamine neurodegeneration. Brain Res. 2015;1622:64–71.
  • Msibi ZNP, Mabandla MV. Oleanolic acid mitigates 6-hydroxydopamine neurotoxicity by attenuating intracellular ROS in PC12 cells and striatal microglial activation in Rat brains. Front Physiol. 2019;10(1059).
  • Tsai SJ, Yin MC. Antioxidative and anti-inflammatory protection of oleanolic acid and ursolic acid in PC12 cells. J Food Sci. 2008;73(7):H174–8.
  • Rai SN, Yadav SK, Singh D, Singh SP. Ursolic acid attenuates oxidative stress in nigrostriatal tissue and improves neurobehavioral activity in MPTP-induced Parkinsonian mouse model. J Chem Neuroanat. 2016;71:41–9.
  • Rai SN, Zahra W, Singh SS, Birla H, Keswani C, Dilnashin H, et al. Anti-inflammatory activity of ursolic acid in MPTP-induced Parkinsonian mouse model. Neurotox Res. 2019;36(3):452–62.
  • Peshattiwar V, Muke S, Kaikini A, Bagle S, Dighe V, Sathaye S. Mechanistic evaluation of ursolic acid against rotenone induced Parkinson's disease- emphasizing the role of mitochondrial biogenesis. Brain Res Bull. 2020;160:150–61.
  • Zahra W, Rai SN, Birla H, Singh SS, Rathore AS, Dilnashin H, et al. Neuroprotection of rotenone-induced parkinsonism by ursolic acid in PD mouse model. CNS Neurol Disord Drug Targets. 2020;19(7):527–40.
  • Shih YH, Chein YC, Wang JY, Fu YS. Ursolic acid protects hippocampal neurons against kainate-induced excitotoxicity in rats. Neurosci Lett. 2004;362(2):136–40.
  • Martín R, Carvalho-Tavares J, Hernández M, Arnés M, Ruiz-Gutiérrez V, Nieto ML. Beneficial actions of oleanolic acid in an experimental model of multiple sclerosis: a potential therapeutic role. Biochem Pharmacol. 2010;79(2):198–208.
  • Martín R, Hernández M, Córdova C, Nieto ML. Natural triterpenes modulate immune-inflammatory markers of experimental autoimmune encephalomyelitis: therapeutic implications for multiple sclerosis. Br J Pharmacol. 2012;166(5):1708–23.
  • Gutierrez B, Gallardo I, Ruiz L, Alvarez Y, Cachofeiro V, Margolles A, et al. Oleanolic acid ameliorates intestinal alterations associated with EAE. J Neuroinflammation. 2020;17(1):363.
  • Kim M, Lee S, Lim H, Lee J, Park JY, Kwon HJ, et al. Oleanolic acid acetate alleviates symptoms of experimental autoimmune encephalomyelitis in mice by regulating toll-like receptor 2 signaling. Front Pharmacol. 2020;11(556391).
  • Honarvar F, Hojati V, Bakhtiari N, Vaezi G, Javan M. Myelin protection by ursolic acid in cuprizone-induced demyelination in mice. Iran J Pharm Res. 2019;18(4):1978–88.
  • Zhang Y, Li X, Ciric B, Curtis MT, Chen WJ, Rostami A, Zhang GX. A dual effect of ursolic acid to the treatment of multiple sclerosis through both immunomodulation and direct remyelination. Proc Natl Acad Sci U S A. 2020;117(16):9082–93.
  • Xu T, Wang X, Zhong B, Nurieva RI, Ding S, Dong C. Ursolic acid suppresses interleukin-17 (IL-17) production by selectively antagonizing the function of RORgamma t protein. J Biol Chem. 2011;286(26):22707–10.
  • Ha JH, Lee KY, Choi HC, Cho J, Kang BS, Lim JC, Lee DU. Modulation of radioligand binding to the GABA(A)-benzodiazepine receptor complex by a new component from Cyperus rotundus. Biol Pharm Bull. 2002;25(1):128–30.
  • Awad R, Muhammad A, Durst T, Trudeau VL, Arnason JT. Bioassay-guided fractionation of lemon balm (Melissa officinalis L.) using an in vitro measure of GABA transaminase activity. Phytother Res. 2009;23(8):1075–81.
  • Kazmi I, Gupta G, Afzal M, Rahman M, Anwar F. Pharmacological evaluation of anxiolytic activity of ursolic acid stearoyl glucoside isolated from Lantana camara. CNS Neurosci Ther. 2012;18(8):707–8.
  • Kazmi I, Afzal M, Ali B, Damanhouri ZA, Ahmaol A, Anwar F. Anxiolytic potential of ursolic acid derivative–a stearoyl glucoside isolated from Lantana camara L. (Verbanaceae). Asian Pac J Trop Med. 2013;6(6):433–7.
  • Colla AR, Rosa JM, Cunha MP, Rodrigues AL. Anxiolytic-like effects of ursolic acid in mice. Eur J Pharmacol. 2015;758:171–6.
  • Yi LT, Li J, Liu Q, Geng D, Zhou YF, Ke XQ, et al. Antidepressant-like effect of oleanolic acid in mice exposed to the repeated forced swimming test. J Psychopharmacol. 2013;27(5):459–68.
  • Yi LT, Li J, Liu BB, Luo L, Liu Q, Geng D. BDNF-ERK-CREB signalling mediates the role of miR-132 in the regulation of the effects of oleanolic acid in male mice. J Psychiatry Neurosci. 2014;39(5):348–59.
  • Dong SQ, Wang SS, Zhu JX, Mu RH, Li CF, Geng D, et al. Oleanolic acid decreases SGK1 in the hippocampus in corticosterone-induced mice. Steroids. 2019;149(108419).
  • Fajemiroye JO, Galdino PM, Florentino IF, Da Rocha FF, Ghedini PC, Polepally PR, et al. Plurality of anxiety and depression alteration mechanism by oleanolic acid. J Psychopharmacol. 2014;28(10):923–34.
  • Fajemiroye JO, Polepally PR, Chaurasiya ND, Tekwani BL, Zjawiony JK, Costa EA. Oleanolic acid acrylate elicits antidepressant-like effect mediated by 5-HT1A receptor. Sci Rep. 2015;5(11582).
  • Chattopadhyay D, Arunachalam G, Mandal SC, Bhadra R, Mandal AB. CNS activity of the methanol extract of Mallotus peltatus (Geist) Muell Arg. leaf: an ethnomedicine of Onge. J Ethnopharmacol. 2003;85(1):99–105.
  • Machado DG, Neis VB, Balen GO, Colla A, Cunha MP, Dalmarco JB, et al. Antidepressant-like effect of ursolic acid isolated from Rosmarinus officinalis L. in mice: evidence for the involvement of the dopaminergic system. Pharmacol Biochem Behav. 2012;103(2):204–11.
  • Colla AR, Oliveira A, Pazini FL, Rosa JM, Manosso LM, Cunha MP, Rodrigues AL. Serotonergic and noradrenergic systems are implicated in the antidepressant-like effect of ursolic acid in mice. Pharmacol Biochem Behav. 2014;124:108–16.
  • Colla ARS, Pazini FL, Lieberknecht V, Camargo A, Rodrigues ALS. Ursolic acid abrogates depressive-like behavior and hippocampal pro-apoptotic imbalance induced by chronic unpredictable stress. Metab Brain Dis. 2021;36(3):437–46.
  • Ramos-Hryb AB, Cunha MP, Pazini FL, Lieberknecht V, Prediger RDS, Kaster MP, Rodrigues ALS. Ursolic acid affords antidepressant-like effects in mice through the activation of PKA, PKC, CAMK-II and MEK1/2. Pharmacol Rep. 2017;69(6):1240–6.
  • Kim JH, Kim GH, Hwang KH. Monoamine oxidase and dopamine β-hydroxylase inhibitors from the fruits of gardenia jasminoides. Biomol Ther (Seoul). 2012;20(2):214–9.
  • Singla RK, Scotti L, Dubey AK. In silico studies revealed multiple neurological targets for the antidepressant molecule ursolic acid. Curr Neuropharmacol. 2017;15(8):1100–6.
  • Ramos-Hryb AB, Platt N, Freitas AE, Heinrich IA, López MG, Leal RB, et al. Protective effects of ursolic acid against cytotoxicity induced by corticosterone: role of protein kinases. Neurochem Res. 2019.
  • Naß J, Abdelfatah S, Efferth T. The triterpenoid ursolic acid ameliorates stress in caenorhabditis elegans by affecting the depression-associated genes skn-1 and prdx2. Phytomedicine. 2021;88(153598).
  • Park SJ, Lee Y, Oh HK, Lee HE, Lee Y, Ko SY, et al. Oleanolic acid attenuates MK-801-induced schizophrenia-like behaviors in mice. Neuropharmacology. 2014;86:49–56.
  • Rong ZT, Gong XJ, Sun HB, Li YM, Ji H. Protective effects of oleanolic acid on cerebral ischemic damage in vivo and H(2)O(2)-induced injury in vitro. Pharm Biol. 2011;49(1):78–85.
  • Cho SO, Ban JY, Kim JY, Ju HS, Lee IS, Song KS, et al. Anti-ischemic activities of aralia cordata and its active component, oleanolic acid. Arch Pharm Res. 2009;32(6):923–32.
  • Caltana L, Rutolo D, Nieto ML, Brusco A. Further evidence for the neuroprotective role of oleanolic acid in a model of focal brain hypoxia in rats. Neurochem Int. 2014;79:79–87.
  • Sapkota A, Choi JW. Oleanolic acid provides neuroprotection against ischemic stroke through the inhibition of microglial activation and NLRP3 inflammasome activation. Biomol Ther (Seoul). 2022;30(1):55–63.
  • Caltana L, Nieto ML, Brusco A. Oleanolic acid: a promising neuroprotective agent for cerebral ischemia. Neural Regen Res. 2015;10(4):540–1.
  • Li L, Zhang X, Cui L, Wang L, Liu H, Ji H, Du Y. Ursolic acid promotes the neuroprotection by activating Nrf2 pathway after cerebral ischemia in mice. Brain Res. 2013;1497:32–9.
  • Wang Y, He Z, Deng S. Ursolic acid reduces the metalloprotease/anti-metalloprotease imbalance in cerebral ischemia and reperfusion injury. Drug Des Devel Ther. 2016;10:1663–74.
  • Wang Y, Li L, Deng S, Liu F, He Z. Ursolic acid ameliorates inflammation in cerebral ischemia and reperfusion injury possibly via high mobility group box 1/toll-like receptor 4/NFκB pathway. Front Neurol. 2018;9(253).
  • Han YW, Liu XJ, Zhao Y, Li XM. Role of oleanolic acid in maintaining BBB integrity by targeting p38MAPK/VEGF/Src signaling pathway in rat model of subarachnoid hemorrhage. Eur J Pharmacol. 2018;839:12–20.
  • Han Y, Tong Z, Wang C, Li X, Liang G. Oleanolic acid exerts neuroprotective effects in subarachnoid hemorrhage rats through SIRT1-mediated HMGB1 deacetylation. Eur J Pharmacol. 2021;893(173811).
  • Han Y, Wang C, Li X, Liang G. Oleanolic acid reduces oxidative stress and neuronal apoptosis after experimental subarachnoid hemorrhage by regulating Nrf2/HO-1 pathway. Drug Dev Res. 2021.
  • Zhang T, Su J, Wang K, Zhu T, Li X. Ursolic acid reduces oxidative stress to alleviate early brain injury following experimental subarachnoid hemorrhage. Neurosci Lett. 2014;579:12–7.
  • Zhang T, Su J, Guo B, Zhu T, Wang K, Li X. Ursolic acid alleviates early brain injury after experimental subarachnoid hemorrhage by suppressing TLR4-mediated inflammatory pathway. Int Immunopharmacol. 2014;23(2):585–91.
  • Ding H, Wang H, Zhu L, Wei W. Ursolic acid ameliorates early brain injury after experimental traumatic brain injury in mice by activating the Nrf2 pathway. Neurochem Res. 2017;42(2):337–46.
  • Miziak B, Chrościńska-Krawczyk M, Czuczwar SJ. Neurosteroids and seizure activity. Front Endocrinol (Lausanne)s. 2020;11(541802).
  • Kazmi I, Afzal M, Gupta G, Anwar F. Antiepileptic potential of ursolic acid stearoyl glucoside by GABA receptor stimulation. CNS Neurosci Ther. 2012;18(9):799–800.
  • Nieoczym D, Socała K, Wlaź P. Assessment of the anticonvulsant potency of ursolic acid in seizure threshold tests in mice. Neurochem Res. 2018;43(5):995–1002.
  • Habtemariam S. Antioxidant and anti-inflammatory mechanisms of neuroprotection by ursolic acid: addressing brain injury, cerebral ischemia, cognition deficit, anxiety, and depression. Oxid Med Cell Longev. 2019: 8512048.
  • Jeon SJ, Lee HJ, Lee HE, Park SJ, Gwon Y, Kim H, et al. Oleanolic acid ameliorates cognitive dysfunction caused by cholinergic blockade via TrkB-dependent BDNF signaling. Neuropharmacology. 2017;113(Pt A):100–9.
  • Tang FR, Loke WK, Wong P, Khoo BC. Radioprotective effect of ursolic acid in radiation-induced impairment of neurogenesis, learning and memory in adolescent BALB/c mouse. Physiol Behav. 2017;175:37–46.
  • Wu DM, Lu J, Zhang YQ, Zheng YL, Hu B, Cheng W, et al. Ursolic acid improves domoic acid-induced cognitive deficits in mice. Toxicol Appl Pharmacol. 2013;271(2):127–36.
  • Wang YJ, Lu J, Wu DM, Zheng ZH, Zheng YL, Wang XH, et al. Ursolic acid attenuates lipopolysaccharide-induced cognitive deficits in mouse brain through suppressing p38/NF-κB mediated inflammatory pathways. Neurobiol Learn Mem. 2011;96(2):156–65.
  • Lu J, Wu DM, Zheng YL, Hu B, Cheng W, Zhang ZF, Shan Q. Ursolic acid improves high fat diet-induced cognitive impairments by blocking endoplasmic reticulum stress and IκB kinase β/nuclear factor-κB-mediated inflammatory pathways in mice. Brain Behav Immun. 2011;25(8):1658–67.
  • Lu J, Wu DM, Zheng YL, Hu B, Zhang ZF, Ye Q, et al. Ursolic acid attenuates D-galactose-induced inflammatory response in mouse prefrontal cortex through inhibiting AGEs/RAGE/NF-κB pathway activation. Cereb Cortex . 2010;20(11):2540–8.
  • Ikeda Y, Murakami A, Ohigashi H. Ursolic acid: an anti- and pro-inflammatory triterpenoid. Mol Nutr Food Res. 2008;52(1):26–42.
  • Jiang Q, Yang X, Du P, Zhang H, Zhang T. Dual strategies to improve oral bioavailability of oleanolic acid: enhancing water-solubility, permeability and inhibiting cytochrome P450 isozymes. Eur J Pharm Biopharm. 2016;99:65–72.
  • Cao F, Gao Y, Wang M, Fang L, Ping Q. Propylene glycol-linked amino acid/dipeptide diester prodrugs of oleanolic acid for PepT1-mediated transport: synthesis, intestinal permeability, and pharmacokinetics. Mol Pharm. 2013;10(4):1378–87.
  • Rada M, Castellano JM, Perona JS, Guinda Á. GC-FID determination and pharmacokinetic studies of oleanolic acid in human serum. Biomed Chromatogr. 2015;29(11):1687–92.
  • de la Torre R, Carbó M, Pujadas M, Biel S, Mesa MD, Covas MI, et al. Pharmacokinetics of maslinic and oleanolic acids from olive oil – Effects on endothelial function in healthy adults. A randomized, controlled, dose-response study. Food Chem. 2020;322(126676).
  • Yang L, Sun Z, Zu Y, Zhao C, Sun X, Zhang Z, Zhang L. Physicochemical properties and oral bioavailability of ursolic acid nanoparticles using supercritical anti-solvent (SAS) process. Food Chem. 2012;132(1):319–25.
  • Yin MC, Lin MC, Mong MC, Lin CY. Bioavailability, distribution, and antioxidative effects of selected triterpenes in mice. J Agric Food Chem. 2012;60(31):7697–701.
  • Tsai SJ, Yin MC. Anti-oxidative, anti-glycative and anti-apoptotic effects of oleanolic acid in brain of mice treated by D-galactose. Eur J Pharmacol. 2012;689(1-3):81–8.
  • Lu YF, Wan XL, Xu Y, Liu J. Repeated oral administration of oleanolic acid produces cholestatic liver injury in mice. Molecules. 2013;18(3):3060–71.
  • Liu J, Lu YF, Wu Q, Xu SF, Shi FG, Klaassen CD. Oleanolic acid reprograms the liver to protect against hepatotoxicants, but is hepatotoxic at high doses. Liver Int. 2019;39(3):427–39.
  • Geerlofs L, He Z, Xiao S, Xiao ZC. Repeated dose (90 days) oral toxicity study of ursolic acid in Han-Wistar rats. Toxicol Rep. 2020;7:610–23.
  • Geerlofs L, He Z, Xiao S, Xiao ZC. 15-Day subchronic developmental toxicity studies of ursolic acid in rats. Food Chem Toxicol. 2020;144(111537).
  • Sultana N. Clinically useful anticancer, antitumor, and antiwrinkle agent, ursolic acid and related derivatives as medicinally important natural product. J Enzyme Inhib Med Chem. 2011;26(5):616–42.
  • Ren Y, Liu Y, Yang Z, Niu R, Gao K, Yang B, et al. Solid inclusion complexes of oleanolic acid with amino-appended β-cyclodextrins (ACDs): preparation, characterization, water solubility and anticancer activity. Mater Sci Eng C Mater Biol Appl. 2016;69:68–76.

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