Monotherapy or Combination Therapy of Oleanolic Acid? From Therapeutic Significance and Drug Delivery to Clinical Studies: A Comprehensive Review

Abstract

Oleanolic acid is a pentacyclic triterpenoid molecule widely distributed throughout medicinal plants. This naturally occurring oleanolic acid has attracted considerable interest due to its wide range of pharmacological characteristics, notably its cytotoxic effects on various human cancer cell lines, making it a potential candidate for extensive therapeutic uses. In vivo studies have shown that oleanolic acid possesses hepatoprotective, cardioprotective, anti-inflammatory, and antimicrobial properties. The inherent obstacles of oleanolic acid, such as low permeability, limited bioavailability, and poor water solubility, have restricted its therapeutic applicability. However, recent developments in drug delivery techniques have given oleanolic acid an additional advantage by overcoming issues with its solubility, stability, and bioavailability. This review briefly summarises the signalling pathways involved in the pharmacological activities of oleanolic acid as a monotherapy and in combination with other drugs. The review devotes a substantial portion to explaining the formulation developments, emphasising nanotechnology as a key factor in the improvement of the therapeutic potential of oleanolic acid. Several investigated novel formulations have been discussed, including liposomes, nanoemulsions, phospholipids, and polymeric nanoparticles, emerging synergistically as an efficient delivery of oleanolic acid and several other drugs. Based on our literature evaluation, it can be inferred that combination therapy had a more favourable outcome than using oleanolic acid alone in in vivo trials, primarily due to its synergistic effects. However, it is essential to note that this finding was inconsistent across all investigations. The combination of oleanolic acid with other drugs has not yet been considered for clinical trials. However, it is interesting that neither therapy has obtained approval from the U. S. Food and Drug Administration.

Keywords

oleanolic acid - combination therapy - pharmacological activity - drug delivery

Publication History

Received: 18 June 2024

Accepted after revision: 06 November 2024

Accepted Manuscript online:
07 January 2025

Article published online:
10 March 2025

• References

• 1 Jäger S, Trojan H, Kopp T, Laszczyk M, Scheffler A. Pentacyclic triterpene distribution in various plants – rich sources for a new group of multi-potent plant extracts. Molecules 2009; 14: 2016-2031
• 2 Raphael TJ, Kuttan G. Effect of naturally occurring triterpenoids glycyrrhizic acid, ursolic acid, oleanolic acid and nomilin on the immune system. Phytomedicine 2003; 10: 483-489
• 3 Gopal V, Mandal V, Mandal SC. HPTLC evaluation of oleanolic acid and ursolic acid from the methanol extract of Wattakaka volubilis . J Acute Dis 2014; 3: 59-61
• 4 Xu XH, Su Q, Zang ZH. Simultaneous determination of oleanolic acid and ursolic acid by RP-HPLC in the leaves of Eriobotrya japonica Lindl. J Pharm Anal 2012; 2: 238-240
• 5 Guo Y, Han B, Luo K, Ren Z, Cai L, Sun L. NOX2-ROS-HIF-1α signaling is critical for the inhibitory effect of oleanolic acid on rectal cancer cell proliferation. Biomed Pharmacother 2017; 85: 733-739
• 6 Shanmugam MK, Dai X, Kumar AP, Tan BKH, Sethi G, Bishayee A. Oleanolic acid and its synthetic derivatives for the prevention and therapy of cancer: preclinical and clinical evidence. Cancer Lett 2014; 346: 206-216
• 7 Lisiak N, Toton E, Rubis B, Majer B, Rybczynska M. The synthetic oleanane triterpenoid HIMOXOL induces autophagy in breast cancer cells via ERK1/2 MAPK pathway and Beclin-1 up-regulation. Anticancer Agents Med Chem 2016; 16: 1066-1076
• 8 Chen L, Zhang Y, Kong X, Peng S, Tian J. Synthesis and biological evaluation of nitric oxide-releasing derivatives of oleanolic acid as inhibitors of HepG2 cell apoptosis. Bioorg Med Chem Lett 2007; 17: 2979-2982
• 9 Xu G, Wang J, Wu F, Wang N, Zhou W, Wang Q, Wang P, Guizhen A, Yang J. YAP and 14-3-3γ are involved in HS-OA-induced growth inhibition of hepatocellular carcinoma cells: A novel mechanism for hydrogen sulfide releasing oleanolic acid. Oncotarget 2016; 7: 52150-52165
• 10 Getachew Y, Cusimano FA, Gopal P, Reisman SA, Shay JW. The synthetic triterpenoid RTA 405 (CDDO-EA) halts progression of liver fibrosis and reduces hepatocellular carcinoma size resulting in increased survival in an experimental model of chronic liver injury. Toxicol Sci 2016; 149: 111-120
• 11 Li H, Wang X, Xiang S, Hu Y, Jiang L, Shu Y. Oleanolic acid induces mitochondrial-dependent apoptosis and G0/G1 phase arrest in gallbladder cancer cells. Drug Des Devel Ther 2015; 9: 3017-3030
• 12 Gao X, Deeb D, Liu Y, Liu P, Zhang Y, Shaw J, Gautam SC. CDDO-Me inhibits tumor growth and prevents recurrence of pancreatic ductal adenocarcinoma. Int J Oncol 2015; 47: 2100-2106
• 13 Tang ZY, Li Y, Tang YT, Ma XD, Tang ZY. Anticancer activity of oleanolic acid and its derivatives: Recent advances in evidence, target profiling and mechanisms of action. Biomed Pharmacother 2022; 145: 112397
• 14 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: 4599
• 15 Verma N, Raghuvanshi DS, Singh RV. Recent advances in the chemistry and biology of oleanolic acid and its derivatives. Eur J Med Chem 2024; 276: 116619
• 16 Pollier J, Goossens A. Oleanolic acid. Phytochemistry 2012; 77: 10-15
• 17 Couch RD, Browning RG, Honda T, Gribble GW, Wright DL, Sporn MB. Studies on the reactivity of CDDO, a promising new chemopreventive and chemotherapeutic agent: implications for a molecular mechanism of action. Bioorg Med Chem Lett 2005; 15: 2215-2219
• 18 Dinkova-Kostova AT, Liby KT, Stephenson KK, Holtzclaw WD, Gao X, Suh N. Extremely potent triterpenoid inducers of the phase 2 response: Correlations of protection against oxidant and inflammatory stress. Proc Natl Acad Sci U S A 2005; 102: 4584-4589
• 19 Janicsák G, Veres K, Zoltán Kakasy A, Máthé I. Study of the oleanolic and ursolic acid contents of some species of the Lamiaceae. Biochem Syst Ecol 2006; 34: 392-396
• 20 Fan JP, Kong T, Zhang L, Tong S, Tian ZY, Duan YH, Zhang XH. Solubilities of ursolic acid and oleanolic acid in four solvents from (283.2 to 329.7) K. J Chem Eng Data 2011; 56: 2723-2725
• 21 Liu L, Wang X. Solubility of oleanolic acid in various solvents from (288.3 to 328.3) K. J Chem Eng Data 2007; 52: 2527-2528
• 22 Xia X, Liu H, Lv H, Zhang J, Zhou J, Zhao Z. Preparation, characterization, and in vitro/vivo studies of oleanolic acid-loaded lactoferrin nanoparticles. Drug Des Devel Ther 2017; 11: 1417-1427
• 23 Chen H, Gao Y, Wang A, Zhou X, Zheng Y, Zhou J. Evolution in medicinal chemistry of ursolic acid derivatives as anticancer agents. Eur J Med Chem 2015; 92: 648-655
• 24 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: 319-325
• 25 Caldeira de Araújo Lopes S, Vinícius Melo Novais M, Salviano Teixeira C, Honorato-Sampaio K, Tadeu Pereira M, Ferreira LA, Braga FC, Cristina Oliveira M. Preparation, physicochemical characterization, and cell viability evaluation of long-circulating and pH-sensitive liposomes containing ursolic acid. Biomed Res Int 2013; 2013: 1-7
• 26 Zhang H, Li X, Ding J, Xu H, Dai X, Hou Z, Zhang K, Sun K, Sun W. Delivery of ursolic acid (UA) in polymeric nanoparticles effectively promotes the apoptosis of gastric cancer cells through enhanced inhibition of cyclooxygenase 2 (COX-2). Int J Pharm 2013; 441: 261-268
• 27 Yin MC, Lin MC, Mong MC, Lin CY. Bioavailability, distribution, and antioxidative effects of selected triterpenes in mice. J Agric Food Chem 2012; 60: 7697-7701
• 28 Kanellos PT, Kaliora AC, Gioxari A, Christopoulou GO, Kalogeropoulos N, Karathanos VT. Absorption and bioavailability of antioxidant phytochemicals and increase of serum oxidation resistance in healthy subjects following supplementation with raisins. Plant Foods Hum Nutr 2013; 68: 411-415
• 29 Zhao L, Li W, Li Y, Xu H, Lv L, Wang X, Chai Y, Zhang G. Simultaneous determination of oleanolic and ursolic acids in rat plasma by HPLC–MS: Application to a pharmacokinetic study after oral administration of different combinations of QingGanSanJie decoction extracts. J Chromatogr Sci 2015; 53: 1185-1192
• 30 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
• 31 Jeong DW, Kim YH, Kim HH, Ji HY, Yoo SD, Choi WR. Dose‐linear pharmacokinetics of oleanolic acid after intravenous and oral administration in rats. Biopharm Drug Dispos 2007; 28: 51-57
• 32 Song M, Hang T, Wang Y, Jiang L, Wu X, Zhang Z, Shen J, Zhang Y. Determination of oleanolic acid in human plasma and study of its pharmacokinetics in Chinese healthy male volunteers by HPLC tandem mass spectrometry. J Pharm Biomed Anal 2006; 40: 190-196
• 33 Rada M, Castellano JM, Perona JS, Guinda Á. GC‐FID determination and pharmacokinetic studies of oleanolic acid in human serum. Biomed Chromatogr 2015; 29: 1687-1692
• 34 Vyas N, Argal A. Isolation and characterization of oleanolic acid from roots of Lantana camara . Asian J Pharm Clin Res 2014; 7: 189-191
• 35 Xia EQ, Wang BW, Xu XR, Zhu L, Song Y, Li HB. Microwave-assisted extraction of oleanolic acid and ursolic acid from Ligustrum lucidum Ait. Int J Mol Sci 2011; 12: 5319-5329
• 36 Johnson E, Ilyas M, Sule M, Eseyin O, Oladimeji H, Etim E. Antimicrobial activity of compounds isolated from the leaves of Aspilia africana (Pers.) C. D. Adams (Asteraceae). Afr J Pharmacol 2016; 5: 149-154
• 37 Pai S, Upadhya V, Hegde H, Joshi RK, Kholkute S. Determination of betulinic acid, oleanolic acid and ursolic acid from Achyranthes aspera L. using RP-UFLC-DAD analysis and evaluation of various parameters for their optimum yield. Indian J Exp Biol 2016; 54: 196-202
• 38 Chunhua Z, Li X, Sun C, Xu CJ, Chen K. Effects of drying methods on the bioactive components in loquat (Eriobotrya japonica Lindl.) flowers. J Med Plant Res 2011; 5: 3037-3041
• 39 Javed S, Ikpefan E, Nahar P, Ismail F, Mahmood Z, Sarker S. Isolation, identification and antiproliferative activity of triterpenes from the genus Monotheca A. DC. Rec Nat Prod 2016; 10: 782-787
• 40 Castellano JM, Guinda A, Macías L, Santos-Lozano JM, Lapetra J, Rada M. Free radical scavenging and α-glucosidase inhibition, two potential mechanisms involved in the anti-diabetic activity of oleanolic acid. Grasas Aceites 2016; 67: e142
• 41 Vetal MD, Chavan RS, Rathod VK. Microwave assisted extraction of ursolic acid and oleanolic acid from Ocimum sanctum . Biotechnol Bioproc E 2014; 19: 720-726
• 42 Yang EJ, Lee W, Ku SK, Song KS, Bae JS. Anti-inflammatory activities of oleanolic acid on HMGB1 activated HUVECs. Food Chem Toxicol 2012; 50: 1288-1294
• 43 Lee W, Yang EJ, Ku SK, Song KS, Bae JS. Anti-inflammatory effects of oleanolic acid on LPS-induced inflammation in vitro and in vivo . Inflammation 2013; 36: 94-102
• 44 Martín R, Cordova C, San Román JA, Gutierrez B, Cachofeiro V, Nieto ML. Oleanolic acid modulates the immune-inflammatory response in mice with experimental autoimmune myocarditis and protects from cardiac injury. Therapeutic implications for the human disease. J Mol Cell Cardiol 2014; 72: 250-562
• 45 Banerjee T, Sar S, Saha S, Baidya A, Sarkar A, Karmakar S, Halder AK, Ghosh N. Herbal Medicines for the Treatment of Liver Cirrhosis. In: Dhara AK, Mandal SC. editors Role of herbal Medicines. Singapore: Springer Nature Singapore; 2023: 185-209
• 46 Wang X, Liu R, Zhang W, Zhang X, Liao N, Wang Z. Oleanolic acid improves hepatic insulin resistance via antioxidant, hypolipidemic and anti-inflammatory effects. Mol Cell Endocrinol 2013; 376: 70-80
• 47 Bednarczyk-Cwynar B, Zaprutko L, Marciniak J, Lewandowski G, Szulc M, Kaminska E. The analgesic and anti-inflammatory effect of new oleanolic acid acyloxyimino derivative. Eur J Pharm Sci 2012; 47: 549-555
• 48 Singh GB, Singh S, Bani S, Gupta BD, Banerjee SK. Anti-inflammatory activity of oleanolic acid in rats and mice. J Pharm Pharmacol 2011; 44: 456-458
• 49 Kapil A, Sharma S. Effect of oleanolic acid on complement in adjuvant- and carrageenan-induced inflammation in rats. J Pharm Pharmacol 2011; 47: 585-587
• 50 Dharmappa K, Kumar R, Nataraju A, Mohamed R, Shivaprasad H, Vishwanath B. Anti-inflammatory activity of oleanolic acid by inhibition of secretory phospholipase A2. Planta Med 2009; 75: 211-215
• 51 Tsai S, Yin MC. Antioxidative and anti‐inflammatory protection of oleanolic acid and ursolic acid in PC12 cells. J Food Sci 2008; 73: H174-H178
• 52 Kashyap D, Sharma A, Tuli HS, Punia S, Sharma AK. Ursolic Acid and Oleanolic Acid: Pentacyclic Terpenoids with Promising Anti-Inflammatory Activities. Recent Pat Inflamm Allergy Drug Discov 2016; 10: 21-33
• 53 Singha S, Das Gupta B, Sarkar A, Jana S, Bharadwaj PK, Sharma N, Haldar PK, Mukherjee PK, Kar A. Chemo-profiling and exploring therapeutic potential of Momordica dioica Roxb. ex Willd. for managing metabolic related disorders: In-vitro studies, and docking based approach. J Ethnopharmacol 2024; 331: 118351
• 54 Paul A, Sarkar A, Banerjee T, Maji A, Sarkar S, Paul S, Karmakar S, Ghosh N, Maity TK. Structural and molecular insights of protein tyrosine phosphatase 1B (PTP1B) and its inhibitors as anti-diabetic agents. J Mol Struct 2023; 1293: 136258
• 55 Ghosh N, Chacko L, Vallamkondu J, Banerjee T, Sarkar C, Singh B, Kalra RS, Bhatti JS, Kandimalla R, Dewanjee S. Clinical strategies and therapeutics for human monkeypox virus: A revised perspective on recent outbreaks. Viruses 2023; 15: 1533
• 56 Sung HY, Kang SW, Kim JL, Li J, Lee ES, Gong JH. Oleanolic acid reduces markers of differentiation in 3 T3-L1 adipocytes. Nutr Res 2010; 30: 831-839
• 57 Li M, Han Z, Bei W, Rong X, Guo J, Hu X. Oleanolic acid attenuates insulin resistance via NF-κB to regulate the IRS1-GLUT4 pathway in HepG2 cells. Evid Based Complement Alternat Med 2015; 2015: 1-9
• 58 Li Y, Wang J, Gu T, Yamahara J, Li Y. Oleanolic acid supplement attenuates liquid fructose-induced adipose tissue insulin resistance through the insulin receptor substrate-1/phosphatidylinositol 3-kinase/Akt signaling pathway in rats. Toxicol Appl Pharmacol 2014; 277: 155-163
• 59 Gamede M, Mabuza L, Ngubane P, Khathi A. The effects of plant-derived oleanolic acid on selected parameters of glucose homeostasis in a diet-induced pre-diabetic rat model. Molecules 2018; 23: 794
• 60 Djeziri FZ, Belarbi M, Murtaza B, Hichami A, Benammar C, Khan NA. Oleanolic acid improves diet-induced obesity by modulating fat preference and inflammation in mice. Biochimie 2018; 152: 110-120
• 61 Wang X, Chen Y, Abdelkader D, Hassan W, Sun H, Liu J. Combination therapy with oleanolic acid and metformin as a synergistic treatment for diabetes. J Diabetes Res 2015; 2015: 1-12
• 62 Mukundwa A, Mukaratirwa S, Masola B. Effects of oleanolic acid on the insulin signaling pathway in skeletal muscle of streptozotocin‐induced diabetic male Sprague‐dawley rats. J Diabetes 2016; 8: 98-108
• 63 Yan Y, Wang S, Gu J, Min Z, Wang R. Effect of nano-oleanolic acid combined with lipid-lowering ketones on insulin resistance in rats with gestational diabetes. J Biomed Nanotechnol 2022; 18: 474-480
• 64 Tabassum N, Ahmad F. Role of natural herbs in the treatment of hypertension. Pharmacogn Rev 2011; 5: 30
• 65 Bachhav SS, Patil SD, Bhutada MS, Surana SJ. Oleanolic acid prevents glucocorticoid‐induced hypertension in rats. Phytother Res 2011; 25: 1435-1439
• 66 Bachhav S, Bhutada M, Patil S, Sharma K, Patil S. Oleanolic acid prevents increase in blood pressure and nephrotoxicity in nitric oxide dependent type of hypertension in rats. Pharmacognosy Res 2015; 7: 385
• 67 Madlala HP, Metzinger T, Van Heerden FR, Musabayane CT, Mubagwa K, Dessy C. Vascular endothelium-dependent and independent actions of oleanolic acid and its synthetic oleanane derivatives as possible mechanisms for hypotensive effects. PLoS One 2016; 11: e0147395
• 68 Zhang S, Liu Y, Wang X, Tian Z, Qi D, Li Y, Jiang H. Antihypertensive activity of oleanolic acid is mediated via downregulation of secretory phospholipase A2 and fatty acid synthase in spontaneously hypertensive rats. Int J Mol Med 2020; 46: 2019-2034
• 69 Yu R, Yang W, Qi D, Gong L, Li C, Li Y, Jiang H. Targeted neurotransmitter metabolomics profiling of oleanolic acid in the treatment of spontaneously hypertensive rats. RSC Adv 2019; 9: 23276-23288
• 70 Ahn YM, Choi YH, Yoon JJ, Lee YJ, Cho KW, Kang DG, Lee HS. Oleanolic acid modulates the renin-angiotensin system and cardiac natriuretic hormone concomitantly with volume and pressure balance in rats. Eur J Pharmacol 2017; 809: 231-241
• 71 Pan Y, Zhou F, Song Z, Huang H, Chen Y, Shen Y, Jia Y, Chen J. Oleanolic acid protects against pathogenesis of atherosclerosis, possibly via FXR-mediated angiotensin (Ang)-(1–7) upregulation. Biomed Pharmacother 2018; 97: 1694-1700
• 72 Luo H, Liu J, Ouyang Q, Xuan C, Wang L, Li T, Liu J. The effects of oleanolic acid on atherosclerosis in different animal models. Acta Biochim Biophys Sin (Shanghai) 2017; 49: 349-354
• 73 Jiang Q, Wang D, Han Y, Han Z, Zhong W, Wang C. Modulation of oxidized-LDL receptor-1 (LOX1) contributes to the antiatherosclerosis effect of oleanolic acid. Int J Biochem Cell Biol 2015; 69: 142-152
• 74 Zhao H, Zhou M, Duan L, Wang W, Zhang J, Wang D. Efficient synthesis and anti-fungal activity of oleanolic acid oxime esters. Molecules 2013; 18: 3615-3629
• 75 Joy Hoskeri H, Krishna V, Vinay Kumar B, Shridar AH, Ramesh Babu K, Sudarshana MS. In vivo prophylactic effects of oleanolic acid isolated from chloroform extract of Flaveria trinervia against ethanol induced liver toxicity in rats. Arch Pharm Res 2012; 35: 1803-1810
• 76 Chen Y, Liu J, Yang X, Zhao X, Xu H. Oleanolic acid nanosuspensions: preparation, in-vitro characterization and enhanced hepatoprotective effect. J Pharm Pharmacol 2010; 57: 259-264
• 77 Banerjee T, Sarkar A, Ali SZ, Bhowmik R, Karmakar S, Halder AK, Ghosh N. Bioprotective role of phytocompounds against the pathogenesis of non-alcoholic fatty liver disease to non-alcoholic steatohepatitis: Unravelling underlying molecular mechanisms. Planta Med 2024; 90: 675-707
• 78 Liu J, Wu Q, Lu YF, Pi J. New insights into generalized hepatoprotective effects of oleanolic acid: key roles of metallothionein and Nrf2 induction. Biochem Pharmacol 2008; 76: 922-928
• 79 Chu F, Zhang W, Guo W, Wang Z, Yang Y, Zhang X, Fang K, Yan M, Lei H. Oleanolic acid-amino acids derivatives: Design, synthesis, and hepatoprotective evaluation in vitro and in vivo . Molecules 2018; 23: 322
• 80 Wang W, Chen K, Xia Y, Mo W, Wang F, Dai W, Niu P. The hepatoprotection by oleanolic acid preconditioning: Focusing on PPAR α activation. PPAR Res 2018; 2018: 1-14
• 81 Liu J, Lu Y, Wu Q, Xu S, Shi F, Klaassen CD. Oleanolic acid reprograms the liver to protect against hepatotoxicants, but is hepatotoxic at high doses. Liver Int 2019; 39: 427-439
• 82 Gutiérrez-Rebolledo GA, Siordia-Reyes AG, Meckes-Fischer M, Jiménez-Arellanes A. Hepatoprotective properties of oleanolic and ursolic acids in antitubercular drug-induced liver damage. Asian Pac J Trop Med 2016; 9: 644-651
• 83 Yamazaki Y, Kakizaki S, Horiguchi N, Takagi H, Mori M, Negishi M. Role of nuclear receptor CAR in carbon tetrachloride-induced hepatotoxicity. World J Gastroenterol 2005; 11: 5966-5972
• 84 Wang X, Bai H, Zhang X, Liu J, Cao P, Liao N. Inhibitory effect of oleanolic acid on hepatocellular carcinoma via ERK–p 53-mediated cell cycle arrest and mitochondrial-dependent apoptosis. Carcinogenesis 2013; 34: 1323-1330
• 85 Liese J, Abhari BA, Fulda S. Smac mimetic and oleanolic acid synergize to induce cell death in human hepatocellular carcinoma cells. Cancer Lett 2015; 365: 47-56
• 86 Zhao X, Liu M, Li D. Oleanolic acid suppresses the proliferation of lung carcinoma cells by miR-122/Cyclin G1/MEF2D axis. Mol Cell Biochem 2015; 400: 1-7
• 87 Amara S, Zheng M, Tiriveedhi V. Oleanolic acid inhibits high salt-induced exaggeration of Warburg-like metabolism in breast cancer cells. Cell Biochem Biophys 2016; 74: 427-434
• 88 Mu D, Guo H, Zhou G, Li J, Su B. Oleanolic acid suppresses the proliferation of human bladder cancer by Akt/mTOR/S6K and ERK1/2 signaling. Int J Clin Exp Pathol 2015; 811: 13864-13870
• 89 Song X, Liu CC, Hong YR, Zhu XC. Anticancer activity of novel oleanolic acid methyl ester derivative in HeLa cervical cancer cells is mediated through apoptosis induction and reactive oxygen species production. Bangladesh J Pharmacol 2015; 10: 896
• 90 Bian M, Sun Y, Liu Y, Xu Z, Fan R, Liu Z, Liu W. A gold(I) complex containing an oleanolic acid derivative as a potential anti‐ovarian‐cancer agent by inhibiting TrxR and activating ROS‐mediated ERS. Chemistry 2020; 26: 7092-7108
• 91 Cheon SY, Jin BR, Kim HJ, An HJ. Oleanolic acid ameliorates benign prostatic hyperplasia by regulating PCNA-dependent cell cycle progression in vivo and in vitro . J Nat Prod 2020; 83: 1183-1189
• 92 Li Y, Xu Q, Yang W, Wu T, Lu X. Oleanolic acid reduces aerobic glycolysis-associated proliferation by inhibiting yes-associated protein in gastric cancer cells. Gene 2019; 712: 143956
• 93 Kim GJ, Jo HJ, Lee KJ, Choi JW, An JH. Oleanolic acid induces p 53-dependent apoptosis via the ERK/JNK/AKT pathway in cancer cell lines in prostatic cancer xenografts in mice. Oncotarget 2018; 9: 26370-26386
• 94 Mbaveng AT, Chi GF, Bonsou IN, Abdelfatah S, Tamfu AN, Yeboah EMO, Kuete V, Efferth T. N-acetylglycoside of oleanolic acid (aridanin) displays promising cytotoxicity towards human and animal cancer cells, inducing apoptotic, ferroptotic and necroptotic cell death. Phytomedicine 2020; 76: 153261
• 95 Peng XP, Li XH, Li Y, Huang XT, Luo ZQ. The protective effect of oleanolic acid on NMDA-induced MLE-12 cells apoptosis and lung injury in mice by activating SIRT1 and reducing NF-κB acetylation. Int Immunopharmacol 2019; 70: 520-529
• 96 Potočnjak I, Šimić L, Vukelić I, Domitrović R. Oleanolic acid attenuates cisplatin-induced nephrotoxicity in mice and chemosensitizes human cervical cancer cells to cisplatin cytotoxicity. Food Chem Toxicol 2019; 132: 110676
• 97 Bao Y, Zhang S, Chen Z, Chen AT, Ma J, Deng G, Xu W, Zhou J, Yu ZQ, Yao G, Chen J. Synergistic chemotherapy for breast cancer and breast cancer brain metastases via paclitaxel-loaded oleanolic acid nanoparticles. Mol Pharm 2020; 17: 1343-1351
• 98 Sarkar A, Paul A, Banerjee T, Maji A, Saha S, Bishayee A, Maity TK. Therapeutic advancements in targeting BCL-2 family proteins by epigenetic regulators, natural, and synthetic agents in cancer. Eur J Pharmacol 2023; 944: 175588
• 99 Sar S, Banerjee T, Kumar A, Baidya A, Saha S, Mondal J, Chaki R, Halder AK, Ghosh N. Role of Natural Polysaccharides in the Management of Lifestyle Diseases. In: Dhara AK, Mandal SC. editors Role of Herbal Medicines. Singapore: Springer Nature Singapore; 2023: 415-441
• 100 Sar S, Banerjee T, Baidya A, Saha S, Kumar A, Halder AK, Ghosh M, Nasare VD, Ghosh N. Pharmacovigilance of Herbal Medicines for Lifestyle Diseases. In: Dhara AK, Mandal SC. editors Role of Herbal Medicines. Singapore: Springer Nature Singapore; 2023: 525-543
• 101 Khan MW, Zhao P, Khan A, Raza F, Raza SM, Sarfraz M. Synergism of cisplatin-oleanolic acid co-loaded calcium carbonate nanoparticles on hepatocellular carcinoma cells for enhanced apoptosis and reduced hepatotoxicity. Int J Nanomedicine 2019; 14: 3753-3771
• 102 Wang R, Yang W, Fan Y, Dehaen W, Li Y, Li H. Design and synthesis of the novel oleanolic acid-cinnamic acid ester derivatives and glycyrrhetinic acid-cinnamic acid ester derivatives with cytotoxic properties. Bioorg Chem 2019; 88: 102951
• 103 Piet M, Paduch R. Ursolic and oleanolic acids in combination therapy inhibit migration of colon cancer cells through down-regulation of the uPA/uPAR-dependent MMPs pathway. Chem Biol Interact 2022; 368: 110202
• 104 Wei J, Liu H, Liu M, Wu N, Zhao J, Xiao L, Han L, Chu E, Lin X. Oleanolic acid potentiates the antitumor activity of 5-fluorouracil in pancreatic cancer cells. Oncol Rep 2012; 28: 1339-1345
• 105 Xu AL, Xue YY, Tao WT, Wang SQ, Xu HQ. Oleanolic acid combined with olaparib enhances radiosensitization in triple negative breast cancer and hypoxia imaging with 18F-FETNIM micro PET/CT. Biomed Pharmacother 2022; 150: 113007
• 106 Wang H, Zhong W, Zhao J, Zhang H, Zhang Q, Liang Y. Oleanolic acid inhibits epithelial–mesenchymal transition of hepatocellular carcinoma by promoting iNOS dimerization. Mol Cancer Ther 2019; 18: 62-74
• 107 Macaşoi I, Pavel I, Moacă A, Avram Ş, David V, Coricovac D. Mechanistic investigations of antitumor activity of a Rhodamine B-oleanolic acid derivative bioconjugate. Oncol Rep 2020; 44: 1169-1183
• 108 Fan JP, Lai XH, Zhang XH, Yang L, Yuan TT, Chen HP. Synthesis and evaluation of the cancer cell growth inhibitory activity of the ionic derivatives of oleanolic acid and ursolic acid with improved solubility. J Mol Liq 2021; 332: 115837
• 109 Wang J, Ren H, Xu QL, Zhou ZY, Wu P, Wei XY. Antibacterial oleanane-type triterpenoids from pericarps of Akebia trifoliata . Food Chem 2015; 168: 623-629
• 110 Kim S, Lee H, Lee S, Yoon Y, Choi KH. Antimicrobial action of oleanolic acid on Listeria monocytogenes, Enterococcus faecium, and Enterococcus faecalis . PLoS One 2015; 10: e0118800
• 111 Jiménez-Arellanes A, Luna-Herrera J, Cornejo-Garrido J, López-García S, Castro-Mussot ME, Meckes-Fischer M. Ursolic and oleanolic acids as antimicrobial and immunomodulatory compounds for tuberculosis treatment. BMC Complement Altern Med 2013; 13: 258
• 112 Ge F, Zeng F, Liu S, Guo N, Ye H, Song Y. In vitro synergistic interactions of oleanolic acid in combination with isoniazid, rifampicin or ethambutol against Mycobacterium tuberculosis . J Med Microbiol 2010; 59: 567-572
• 113 Zhou Y, Guo Y, Sun X, Ding R, Wang Y, Niu X. Application of oleanolic acid and its analogues in combating pathogenic bacteria in vitro/vivo by a two-pronged strategy of β-lactamases and hemolysins. ACS Omega 2020; 5: 11424-11438
• 114 Gao D, Tang S, Tong Q. Oleanolic acid liposomes with polyethylene glycol modification: promising antitumor drug delivery. Int J Nanomedicine 2012; 7: 3517-3526
• 115 Justo OR, Moraes AM. Kanamycin incorporation in lipid vesicles prepared by ethanol injection designed for tuberculosis treatment. J Pharm Pharmacol 2010; 57: 23-30
• 116 Chen-yu G, Chun-fen Y, Qi-lu L, Qi T, Yan-wei X, Wei-na L, Guang-xi Z. Development of a quercetin-loaded nanostructured lipid carrier formulation for topical delivery. Int J Pharm 2012; 430: 292-298
• 117 Luo Y, Liu Z, Zhang X, Huang J, Yu X, Li J, Xiong D, Sun X, Zhong Z. Effect of a controlled-release drug delivery system made of oleanolic acid formulated into multivesicular liposomes on hepatocellular carcinoma in vitro and in vivo . Int J Nanomedicine 2016; 11: 3111-3129
• 118 Alvarado HL, Abrego G, Souto EB, Garduño-Ramirez ML, Clares B, García ML, Calpena AC. Nanoemulsions for dermal controlled release of oleanolic and ursolic acids: In vitro, ex vivo and in vivo characterization. Colloids Surf B Biointerfaces 2015; 130: 40-47
• 119 Zhang L, Chen Y, Shi R, Kang T, Pang G, Wang B, Zhao Y, Zeng X, Zou C, Wu P, Li J. Synthesis of hollow nanocages MOF-5 as drug delivery vehicle to solve the load-bearing problem of insoluble antitumor drug oleanolic acid (OA). Inorg Chem Commun 2018; 96: 20-23
• 120 Xi J, Chang Q, Chan CK, Meng ZY, Wang GN, Sun JB. Formulation development and bioavailability evaluation of a self-nanoemulsified drug delivery system of oleanolic acid. AAPS PharmSciTech 2009; 10: 172-182
• 121 Zhang K, Lv S, Li X, Feng Y, Li X, Liu L, Li S, Li Y. Preparation, characterization, and in vivo pharmacokinetics of nanostructured lipid carriers loaded with oleanolic acid and gentiopicrin. Int J Nanomedicine 2013; 8: 3227-3239
• 122 Kumbham S, Paul M, Bhatt H, Ghosh B, Biswas S. Oleanolic acid-conjugated poly (D, l-lactide)-based micelles for effective delivery of doxorubicin and combination chemotherapy in oral cancer. J Mol Liq 2020; 320: 114389
• 123 Sarfraz M, Afzal A, Raza SM, Bashir S, Madni A, Khan MW. Liposomal co-delivered oleanolic acid attenuates doxorubicin-induced multi-organ toxicity in hepatocellular carcinoma. Oncotarget 2017; 8: 47136-47153
• 124 Khan MW, Zou C, Hassan S, Din FU, Abdoul Razak MY, Nawaz A. Cisplatin and oleanolic acid Co-loaded pH-sensitive CaCO₃ nanoparticles for synergistic chemotherapy. RSC Adv 2022; 12: 14808-14818
• 125 Sibiya HP, Mabandla MV, Musabayane CT. The effects of transdermally delivered oleanolic acid on malaria parasites and blood glucose homeostasis in P. berghei-infected male sprague-dawley rats. PLoS One 2016; 11: e0167132
• 126 Chen X, Niu S, Bremner DH, Zhang X, Zhang H, Zhang Y. Co-delivery of doxorubicin and oleanolic acid by triple-sensitive nanocomposite based on chitosan for effective promoting tumor apoptosis. Carbohydr Polym 2020; 247: 116672
• 127 Xue C, Lv H, Li Y, Dong N, Wang Y, Zhou J. Oleanolic acid reshapes the gut microbiota and alters immune‐related gene expression of intestinal epithelial cells. J Sci Food Agric 2022; 102: 764-773
• 128 Wang W, Wu L, Li J, Ji J, Chen K, Yu Q. Alleviation of hepatic ischemia reperfusion injury by oleanolic acid pretreating via reducing HMGB1 release and inhibiting apoptosis and autophagy. Mediators Inflamm 2019; 2019: 1-10
• 129 Loesche A, Köwitsch A, Lucas SD, Al-Halabi Z, Sippl W, Al-Harrasi A. Ursolic and oleanolic acid derivatives with cholinesterase inhibiting potential. Bioorg Chem 2019; 85: 23-32
• 130 Wang K, Sun W, Zhang L, Guo W, Xu J, Liu S. Oleanolic acid ameliorates Aβ25–35 injection-induced memory deficit in alzheimerʼs disease model rats by maintaining synaptic plasticity. CNS Neurol Disord Drug Targets 2018; 17: 389-399
• 131 Han YW, Liu XJ, Zhao Y, Li XM. Role of Oleanolic acid in maintaining BBB integrity by targeting p 38MAPK/VEGF/Src signaling pathway in rat model of subarachnoid hemorrhage. Eur J Pharmacol 2018; 839: 12-20
• 132 Wang JL, Ren CH, Feng J, Ou CH, Liu L. Oleanolic acid inhibits mouse spinal cord injury through suppressing inflammation and apoptosis via the blockage of p 38 and JNK MAPKs. Biomed Pharmacother 2020; 123: 109752
• 133 Hong DS, Kurzrock R, Supko JG, He X, Naing A, Wheler J. A phase I first-in-human trial of bardoxolone methyl in patients with advanced solid tumors and lymphomas. Clin Cancer Res 2012; 18: 3396-3406
• 134 Pergola PE, Raskin P, Toto RD, Meyer CJ, Huff JW, Grossman EB, Krauth M, Ruiz S, Audhya P, Christ-Schmidt H, Wittes J, Warnock DG. BEAM Study Investigators. Bardoxolone methyl and kidney function in CKD with type 2 diabetes. N Engl J Med 2011; 365: 327-336
• 135 De Zeeuw D, Akizawa T, Audhya P, Bakris GL, Chin M, Christ-Schmidt H, Goldsberry A, Houser M, Krauth M, Lambers Heerspink HJ, McMurray JJ, Meyer CJ, Parving HH, Remuzzi G, Toto RD, Vaziri ND, Wanner C, Wittes J, Wrolstad D, Chertow GM. BEACON Trial Investigators. Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. N Engl J Med 2013; 369: 2492-2503
• 136 Chen RJ, Liu X, Li PM, Zhang L, Zhao L, Zhang XL. Pharmacokinetic profiles of oleanolic acid formulations in healthy Chinese male volunteers. Chin Phar J 2010; 45: 621-626