Letter to the editor
Recent studies on ursolic acid and its biological and pharmacological activity
Sook Young Lee1, Yong Joo Kim2, Sun Ok Chung2, Sang Un Park31Regional Innovation Center for Dental Science and Engineering, Chosun University, 309 Pilmun-daero, Dong-gu, Gwangju, 501-759, Korea
2Department of Biosystems Machinery Engineering, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon, 305-764, Korea
3Department of Crop Science, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon, 305-764, Korea
EXCLI J 2016;15:Doc221
Ursolic acid (3-beta-3-hydroxy-urs-12-ene-28-oic-acid; UA) is a lipophilic pentacyclic triterpenoid; it was found to be present in the epicuticular waxes of apples in 1920. It is widely found naturally in the peels of fruits, as well as in many herbs and spices such as lavender, oregano, thyme, rosemary, and thyme (Woźniak et al., 2015). UA has been confirmed to have several biological and pharmacological effects, such as anti-inflammatory (Baricevic et al., 2001), antitumor (Baglin et al., 2003), antiplatelet aggregation (Babalola et al., 2013), anti-HIV (Kashiwada et al., 2000), and anti-Mycobacterium tuberculosis effects (Cantrell et al., 2001).
Its many pharmaceutical and biological properties make it an interesting material for application in the pharmaceutical, food, and cosmetics industries. Herein, we review the most recent studies on UA and its biological and pharmacological activities (Table 1(Tab. 1)). (References in Table 1: Meng et al., 2015; He et al., 2015; Wang et al., 2015; Yang et al., 2015; Chu et al., 2015; Jeon et al., 2015; Cho et al., 2015; Yuliang et al., 2015; Bakhtiari et al., 2015; Prissadova et al., 2015; Yuan et al., 2015; Li et al., 2015; Xu et al., 2015; Xiang et al., 2015; Jiang et al., 2015; Gao et al., 2015; Kim and Moon, 2015; Yie et al., 2015; Kim et al., 2015; Chen et al., 2015; Ma et al., 2015; Hu et al., 2015; Jia et al., 2015; Podder et al., 2015; Zhang et al., 2014; Zou et al., 2014; Weng et al., 2014; Kalani et al., 2014; Hwang et al., 2014; Bang et al., 2014; He et al., 2014; Castro et al., 2015; Liu et al., 2013; Sundaresan et al., 2014; Baek et al., 2014; Lee et al., 2014; Saini et al., 2014; Chun et al., 2014; Ou et al., 2014; Li et al., 2014; Ma et al., 2014; Qu et al., 2013; Han et al., 2014; Kim et al., 2014; Deng et al., 2014; Ling et al., 2013; do Nascimento et al., 2014; Wang et al., 2013; Nam and Kim et al., 2013; Lin et al., 2013; Song et al., 2014; Zhou et al., 2013)
This research was supported by Agriculture, Food and Rural Affairs Research Center Support Program, Ministry of Agriculture, Food and Rural Affairs.
Conflict of interest
The authors declare no conflict of interest.
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2. Baek SY, Lee J, Lee DG, Park MK, Lee J, Kwok SK, et al. Ursolic acid ameliorates autoimmune arthritis via suppression of Th17 and B cell differentiation. Acta Pharmacol Sin. 2014;35:1177-87.
3. Baglin I, Mitaine-Offer AC, Nour M, Tan CC, Lacaille-Dubois MA. A review of natural and modified betulinic, ursolic and echnocystic acid derivatives as potential antitumour and anti-HIV agents. Mini Rev Med Chem. 2003;3:525-39.
4. Bakhtiari N, Hosseinkhani S, Tashakor A, Hemmati R. Ursolic acid ameliorates aging-metabolic phenotype through promoting of skeletal muscle rejuvenation. Med Hypotheses. 2015;85:1-6.
5. Bang HS, Seo DY, Chung YM, Oh KM, Park JJ, Arturo F, et al. Ursolic acid-induced elevation of serum irisin augments muscle strength during resistance training in men. Korean J Physiol Pharmacol. 2014;18:441-6.
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8. Castro AJ, Frederico MJ, Cazarolli LH, Mendes CP, Bretanha LC, Schmidt ÉC, et al. The mechanism of action of ursolic acid as insulin secretagogue and insulinomimetic is mediated by cross-talk between calcium and kinases to regulate glucose balance. Biochim Biophys Acta. 2015;1850:51-61.
9. Chen J, Wong HS, Ko KM. Mitochondrial reactive oxygen species production mediates ursolic acid-induced mitochondrial uncoupling and glutathione redox cycling, with protection against oxidant injury in H9c2 cells. Food Funct. 2015;6:549-57.
10. Cho J, Rho O, Junco J, Carbajal S, Siegel D, Slaga TJ, et al. Effect of combined treatment with ursolic acid and resveratrol on skin tumor promotion by 12-O-Tetradecanoylphorbol-13-Acetate. Cancer Prev Res. 2015;8:817-25.
11. Chu X, He X, Shi Z, Li C, Guo F, Li S, et al. Ursolic acid increases energy expenditure through enhancing free fatty acid uptake and β-oxidation via an UCP3/AMPK-dependent pathway in skeletal muscle. Mol Nutr Food Res. 2015;59:1491-503.
12. Chun J, Lee C, Hwang SW, Im JP, Kim JS. Ursolic acid inhibits nuclear factor-κB signaling in intestinal epithelial cells and macrophages, and attenuates experimental colitis in mice. Life Sci. 2014;110:23-34.
13. Deng L, Zhang R, Tang F, Li C, Xing YY, Xi T. Ursolic acid induces U937 cells differentiation by PI3K/Akt pathway activation. Chin J Nat Med. 2014;12:15-9.
14. do Nascimento PG, Lemos TL, Bizerra AM, Arriaga ÂM, Ferreira DA, Santiago GM, et al. Antibacterial and antioxidant activities of ursolic acid and derivatives. Molecules. 2014;19:1317-27.
15. Gao Y, Li Z, Xie X, Wang C, You J, Mo F, et al. Dendrimeric anticancer prodrugs for targeted delivery of ursolic acid to folate receptor-expressing cancer cells: synthesis and biological evaluation. Eur J Pharm Sci. 2015;70:55-63.
16. Han YY, Xue XW, Shi ZM, Wang PY, Wu XR, Wang XJ. Oleanolic acid and ursolic acid inhibit proliferation in transformed rat hepatic oval cells. World J Gastroenterol. 2014;20:1348-56.
17. He W, Shi F, Zhou ZW, Li B, Zhang K, Zhang X, et al. A bioinformatic and mechanistic study elicits the antifibrotic effect of ursolic acid through the attenuation of oxidative stress with the involvement of ERK, PI3K/Akt, and p38 MAPK signaling pathways in human hepatic stellate cells and rat liver. Drug Des Devel Ther. 2015;9:3989-4104.
18. He Y, Li W, Li Y, Zhang S, Wang Y, Sun C. Ursolic acid increases glucose uptake through the PI3K signaling pathway in adipocytes. PloS One. 2014;9:e110711.
19. Hu Z, Gu Z, Sun M, Zhang K, Gao P, Yang Q, et al. Ursolic acid improves survival and attenuates lung injury in septic rats induced by cecal ligation and puncture. J Surg Res. 2015;194:528-36.
20. Hwang TL, Shen HI, Liu FC, Tsai HI, Wu YC, Chang FR, et al. Ursolic acid inhibits superoxide production in activated neutrophils and attenuates trauma-hemorrhage shock-induced organ injury in rats. PLoS One. 2014;9:e111365.
21. Jeon SJ, Park HJ, Gao Q, Pena IJ, Park SJ, Lee HE, et al. Ursolic acid enhances pentobarbital-induced sleeping behaviors via GABAergic neurotransmission in mice. Eur J Pharmacol. 2015;762:443-8.
22. Jia Y, Kim S, Kim J, Kim B, Wu C, Lee JH, et al. Ursolic acid improves lipid and glucose metabolism in high-fat-fed C57BL/6J mice by activating peroxisome proliferator-activated receptor alpha and hepatic autophagy. Mol Nutr Food Res. 2015;59:344-54.
23. Jiang C, Xiao F, Gu X, Zhai Z, Liu X, Wang W, et al. Inhibitory effects of ursolic acid on osteoclastogenesis and titanium particle-induced osteolysis are mediated primarily via suppression of NF-κB signaling. Biochimie. 2015;111:107-18.
24. Kalani K, Kushwaha V, Sharma P, Verma R, Srivastava M, Khan F, et al. In vitro, in silico and in vivo studies of ursolic acid as an anti-filarial agent. PLoS One. 2014;9:e111244.
25. Kashiwada Y, Nagao T, Hashimoto A, Ikeshiro Y, Okabe H, Consentino LM, et al. Anti-AIDS agents 38. Anti-HIV activity of 3-O-acyl ursolic acid derivatives. J Nat Prod. 2000;63:1619-22.
26. Kim ES, Moon A. Ursolic acid inhibits the invasive phenotype of SNU-484 human gastric cancer cells. Oncol Lett. 2015;9:897-902.
27. Kim JH, Kim YH, Song GY, Kim DE, Jeong YJ, Liu KH, et al. Ursolic acid and its natural derivative corosolic acid suppress the proliferation of APC-mutated colon cancer cells through promotion of β-catenin degradation. Food Chem Toxicol. 2014;67:87-95.
28. Kim M, Sung B, Kang YJ, Kim DH, Lee Y, Hwang SY, et al. The combination of ursolic acid and leucine potentiates the differentiation of C2C12 murine myoblasts through the mTOR signaling pathway. Int J Mol Med. 2015;35:755-62.
29. Lee J, Lee HI, Seo KI, Cho HW, Kim MJ, Park EM, et al. Effects of ursolic acid on glucose metabolism, the polyol pathway and dyslipidemia in non-obese type 2 diabetic mice. Indian J Exp Biol. 2014;52:683-91.
30. Li JS, Wang WJ, Sun Y, Zhang YH, Zheng L. Ursolic acid inhibits the development of nonalcoholic fatty liver disease by attenuating endoplasmic reticulum stress. Food Funct. 2015;6:1643-51.
31. Li Y, Lu X, Qi H, Li X, Xiao X, Gao J. Ursolic acid induces apoptosis through mitochondrial intrinsic pathway and suppression of ERK1/2 MAPK in HeLa cells. J Pharmacol Sci. 2014;125:202-10.
32. Lin J, Chen Y, Wei L, Hong Z, Sferra TJ, Peng J. Ursolic acid inhibits colorectal cancer angiogenesis through suppression of multiple signaling pathways. Int J Oncol. 2013;43:1666-74.
33. Ling C, Jinping L, Xia L, Renyong Y. Ursolic acid provides kidney protection in diabetic rats. Curr Ther Res Clin Exp. 2013;75:59-63.
34. Liu B, Liu Y, Yang G, Xu Z, Chen J. Ursolic acid induces neural regeneration after sciatic nerve injury. Neural Regen Res. 2013;8:2510-9.
35. Ma JQ, Ding J, Xiao ZH, Liu CM. Ursolic acid ameliorates carbon tetrachloride-induced oxidative DNA damage and inflammation in mouse kidney by inhibiting the STAT3 and NF-κB activities. Int Immunopharmacol. 2014;21:389-95.
36. Ma JQ, Ding J, Zhang L, Liu CM. Protective effects of ursolic acid in an experimental model of liver fibrosis through Nrf2/ARE pathway. Clin Res Hepatol Gastroenterol. 2015;39:188-97.
37. Meng Y, Lin ZM, Ge N, Zhang DL, Huang J, Kong F. Ursolic acid induces apoptosis of prostate cancer cells via the PI3K/Akt/mTOR pathway. Am J Chin Med. 2015;43:1471-86.
38. Nam H, Kim MM. Ursolic acid induces apoptosis of SW480 cells via p53 activation. Food Chem Toxicol. 2013;62:579-83.
39. Ou X, Liu M, Luo H, Dong LQ, Liu F. Ursolic acid inhibits leucine-stimulated mTORC1 signaling by suppressing mTOR localization to lysosome. PLoS One. 2014;9:e95393.
40. Podder B, Jang WS, Nam KW, Lee BE, Song HY. Ursolic acid activates intracellular killing effect of macrophages during mycobacterium tuberculosis infection. J Microbiol Biotechnol. 2015;25:738-44.
41. Prissadova N, Bozov P, Marinkov K, Badakov H, Kristev A. effects of ursolic acid on contractile activity of gastric smooth muscles. Nat Prod Commun. 2015;10:565-6.
42. Saini P, Gayen P, Kumar D, Nayak A, Mukherjee N, Mukherjee S, et al. Antifilarial effect of ursolic acid from Nyctanthes arbortristis: molecular and biochemical evidences. Parasitol Int. 2014;63:717-28.
43. Song J, Wang Y, Song Y, Chan H, Bi C, Yang X, et al. Development and characterisation of ursolic acid nanocrystals without stabiliser having improved dissolution rate and in vitro anticancer activity. AAPS Pharm Sci Tech. 2014;15:11-9.
44. Sundaresan A, Radhiga T, Pugalendi KV. Effect of ursolic acid and Rosiglitazone combination on hepatic lipid accumulation in high fat diet-fed C57BL/6J mice. Eur J Pharmacol. 2014;741:297-303.
45. Wang W, Zhao C, Jou D, Lü J, Zhang C, Lin L, et al. Ursolic acid inhibits the growth of colon cancer-initiating cells by targeting STAT3. Anticancer Res. 2013;33:4279-84.
46. Wang Y, Song J, Chow SF, Chow AH, Zheng Y. Particle size tailoring of ursolic acid nanosuspensions for improved anticancer activity by controlled antisolvent precipitation. Int J Pharm. 2015;494:479-89.
47. Weng H, Tan ZJ, Hu YP, Shu YJ, Bao RF, Jiang L, et al. Ursolic acid induces cell cycle arrest and apoptosis of gallbladder carcinoma cells. Cancer Cell Int. 2014;14:96.
48. Woźniak Ł, Skąpska S, Marszałek K. Ursolic acid - a pentacyclic triterpenoid with a wide spectrum of pharmacological activities. Molecules. 2015;20:20614-41.
49. Xiang L, Chi T, Tang Q, Yang X, Ou M, Chen X, et al. A pentacyclic triterpene natural product, ursolic acid and its prodrug US597 inhibit targets within cell adhesion pathway and prevent cancer metastasis. Oncotarget. 2015;6:9295-312.
50. Xu H, Zhang M, Li XL, Li H, Yue LT, Zhang XX, et al. Low and high doses of ursolic acid ameliorate experimental autoimmune myasthenia gravis through different pathways. J Neuroimmunol. 2015;281:61-7.
51. Yang Y, Jiang M, Hu J, Lv X, Yu L, Qian X, et al. Enhancement of radiation effects by ursolic acid in BGC-823 human adenocarcinoma gastric cancer cell line. PLoS One. 2015;10:e0133169.
52. Yie Y, Zhao S, Tang Q, Zheng F, Wu J, Yang L, et al. Ursolic acid inhibited growth of hepatocellular carcinoma HepG2 cells through AMPKα-mediated reduction of DNA methyltransferase 1. Mol Cell Biochem. 2015;402:63-74.
53. Yuan Y, Gao Y, Song G, Lin S. Ursolic acid and oleanolic acid from Eriobotrya fragrans inhibited the viability of A549 cells. Nat Prod Commun. 2015;10:239-42.
54. Yuliang W, Zejian W, Hanlin S, Ming Y, Kexuan T. The hypolipidemic effect of artesunate and ursolic acid in rats. Pak J Pharm Sci. 2015;28:871-4.
55. 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;23:585-91.
56. Zhou L, Ding Y, Chen W, Zhang P, Chen Y, Lv X. The in vitro study of ursolic acid and oleanolic acid inhibiting cariogenic microorganisms as well as biofilm. Oral Dis. 2013;19:494-500.
57. Zou Y, Lee Y, Huh J, Park JW. Synergistic effect of xylitol and ursolic acid combination on oral biofilms. Restor Dent Endod. 2014;39:288-95.
Table 1: Recent studies on ursolic acid and its biological and pharmacological activities