Oleanolic Acid: Extraction, Characterization and Biological Activity

José M Castellano, Sara Ramos-Romero, Javier S Perona, José M Castellano, Sara Ramos-Romero, Javier S Perona

Abstract

Oleanolic acid, a pentacyclic triterpenoid ubiquitously present in the plant kingdom, is receiving outstanding attention from the scientific community due to its biological activity against multiple diseases. Oleanolic acid is endowed with a wide range of biological activities with therapeutic potential by means of complex and multifactorial mechanisms. There is evidence suggesting that oleanolic acid might be effective against dyslipidemia, diabetes and metabolic syndrome, through enhancing insulin response, preserving the functionality and survival of β-cells and protecting against diabetes complications. In addition, several other functions have been proposed, including antiviral, anti-HIV, antibacterial, antifungal, anticarcinogenic, anti-inflammatory, hepatoprotective, gastroprotective, hypolipidemic and anti-atherosclerotic activities, as well as interfering in several stages of the development of different types of cancer; however, due to its hydrophobic nature, oleanolic acid is almost insoluble in water, which has led to a number of approaches to enhance its biopharmaceutical properties. In this scenario, the present review aimed to summarize the current knowledge and the research progress made in the last years on the extraction and characterization of oleanolic acid and its biological activities and the underlying mechanisms of action.

Keywords: biological activities; characterization; diseases; mechanisms; oleanolic acid; structure.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Chemical structure of oleanolic acid.
Figure 2
Figure 2
Oleanolic acid in the form of prismatic crystals.
Figure 3
Figure 3
Absorbance spectrum of oleanolic acid.
Figure 4
Figure 4
Mass spectrum of oleanolic acid, showing five major m/z fragments: 203.2; 202.2; 189.2; 73.1; 187.2.

References

    1. Tong H., Wu H., Zheng Y., Xi J., Chow A.H., Chan C.K. Physical characterization of oleanolic acid nonsolvate and solvates prepared by solvent recrystallization. Int. J. Pharm. 2008;355:195–202. doi: 10.1016/j.ijpharm.2007.12.005.
    1. Neil M.J., Smith A., Heckelman P.E. The Merck Index. 13th ed. Merck & Co., Inc.; Kenilworth, NJ, USA: 2001.
    1. Albi T., Guinda A., Lanzon A. Obtaining procedure and determination of terpenic acids of olive leaf (Olea europaea) Grasas Aceites. 2001;52:275–278. doi: 10.3989/gya.2001.v52.i5.367.
    1. Verma S.C., Jain C.L., Nigam S., Padhi M.M. Rapid extraction, isolation, and quantification of oleanolic acid from Lantana camara L. Roots using microwave and HPLC-PDA techniques. Acta Chromatogr. 2013;25:181–199. doi: 10.1556/AChrom.25.2013.1.12.
    1. Guinda Á., Pérez-Camino M.C., Lanzón A. Supplementation of oils with oleanolic acid from the olive leaf (Olea europaea) Eur. J. Lipid Sci. Technol. 2004;106:22–26. doi: 10.1002/ejlt.200300769.
    1. Tostes J.B.D.F., Nakamura M.J., de Saboya C.G.F., Mazzei J.L., Siani A.C. Efficient and selective method to separate triterpene acids by direct treatment of apple peels with alkaline ethanol. Sep. Sci. Technol. 2016;51:1986–1993. doi: 10.1080/01496395.2016.1200088.
    1. Jin I.J., Ko Y.I., Kim Y.M., Han S.K. Solubilization of oleanolic acid and ursolic acid by cosolvency. Arch. Pharmacal Res. 1997;20:269–274. doi: 10.1007/BF02976156.
    1. Jäger S., Winkler K., Pfüller U., Scheffler A. Solubility Studies of Oleanolic Acid and Betulinic Acid in Aqueous Solutions and Plant Extracts of Viscum album L. Planta Med. 2007;73:157–162. doi: 10.1055/s-2007-967106.
    1. Schneider P., Hosseiny S., Szczotka M., Jordan V., Schlitter K. Rapid solubility determination of the triterpenes oleanolic acid and ursolic acid by UV-spectroscopy in different solvents. Phytochem. Lett. 2009;2:85–87. doi: 10.1016/j.phytol.2008.12.004.
    1. Xia E.-Q., Yu Y.-Y., Xu X.-R., Deng G.-F., Guo Y.-J., Li H.-B. Ultrasound-assisted extraction of oleanolic acid and ursolic acid from Ligustrum lucidum Ait. Ultrason. Sonochem. 2012;19:772–776. doi: 10.1016/j.ultsonch.2011.11.014.
    1. Schneider P., Bischoff F., Müller U., Bart H.-J., Schlitter K., Jordan V. Plant Extraction with Aqueous Two-Phase Systems. Chem. Eng. Technol. 2011;34:452–458. doi: 10.1002/ceat.201000420.
    1. Wang L., Weller C.L. Recent advances in extraction of nutraceuticals from plants. Trends Food Sci. Technol. 2006;17:300–312. doi: 10.1016/j.tifs.2005.12.004.
    1. Dong J., Liu Y., Liang Z., Wang W. Investigation on ultrasound-assisted extraction of salvianolic acid B from Salvia miltiorrhiza root. Ultrason. Sonochem. 2010;17:61–65. doi: 10.1016/j.ultsonch.2009.05.006.
    1. Wei M.-C., Yang Y.-C. Extraction characteristics and kinetic studies of oleanolic and ursolic acids from Hedyotis diffusa under ultrasound-assisted extraction conditions. Sep. Purif. Technol. 2014;130:182–192. doi: 10.1016/j.seppur.2014.04.029.
    1. Guinda Á., Rada M., Delgado T., Adánez M.P.G., Castellano J.M. Pentacyclic Triterpenoids from Olive Fruit and Leaf. J. Agric. Food Chem. 2010;58:9685–9691. doi: 10.1021/jf102039t.
    1. Guinda A., Rada M., Delgado T., Castellano J.M. Pentacyclic triterpenic acids from Argania spinosa. Eur. J. Lipid Sci. Technol. 2010;113:231–237. doi: 10.1002/ejlt.201000342.
    1. Geană E.I., Ionete R.E., Ciocarlan A., Aricu A., Fulga A., Ungur N., Podogova M., Nikolaeva D. HPLC determination of oleanolic and ursolic acid in Apples and apple pomace. Prog. Cryog. Isot. Sep. 2014;17:53–62.
    1. Wei M.-C., Yang Y.-C., Hong S.-J. Determination of Oleanolic and Ursolic Acids inHedyotis diffusaUsing Hyphenated Ultrasound-Assisted Supercritical Carbon Dioxide Extraction and Chromatography. Evid. Based Complement. Altern. Med. 2015;2015:1–10. doi: 10.1155/2015/450547.
    1. Kaur P., Gupta R., Dey A., Pandey D.K. Simultaneous quantification of oleanolic acid, ursolic acid, betulinic acid and lupeol in different populations of five Swertia species by using HPTLC-densitometry: Comparison of different extraction methods and solvent selection. Ind. Crop. Prod. 2019;130:537–546. doi: 10.1016/j.indcrop.2018.12.089.
    1. Zhang X., Li X., He Q., Zhang B., Zheng X. Ionic Liquid Based Ultrasonic-Assisted Extraction of Oleanolic Acid from Grape Seeds. Open Access Libr. J. 2017;4:e4148. doi: 10.4236/oalib.1104148.
    1. Anekpankul T., Goto M., Sasaki M., Pavasant P., Shotipruk A. Extraction of anti-cancer damnacanthal from roots of Morinda citrifolia by subcritical water. Sep. Purif. Technol. 2007;55:343–349. doi: 10.1016/j.seppur.2007.01.004.
    1. Da Porto C., Decorti D. Supercritical CO2 extraction of grappa volatile compounds. Int. J. Food Sci. Technol. 2009;44:1927–1932. doi: 10.1111/j.1365-2621.2009.01999.x.
    1. Cai J., Liu B., Su Q. Comparison of simultaneous distillation extraction and solid-phase microextraction for the determination of volatile flavor components. J. Chromatogr. A. 2001;930:1–7. doi: 10.1016/S0021-9673(01)01187-6.
    1. Terigar B., Balasubramanian S., Boldor D., Xu Z., Lima M., Sabliov C. Continuous microwave-assisted isoflavone extraction system: Design and performance evaluation. Bioresour. Technol. 2010;101:2466–2471. doi: 10.1016/j.biortech.2009.11.039.
    1. Henry M.C., Yonker C.R. Supercritical Fluid Chromatography, Pressurized Liquid Extraction, and Supercritical Fluid Extraction. Anal. Chem. 2006;78:3909–3916. doi: 10.1021/ac0605703.
    1. Zhang S., Zu Y.-G., Fu Y.-J., Luo M., Liu W., Li J., Efferth T. Supercritical carbon dioxide extraction of seed oil from yellow horn (Xanthoceras sorbifolia Bunge.) and its anti-oxidant activity. Bioresour. Technol. 2010;101:2537–2544. doi: 10.1016/j.biortech.2009.11.082.
    1. Li H.-B., Chen F. Preparative isolation and purification of phillyrin from the medicinal plant Forsythia suspensa by high-speed counter-current chromatography. J. Chromatogr. A. 2005;1083:102–105. doi: 10.1016/j.chroma.2005.06.025.
    1. Yang Y.-C., Wei M.-C., Huang T.-C. Optimisation of an Ultrasound-assisted Extraction Followed by RP-HPLC Separation for the Simultaneous Determination of Oleanolic Acid, Ursolic Acid and Oridonin Content in Rabdosia rubescens. Phytochem. Anal. 2012;23:627–636. doi: 10.1002/pca.2365.
    1. Chandrapala J., Oliver C.M., Kentish S., Ashok Kumar M. Use of Power Ultrasound to Improve Extraction and Modify Phase Transitions in Food Processing. Food Rev. Int. 2013;29:67–91. doi: 10.1080/87559129.2012.692140.
    1. Xia E.-Q., Song Y., Ai X.-X., Guo Y.-J., Xu X.-R., Li H.-B. A New High-Performance Liquid Chromatographic Method for the Determination and Distribution of Linalool in Michelia alba. Molecules. 2010;15:4890–4897. doi: 10.3390/molecules15074890.
    1. Yang Y.-C., Wei M.-C., Lian F.-Y., Huang T.-C. Simultaneous extraction and quantitation of oleanolic acid and ursolic acid Fromscutellaria barbata d. don by ultrasound-assisted extraction and high-performance liquid chromatography. Chem. Eng. Commun. 2013;201:482–500. doi: 10.1080/00986445.2013.777901.
    1. Wanigasekara E., Perera S., Crank J.A., Sidisky L., Shirey R., Berthod A., Armstrong D.W. Bonded ionic liquid polymeric material for solid-phase microextraction GC analysis. Anal. Bioanal. Chem. 2009;396:511–524. doi: 10.1007/s00216-009-3254-2.
    1. Cláudio A.F., Freire M., Freire C., Silvestre A., Coutinho J.A. Extraction of vanillin using ionic-liquid-based aqueous two-phase systems. Sep. Purif. Technol. 2010;75:39–47. doi: 10.1016/j.seppur.2010.07.007.
    1. Ekezie F.-G.C., Sun D.-W., Cheng J.-H. Acceleration of microwave-assisted extraction processes of food components by integrating technologies and applying emerging solvents: A review of latest developments. Trends Food Sci. Technol. 2017;67:160–172. doi: 10.1016/j.tifs.2017.06.006.
    1. Chan C.-H., Yusoff R., Ngoh G.-C., Kung F.W.-L. Microwave-assisted extractions of active ingredients from plants. J. Chromatogr. A. 2011;1218:6213–6225. doi: 10.1016/j.chroma.2011.07.040.
    1. Vetal M.D., Chavan R.S., Rathod V.K. Microwave assisted extraction of ursolic acid and oleanolic acid from Ocimum sanctum. Biotechnol. Bioprocess Eng. 2014;19:720–726. doi: 10.1007/s12257-013-0798-y.
    1. Fang X., Wang J., Yu X., Zhang G., Zhao J. Optimization of microwave-assisted extraction followed by RP-HPLC for the simultaneous determination of oleanolic acid and ursolic acid in the fruits of Chaenomeles sinensis. J. Sep. Sci. 2010;33:1147–1155. doi: 10.1002/jssc.200900726.
    1. Zhang H.-F., Yang X.-H., Wang Y. Microwave assisted extraction of secondary metabolites from plants: Current status and future directions. Trends Food Sci. Technol. 2011;22:672–688. doi: 10.1016/j.tifs.2011.07.003.
    1. Sánchez-Avila N., Priego-Capote F., Jimenez J.R., Luquedecastro M. Fast and selective determination of triterpenic compounds in olive leaves by liquid chromatography–tandem mass spectrometry with multiple reaction monitoring after microwave-assisted extraction. Talanta. 2009;78:40–48. doi: 10.1016/j.talanta.2008.10.037.
    1. Tian Y.-Q., Zhao H.-T., Zhang X.-L., Zhang W.-T., Liu X.-C., Gao S.-H. Comparison of different extraction techniques and optimization of the microwave-assisted extraction of saponins from Aralia elata (Miq.) Seem fruits and rachises. Chem. Pap. 2020;74:3077–3087. doi: 10.1007/s11696-020-01140-2.
    1. Durante M., Ferramosca A., Treppiccione L., Di Giacomo M., Zara V., Montefusco A., Piro G., Mita G., Bergamo P., Lenucci M. Application of response surface methodology (RSM) for the optimization of supercritical CO2 extraction of oil from patè olive cake: Yield, content of bioactive molecules and biological effects In Vivo. Food Chem. 2020;332:127405. doi: 10.1016/j.foodchem.2020.127405.
    1. Yang Y.-C., Wei M.-C., Huang T.-C., Lee S.-Z. Extraction of protocatechuic acid from Scutellaria barbata D. Don using supercritical carbon dioxide. J. Supercrit. Fluids. 2013;81:55–66. doi: 10.1016/j.supflu.2013.04.007.
    1. Castola V., Marongiu B., Bighelli A., Floris C., Laï A., Casanova J. Extractives of cork (Quercus suber L.): Chemical composition of dichloromethane and supercritical CO2 extracts. Ind. Crop. Prod. 2005;21:65–69. doi: 10.1016/j.indcrop.2003.12.007.
    1. Domingues R.M., de Melo M.M., Oliveira E.L., Neto C.P., Silvestre A.J., Silva C.M. Optimization of the supercritical fluid extraction of triterpenic acids from Eucalyptus globulus bark using experimental design. J. Supercrit. Fluids. 2013;74:105–114. doi: 10.1016/j.supflu.2012.12.005.
    1. Pérez-Camino M.C., Cert A. Quantitative Determination of Hydroxy Pentacyclic Triterpene Acids in Vegetable Oils. J. Agric. Food Chem. 1999;47:1558–1562. doi: 10.1021/jf980881h.
    1. Jemmali Z., Chartier A., Dufresne C., Elfakir C. Optimization of the derivatization protocol of pentacyclic triterpenes prior to their gas chromatography–mass spectrometry analysis in plant extracts. Talanta. 2016;147:35–43. doi: 10.1016/j.talanta.2015.09.026.
    1. Domingues R., Sousa G., Freire C., Silvestre A., Neto C. Eucalyptus globulus biomass residues from pulping industry as a source of high value triterpenic compounds. Ind. Crop. Prod. 2010;31:65–70. doi: 10.1016/j.indcrop.2009.09.002.
    1. Leipold D., Wünsch G., Schmidt M., Bart H.-J., Bley T., Neuhaus H.E., Bergmann H., Richling E., Muffler K., Ulber R. Biosynthesis of ursolic acid derivatives by microbial metabolism of ursolic acid with Nocardia sp. strains—Proposal of new biosynthetic pathways. Process Biochem. 2010;45:1043–1051. doi: 10.1016/j.procbio.2010.03.013.
    1. Martelanc M., Vovk I., Simonovska B. Separation and identification of some common isomeric plant triterpenoids by thin-layer chromatography and high-performance liquid chromatography. J. Chromatogr. A. 2009;1216:6662–6670. doi: 10.1016/j.chroma.2009.07.038.
    1. Huang Y., Zhang T., Zhou H., Feng Y., Fan C., Chen W., Crommen J., Jiang Z. Fast separation of triterpenoid saponins using supercritical fluid chromatography coupled with single quadrupole mass spectrometry. J. Pharm. Biomed. Anal. 2016;121:22–29. doi: 10.1016/j.jpba.2015.12.056.
    1. Kontogianni V.G., Exarchou V., Troganis A., Gerothanassis I.P. Rapid and novel discrimination and quantification of oleanolic and ursolic acids in complex plant extracts using two-dimensional nuclear magnetic resonance spectroscopy—Comparison with HPLC methods. Anal. Chim. Acta. 2009;635:188–195. doi: 10.1016/j.aca.2009.01.021.
    1. Liu H., Shi Y., Wang D., Yang G., Yu A., Zhang H. MECC determination of oleanolic acid and ursolic acid isomers in Ligustrum lucidum Ait. J. Pharm. Biomed. Anal. 2003;32:479–485. doi: 10.1016/S0731-7085(03)00235-8.
    1. Yang P., Li Y., Liu X., Jiang S. Determination of free isomeric oleanolic acid and ursolic acid in Pterocephalus hookeri by capillary zone electrophoresis. J. Pharm. Biomed. Anal. 2007;43:1331–1334. doi: 10.1016/j.jpba.2006.10.042.
    1. Tavares M.C.H., Vilegas J.H.Y., Lanças F.M. Separation of underivatised triterpene acids by capillary supercritical fluid chromatography. Phytochem. Anal. 2001;12:134–137. doi: 10.1002/pca.536.
    1. Giménez E., Juan M.E., Calvo-Melià S., Barbosa J., Sanz-Nebot V., Planas J.M. Pentacyclic triterpene in Olea europaea L: A simultaneous determination by high-performance liquid chromatography coupled to mass spectrometry. J. Chromatogr. A. 2015;1410:68–75. doi: 10.1016/j.chroma.2015.07.064.
    1. Wang Z., Zuo G., Hwang S.H., Kwon S.H., Kang Y.-H., Lee J.-Y., Lim S.S. Affinity measurement of ligands in Perilla frutescens extract towards α-glucosidase using affinity-based ultrafiltration-high-performance liquid chromatography. J. Chromatogr. B. 2019;1125:121725. doi: 10.1016/j.jchromb.2019.121725.
    1. Mahato S.B., Nandy A.K., Roy G. Triterpenoids. Phytochemistry. 1992;31:2199–2249. doi: 10.1016/0031-9422(92)83257-Y.
    1. Connolly J.D., Hill R.A. Triterpenoids. Nat. Prod. Rep. 2008;25:794–830. doi: 10.1039/b718038c.
    1. Seo S., Yoshimura Y., Uomori A., Takeda K., Seto H., Ebizuka Y., Sankawa U. Biosynthesis of triterpenes, ursolic acid and oleanolic acid in tissue cultures of Rabdosia japonica Hara fed [5-13C2H2]mevalonolactone and [2-13C2H3]acetate. J. Am. Chem. Soc. 1988;110:1740–1745. doi: 10.1021/ja00214a013.
    1. Benveniste P. Arabidopsis Book. American Society of Plant Biologists; Rockville, MD, USA: 2002. Sterol Metabolism; p. e0004.
    1. Humphrey A.J., Beale M.H. Plant Secondary Metabolites. Blackwell Publishing; Singapore: 2006. Terpenes; pp. 47–101.
    1. Stiti N., Triki S., Hartmann M.-A. Formation of Triterpenoids throughout Olea europaea Fruit Ontogeny. Lipids. 2007;42:55–67. doi: 10.1007/s11745-006-3002-8.
    1. Herrera J.B.R., Bartel B., Wilson W.K., Matsuda S.P. Cloning and characterization of the Arabidopsis thaliana lupeol synthase gene. Phytochemistry. 1998;49:1905–1911. doi: 10.1016/S0031-9422(98)00366-5.
    1. Ebizuka Y., Katsube Y., Tsutsumi T., Kushiro T., Shibuya M. Functional genomics approach to the study of triterpene biosynthesis. Pure Appl. Chem. 2003;75:369–374. doi: 10.1351/pac200375020369.
    1. Abe I., Rohmer M., Prestwich G.D. Enzymatic cyclization of squalene and oxidosqualene to sterols and triterpenes. Chem. Rev. 1993;93:2189–2206. doi: 10.1021/cr00022a009.
    1. Mahato S.B., Sarkar S.K., Poddar G. Triterpenoid saponins. Phytochemistry. 1988;27:3037–3067. doi: 10.1016/0031-9422(88)80001-3.
    1. Abe F., Yamauchi T., Nagao T., Kinjo J., Okabe H., Higo H., Akahane H. Ursolic Acid as a Trypanocidal Constituent in Rosemary. Biol. Pharm. Bull. 2002;25:1485–1487. doi: 10.1248/bpb.25.1485.
    1. Allouche Y., Jiménez A., Uceda M., Aguilera M.P., Gaforio J.J., Beltrán G. Triterpenic Content and Chemometric Analysis of Virgin Olive Oils from Forty Olive Cultivars. J. Agric. Food Chem. 2009;57:3604–3610. doi: 10.1021/jf803237z.
    1. Yamaguchi H., Noshita T., Kidachi Y., Umetsu H., Hayashi M., Komiyama K., Funayama S., Ryoyama K. Isolation of Ursolic Acid from Apple Peels and Its Specific Efficacy as a Potent Antitumor Agent. J. Health Sci. 2008;54:654–660. doi: 10.1248/jhs.54.654.
    1. He X., Liu R.H. Triterpenoids Isolated from Apple Peels Have Potent Antiproliferative Activity and May Be Partially Responsible for Apple’s Anticancer Activity. J. Agric. Food Chem. 2007;55:4366–4370. doi: 10.1021/jf063563o.
    1. Tian L.-T., Ma L., Du N.-S. Survey of pharmacology of oleanolic acid. China J. Chin. Mater. Med. 2002;27:884–901.
    1. Liu J. Oleanolic acid and ursolic acid: Research perspectives. J. Ethnopharmacol. 2005;100:92–94. doi: 10.1016/j.jep.2005.05.024.
    1. Dzubak P., Hajduch M., Vydra D., Hustova A., Kvasnica M., Biedermann D., Markova L., Urban M., Sarek J. Pharmacological activities of natural triterpenoids and their therapeutic implications. Nat. Prod. Rep. 2006;23:394–411. doi: 10.1039/b515312n.
    1. Dini I., Tenore G.C., Dini A. Saponins in Ipomoea batatas tubers: Isolation, characterization, quantification and antioxidant properties. Food Chem. 2009;113:411–419. doi: 10.1016/j.foodchem.2008.07.053.
    1. Juan M.E., Wenzel U., Ruiz-Gutierrez V., Daniel H., Planas J.M. Olive Fruit Extracts Inhibit Proliferation and Induce Apoptosis in HT-29 Human Colon Cancer Cells. J. Nutr. 2006;136:2553–2557. doi: 10.1093/jn/136.10.2553.
    1. Kuo R.-Y., Qian K., Morris-Natschke S.L., Lee K.-H. Plant-derived triterpenoids and analogues as antitumor and anti-HIV agents. Nat. Prod. Rep. 2009;26:1321–1344. doi: 10.1039/b810774m.
    1. Yamai H., Sawada N., Yoshida T., Seike J., Takizawa H., Kenzaki K., Miyoshi T., Kondo K., Bando Y., Ohnishi Y., et al. Triterpenes augment the inhibitory effects of anticancer drugs on growth of human esophageal carcinoma cells in vitro and suppress experimental metastasis In Vivo. Int. J. Cancer. 2009;125:952–960. doi: 10.1002/ijc.24433.
    1. Eloy J.O., Saraiva J., de Albuquerque S., Marchetti J.M. Preparation, characterization and evaluation of the In Vivo trypanocidal activity of ursolic acid-loaded solid dispersion with poloxamer 407 and sodium caprate. Braz. J. Pharm. Sci. 2015;51:101–109. doi: 10.1590/S1984-82502015000100011.
    1. Jinhua W. Ursolic acid: Pharmacokinetics process In Vitro and In Vivo, a mini review. Arch. Der Pharm. 2019;352:e1800222. doi: 10.1002/ardp.201800222.
    1. Song M., Hang T.-J., Wang Y., Jiang L., Wu X.-L., 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. doi: 10.1016/j.jpba.2005.06.034.
    1. Chen R.-J., Liu X., Li P.-M., Zhang L., Zhao L., Zhang X.-L. Pharmacokinetic profiles of oleanolic acid formulations in healthy Chinese male volunteers. Chin. Pharm. J. 2010;45:621–626.
    1. Rada M., Castellano J.M., Perona J.S., Guinda Á. GC-FID determination and pharmacokinetic studies of oleanolic acid in human serum. Biomed. Chromatogr. 2015;29:1687–1692. doi: 10.1002/bmc.3480.
    1. De la Torre R., Carbó M., Pujadas M., Biel S., Mesa M.-D., Covas M.-I., Expósito M., Espejo J.-A., Sanchez-Rodriguez E., Díaz-Pellicer P., 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. doi: 10.1016/j.foodchem.2020.126676.
    1. Rada M., Ruiz-Gutiérrez V., Guinda Á. Determination of Triterpenic Acids in Human Serum by High-Performance Liquid Chromatography: Triterpenoid Interaction with Serum Protein. J. Agric. Food Chem. 2011;59:2308–2313. doi: 10.1021/jf1039537.
    1. Peng W., Ding F., Jiang Y.-T., Peng Y.-K. Bioavailability and Activity of Natural Food Additive Triterpenoids as Influenced by Protein. J. Agric. Food Chem. 2014;62:2271–2283. doi: 10.1021/jf4049512.
    1. Dopierala K., Krajewska M.M., Weiss M. Physicochemical Characterization of Oleanolic Acid—Human Serum Albumin Complexes for Pharmaceutical and Biosensing Applications. Langmuir. 2020;36:3611–3623. doi: 10.1021/acs.langmuir.0c00087.
    1. Bhattacharya A.A., Grüne T., Curry S. Crystallographic analysis reveals common modes of binding of medium and long-chain fatty acids to human serum albumin. J. Mol. Biol. 2000;303:721–732. doi: 10.1006/jmbi.2000.4158.
    1. Subramanyam R., Gollapudi A., Bonigala P., Chinnaboina M., Amooru D.G. Betulinic acid binding to human serum albumin: A study of protein conformation and binding affinity. J. Photochem. Photobiol. B Biol. 2009;94:8–12. doi: 10.1016/j.jphotobiol.2008.09.002.
    1. Liu J. Pharmacology of oleanolic acid and ursolic acid. J. Ethnopharmacol. 1995;49:57–68. doi: 10.1016/0378-8741(95)90032-2.
    1. Yunoki K., Sasaki G., Tokuji Y., Kinoshita M., Naito A., Aida K., Ohnishi M. Effect of Dietary Wine Pomace Extract and Oleanolic Acid on Plasma Lipids in Rats Fed High-Fat Diet and Its DNA Microarray Analysis. J. Agric. Food Chem. 2008;56:12052–12058. doi: 10.1021/jf8026217.
    1. De Melo C.L., Queiroz M.G.R., Fonseca S.G., Bizerra A.M.C., Lemos T.L., Melo T.S., Santos F.A., Rao V.S. Oleanolic acid, a natural triterpenoid improves blood glucose tolerance in normal mice and ameliorates visceral obesity in mice fed a high-fat diet. Chem. Interact. 2010;185:59–65. doi: 10.1016/j.cbi.2010.02.028.
    1. Kalaiarasi P., Kaviarasan K., Pugalendi K.V. Hypolipidemic activity of 18β-glycyrrhetinic acid on streptozotocin-induced diabetic rats. Eur. J. Pharmacol. 2009;612:93–97. doi: 10.1016/j.ejphar.2009.04.003.
    1. 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. doi: 10.1016/j.biocel.2015.10.023.
    1. 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. doi: 10.1016/j.biopha.2017.11.151.
    1. Wang X., Liu R., Zhang W., Zhang X., Liao N., Wang Z., Li W., Qin X., Hai C. Oleanolic acid improves hepatic insulin resistance via antioxidant, hypolipidemic and anti-inflammatory effects. Mol. Cell. Endocrinol. 2013;376:70–80. doi: 10.1016/j.mce.2013.06.014.
    1. Gamede M., Mabuza L., Ngubane P., Khathi A. Plant-Derived Oleanolic Acid (OA) Ameliorates Risk Factors of Cardiovascular Diseases in a Diet-Induced Pre-Diabetic Rat Model: Effects on Selected Cardiovascular Risk Factors. Molecules. 2019;24:340. doi: 10.3390/molecules24020340.
    1. Molepo M., Ayeleso A., Nyakudya T., Erlwanger K., Mukwevho E. A Study on Neonatal Intake of Oleanolic Acid and Metformin in Rats (Rattus norvegicus) with Metabolic Dysfunction: Implications on Lipid Metabolism and Glucose Transport. Molecules. 2018;23:2528. doi: 10.3390/molecules23102528.
    1. Nakajima K., Maeda N., Oiso S., Kariyazono H. Decreased Plasma Octanoylated Ghrelin Levels in Mice by Oleanolic Acid. J. Oleo Sci. 2019;68:103–109. doi: 10.5650/jos.ess18148.
    1. 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. doi: 10.3892/ijmm.2020.4744.
    1. Chen S., Wen X., Zhang W., Wang C., Liu J., Liu C. Hypolipidemic effect of oleanolic acid is mediated by the miR-98-5p/PGC-1β axis in high-fat diet-induced hyperlipidemic mice. FASEB J. 2016;31:1085–1096. doi: 10.1096/fj.201601022R.
    1. 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. 2017;49:349–354. doi: 10.1093/abbs/gmx013.
    1. Huang T.H.W., Yang Q., Harada M., Li G.Q., Yamahara J., Roufogalis B.D., Li Y. Pomegranate Flower Extract Diminishes Cardiac Fibrosis in Zucker Diabetic Fatty Rats—Modulation of cardiac endothelin-1 and nuclear factor-kappa B pathways. J. Cardiovasc. Pharmacol. 2005;46:856–862. doi: 10.1097/01.fjc.0000190489.85058.7e.
    1. Lee W.S., Im K.-R., Park Y.-D., Sung N.-D., Jeong T.-S. Human ACAT-1 and ACAT-2 Inhibitory Activities of Pentacyclic Triterpenes from the Leaves of Lycopus lucidus TURCZ. Biol. Pharm. Bull. 2006;29:382–384. doi: 10.1248/bpb.29.382.
    1. Kuroda M., Mimaki Y., Ohtomo T., Yamada J., Nishiyama T., Mae T., Kishida H., Kawada T. Hypoglycemic effects of clove (Syzygium aromaticum flower buds) on genetically diabetic KK-Ay mice and identification of the active ingredients. J. Nat. Med. 2012;66:394–399. doi: 10.1007/s11418-011-0593-z.
    1. Sung H.-Y., Kang S.-W., Kim J.-L., Li J., Lee E.-S., Gong J.-H., Han S.J., Kang Y.-H. Oleanolic acid reduces markers of differentiation in 3T3-L1 adipocytes. Nutr. Res. 2010;30:831–839. doi: 10.1016/j.nutres.2010.10.001.
    1. Quang T.H., Ngan N.T.T., Van Minh C., Van Kiem P., Thao N.P., Tai B.H., Nhiem N.X., Song S.B., Kim Y.H. Effect of triterpenes and triterpene saponins from the stem bark of Kalopanax pictus on the transactivational activities of three PPAR subtypes. Carbohydr. Res. 2011;346:2567–2575. doi: 10.1016/j.carres.2011.08.029.
    1. Luo H.-Q., Shen J., Chen C.-P., Ma X., Lin C., Ouyang Q., Xuan C.-X., Liu J., Sun H.-B., Liu J. Lipid-lowering effects of oleanolic acid in hyperlipidemic patients. Chin. J. Nat. Med. 2018;16:339–346. doi: 10.1016/S1875-5364(18)30065-7.
    1. Ortiz-Andrade R., Jiménez D.N.S.C.G., Castillo-España P., Ramírez-Ávila G., Villalobos-Molina R., Estrada-Soto S. α-Glucosidase inhibitory activity of the methanolic extract from Tournefortia hartwegiana: An anti-hyperglycemic agent. J. Ethnopharmacol. 2007;109:48–53. doi: 10.1016/j.jep.2006.07.002.
    1. Komaki E., Yamaguchi S., Maru I., Kinoshita M., Kakehi K., Ohta Y., Tsukada Y. Identification of Anti-.ALPHA.-Amylase Components from Olive Leaf Extracts. Food Sci. Technol. Res. 2003;9:35–39. doi: 10.3136/fstr.9.35.
    1. Hsu J.-H., Wu Y.-C., Liu I.-M., Cheng J.-T. Release of acetylcholine to raise insulin secretion in Wistar rats by oleanolic acid, one of the active principles contained in Cornus officinalis. Neurosci. Lett. 2006;404:112–116. doi: 10.1016/j.neulet.2006.05.025.
    1. Gilon P. Mechanisms and Physiological Significance of the Cholinergic Control of Pancreatic-Cell Function. Endocr. Rev. 2001;22:565–604. doi: 10.1210/er.22.5.565.
    1. Whalley N.M., Pritchard L.E., Smith D.M., White A. Processing of proglucagon to GLP-1 in pancreatic α-cells: Is this a paracrine mechanism enabling GLP-1 to act on β-cells? J. Endocrinol. 2011;211:99–106. doi: 10.1530/JOE-11-0094.
    1. Sato H., Genet C., Strehle A., Thomas C., Lobstein A., Wagner A., Mioskowski C., Auwerx J., Saladin R. Anti-hyperglycemic activity of a TGR5 agonist isolated from Olea europaea. Biochem. Biophys. Res. Commun. 2007;362:793–798. doi: 10.1016/j.bbrc.2007.06.130.
    1. Genet C., Strehle A., Schmidt C., Boudjelal G., Lobstein A., Schoonjans K., Souchet M., Auwerx J., Saladin R., Wagner A. Structure−Activity Relationship Study of Betulinic Acid, A Novel and Selective TGR5 Agonist, and Its Synthetic Derivatives: Potential Impact in Diabetes. J. Med. Chem. 2010;53:178–190. doi: 10.1021/jm900872z.
    1. Maczewsky J., Kaiser J., Gresch A., Gerst F., Düfer M., Krippeit-Drews P., Drews G. TGR5 Activation Promotes Stimulus-Secretion Coupling of Pancreatic β-Cells via a PKA-Dependent Pathway. Diabetes. 2018;68:324–336. doi: 10.2337/db18-0315.
    1. Liu J., Lu Y.-F., Wu Q., Xu S.-F., Shi F.-G., Klaassen C.D. Oleanolic acid reprograms the liver to protect against hepatotoxicants, but is hepatotoxic at high doses. Liver Int. 2019;39:427–439. doi: 10.1111/liv.13940.
    1. Bu Y., Shi T., Meng M., Kong G., Tian Y., Chen Q., Yao X., Feng G., Cheng H., Lu Z. A novel screening model for the molecular drug for diabetes and obesity based on tyrosine phosphatase Shp2. Bioorg. Med. Chem. Lett. 2011;21:874–878. doi: 10.1016/j.bmcl.2010.11.049.
    1. Teodoro T., Zhang L., Alexander T., Yue J., Vranic M., Volchuk A. Oleanolic acid enhances insulin secretion in pancreatic β-cells. FEBS Lett. 2008;582:1375–1380. doi: 10.1016/j.febslet.2008.03.026.
    1. Zito C.I., Kontaridis M.I., Fornaro M., Feng G.-S., Bennett A.M. SHP-2 regulates the phosphatidylinositide 3?-kinase/Akt pathway and suppresses caspase 3-mediated apoptosis. J. Cell. Physiol. 2004;199:227–236. doi: 10.1002/jcp.10446.
    1. White S.A., James R.F.L., Swift S.M., Kimber R.M., Nicholson M.L. Human islet cell transplantation—Future prospects. Diabet. Med. 2001;18:78–103. doi: 10.1046/j.1464-5491.2001.00465.x.
    1. Nataraju A., Saini D., Ramachandran S., Benshoff N., Liu W., Chapman W., Mohanakumar T. Oleanolic Acid, a Plant Triterpenoid, Significantly Improves Survival and Function of Islet Allograft. Transplantation. 2009;88:987–994. doi: 10.1097/TP.0b013e3181b9cbc4.
    1. Jung S.H., Ha Y.J., Shim E.K., Choi S.Y., Jin J.L., Yun-Choi H.S., Lee J.R. Insulin-mimetic and insulin-sensitizing activities of a pentacyclic triterpenoid insulin receptor activator. Biochem. J. 2007;403:243–250. doi: 10.1042/BJ20061123.
    1. Galic S., Hauser C., Kahn B.B., Haj F.G., Neel B.G., Tonks N.K., Tiganis T. Coordinated Regulation of Insulin Signaling by the Protein Tyrosine Phosphatases PTP1B and TCPTP. Mol. Cell. Biol. 2005;25:819–829. doi: 10.1128/MCB.25.2.819-829.2005.
    1. Ramírez-Espinosa J.J., Rios M.Y., López-Martínez S., López-Vallejo F., Medina-Franco J.L., Paoli P., Camici G., Navarrete-Vázquez G., Ortiz-Andrade R., Estrada-Soto S. Antidiabetic activity of some pentacyclic acid triterpenoids, role of PTP–1B: In Vitro, In Silico, and In Vivo approaches. Eur. J. Med. Chem. 2011;46:2243–2251. doi: 10.1016/j.ejmech.2011.03.005.
    1. Qiu W.-W., Shen Q., Yang F., Wang B., Zou H., Li J.-Y., Li J., Tang J. Synthesis and biological evaluation of heterocyclic ring-substituted maslinic acid derivatives as novel inhibitors of protein tyrosine phosphatase 1B. Bioorg. Med. Chem. Lett. 2009;19:6618–6622. doi: 10.1016/j.bmcl.2009.10.017.
    1. Feng J., Zhang P., Chen X., He G. PI3K and ERK/Nrf2 pathways are involved in oleanolic acid-induced heme oxygenase-1 expression in rat vascular smooth muscle cells. J. Cell. Biochem. 2011;112:1524–1531. doi: 10.1002/jcb.23065.
    1. Yang J., Li X., Yang H., Long C. Oleanolic Acid Improves the Symptom of Renal Ischemia Reperfusion Injury via the PI3K/AKT Pathway. Urol. Int. 2020;105:215–220. doi: 10.1159/000506778.
    1. Kang Y.-M., Lee M., An H.-J. Oleanolic acid protects against mast cell-mediated allergic responses by suppressing Akt/NF-κB and STAT1 activation. Phytomedicine. 2020;80:153340. doi: 10.1016/j.phymed.2020.153340.
    1. Zhou W., Zeng X., Wu X. Effect of Oleanolic Acid on Apoptosis and Autophagy of SMMC-7721 Hepatoma Cells. Med. Sci. Monit. 2020;26:e921606-1–e921606-12. doi: 10.12659/MSM.921606.
    1. Zeng X., Wang Y.-P., Cantley J., Iseli T.J., Molero J.C., Hegarty B.D., Kraegen E.W., Ye Y., Ye J.-M. Oleanolic Acid Reduces Hyperglycemia beyond Treatment Period with Akt/FoxO1-Induced Suppression of Hepatic Gluconeogenesis in Type-2 Diabetic Mice. PLoS ONE. 2012;7:e42115. doi: 10.1371/journal.pone.0042115.
    1. Ha D.T., Tuan D.T., Thu N.B., Nhiem N.X., Ngoc T.M., Yim N., Bae K. Palbinone and triterpenes from Moutan Cortex (Paeonia suffruticosa, Paeoniaceae) stimulate glucose uptake and glycogen synthesis via activation of AMPK in insulin-resistant human HepG2 Cells. Bioorg. Med. Chem. Lett. 2009;19:5556–5559. doi: 10.1016/j.bmcl.2009.08.048.
    1. Liu J., Sun H., Duan W., Mu D., Zhang L. Maslinic Acid Reduces Blood Glucose in KK-Ay Mice. Biol. Pharm. Bull. 2007;30:2075–2078. doi: 10.1248/bpb.30.2075.
    1. Saha P.K., Reddy V.T., Konopleva M., Andreeff M., Chan L. The triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic-acid methyl ester has potent anti-diabetic effects in diet-induced diabetic mice and Lepr(db/db) mice. J. Biol. Chem. 2010;285:40581–40592. doi: 10.1074/jbc.M110.176545.
    1. Matumba M.G., Ayeleso A.O., Nyakudya T., Erlwanger K., Chegou N.N., Mukwevho E. Long-Term Impact of Neonatal Intake of Oleanolic Acid on the Expression of AMP-Activated Protein Kinase, Adiponectin and Inflammatory Cytokines in Rats Fed with a High Fructose Diet. Nutrients. 2019;11:226. doi: 10.3390/nu11020226.
    1. Sangeetha K.N., Sujatha S., Muthusamy V.S., Anand S., Nithya N., Velmurugan D., Balakrishnan A., Lakshmi B.S. 3β-taraxerol of Mangifera indica, a PI3K dependent dual activator of glucose transport and glycogen synthesis in 3T3-L1 adipocytes. Biochim. Biophys. Acta BBA Gen. Subj. 2010;1800:359–366. doi: 10.1016/j.bbagen.2009.12.002.
    1. Ahamed K.B.M., Gowdru H.B., Rajashekarappa S., Malleshappa K.S.H., Krishna V. Molecular docking of glycogen synthase kinase3-β inhibitor oleanolic acid and its wound-healing activity in rats. Med. Chem. Res. 2012;22:156–164. doi: 10.1007/s00044-012-0014-1.
    1. Jang S.-M., Kim M.-J., Choi M.-S., Kwon E.-Y., Lee M.-K. Inhibitory effects of ursolic acid on hepatic polyol pathway and glucose production in streptozotocin-induced diabetic mice. Metabolism. 2010;59:512–519. doi: 10.1016/j.metabol.2009.07.040.
    1. Liu J., Wang X., Luo D., Sun H.-B., Shang J., Zhang L.-Y. Anti-proliferative effect of pentacyclic triterpenes associated with glycogen accumulation in A549 cells. Chin. J. New Drugs. 2011;20:2350–2353.
    1. Wen X., Sun H., Liu J., Wu G., Zhang L., Wu X., Ni P. Pentacyclic triterpenes. Part 1: The first examples of naturally occurring pentacyclic triterpenes as a new class of inhibitors of glycogen phosphorylases. Bioorg. Med. Chem. Lett. 2005;15:4944–4948. doi: 10.1016/j.bmcl.2005.08.026.
    1. Wen X., Sun H., Liu J., Cheng K., Zhang P., Zhang L., Hao J., Zhang L., Ni P., Zographos S.E., et al. Naturally Occurring Pentacyclic Triterpenes as Inhibitors of Glycogen Phosphorylase: Synthesis, Structure—Activity Relationships, and X-ray Crystallographic Studies. J. Med. Chem. 2008;51:3540–3554. doi: 10.1021/jm8000949.
    1. Neto J.C.G.L., Xavier M.D.A., Borges J.W.P., de Araújo M.F.M., Damasceno M.M.C., Freitas R. Prevalence of Metabolic Syndrome in individuals with Type 2 Diabetes Mellitus. Rev. Bras. Enferm. 2017;70:265–270. doi: 10.1590/0034-7167-2016-0145.
    1. Mc Cullough A.J. Epidemiology of the metabolic syndrome in the USA. J. Dig. Dis. 2011;12:333–340. doi: 10.1111/j.1751-2980.2010.00469.x.
    1. Fernández-Aparicio Á., Schmidt-Rio Valle J., Perona J.S., Correa-Rodríguez M., Castellano J.M., González-Jiménez E., Aparicio F., Valle S.-R., Rodríguez C., Jiménez G. Potential Protective Effect of Oleanolic Acid on the Components of Metabolic Syndrome: A Systematic Review. J. Clin. Med. 2019;8:1294. doi: 10.3390/jcm8091294.
    1. Ahn Y.M., Choi Y.H., Yoon J.J., Lee Y.J., Cho K.W., Kang D.G., Lee H.S. 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. doi: 10.1016/j.ejphar.2017.05.030.
    1. Patil S.D., Bachhav S.S., Bhutada M.S., Patil S.P., Sharma K.S. Oleanolic acid prevents increase in blood pressure and nephrotoxicity in nitric oxide dependent type of hypertension in rats. Pharmacogn. Res. 2015;7:385–392. doi: 10.4103/0974-8490.159575.
    1. Madlala H.P., Van Heerden F., Mubagwa K., Musabayane C.T. Changes in Renal Function and Oxidative Status Associated with the Hypotensive Effects of Oleanolic Acid and Related Synthetic Derivatives in Experimental Animals. PLoS ONE. 2015;10:e0128192. doi: 10.1371/journal.pone.0128192.
    1. 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. doi: 10.1016/j.taap.2014.03.016.
    1. Lee E.Y., Kim H.M., Kang J.S., Yadav D., Kwon M.-H., Kim Y.M., Kim H.S., Chung C. Oleanolic acid and N-acetylcysteine ameliorate diabetic nephropathy through reduction of oxidative stress and endoplasmic reticulum stress in a type 2 diabetic rat model. Nephrol. Dial. Transplant. 2015;31:391–400. doi: 10.1093/ndt/gfv377.
    1. 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;2015:973287. doi: 10.1155/2015/973287.
    1. 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. doi: 10.3390/molecules23040794.
    1. Djeziri F.Z., Belarbi M., Murtaza B., Hichami A., Benammar C., Khan N.A. Oleanolic acid improves diet-induced obesity by modulating fat preference and inflammation in mice. Biochimie. 2018;152:110–120. doi: 10.1016/j.biochi.2018.06.025.
    1. Claro-Cala C.M., Quintela J.C., Pérez-Montero M., Miñano J., De Sotomayor M.A., Herrera M.D., Rodríguez-Rodríguez A.R. Pomace Olive Oil Concentrated in Triterpenic Acids Restores Vascular Function, Glucose Tolerance and Obesity Progression in Mice. Nutrients. 2020;12:323. doi: 10.3390/nu12020323.
    1. Gamede M., Mabuza L., Ngubane P., Khathi A. Plant-derived oleanolic acid ameliorates markers of subclinical inflammation and innate immunity activation in diet-induced pre-diabetic rats. Ther. Adv. Endocrinol. Metab. 2020;11:2042018820935771. doi: 10.1177/2042018820935771.
    1. Su S., Wu G., Cheng X., Fan J., Peng J., Su H., Xu Z., Cao M., Long Z., Hao Y., et al. Oleanolic acid attenuates PCBs-induced adiposity and insulin resistance via HNF1b-mediated regulation of redox and PPARγ signaling. Free Radic. Biol. Med. 2018;124:122–134. doi: 10.1016/j.freeradbiomed.2018.06.003.
    1. Yin M.-C., Chan K.-C. Nonenzymatic Antioxidative and Antiglycative Effects of Oleanolic Acid and Ursolic Acid. J. Agric. Food Chem. 2007;55:7177–7181. doi: 10.1021/jf071242m.
    1. Gao D., Li Q., Li Y., Liu Z., Fan Y., Liu Z., Zhao H., Li J., Han Z. Antidiabetic and antioxidant effects of oleanolic acid from Ligustrum lucidum Ait in alloxan-induced diabetic rats. Phytother. Res. 2009;23:1257–1262. doi: 10.1002/ptr.2603.
    1. Lowell B.B., Shulman G.I. Mitochondrial Dysfunction and Type 2 Diabetes. Science. 2005;307:384–387. doi: 10.1126/science.1104343.
    1. Allouche Y., Warleta F., Campos M., Sánchez-Quesada C., Uceda M., Beltrán G., Gaforio J.J. Antioxidant, Antiproliferative, and Pro-apoptotic Capacities of Pentacyclic Triterpenes Found in the Skin of Olives on MCF-7 Human Breast Cancer Cells and Their Effects on DNA Damage. J. Agric. Food Chem. 2010;59:121–130. doi: 10.1021/jf102319y.
    1. Gutierrez B., Gallardo I., Ruiz L., Alvarez Y., Cachofeiro V., Margolles A., Hernandez M., Nieto M.L. Oleanolic acid ameliorates intestinal alterations associated with EAE. J. Neuroinflamm. 2020;17:363. doi: 10.1186/s12974-020-02042-6.
    1. Cheng K., Liu J., Sun H., Xie J. Synthesis of Oleanolic Acid Dimers as Inhibitors of Glycogen Phosphorylase. Chem. Biodivers. 2010;7:690–697. doi: 10.1002/cbdv.200900086.
    1. Dharmappa K.K., Kumar R.V., Nataraju A., Mohamed R., Shivaprasad H.V., Vishwanath B.S. Anti-Inflammatory Activity of Oleanolic Acid by Inhibition of Secretory Phospholipase A2. Planta Med. 2009;75:211–215. doi: 10.1055/s-0028-1088374.
    1. Tsai S.-J., Yin M.-C. Antioxidative and Anti-Inflammatory Protection of Oleanolic Acid and Ursolic Acid in PC12 Cells. J. Food Sci. 2008;73:H174–H178. doi: 10.1111/j.1750-3841.2008.00864.x.
    1. Du Y., Ko K.M. Oleanolic Acid Protects against Myocardial Ischemia-Reperfusion Injury by Enhancing Mitochondrial Antioxidant Mechanism Mediated by Glutathione and α-Tocopherol in Rats. Planta Med. 2006;72:222–227. doi: 10.1055/s-2005-916197.
    1. Soobrattee M., Neergheen V., Luximon-Ramma A., Aruoma O., Bahorun T. Phenolics as potential antioxidant therapeutic agents: Mechanism and actions. Mutat. Res. Mol. Mech. Mutagen. 2005;579:200–213. doi: 10.1016/j.mrfmmm.2005.03.023.
    1. Weir G.C., Bonner-Weir S. Five Stages of Evolving Beta-Cell Dysfunction During Progression to Diabetes. Diabetes. 2004;53:S16–S21. doi: 10.2337/diabetes.53.suppl_3.S16.
    1. Festa A., D’Agostino R., Howard G., Mykkanen L., Tracy R.P., Haffner S.M. Chronic subclinical inflammation as part of the insulin resistance syndrome—The Insulin Resistance Atherosclerosis Study (IRAS) Circulation. 2000;102:42–47. doi: 10.1161/01.CIR.102.1.42.
    1. Fabbrini E., Magkos F., Mohammed B.S., Pietka T., Abumrad N.A., Patterson B.W., Okunade A., Klein S. Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity. Proc. Natl. Acad. Sci. USA. 2009;106:15430–15435. doi: 10.1073/pnas.0904944106.
    1. Blandino G., Inturri R., Lazzara F., Di Rosa M., Malaguarnera L. Impact of gut microbiota on diabetes mellitus. Diabetes Metab. 2016;42:303–315. doi: 10.1016/j.diabet.2016.04.004.
    1. Ramos-Romero S., Hereu M., Atienza L., Casas J., Jáuregui O., Amézqueta S., Dasilva G., Medina I., Nogués M.R., Romeu M., et al. Mechanistically different effects of fat and sugar on insulin resistance, hypertension, and gut microbiota in rats. Am. J. Physiol. Metab. 2018;314:E552–E563. doi: 10.1152/ajpendo.00323.2017.
    1. Cani P.D., Amar J., Iglesias M.A., Poggi M., Knauf C., Bastelica D., Neyrinck A.M., Fava F., Tuohy K.M., Chabo C.W., et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes. 2007;56:1761–1772. doi: 10.2337/db06-1491.
    1. Janssen A.W.F., Kersten S. Potential mediators linking gut bacteria to metabolic health: A critical view. J. Physiol. 2016;595:477–487. doi: 10.1113/JP272476.
    1. Peng M., Zhao X., Biswas D. Polyphenols and tri-terpenoids from Olea europaea L. in alleviation of enteric pathogen infections through limiting bacterial virulence and attenuating inflammation. J. Funct. Foods. 2017;36:132–143. doi: 10.1016/j.jff.2017.06.059.
    1. Callejo M.N., Gallardo I., Gutierrez B., Cabero M., Ruiz L., Alvarez Y., Simon I., Calvo H., Munoz J., Margolles A., et al. Oleanolic acid protection against experimental autoimmune myocarditis modulates the microbiota and the intestinal barrier integrity. Eur. Hear. J. 2020;41:ehaa946.3716. doi: 10.1093/ehjci/ehaa946.3716.
    1. Dinh C.H.L., Yu Y., Szabo A., Zhang Q., Zhang P., Huang X.-F. Bardoxolone Methyl Prevents High-Fat Diet-Induced Colon Inflammation in Mice. J. Histochem. Cytochem. 2016;64:237–255. doi: 10.1369/0022155416631803.
    1. Chen X., Zhang Y., Ma W., Wang Z. Effects of Ligustrum lucidum on egg production, egg quality, and caecal microbiota of hens during the late laying period. Ital. J. Anim. Sci. 2020;19:687–696. doi: 10.1080/1828051X.2020.1780167.
    1. Feng Z., Wu C., Zhou J., Wu F., Li J., Li T., Yin Y. Disturbance of the intestinal microbial community by ursolic acid contributes to its function as a regulator of fat deposition. J. Funct. Foods. 2015;14:456–468. doi: 10.1016/j.jff.2015.02.015.
    1. Sun Q., He M., Zhang M., Zeng S., Chen L., Zhou L., Xu H. Ursolic acid: A systematic review of its pharmacology, toxicity and rethink on its pharmacokinetics based on PK-PD model. Fitoterapia. 2020;147:104735. doi: 10.1016/j.fitote.2020.104735.
    1. Hao W., Kwek E., He Z., Zhu H., Liu J., Zhao Y., Ma K.Y., He W.-S., Chen Z.-Y. Ursolic acid alleviates hypercholesterolemia and modulates the gut microbiota in hamsters. Food Funct. 2020;11:6091–6103. doi: 10.1039/D0FO00829J.
    1. Staats S., Wagner A.E., Lüersen K., Künstner A., Meyer T., Kahns A.K., Derer S., Graspeuntner S., Rupp J., Busch H., et al. Dietary ursolic acid improves health span and life span in male Drosophila melanogaster. BioFactors. 2019;45:169–186. doi: 10.1002/biof.1467.
    1. Wan S., Huang C., Wang A., Zhu X. Ursolic acid improves the bacterial community mapping of the intestinal tract in liver fibrosis mice. PeerJ. 2020;8:e9050. doi: 10.7717/peerj.9050.
    1. Wan S.-Z., Liu C., Huang C.-K., Luo F.-Y., Zhu X. Ursolic Acid Improves Intestinal Damage and Bacterial Dysbiosis in Liver Fibrosis Mice. Front. Pharmacol. 2019;10:13. doi: 10.3389/fphar.2019.01321.
    1. Zhang W., Gan D., Jian J., Huang C., Luo F., Wan S., Jiang M., Wan Y., Wang A., Li B., et al. Protective Effect of Ursolic Acid on the Intestinal Mucosal Barrier in a Rat Model of Liver Fibrosis. Front. Physiol. 2019;10:956. doi: 10.3389/fphys.2019.00956.
    1. Wan S., Luo F., Huang C., Liu C., Luo Q., Zhu X. Ursolic acid reverses liver fibrosis by inhibiting interactive NOX4/ROS and RhoA/ROCK1 signalling pathways. Aging. 2020;12:10614–10632. doi: 10.18632/aging.103282.
    1. Bala V., Rajagopal S., Kumar D.P., Nalli A.D., Mahavadi S., Sanyal A.J., Grider J.R., Murthy K.S. Release of GLP-1 and PYY in response to the activation of G protein-coupled bile acid receptor TGR5 is mediated by Epac/PLC-ε pathway and modulated by endogenous H2S. Front. Physiol. 2014;5:420. doi: 10.3389/fphys.2014.00420.
    1. Jain A.K., Sharma A., Arora S., Blomenkamp K., Jun I.C., Luong R., Westrich D.J., Mittal A., Buchanan P.M., Guzman M.A., et al. Preserved Gut Microbial Diversity Accompanies Upregulation of TGR5 and Hepatobiliary Transporters in Bile Acid—Treated Animals Receiving Parenteral Nutrition. J. Parenter. Enter. Nutr. 2016;41:198–207. doi: 10.1177/0148607116661838.
    1. Ladurner A., Zehl M., Grienke U., Hofstadler C., Faur N., Pereira F.C., Berry D., Dirsch V.M., Rollinger J.M. Allspice and Clove As Source of Triterpene Acids Activating the G Protein-Coupled Bile Acid Receptor TGR5. Front. Pharmacol. 2017;8:468. doi: 10.3389/fphar.2017.00468.
    1. Loubinoux J., Valente F.M., Pereira I.A., Costa A., Grimont P.A., Le Faou A.E. Reclassification of the only species of the genus Desulfomonas, Desulfomonas pigra, as Desulfovibrio piger comb. nov. Int. J. Syst. Evol. Microbiol. 2002;52:1305–1308. doi: 10.1099/ijs.0.02175-0.
    1. Scanlan P.D., Shanahan F., Marchesi J.R. Culture-independent analysis of desulfovibrios in the human distal colon of healthy, colorectal cancer and polypectomized individuals. FEMS Microbiol. Ecol. 2009;69:213–221. doi: 10.1111/j.1574-6941.2009.00709.x.
    1. Takada K., Nakane T., Masuda K., Ishii H. Ursolic acid and oleanolic acid, members of pentacyclic triterpenoid acids, suppress TNF-α-induced E-selectin expression by cultured umbilical vein endothelial cells. Phytomedicine. 2010;17:1114–1119. doi: 10.1016/j.phymed.2010.04.006.
    1. Saaby L., Jäger A.K., Moesby L., Hansen E.W., Christensen S.B. Isolation of immunomodulatory triterpene acids from a standardized rose hip powder (Rosa canina L.) Phytother. Res. 2011;25:195–201. doi: 10.1002/ptr.3241.
    1. An Q., Hu Q., Wang B., Cui W., Wu F., Ding Y. Oleanolic acid alleviates diabetic rat carotid artery injury through the inhibition of NLRP3 inflammasome signaling pathways. Mol. Med. Rep. 2017;16:8413–8419. doi: 10.3892/mmr.2017.7594.
    1. Jäger S., Trojan H., Kopp T., Laszczyk M.N., Scheffler A. Pentacyclic Triterpene Distribution in Various Plants—Rich Sources for a New Group of Multi-Potent Plant Extracts. Molecules. 2009;14:2016–2031. doi: 10.3390/molecules14062016.
    1. Castellano J.M., Espinosa J.M., Perona J.S. Modulation of Lipid Transport and Adipose Tissue Deposition by Small Lipophilic Compounds. Front. Cell Dev. Biol. 2020;8:555359. doi: 10.3389/fcell.2020.555359.
    1. Furtado N.A.J.C., Pirson L., Edelberg H., Miranda L.M., Loira-Pastoriza C., Preat V., Larondelle Y., André C.M. Pentacyclic Triterpene Bioavailability: An Overview of In Vitro and In Vivo Studies. Molecules. 2017;22:400. doi: 10.3390/molecules22030400.
    1. Xu L.Z., Wan Z.X. The effect of oleanolic acid on acute hepatitis (70 cases) Hum. Med. 1980;7:50–52.
    1. Minich D.M., Bland J.S., Katke J., Darland G., Hall A., Lerman R.H., Lamb J., Carroll B., Tripp M. Clinical safety and efficacy of NG440: A novel combination of rho iso-alpha acids from hops, rosemary, and oleanolic acid for inflammatory conditions. Can. J. Physiol. Pharmacol. 2007;85:872–883. doi: 10.1139/Y07-055.
    1. Santos-Lozano J.M., Rada M., Lapetra J., Guinda Á., Jiménez-Rodríguez M.C., Cayuela J.A., Ángel-Lugo A., Vilches-Arenas Á., Gómez-Martín A.M., Ortega-Calvo M., et al. Prevention of type 2 diabetes in prediabetic patients by using functional olive oil enriched in oleanolic acid: The PREDIABOLE study, a randomized controlled trial. Diabetes Obes. Metab. 2019;21:2526–2534. doi: 10.1111/dom.13838.
    1. Castellano J.M., Garcia-Rodriguez S., Espinosa J.M., Millan-Linares M.C., Rada M., Perona J.S. Oleanolic Acid Exerts a Neuroprotective Effect Against Microglial Cell Activation by Modulating Cytokine Release and Antioxidant Defense Systems. Biomolecules. 2019;9:683. doi: 10.3390/biom9110683.
    1. Castellano J.M., Guinda A., Delgado T., Rada M., Cayuela J.A. Biochemical Basis of the Antidiabetic Activity of Oleanolic Acid and Related Pentacyclic Triterpenes. Diabetes. 2013;62:1791–1799. doi: 10.2337/db12-1215.
    1. Xue M., Rabbani N., Momiji H., Imbasi P., Anwar M.M., Kitteringham N., Park B.K., Souma T., Moriguchi T., Yamamoto M., et al. Transcriptional control of glyoxalase 1 by Nrf2 provides a stress-responsive defence against dicarbonyl glycation. Biochem. J. 2012;443:213–222. doi: 10.1042/BJ20111648.

Source: PubMed

3
Abonneren