The natural sources,extraction,and nephroprotective function of oleanolic acid and ursolic acid:a review

Oleanolic acid(OA)and ursolic acid(UA)are commonly present in the cuticular wax of many edible fruits and medicinal herbs.OA and UA belong to the group of bioactive pentacyclic triterpenoids,exhibiting a wide range of beneficial effects including protection for the kidneys,liver,heart,gastrointestinal tract,and spinal cord.Additionally,OA and UA exhibit antioxidant,anti-ferroptotic,anti-apoptotic,anti-inflammatory,anti-tumor,anti-viral,anti-diabetic,anti-microbial,anti-parasitic,analgesic,wound-healing,hypolipidemic,and hypoglycemic properties,often without notable side effects.Due to the extensive array of their positive functions,it is not feasible to thoroughly cover all aspects in this review.Therefore,the primary focus lies on reviewing the natural sources,extraction,and nephroprotective properties of OA and UA.To summarize,current literatures highlight the nephroprotective mechanisms of OA and UA,primarily involving inhibiting oxidative stress,endoplasmic reticulum stress,glycative stress,dyslipidemia,inflammation,apoptosis,pyroptosis,and renal fibrosis,promoting diuresis,as well as fine-tuning autophagy.

TWO NEW OLEANOLIC ACID SAPONINS FROM ASTER YUNNANENSIS

Two new oleanolic acid saponins named asteryunnanoside F and G were isolated from the roots. of Aster yunnenensis. The chemical structures were determined as oleanolic acid-28-O-βD-glucopyranosyl-(1→6)-β-D-glucO and 3-O-β-Dglucopyranosyl-oleanolic acid-28-O-βD-glucopyranosyl-(1→6)[-rhamn by speCtral data,especially 2D NMR anajysis (COSY, HETCOR, HOHAHA and ROESY), and Chemical transformations.

Effects of Oleanolic Acid on the Immune Complex Allergic Reaction and Inflammation

When oleanolic acid (OA) was administered ig before and after sensitization on d 1 to d 5 and d 11 to d 17,it had no apparent effect on Arthus reaction.When it was administered at 48,24 and 1 h before challenge,however,Arthus reaction was significantly inhibited.OA showed markedly suppressive effects on reversible passive Arthus reaction and leukocyte migratory response.It could significantly stabilize erythrocyte membrane,inhibit the swelling of the rat's hind paw induced by in- jecting mycostatin,reduce the acid phosphatase content in the inflammatory exudate,suppress the syn- thesis or release of PGE,histamine,LTB4 and kinin,and the phlogistic action of PGE_2,histamine,5- HT and kinin.In addition,it could decrease the content of malonyldialdehyde (MDA) in hepatic tissue of alcohol-intoxicated mice,and increase the activity of catalase (CAT) in hepatic tissue of mice.OA had no apparent effect on the activity of super-oxide dismutase (SOD) in rat serum,on the content of immune complex in serum of rat with Arthus reaction,on the phagocytosis of monocytc-macrophage system,on the clearance of enzyme-containing immune complex by macrophage,or on the activity of total complement.

Application of hot melt extrusion to enhance the dissolution and oral bioavailability of oleanolic acid

The aim of this study was to improve the in vitro dissolution rate and oral bioavailability of oleanolic acid(OA), a water insoluble drug belonging to BCS class IV. Hot melt extrusion(HME) was applied to develop OA amorphous solid dispersions. The characterizations of the optimal formulation were performed by differential scanning calorimetry, X-ray powder diffraction, Fourier transform infrared spectroscopy and in vitro dissolution test.The in vivo pharmacokinetic study was conducted in rats. As a result, OA solid dispersion based on PVP VA 64(OA-PVP) was successfully prepared. In the dissolution medium containing 0.3% SDS, OA-PVP dramatically increased the releasing rate of OA compared with the physical mixture(PM-PVP) and commercial tablet. Furthermore, OA-PVP exhibited higher AUC(P < 0.05) and Cmax(P < 0.05) than PM-PVP and commercial tablet. The superior dissolution property and bioavailability of OA-PVP mainly attributed to the amorphous state of OA in PVP VA64 and the well dispersion caused by thermal melting and shearing. Overall, hot melt extrusion was an efficient strategy to enhance the dissolution rate and oral bioavailability of OA.

Effects of ursolic acid and oleanolic acid on human colon carcinoma cell line HCT15

AIM: Ursolic acid (UA) and oleanolic acid (OA) are triperpene acids having a similar chemical structure and are distributed wildly in plants all over the world. In recent years, it was found that they had marked anti-tumor effects. There is little literature currently available regarding their effects on colon carcinoma cells. The present study was designed to investigate their inhibitory effects on human colon carcinoma cell line HCT15. METHODS: HCT15 cells were cultured with different drugs. The treated cells were stained with hematoxylin-eosin and their morphologic changes observed under a light microscope. The cytotoxicity of these drugs was evaluated by tetrazolium dye assay. Cell cycle analysis was performed by flow cytometry (FCM). Data were expressed as means +/-SEM and Analysis of variance and Student' t-test for individual comparisons. RESULTS: Twenty-four to 72 h after UA or OA 60 micromol/L treatment, the numbers of dead cells and cell fragments were increased and most cells were dead at the 72nd hour. The cytotoxicity of UA was stronger than that of OA. Seventy-eight hours after 30 micromol/L of UA or OA treatment, a number of cells were degenerated, but cell fragments were rarely seen. The IC(50) values for UA and OA were 30 and 60 micromol/L, respectively. Proliferation assay showed that proliferation of UA and OA-treated cells was slightly increased at 24h and significantly decreased at 48 h and 60 h, whereas untreated control cells maintained an exponential growth curve. Cell cycle analysis by FCM showed HCT15 cells treated with UA 30 and OA 60 for 36 h and 72 h gradually accumulated in G(0)/G(1) phase (both drugs P【0.05 for 72 h), with a concomitant decrease of cell populations in S phase (both drugs P【0.01 for 72 h) and no detectable apoptotic fraction. CONCLUSION: UA and OA have significant anti-tumor activity. The effect of UA is stronger than that of OA. The possible mechanism of action is that both drugs have an inhibitory effect on tumor cell proliferation through cell-cycle arrest.

Prophylactic and therapeutic roles of oleanolic acid and its derivatives in several diseases

Oleanolic acid(OA)and its derivatives are widely found in diverse plants and are naturally effective pentacyclic triterpenoid compounds with broad prophylactic and therapeutic roles in various diseases such as ulcerative colitis,multiple sclerosis,metabolic disorders,diabetes,hepatitis and different cancers.This review assembles and presents the latest in vivo reports on the impacts of OA and OA derivatives from various plant sources and the biological mechanisms of OA activities.Thus,this review presents sufficient data proposing that OA and its derivatives are potential alternative and complementary therapies for the treatment and management of several diseases.

Simultaneous determination of oleanolic acid and ursolic acid by RP-HPLC in the leaves of Eriobotrya japonica Lindl

Oleanolic acid(OA) and ursolic acid(UA) are isomeric triterpenic acids and only one methyl’s position is different between them.OA and UA always exist in the same plant,so it is difficult to separate them when determining contents by RP-HPLC.In this study,a very simple mobile phase for HPLC was developed to simultaneously determine UA and OA,and the factors affecting separation were also discussed.The mobile phase is methanol:water(95:5) with flow rate 0.4 mL/min.The retention time for OA and UA was 20.58 and 21.57 min,respectively,the resolution was 1.61.The average contents of OA and UA of three Loquat leaves sets were 1.4 mg/g and 5.6 mg/g,respectively.Regarding the HPLC,we found that changing mobile phase,adjusting the pH value or adding ion-pairing agent could not affect the separation between UA and OA greatly.While adjustment of the flow rate and column temperature could improve the resolution greatly.

Preparation and characterization of solidified oleanolic acid–phospholipid complex aiming to improve the dissolution of oleanolic acid

The purpose of this study was to prepare the oleanolic acid–phospholipid complex (OAPC) and then solidify it employing fumed silica by simple solvent evaporation technique to improve dissolution rate of oleanolic acid and oleanolic acid–phospholipid complex. The process of OA-PC was optimized and the type and proportion of fumed silica were studied by dissolution text. The structures of the phospholipid complex and solidified powder were also characterized by differential scanning calorimetry, X-ray diffraction, and scanning electron microscope. In the dissolution tests, OA from solidified powder was further released compared with that from pure OA and OA-PC in different kinds of dissolution media. These results suggest that the method of preparing solidified powder of oleanolic acid–phospholipid complex is suitable for enhancing the dissolution rate of OA and OA-PC.

Host-guest interaction of β-cyclodextrin with isomeric ursolic acid and oleanolic acid:physicochemical characterization and molecular modeling study

Ursolic acid(UA) and oleanolic acid(OA) are insoluble drugs. The objective of this study was to encapsulate them into β-cyclodextrin(β-CD) and compare the solubility and intermolecular force of β-CD with the two isomeric triterpenic acids. The host-guest interaction was explored in liquid and solid state by ultraviolet-visible absorption,1H NMR, phase solubility analysis, and differential scanning calorimetry, X-ray powder diffractometry, and molecular modeling studies. Both experimental and theoretical studies revealed that β-CD formed 1: 1 water soluble inclusion complexes and the complexation process was naturally favorable. In addition, the overall results suggested that ring E with a carboxyl group of the drug was encapsulated into the hydrophobic CD nanocavity. Therefore, a clear different inclusion behavior was observed, and UA exhibited better affinity to β-CD compared with OA in various media due to little steric interference, which was beneficial to form stable inclusion complex with β-CD and increase its water solubility effectively.

Research advances in phytochemistry,pharmacology and toxicology of oleanolic acid

Oleanolic acid(OA)is a pentacyclic triterpenoid chemical component that exists in natural plants with a molecular formula of C30H48O3 and a molecular weight at 456.71 g·mol-1.OA is widespread in traditional Chinese herbal medicine(Ligustri Lucidi Fructus,Achyranthis Bidentate Radix,Red Sage)and berries(blueberries,grapes).In recent years,because of the extensive pharmacological effects of OA,its advantages in disease treatment have become increasingly prominent and gradually attracted the attention of pharmaceutical researchers.OA has effective therapeutic effects on a series of chronic diseases such as inflammation,cancer,diabetes,and cardiovascular diseases through multiple signaling pathways and various targets.Especially in cancers,such as colorectal cancer,liver cancer,gastric cancer,lung cancer,breast cancer and other malignancies,OA presents substantial efficacy.However,its poor aqueous solubility,needy bioavailability,and unsatisfactory pharmacological activity excessively restrict its clinical application.More importantly,the improper utilization of OA can cause adverse reactions,toxic effects and even damage to organs in some specific situations.With the discovery of various pharmacological effects,the complex action mechanisms of OA,the continuous progress in structural modification of OA,as well as the synthesis of OA derivatives,its application is expanding gradually.Among numerous studies,there is a clear indication that OA and its derivatives,if fully developed,may provide an alternative and cheaper treatment for a variety of chronic diseases.However,the specific molecular mechanisms of OA and its derivatives as an alternative therapy and supplementary therapy for cancer,diabetes,cardiovascular disease and other chronic diseases remain to be clarified.Therefore,it is necessary to further study the pharmacokinetics,pharmacological activity,specific targets and related mechanisms of OA to lay a solid foundation for drug development and the application of OA in clinical settings.

Polymeric nanoparticles developed by vitamin E-modified aliphatic polycarbonate polymer to promote oral absorption of oleanolic acid

Oleanolic acid (OA) exhibited good pharmacological activities in the clinical treatment of hypoglycemia, immune regulation, acute jaundice and chronic toxic hepatitis. However, the oral delivery of OA is greatly limited by its inferior water solubility and poor intestinal mucosa permeability. Herein, we developed a novel polymeric nanoparticle (NP) delivery system based on vitamin E modified aliphatic polycarbonate (mPEG-PCC-VE) to facilitate oral absorption of OA. OA encapsulated mPEG-PCC-VE NPs (OA/mPEG-PCC-VE NPs) showed uniform particle size of about 170 nm with high drug loading capability (8.9%). Furthermore, the polymeric mPEG-PCC-VE NPs, with good colloidal stability and pH-sensitive drug release characteristics, significantly enhanced the in vitro dissolution of OA in the alkaline medium. The in situ single pass intestinal perfusion (SPIP) studies performed on rats demonstrated that the OA/m PEG-PCC-VE NPs showed significantly improved permeability in the whole intestinal tract when compared to OA solution, especially for duodenum and colon. As a result, the in vivo pharmacokinetics study indicated that the bioavailability of OA/m PEG-PCC-VE NPs showed 1.5-fold higher than commercially available OA tablets. These results suggest that mPEGPCC-VE NPs are a promising platform to facilitate the oral delivery of OA.

Determination of Oleanolic Acid in Achyranthes aspera L. of Different Production Areas by HPLC

[Objectives] To determine the content of oleanolic acid in 10 batches of Achyranthes aspera L. from different production areas,and to establish a high performance liquid chromatography( HPLC) method for the determination of oleanolic acid in A. aspera. [Methods]Agilent C18 liquid chromatography column( 250 mm × 4. 6 mm,5 μm) was used for gradient elution with acetonitrile∶ water = 61∶ 39 as the mobile phase. The flow rate was 1 mL/min,the detection wavelength was 210 nm,and the column temperature was 35℃. [Results] The oleanolic acid injection volume showed a good linear relationship with the peak area in the range of 0. 382-7. 640 μg. The linear equation of oleanolic acid was: A = 530. 76 C,R = 1. 000 0; the range of sample recovery rate was 96. 03%-102. 73%,and the RSD value was 2. 16%( n =9). The content of the oleanolic acid was the highest in A. aspera produced in Guilin City of Guangxi( 0. 92%),and the lowest oleanolic acid content was in sample of Sitang in Nanning City of Guangxi( 0. 27%). It is recommended that the oleanolic acid content of A. aspera should not be lower than 0. 20%. [Conclusions]The HPLC method is accurate,reliable,easy to operate,and has good resolution. It is suitable for the determination of the content of oleic acid in A. aspera. It can provide reference for the quality control and standard drafting of A. aspera.

S-adenosyl-L-methionine, trehalose and oleanolic acid in few plants

S-Adenosyl-L-Methionine (AdoMet), S-Adenosyl- L-Homocysteine (AdoHcy), adenosine, trehalose and oleanolic acid were measured in six medicinal herbs and three spices. The findings showed that AdoMet content was forty six fold higher in the leaves of Catharanthus roseus as compared with average AdoMet content of rest of the plants. In comparison to other plants, Withania somnifera had very high AdoHcy: Ado-Met and adenosine: AdoMet ratios indicating it may have contained high AdoMet. Trehalose was found to be twenty fold and nine fold higher in bulb of Allium cepa and root of Withania somnifera respectively with respect to average trehalose content of rest of the plants. Ocimum sanctum appeared to be a rich source of oleanolic acid. It appeared from our study that Catharanthus roseus, Allium cepa and Ocimum sanctum could be utilized as natural sources of AdoMet, trehalose and oleanolic acid respectively.

Effect of MeJA and Light on the Accumulation of Betulin and Oleanolic Acid in the Saplings of White Birch (<i>Betula platyphylla</i>Suk.)

In this study, we investigated the effect of different types of light and MeJA treatment on the accumulation of betulin and oleanolic acid in various organs of white birch. Our results showed that betulin and oleanolic were accumulated mainly in the stalk skin. The content of both substances in the stalk skin was significantly affected by seasons with a peak accumulation in August. The content of oleanolic and betulin was significantly decreased in the stem skin treated with 4 types of light (red, yellow, blue and green) compared with the plant with normal illumination. In contrast, oleanolic acid in leaves was increased by 13.28 folds when the white birch was treated with green light. Betulin was increased by 1.959 folds in leaves of white birch treated with blue light. The highest content of betulin and oleanolic acid in various organs of birch with appropriate shading treatment (light transmittance: 50%) was increased by 45.09% and 30.50%, respectively, in comparison with those with non-shading treatment. Content of oleanolic acid and betulin can be significantly improved in various parts of birch after treatment with different concentration of MeJA. The study lays the foundation to metabolic regulation of oleanolic acid and betulin in birch.

Metals Complexes Formed with Oleanolic Acid

The oleanolic acid possesses diverse pharmacological properties, it is considered as a good starting material for creating new compounds. The oleanolic acid isolated of Plumeria obtusa leaves was used as raw material to obtained calcium, magnesium, zinc, nickel and copper complexes. The structures of complexes were confirmed by HRMS, 1H NMR, and 13C NMR. Five new compounds were synthesized to promote increased biological activity of oleanolic acid and PCR assays for the different type of cancer.

HPLC Determination of Oleanolic Acid and Ursolic Acid in Chaenomeles cathayensis from Guizhou

[Objectives]This study was conducted to establish a method for determining the contents of Chaenomeles cathayensis(Hemsl.)Schneid.,and analyze the changes in effective components of C.cathayensis grown in Guizhou,so as to provide data support for the production and quality control of C.cathayensis.[Methods]The contents of ursolic acid and oleanolic acid in C.cathayensis in different areas of Guizhou were determined.The HPLC method was adopted under following conditions:chromatographic column waters C18 column(4.6 mm×150 mm,5.0μm);mobile phase:methanol-0.1 mol/L ammonium acetate(85∶15);column temperature:25℃;detection wavelength:257 nm;flow rate 1.0 ml/min.[Results]Through methodological investigations,HPLC could be used to detect the contents of the two terpenoids oleanolic acid and ursolic acid in C.cathayensis from Guizhou.The content of oleanolic acid ranged from 0.076%to 0.144%,and the content of ursolic acid ranged from 0.201%to 0.439%.[Conclusions]A method for determining the contents of C.cathayensis was established using the HPLC method with oleanolic acid and ursolic acid as the index components.The method is accurate,reliable,and simple and easy to implement,and can serve as a reference and support for quality evaluation and standard improvement of C.cathayensis.

Differential Effects of Ursolic Acid and Oleanolic Acid on Mitochondrial ATP Generation in H9c2 Cardiomyocytes and Lipopolysaccharide-Induced Cell Proliferation in Mouse Splenocytes: Yang versus Yin

In the present study, two cell-based systems for assessing Yang and Yin activities were for the first time used to investigate the effect of ursolic acid (UA) and oleanolic acid (OA). The results indicated that while UA was only active in the Yang assay, OA produced activity in the Yin assay. The Yang/Yin activity of UA/OA may be attributed to their distinct molecular structures, which confer their differential ability to interact with mitochondrial membrane or cellular membrane lipids, with resultant membrane fluidization and potentiation of biological responses.

A review of structural modification and biological activities of oleanolic acid

Oleanolic acid(OA),a pentacyclic triterpenoid,exhibits a broad spectrum of biological activities,including antitumor,antiviral,antibacterial,anti-inflammatory,hepatoprotective,hypoglycemic,and hypolipidemic effects.Since its initial isolation and identification,numerous studies have reported on the structural modifications and pharmacological activities of OA and its derivatives.Despite this,there has been a dearth of comprehensive reviews in the past two decades,leading to challenges in subsequent research on OA.Based on the main biological activities of OA,this paper comprehensively summarized the modification strategies and structureactivity relationships(SARs)of OA and its derivatives to provide valuable reference for future investigations into OA.

Allosterically activating SHP2 by oleanolic acid inhibits STAT3-Th17 axis for ameliorating colitis

Src homology 2 domain-containing tyrosine phosphatase 2(SHP2)is an essential tyrosine phosphatase that is pivotal in regulating various cellular signaling pathways such as cell growth,differentiation,and survival.The activation of SHP2 has been shown to have a therapeutic effect in colitis and Parkinson's disease.Thus,the identification of SHP2 activators and a complete understanding of their mechanism is required.We used a two-step screening assay to determine a novel allosteric activator of SHP2 that stabilizes it in an open conformation.Oleanolic acid was identified as a suitable candidate.By binding to R362,K364,and K366 in the active center of the PTP domain,oleanolic acid maintained the active open state of SHP2,which facilitated the binding between SHP2 and its substrate.This oleanolic acid-activated SHP2 hindered Th17 differentiation by disturbing the interaction between STAT3 and IL-6Rαand inhibiting the activation of STAT3.Furthermore,via the activation of SHP2 and subsequent attenuation of the STAT3-Th17 axis,oleanolic acid effectively mitigated colitis in mice.This protective effect was abrogated by SHP2 knockout or administration of the SHP2 inhibitor SHP099.These findings underscore the potential of oleanolic acid as a promising therapeutic agent for treating inflammatory bowel diseases.

Oleanolic acid improved intestinal immune function by activating and potentiating bile acids receptor signaling in E. coli-challenged piglets

Background Infection with pathogenic bacteria during nonantibiotic breeding is one of the main causes of animal intestinal diseases.Oleanolic acid(OA)is a pentacyclic triterpene that is ubiquitous in plants.Our previous work demonstrated the protective effect of OA on intestinal health,but the underlying molecular mechanisms remain unclear.This study investigated whether dietary supplementation with OA can prevent diarrhea and intestinal immune dysregulation caused by enterotoxigenic Escherichia coli(ETEC)in piglets.The key molecular role of bile acid receptor signaling in this process has also been explored.Results Our results demonstrated that OA supplementation alleviated the disturbance of bile acid metabolism in ETEC-infected piglets(P<0.05).OA supplementation stabilized the composition of the bile acid pool in piglets by regulating the enterohepatic circulation of bile acids and significantly increased the contents of UDCA and CDCA in the ileum and cecum(P<0.05).This may also explain why OA can maintain the stability of the intestinal microbiota structure in ETEC-challenged piglets.In addition,as a natural ligand of bile acid receptors,OA can reduce the severity of intestinal inflammation and enhance the strength of intestinal epithelial cell antimicrobial programs through the bile acid receptors TGR5 and FXR(P<0.05).Specifically,OA inhibited NF-κB-mediated intestinal inflammation by directly activating TGR5 and its downstream c AMP-PKA-CREB signaling pathway(P<0.05).Furthermore,OA enhanced CDCA-mediated MEK-ERK signaling in intestinal epithelial cells by upregulating the expression of FXR(P<0.05),thereby upregulating the expression of endogenous defense molecules in intestinal epithelial cells.Conclusions In conclusion,our findings suggest that OA-mediated regulation of bile acid metabolism plays an important role in the innate immune response,which provides a new diet-based intervention for intestinal diseases caused by pathogenic bacterial infections in piglets.