Oleanolic acid and ursolic acid: Research perspectives

doi:10.1016/j.jep.2005.05.024

Journal of Ethnopharmacology

Volume 100, Issues 1–2, 22 August 2005, Pages 92-94

https://doi.org/10.1016/j.jep.2005.05.024 Get rights and content

Abstract

Oleanolic acid and ursolic acid are ubiquitous triterpenoids in plant kingdom, medicinal herbs, and are integral part of the human diet. During the last decade over 700 research articles have been published on their research, reflecting tremendous interest and progress in our understanding of these triterpenoids. This included the isolation and purification of these tritepernoids from various plants and herbs, the chemical modifications to make more effective and water soluble derivatives, the pharmacological research on their beneficial effects, the toxicity studies, and the clinical use of these triterpenoids in various diseases including anticancer chemotherapies. A briefly commentary is attempted here for their research perspectives.

Section snippets

“Dose differentiates a poison from a remedy”

Paracelsus pointed out in the 16th century that “All substances are poisons; there is none which is not poison. The right dose differentiates a poison from a remedy”. Like many herbal ingredients, the selection of the appropriate dose of these triperpenoids is critical. Although these triterpenoids are relatively safe, toxicities do occur in certain circumstances. For example, low-doses of oleanolic acid are hepatoprotective, while the high-dose could produce cholestasis and hepatotoxicity.

Chemical modifications of oleanolic acid

A major advancement during the past 10 years is the synthesis of derivatives from the natural triterpenoids such as oleanolic acid. For example, the oleanolic acid derivative 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) has been generated, which is more potent than the parent compound in anti-inflammatory actions and more effective in inhibiting iNOS and COX2 as a basis of its anti-inflammatory effects (Suh et al., 1998). Other synthetic derivatives, such as carbenoxone and uvaol

Mixtures and chemical interactions

One major feature of the traditional medicine is the use of herb mixtures. Modern pure compound research is necessary to advance our knowledge of their structure–activity relationships and the mechanism of their biological actions. However, the mixtures of these active ingredients are more effective than a single compound in producing desired biological effects, and are the common practice in health care and clinical treatments. For example, oleanolic acid has been used in the formula of

Hepatoprotection perspectives

Oleanolic acid and ursolic acid are well known for their hepatoprotective effects for both acute chemically induced liver injury and chronic liver fibrosis and cirrhosis (Liu, 1995). They are still used alone or in combination with other hepatoprotective ingredients as oral medications. The beneficial effects of these triterpenoids on the liver could be due to their anti-oxidant and anti-inflammatory actions, and their effects on drug-metabolizing enzymes. These triterpenoids are effective

Chemotherapy perspectives

Oleanolic acid and ursolic acid have been shown to act at various stages of tumor development to inhibit tumor initiation and promotion, as well as to induce tumor cell differentiation and apoptosis. In the two-stage mouse skin carcinogenesis model, the protection of oleanolic acid against 12-O-teradecanoyl phorbol-13-acetate promoted carcinogenesis is associated with inhibition of aberrant gene expression (Oguro et al., 1998). Oleanolic acid derivatives are also effective for acute myeloid

Signal transduction pathways

The advance of molecular biology techniques has greatly helped our understanding of these triterpenoids. More and more sophisticated studies have been directed at the molecular levels to understand the mechanism of their biological effects. For example, the involvement of MAP kinase pathways (JNK) has been demonstrated in oleanolic acid derivative induced apoptosis in lung cancer cells and in leukemia cells (Zou et al., 2004). The induction of the phase-2 enzymes such as heme oxygenase 1 and

Other pharmacological effects

A variety of novel pharmacological effects produced by these triterpenoids have been reported, including their beneficial effects on cardiovascular systems (Somova et al., 2003), interaction with cytochrome P450s (Kim et al., 2004), protection against kainate-induced excitotoxicity in rat hippocampal neurons and immunomodulatory effects, as well as its effects on intracellular redox balance and osteoclast formation. The monoclonal antibody against oleanolic acid has also been generated. These

Acknowledgements

The author thanks critical review by Drs. Wei Qu, Yaxiong Xie and Larry Keefer for their critical comments on this commentary. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services.

References (15)

C. Farina et al.
Synthesis and anti-ulcer activity of new derivatives of glycyrrhetic, oleanolic and ursolic acids
Pharmacology
(1998)
K.A. Kim et al.
Inhibition of cytochrome P450 activities by oleanolic acid and ursolic acid in human liver microsomes
Life Sciences
(2004)
J. Liu
Pharmacology of oleanolic acid and ursolic acid
Journal of Ethnopharmacology
(1995)
Y. Liu et al.
Protection against carbon tetrachloride hepatotoxicity by oleanolic acid is not mediated through metallothionein
Toxicology Letters
(1998)
S. Murakami et al.
Ursolic acid, an antagonist for transforming growth factor (TGF)-beta1
FEBS Letters
(2004)
T. Oguro et al.
Inhibitory effect of oleanolic acid on 12-O-tetradecanoylphorbol-13-acetate-induced gene expression in mouse skin
Toxicological Sciences
(1998)
L.O. Somova et al.
Cardiovascular, antihyperlipidemic and antioxidant effects of oleanolic and ursolic acids in experimental hypertension
Phytomedicine
(2003)

There are more references available in the full text version of this article.

Cited by (642)

The oral administration of Lotus corniculatus L. attenuates acute and chronic pain models in male rats
2024, Journal of Ethnopharmacology
Lotus corniculatus L. (Fabaceae) traditionally used in Persian folk medicine to heal peritoneal inflammation and back pain.
To explore the antinociceptive (acute pain) and anti-neuropathic (chronic pain) activities of Lotus corniculatus leaves essential oil (LCEO) in addition to uncovering the possible mechanisms of antinociception.
LCEO as well as the pure oleanolic acid (OA) compound, were assayed for their effects on acute (formalin induced paw licking test or FIPT) and chronic (cervical contusion injury models on the fifth cervical vertebra or CCS; 14-day intervals) pain. The possible involvements of NO-cGMP-K⁺ channel, TRPV, dopamine, cannabinoid, PPAR, adrenergic, and opioid mechanisms in the antinociceptive activity of LCEO have studied by formalin test. The levels of p53 and inflammatory markers were measured using a streptavidin biotin immune peroxidase complex and ELISA methods, respectively.
The LCEO and OA exerted antinociceptive activity in the first-phase of FIPT. Pretreatment with antagonists of TRPV1, dopamine D2, cannabinoid type1 and 2, and NO-cGMP-K⁺ channel blockers (glibenclamide, L-NAME and methylene blue) attenuated the antinociceptive effect of LCEO in FIPT. In addition, LCEO and OA meaningfully reduced hyperalgesia (days 6–14) and mechanical allodynia (days 2–14) in the CCS model. LCEO suppressed the apoptotic marker (p53) in CCS model and also ameliorated IL-2, TNF-α, and IL-1 in the spinal cord.
Finally, LCEO inhibited acute (possibly via the modulation of opioid, TRPV, dopamine, cannabinoid mechanisms as well as NO-cGMP-K⁺ channel) and chronic pain (via suppressing apoptotic and inflammatory markers) in male rats. The results also suggest that OA has analgesic activity against acute and chronic pain conditions.
Beneficial effects of oleanolic acid on hepatopancreas oxidative stress and intestinal microbiota structure of red swamp crayfish (Procambarus clarkia)
2023, Aquaculture Reports
This study aimed to evaluate the beneficial effects of oleanolic acid (OA) in the culture of red swamp crayfish (Procambarus clarkia) by investigating the impact of dietary OA on growth performance, hepatopancreas antioxidant activity, innate immunity, and intestinal microbiota structure. An eight-week feeding trial was conducted using different dietary OA concentrations: 0, 250, 500, 750, and 1000 mg·kg^–1. The results revealed that the groups with 500–1000 mg·kg^–1 OA exhibited increased final body weight, weight gain rate, and specific growth rate, as well as decreased feed conversion ratio compared to those in the control group (P < 0.05). Serum alanine transaminase (ALT) and aspartate transaminase (AST) activities showed a linear decrease with increasing dietary OA concentration. OA demonstrated hypolipidemic effects by reducing serum glucose, total cholesterol, triglyceride, and low-density lipoprotein cholesterol levels, while increasing serum high-density lipoprotein cholesterol levels (P < 0.05). OA500 to OA1000 groups exhibited significantly higher trypsin activity compared to that of the control, while lipase activity linearly decreased with increasing dietary OA concentration. The antioxidant capacity, as indicated by glutathione level in the hepatopancreas, showed significant differences between the OA treatment group and the control group. However, dietary OA did not significantly alter the structure of the intestinal microbiota. These findings suggest that dietary OA supplementation effectively improves the growth performance and enhanced the innate immunity of crayfish. Furthermore, OA significantly promotes the antioxidant capacity, thereby protecting the hepatopancreas from oxidative damage. The optimal dose range of dietary OA for application in crustacean culture is recommended to be between 500 and 1000 mg·kg⁻¹.
Pentacyclic triterpene-amino acid derivatives induced apoptosis and autophagy in tumor cells, affected the JNK and PI3K/AKT/mTOR pathway
2023, Bioorganic and Medicinal Chemistry
A series of pentacyclic triterpene-amino acid derivatives were synthesized and tested for anti-proliferative activity. The results showed that most of the target compounds had good anti-proliferative activity. 2c did not contain protecting groups and hydrochloride, had excellent cytotoxicity, so it had been selected for further study in the mechanism of action in T24 cells. The data from transcriptome sequencing indicated that 2c was found to be closely related to apoptosis and autophagy. Observation of fluorescence staining and analysis from flow cytometry demonstrated that 2c induced apoptosis and cause cell cycle arrest in S/G2 phase in T24 cells. Molecular mechanism studies exhibited that 2c induced apoptosis in the intrinsic and extrinsic pathways. 2c also induced cellular autophagy in T24 cells. Results from Western Blotting showed that 2c could activate JNK pathway and inhibit PI3K/AKT/mTOR pathway. In conclusion, 2c was deserved further investigation in the field of anti-tumor.
Effects of oleanolic acid and ursolic acid on depression-like behaviors induced by maternal separation in mice
2023, European Journal of Pharmacology
Oleanolic acid (OA) and ursolic acid (UA) are structural isomeric triterpenoids. Both triterpenoids have been reported to be able to improve depression. However, no studies have compared their effects in the same system. Whether OA or UA could ameliorate depression-like behaviors in maternal separation (MS)-induced depression-like model was investigated. MS model is a well-accepted mouse model that can reflect the phenotype and pathogenesis of depression. Depression is a mental illness caused by neuroinflammation or changes in neuroplasticity in certain brain regions, such as the prefrontal cortex and hippocampus. Depression-like behaviors were measured using splash test or forced swimming test. In addition, anxiety-like behaviors were also measured using the open field test or elevated plus-maze test. MS-treated female mice showed greater depression-like behaviors than male mice, and that OA improved several depression-like behaviors, whereas UA only relieved anxiety-like behavior of MS-treated mice. Microglial activation, expression levels of TNF-α, and mRNA levels of IDO1 were increased in the hippocampi of MS-treated female mice. However, OA and UA treatments attenuated such increases. In addition, expression levels of synaptophysin and PSD-95 were decreased in the hippocampi of MS-treated female mice. These decreased expression levels of synaptophysin were reversed by both OA and UA treatments, although decreased PSD-95 expression levels were only reversed by OA treatment. Our findings suggest that MS cause depression-like behaviors through female-specific neuroinflammation, changes of tryptophan metabolism, and alterations of synaptic plasticity. Our findings also suggest that OA could reverse MS-induced depression-like behaviors more effectively than UA.
Oleanolic acid inhibits mercury chloride induced-liver ferroptosis by regulating ROS/iron overload
2023, Ecotoxicology and Environmental Safety
Mercury chloride can cause severe liver injury, which involves multiple mechanisms. Ferroptosis plays an important role in regulating the development and progression of liver pathology. Oleanolic acid (OA), a triterpenoid compound widely exists in fruits, has liver protective properties. In this study, we investigated the role of ferroptosis in mercury chloride-induced liver injury and the intervention effect of OA, and clarified the potential mechanism. We found that mercury chloride-induced oxidative stress in liver tissues and cells, leading to lipid peroxidation and iron overload, thereby reducing the expression levels of GPX4 and SLC7A11, and increasing the expression level of TRF1, OA pretreatment improved the changes of GPX4, SLC7A11 and TRF1 induced by mercury chloride, which were related to its inhibition of oxidative stress. Furthermore, We pretreated cells with OA, VC, and Fer-1, respectively and found that VC pretreatment reduced oxidative stress and significantly reversed the gene and protein expressions of GPX4, SLC7A11, and TRF1 in mercury chloride-exposed cells (P < 0.05, vs. HgCl₂ group), however, the protein expression level of GPX4 in OA pre-treatment group was lower than that in VC pre-treatment group (P < 0.05). Fer-1 pretreatment decreased the level of iron ions in cells, increased the gene and protein expression levels of GPX4 and SLC7A11, and decreased the gene and protein expression levels of TRF1 (P < 0.05, vs. HgCl₂ group), however, the protein expression levels of GPX4 and SLC7A11 in OA pre-treatment group were lower than those in Fer-1 pre-treatment group (P < 0.05). Moreover, vivo experiments also demonstrated that pre-treatment with OA, VC, and Fer-1 reversed the changes in gene expression levels of Nrf2 and SOD1, and protein expression of GPX4 induced by mercury chloride (P < 0.05, vs. HgCl₂ group), meanwhile, the difference was not statistically significant among OA, VC, and Fer-1 pretreatment. The improvement effect of OA pretreatment on the change in TFR1 protein expression caused by mercury chloride was similar to that of Fer-1 and VC, however, the intervention effect of OA on SLC7A11 protein expression was not as good as Fer-1 and VC pre-treatment. To sum up, all these results suggest that ferroptosis is involved in mercury chloride-induced liver injury, OA pretreatment alleviated mercury chloride-induced ferroptosis by inhibiting ROS production and iron ion overload, and then alleviate the liver injury.
A review on terpenes for treatment of gastric cancer: current status and nanotechnology-enabled future
2023, RSC Sustainability
Eighty-five percent of gastric cancer is caused by Helicobacter pylori infection. Delays in detection, limited efficacy, and significant side effects of the available treatments lead to a 5-year survival chance of only 32%. Therefore, better remedies are required. Numerous studies have been published on herbal medications offering an edge over conventional medicines. Secondary metabolites such as different polyphenolic compounds including terpenes are key players for therapeutic advantages. The antimicrobial, anticarcinogenic, anti-inflammatory, etc. activities of biocompatible active ingredients make these compounds suitable for therapeutic use. Despite such advantages, the use of herbal medicine in gastric cancer treatment is limited. In this article, we describe the therapeutic potential and limitations of terpenes followed by the potential advantages offered by the combinatorial effects of terpenes with their nanoconjugates. These include increasing the anticancer and antimicrobial potency of drugs as well as resolving drawbacks including targeted delivery, stability, half-life, etc, thus making them suitable for gastric cancer treatment. The article concludes with a detailed discussion on the challenges encountered in deploying targeted secondary metabolites and their future developmental prospects to provide ideas and insights for future research.

View all citing articles on Scopus

View full text

Published by Elsevier Ireland Ltd.

Perspective paperOleanolic acid and ursolic acid: Research perspectives

Abstract

Section snippets

“Dose differentiates a poison from a remedy”

Chemical modifications of oleanolic acid

Mixtures and chemical interactions

Hepatoprotection perspectives

Chemotherapy perspectives

Signal transduction pathways

Other pharmacological effects

Acknowledgements

Pharmacology

Life Sciences

Journal of Ethnopharmacology

Toxicology Letters

FEBS Letters

Toxicological Sciences

Phytomedicine

Perspective paper
Oleanolic acid and ursolic acid: Research perspectives