Ursolic acid

1 Antennaria sp. 2 Aralia sp. 3 Arbutus sp. 4 Arctium sp. 5 Arctostaphylos sp. 6 Berberis sp. 7 Bursera sp. 8 Calamintha sp. 9 Calluna sp. 10 Castanea sp. 11 Catalpa sp. 12 Cecropia sp. 13 Chimaphila sp. 14 Chionanthus sp. 15 Corchorus sp. 16 Cornus sp. 17 Crataegus sp. 18 Crocus sp. 19 Epilobium sp. 20 Fraxinus sp. 21 Glechoma sp. 22 Hydnocarpus sp. 23 Hyssopus sp. 24 Ilex sp. 25 Jacaranda sp. 26 Knautia sp. 27 Lavandula sp. 28 Leonurus sp. 29 Lycopus sp. 30 Mallotus sp. 31 Melaleuca sp. 32 Melissa sp. 33 Mentha sp. 34 Morinda sp. 35 Nardostachys sp. 36 Nepeta sp. 37 Nerium sp. 38 Ocimum sp. 39 Origanum sp. 40 Potentilla sp. 41 Punica sp. 42 Rhododendron sp. 43 Rosa sp. 44 Rosmarinus sp. 45 Salvia sp. 46 Sambucus sp. 47 Sanguisorba sp. 48 Sarcopoterium sp. 49 Satureja sp. 50 Schinus sp. 51 Shorea sp. 52 Sorbus sp. 53 Strophanthus sp. 54 Tecoma sp. 55 Thymus sp. 56 Uncaria sp. 57 Urtica sp. 58 Vaccinium sp. 59 Viburnum sp. 60 Vinca sp. 61 Viola sp. 62 Viscum sp. 63 Vitex sp.

Ursolic acid(Bungeolic acid) is a natural pentacyclic triterpenoid carboxylic acid, exerts anti-tumor effects and is an effective compound for cancer prevention and therapy. IC50 value: Target: in vitro: UA induced phosphorylation of AMP-activated protein kinase alpha (AMPKα) and suppressed the protein expression of DNA methyltransferase 1 (DNMT1) in the dose-dependent manner [1]. The combination of ursolic acid (0.5 μM) and leucine (10 μM) proved to be the most effective in promoting myogenic differentiation. The combination of ursolic acid and leucine significantly increased CK activity than treatment with either agent alone. The level of myosin heavy chain, a myogenic differentiation marker protein, was also enhanced by the combination of ursolic acid and leucine [2]. Ursolic acid efficiently induced apoptosis, possibly via the downregulation of B-cell lymphoma 2 (Bcl-2), the upregulation of Bcl-2-associated X protein and the proteolytic activation of caspase-3. Furthermore, the activation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase was increased by the administration of ursolic acid. In addition, ursolic acid significantly suppressed the invasive phenotype of the SNU-484 cells and significantly decreased the expression of matrix metalloproteinase (MMP)-2 [3]. ursolic acid (UA) potently induces the apoptosis of gastric cancer SGC-7901 cells. Further mechanistic studies revealed that the ROCK1/PTEN signaling pathway plays a critical role in UA-mediated mitochondrial translocation of cofilin-1 and apoptosis [4]. in vivo: UA treatment markedly improved the survival of septic rats, and attenuated CLP-induced lung injury, including reduction of lung wet/dry weight ratio, infiltration of leukocytes and proteins, myeloperoxidase activity, and malondialdehyde content. In addition, UA significantly decreased the serum levels of tumor necrosis factor-α, interleukin-6, and interleukin-1β, inhibited the expression of inducible nitric oxide synthase and cyclooxygenase-2 in the lung, which are involved in the productions of nitric oxide and prostaglandin E2 [5].

References:
[1]. Yie Y, et al. Ursolic acid inhibited growth of hepatocellular carcinoma HepG2 cells through AMPKα-mediated reduction of DNA methyltransferase 1. Mol Cell Biochem. 2014 Dec 30. [2]. Kim M, et al. The combination of ursolic acid and leucine potentiates the differentiation of C2C12 murine myoblasts through the mTOR signaling pathway. Int J Mol Med. 2015 Mar;35(3):755-62. [3]. Kim ES, et al. Ursolic acid inhibits the invasive phenotype of SNU-484 human gastric cancer cells. Oncol Lett. 2015 Feb;9(2):897-902. [4]. Li R, et al. Ursolic Acid Promotes Apoptosis of SGC-7901 Gastric Cancer Cells through ROCK/PTEN Mediated Mitochondrial Translocation of Cofilin-1. Asian Pac J Cancer Prev. 2014;15(22):9593-7. [5]. Hu Z, et al. Ursolic acid improves survival and attenuates lung injury in septic rats induced by cecal ligation and puncture. J Surg Res. 2014 Oct 22. pii: S0022-4804(14)00967-6.

Ursolic acid isolated from the seed of Cornus officinalis ameliorates colitis in mice by inhibiting the binding of lipopolysaccharide to Toll-like receptor 4 on macrophages.[Pubmed:25213465]

J Agric Food Chem. 2014 Oct 8;62(40):9711-21.

Ursolic acid, which was isolated from an ethanol extract of Cornus officinalis seed, potently inhibited nuclear factor kappa light-chain enhancer of activated B cells (NF-kappaB) activation in lipopolysaccharide (LPS)-stimulated peritoneal macrophages. Therefore, we investigated the anti-inflammatory mechanism of Ursolic acid in LPS-stimulated macrophages and colitic mice. Ursolic acid inhibited phosphorylation of interleukin 1 receptor-associated kinase (IRAK)1, TAK1, inhibitor of nuclear factor kappaB kinase subunit beta (IKKbeta), and IkappaBalpha as well as activation of NF-kappaB and MAPKs in LPS-stimulated macrophages. Ursolic acid suppressed LPS-stimulated interleukin (IL)-1beta, IL-6, tumor necrosis factor (TNF)-alpha, cyclooxygenase (COX)-2, and inducible NO synthetase (iNOS) expression as well as PGE2 and NO levels. Ursolic acid not only inhibited the Alexa Fluor 488-conjugated LPS-mediated shift of macrophages but also reduced the intensity of fluorescent LPS bound to the macrophages transiently transfected with or without MyD88 siRNA. However, Ursolic acid did not suppress NF-kappaB activation in peptidoglycan-stimulated macrophages. Oral administration of Ursolic acid significantly inhibited 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colon shortening and myeloperoxidase (MPO) activity in mice. Ursolic acid also suppressed TNBS-induced COX-2 and iNOS expression as well as NF-kappaB activation in colon tissues. Ursolic acid (20 mg/kg) also inhibited TNBS-induced IL-1beta, IL-6, TNF-alpha by 93, 86, and 85%, respectively (p < 0.05). However, Ursolic acid reversed TNBS-mediated downregulation of IL-10 expression to 79% of the normal control group (p < 0.05). On the basis of these findings, Ursolic acid may ameliorate colitis by regulating NF-kappaB and MAPK signaling pathways via the inhibition of LPS binding to TLR4 on immune cells.

[Effect of ursolic acid on proliferation of T lymphoma cell lines Hut-78 cells and its mechanism].[Pubmed:25778894]

Zhonghua Xue Ye Xue Za Zhi. 2015 Feb;36(2):153-7.

OBJECTIVE: To investigate the effects of Ursolic acid on T cell lymphoma cell lines-Hut-78 cells and its mechanism. METHODS: Inhibition of Hut-78 cells proliferation by Ursolic acid at different concentration (10, 20, 40 and 80 mumol/L) for different incubation time (4, 12, 24, 48 and 72 h)was examined by MTT method, and early apoptosis by flow cytometry. The protein expressions of p65, p50, p52 and p100, and caspase-8, caspase-3 and caspase-9 were detected by Western blot. VEGF and COX-2 mRNA expressions were measured by reverse transcription polymerase chain reaction (RT-PCR). RESULTS: It was showed that Ursolic acid inhibited proliferation of Hut-78 cells (P<0.05). Apoptosis of Hut-78 cells was induced by 10, 20, 40 and 80 mumol/L Ursolic acid treatment (P<0.01). Likewise, expression of p65 and p50 proteins were down-regulated by Ursolic acid treatment (10, 20, 40 and 80 mumol/L) (P<0.01), but there was no significant change in the expression of p52 and p100. Moreover, Ursolic acid could up-regulate expression of caspase-8, caspase-3 and caspase-9 protein (P<0.01). RT-PCR examination showed that VEGF and COX-2 mRNA expression decreased by Ursolic acid treatment. CONCLUSION: Inhibition of Hut-78 cells proliferation may be related to Ursolic acid induced apoptosis through h death receptors and mitochondrial pathways. NF-kappaB classical signal pathway may be one of its mechanisms, and VEGF and cox-2 may also be involved.

Cardiovascular, antihyperlipidemic and antioxidant effects of oleanolic and ursolic acids in experimental hypertension.[Pubmed:12725563]

Phytomedicine. 2003 Mar;10(2-3):115-21.

Cardiovascular (systolic and diastolic blood pressure, heart rate), antihyperlipidemic (tryglycerides, total cholesterol and lipoprotein fractions), antioxidant (glutathione peroxidase--GPx, and superoxide dismutase--SOD), diuretic/saluretic and hypoglycemic activity of 98% pure oleanolic (OA) and ursolic (UA) acid were studied in Dahl salt-sensitive (DSS), insulin resistant rat model of genetic hypertension. Both OA and UA displayed low toxicity, with LC50 0.10 and 0.95 mg/ml, respectively. Although both triterpenoids did not have direct hypotensive effect, after 6-week application in a daily dose 60 mg/kg b.w., i.p., they prevented the development of severe hypertension. The antihypertensive effect was attributed to their potent diuretic-natriuretic-saluretic activity; direct cardiac effect (heart rate decrease by 34% and 32%, respectively); antihyperlipidemic (more than two times decrease of LDL and triglycerides); antioxidant (GPx increase by 12% and 10%, respectively; SOD increase by 12% and 22%, respectively), and hypoglycemic (blood glucose decrease by 20% and 50%, respectively) effects on the DSS rats. Except for the antihyperlipidemic effects, the other described above in vivo antihypertensive effects of OA and UA are reported for the first time and the underlying mechanisms are currently under investigation.

Ursolic acid inhibits the invasive phenotype of SNU-484 human gastric cancer cells.[Pubmed:25621065]

Oncol Lett. 2015 Feb;9(2):897-902.

Metastasis is a major cause of cancer-related mortality in patients with gastric cancer. Ursolic acid, a pentacyclic triterpenoid compound derived from medicinal herbs, has been demonstrated to exert anticancer effects in various cancer cell systems. However, to the best of our knowledge, the inhibitory effect of Ursolic acid on the invasive phenotype of gastric cancer cells has yet to be reported. Therefore, the aim of the present study was to investigate the effect of Ursolic acid on the invasiveness of SNU-484 human gastric cancer cells. Ursolic acid efficiently induced apoptosis, possibly via the downregulation of B-cell lymphoma 2 (Bcl-2), the upregulation of Bcl-2-associated X protein and the proteolytic activation of caspase-3. Furthermore, the activation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase was increased by the administration of Ursolic acid. In addition, Ursolic acid significantly suppressed the invasive phenotype of the SNU-484 cells and significantly decreased the expression of matrix metalloproteinase (MMP)-2, indicating that MMP-2 may be responsible for the anti-invasive activity of Ursolic acid. Taken together, the results of the present study demonstrate that Ursolic acid induces apoptosis and inhibits the invasive phenotype of gastric cancer cells; therefore, Ursolic acid may have a potential application as a chemopreventive agent to prevent the metastasis of gastric cancer or to alleviate the process of metastasis.

Anxiolytic-like effects of ursolic acid in mice.[Pubmed:25861934]

Eur J Pharmacol. 2015 Jul 5;758:171-6.

Ursolic acid is a pentacyclic triterpenoid that possesses several biological and neuropharmacological effects including antidepressant-like activity. Anxiety disorders represent common and disability psychiatric conditions that are often associated with depressive symptoms. This work investigated the anxiolytic-like effects of Ursolic acid administration in different behavioral paradigms that evaluate anxiety in mice: open field test, elevated plus maze test, light/dark box test and marble burying test. To this end, mice were administered with Ursolic acid (0.1, 1 and 10mg/kg, p.o.) or diazepam (2mg/kg, p.o.), positive control, and submitted to the behavioral tests. The results show that Ursolic acid (10mg/kg) elicited an anxiolytic-like effect observed by the increased total time in the center and decreased number of rearings responses in the open field test and an increased percentage of entries and total time spent in the open arms of elevated plus maze, similarly to diazepam. No significant effects of Ursolic acid were shown in the light/dark box and marble burying test. These data indicate that Ursolic acid exhibits anxiolytic-like effects in the open field and elevated plus maze test, but not in the light/dark box and marble burying test, showing the relevance of testing several behavioral paradigms in the evaluation of anxiolytic-like actions. Of note, the results extend the understanding on the effects of Ursolic acid in the central nervous system and suggest that it may be a novel approach for the management of anxiety-related disorders.

Ursolic acid ameliorates cognition deficits and attenuates oxidative damage in the brain of senescent mice induced by D-galactose.[Pubmed:17692828]

Biochem Pharmacol. 2007 Oct 1;74(7):1078-90.

Ursolic acid (UA), a pentracyclic triterpene, is reported to have an antioxidant activity. Here we assessed the protective effect of UA against the d-galactose (D-gal)-induced neurotoxicity. We found that UA markedly reversed the D-gal induced learning and memory impairment by behavioral tests. The following antioxidant defense enzymes were measured: superoxide dismutases (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR). The content of the lipid peroxidation product malondialdehyde (MDA) was also analyzed. Our results indicated that the neuroprotective effect of UA against D-gal induced neurotoxicity might be caused, at least in part, by the increase in the activity of antioxidant enzymes with a reduction in lipid peroxidation. And UA also inhibited the activation of caspase-3 induced by D-gal. Furthermore, we found that UA significantly increased the level of growth-associated protein GAP43 in the brain of D-gal-treated mice. These results suggest that the pharmacological action of UA may offer a novel therapeutic strategy for the treatment of age-related conditions.

Ursolic acid, a potential PPARgamma agonist, suppresses ovalbumin-induced airway inflammation and Penh by down-regulating IL-5, IL-13, and IL-17 in a mouse model of allergic asthma.[Pubmed:23201068]

Eur J Pharmacol. 2013 Feb 15;701(1-3):131-43.

Allergic asthma is a chronic airway disorder characterized by airway hyperresponsiveness to allergens, chronic airway inflammation, airway edema, increased mucus secretion, excess production of Th2 cytokines, and eosinophil accumulation in the lungs. Ursolic acid is known for its pharmacological effects, such as its anti-tumor, anti-inflammatory and antimicrobial activities. To investigate the anti-asthmatic effects and mechanism of Ursolic acid, we studied the development of pulmonary eosinophilic inflammation and enhanced pause (Penh) in a mouse model of allergic asthma. In this study, BALB/c mice were systemically sensitized to ovalbumin followed by intratracheal, intraperitoneal, and aerosol allergen challenges. We investigated the effect of Ursolic acid and Cyclosporin A (CsA) on Penh, pulmonary eosinophilic infiltration, various immune cell phenotypes, Th2 cytokines, IL-17 production, and ovalbumin specific IgE production in a mouse model of asthma. In BALB/c mice, Ursolic acid had suppressed eosinophil infiltration, allergic airway inflammation, and Penh, which occurred by suppressing the production of IL-5, IL-13, IL-17, and ovalbumin-specific IgE by blocking the GATA-3 and STAT6 pathways. Our data suggest the therapeutic mechanism of Ursolic acid in asthma is based on reductions of Th2 cytokines (IL-5 and IL-13), ovalbumin-specific IgE production, and eosinophil infiltration via the Th2-GATA-3, STAT6, and IL-17-NF-kappaB pathways.

Protective effects of ursolic acid in an experimental model of liver fibrosis through Nrf2/ARE pathway.[Pubmed:25459994]

Clin Res Hepatol Gastroenterol. 2015 Apr;39(2):188-97.

AIM: Liver fibrosis is a reversible wound-healing response that occurs following liver injury. In this study, we aimed to investigate the possible protective effects of Ursolic acid in liver fibrosis induced by carbon tetrachloride (CCl4). METHODS: ICR mice were randomly divided into six groups (Group 1: normal; Group 2: CCl4-treated group; Group 3: CCl4 plus Ursolic acid 25mg/kg group; Group 4: CCl4 plus Ursolic acid 50mg/kg group; Group 5: CCl4 plus colchicine 1mg/kg group; Group 6: Ursolic acid 50mg/kg group). Mice were administered with CCl4 (2 mL of CCl4 in olive oil (1:1, v/v) per kg body weight twice weekly) by intraperitoneal injection and oral injection of colchicine (1mg/kg) or Ursolic acid (25, 50mg/kg) daily. After six weeks, serum aminotransferase activity, hepatic reactive oxygen species (ROS) production, thiobarbituric acid reactive substances (TBARS), antioxidase (SOD, CAT, GPx) activity and histopathological analysis were performed. The levels of nuclear factor E2-related factor 2 (Nrf2), NAD(P)H: quinone oxidoreductase-1 (NQO1), glutathione S-transferase (GST) and heme oxygenase-1 (HO-1), tumor necrosis factor-alpha (TNF-alpha), prostaglandin E2 (PGE2) and inducible nitric oxide synthase (iNOS), Bcl-2 and caspase-3 were measured. RESULTS: Ursolic acid significantly prevented CCl4-induced hepatotoxicity and fibrosis, indicated by both diagnostic indicators and histopathological analysis. CCl4-induced profound elevations of oxidative stress, inflammation and apoptosis in liver were suppressed by Ursolic acid. CONCLUSIONS: These results suggest that Ursolic acid has the hepatoprotective actions. The inhibition of CCl4-induced liver fibrosis, inflammation and apoptosis by Ursolic acid is due at least in part to its ability to modulate the Nrf2/ARE signalling pathway.

Ursolic acid (Prunol) is a natural pentacyclic triterpenoid carboxylic acid, exerts anti-tumor effects and is an effective compound for cancer prevention and therapy.

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