Naturally occurring pentacyclic triterpenoid

In a dose-dependent manner, ursolic acid phosphorylates AMP-activated protein kinase α (AMPKα) and suppresses DNA methyltransferase 1 (DNMT1) protein production [1]. The best combination for increasing myogenic differentiation was found to be leucine (10 μM) and ursolic acid (0.5 μM). When leucine and ursolic acid were administered together, CK activity was noticeably higher than when either medication was used alone. Leucine and ursolic acid also raise myosin heavy chain levels, which is a marker protein for myogenic differentiation [2]. By upregulating Bcl-2-related X protein, downregulating B-cell lymphoma 2 (Bcl-2), and activating caspase-3, ursolic acid has the potential to efficiently trigger apoptosis. Moreover, ursolic acid delivery increased c-Jun N-terminal kinase and p38 mitogen-activated protein kinase activation. Furthermore, ursolic acid dramatically decreased the expression of matrix metalloproteinase (MMP)-2 and prevented the invasive behavior of SNU-484 cells [3]. Gastric cancer SGC-7901 cells are efficiently subjected to apoptotic induction by ursolic acid (UA). Subsequent mechanistic investigations have demonstrated that ursolic acid-mediated cofilin-1 mitochondrial translocation and apoptosis are significantly influenced by the ROCK1/PTEN signaling pathway [4].

Treatment with ursolic acid reduced lung harm caused by CLP and increased the survival rate of septic rats. It also decreased lung wet/dry weight ratio, leukocyte and protein infiltration, myeloperoxidase activity, and malondialdehyde concentration. ..Furthermore, ursolic acid decreased the expression of cyclooxygenase and inducible nitric oxide synthase, two enzymes involved in the generation of nitric oxide in the lungs, and dramatically lowered serum levels of interleukin-6, interleukin-1β, and tumor necrosis factor-α. prostaglandin E2 and oxides[5].

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The results revealed that Ursolic acid (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. Conclusions: These findings indicate that UA exerts protective effects on CLP-induced septic rats. UA may be a potential therapeutic agent against sepsis.

Aging causes phenotypic changes in skeletal muscle progenitor cells that lead to the progressive loss of myogenic differentiation and thus a decrease in muscle mass. The naturally occurring triterpene, ursolic acid, has been reported to be an effective agent for the prevention of muscle loss by suppressing degenerative muscular dystrophy. Leucine, a branched-chain amino acid, and its metabolite, β-hydroxy-β-methylbutyric acid, have been reported to enhance protein synthesis in skeletal muscle. Therefore, the aim of the present study was to investigate whether the combination of ursolic acid and leucine promotes greater myogenic differentiation compared to either agent alone in C2C12 murine myoblasts. Morphological changes were observed and creatine kinase (CK) activity analysis was performed to determine the conditions through which the combination of ursolic acid and leucine would exert the most prominent effects on muscle cell differentiation. The effect of the combination of ursolic acid and leucine on the expression of myogenic differentiation marker genes was examined by RT-PCR and western blot analysis. 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. The combination of ursolic acid and leucine significantly induced the expression of myogenic differentiation marker genes, such as myogenic differentiation 1 (MyoD) and myogenin, at both the mRNA and protein level. In addition, the number of myotubes and the fusion index were increased. These findings indicate that the combination of ursolic acid and leucine promotes muscle cell differentiation, thus suggesting that this combination of agents may prove to be beneficial in increasing muscle mass.[2]

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Ursolic acid, extracted from the traditional Chinese medicine bearberry, can induce apoptosis of gastric cancer cells. However, its pro-apoptotic mechanism still needs further investigation. More and more evidence demonstrates that mitochondrial translocation of cofilin-1 appears necessary for the regulation of apoptosis. Here, we report that 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. These findings imply that induction of apoptosis by ursolic acid stems primarily from the activation of ROCK1 and PTEN, resulting in the translocation of cofilin-1 from cytoplasm to mitochondria, release of cytochrome c, activation of caspase-3 and caspase-9, and finally inducing apoptosis of gastric cancer SGC-7901 cells.[4]

Hepatocellular carcinoma (HCC), the major histological subtype of primary liver cancer, remains one of the most common malignancies worldwide. Due to the complicated pathogenesis of this malignancy, the outcome for comprehensive treatment is limited. Chinese herbal medicine (CHM) is emerging as a promising choice for its multi-targets and coordinated intervention effects against HCC. Ursolic acid (UA), a natural pentacyclic triterpenoid carboxylic acid found in CHM, exerts anti-tumor effects and is emerging as an effective compound for cancer prevention and therapy. However, the molecular mechanisms underlying the action of UA remain largely unknown. In this study, we showed that UA inhibited the growth of HCC cells and induced apoptosis in the dose- and time-dependent fashion. Furthermore, we found that 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. The inhibitor of AMPK, compound C blocked, while an activator of AMPK, metformin augmented the effect of UA on DNMT1 expression. In addition, UA suppressed the expression of transcription factor Sp1. Conversely, overexpression of Sp1 reversed the effect of UA on DNMT1 expression and cell growth. Collectively, our results show for the first time that UA inhibits growth of HCC through AMPKα-mediated inhibition of Sp1; this in turn results in inhibition of DNMT1. This study reveals a potential novel mechanism by which UA controls growth of HCC cells and suggests that DNMT1 could be novel target for HCC chemoprevention and treatment.[1]

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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.[3]

A rat model of sepsis induced by cecal ligation and puncture (CLP) was used. Rats were injected intraperitoneally with Ursolic acid (UA)(10 mg/kg) after CLP, and then the survival was determined twice a day for 4 d. The protective effects of UA on CLP-induced acute lung injury were assayed at 24 h after CLP.

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CLP-induced sepsis [1]
The rats were randomly divided into four groups as follows: sham group, CLP group, sham plus Ursolic acid (UA) (10 mg/kg, intraperitoneally [i.p.]) group, and CLP plus Ursolic acid (UA) (10 mg/kg, i.p.) group. Each group contained 20 rats. The CLP-induced sepsis model was performed according to as previously described. Briefly, all rats were fasting but provided water ad libitum for 6 h before undergoing CLP surgery. After chloral hydrate anesthesia (350 mg/kg, i.p.), the abdominal region was disinfected and 1.5 cm incision was made, the cecum was then gently isolated with tightly ligation and punctured three times with an 18-gauge needle. Thereafter, the cecum was repositioned, and the abdomen was subsequently closed. For sham and Ursolic acid (UA) group alone, rats underwent the same surgical procedures, but the cecum was neither ligated nor punctured. Saline (0.5 mL/10 g body weight) was given subcutaneously to rats for fluid resuscitation. For the Ursolic acid (UA) treatment group, rats received intraperitoneal administration of Ursolic acid (UA) (10 mg/kg) after CLP surgery. Rats in control and CLP groups were only given vehicle. One half of rats in each group were sacrificed at 24 h after CLP operation, the samples including blood, lung tissue, and bronchoalveolar lavage fluid (BALF) were collected for subsequent studies. The other half of rats were used to record the survival rate. Survival was monitored twice a day for 4 d (n = 10 in each group).

Interactions
This study investigated the effects of oral ursolic acid (UA) on the formation of abnormal crypt foci (ACF) and intestinal sphingomyelinase (SMase) activity in rats treated with azomethane (AOM). Sprague-Dawley rats were divided into eight groups, receiving either AOM or a carrier treatment, and fed a normal diet or a pelleted diet containing 0.11% UA during the initial or promotion/progression phases. The formation of ACF in the colon and the activity of three mucosal SMases were examined. UA significantly reduced the incidence of ACFs with three or more crypts in the initial group, but had no significant effect in the promotion/progression group. AOM reduced the activity of basic mucosal SMases, and UA could not reverse this inhibitory effect. However, in both the AOM-treated group and normal rats, UA significantly increased the activity of neutral colonic SMases and slightly increased the activity of acidic SMases. These results indicate that ursolic acid (UA) has a chemopreventive effect in the initiation stage of colon cancer, which is related to alterations in sphingomyelin (SM) metabolism. ...This study used a micronucleus assay to examine the antimutagenic potential of ursolic acid (UA) and oleanolic acid (OA) in the peripheral blood and bone marrow of Balb/c mice. Mice were randomly assigned to 10 treatment groups: UA group (80 mg/kg body weight); OA group (80 mg/kg body weight); UA and OA mixture group (80 mg/kg body weight); the antitumor drug doxorubicin (DXR, 90 mg/kg body weight); DMSO and DXR group; UA and DXR group; OA and DXR group; UA, OA, and DXR group; and a negative control and solvent control. UA, OA, and UA/OA mixtures were administered by gavage followed by intraperitoneal injection of DXR. The results showed that the micronucleus frequency was significantly reduced in the group treated with both triterpenoids and DXR compared to the DXR monotherapy group. These results indicate that ursolic acid (UA) and oleanolic acid (OA) possess antimutagenic activity under experimental conditions. This study investigated the effects of ursolic acid (UA) and oleanolic acid (OA) on the formation of abnormal cryptic foci (ACF) induced by 1,2-dimethylhydrazine (DMH) in the colon of male Wistar rats. To induce ACF, animals were subcutaneously injected with DMH twice weekly (40 mg/kg body weight) for two weeks. During and after DMH treatment, rats were administered UA, OA, and a mixture of UA and OA by gavage five times weekly at a dose of 25 mg/kg body weight/day for four weeks. All animals were sacrificed at week 5 for ACF assessment. Results showed that the incidence of ACF was significantly reduced in the triterpenoid-DMH combined treatment group compared to the DMH-only group, indicating that UA and OA can inhibit ACF formation and have a protective effect against colon cancer. This study also aimed to evaluate the effects of chloroform extract of Terminalia catappa leaves (TCCE) on carbon tetrachloride (CCl₄)-induced acute liver injury and D-galactosamine (D-GalN)-induced hepatocellular injury. Furthermore, this study investigated the effects of two isolated components of TCCE—ursolic acid and asiatic acid—on mitochondria and free radicals to determine the mechanism by which TCCE exerts its hepatotoxic effects. In acute liver injury experiments, carbon tetrachloride (CCl₄) induced significant increases in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities (5.7-fold and 2.0-fold, respectively), which were reversed by pretreatment with 50 and 100 mg/kg TCCE and alleviated significant morphological changes. In hepatocyte injury experiments, D-galactosamine (D-GalN) induced increases in ALT and AST levels in primary cultured hepatocytes (1.9-fold and 2.1-fold, respectively) were blocked by pretreatment with 0.05, 0.1, and 0.5 g/L TCCE. In addition, 50–500 μM ursolic acid and asiatic acid dose-dependently inhibited Ca²⁺-induced mitochondrial swelling. Both ursolic acid and asiatic acid exhibited dose-dependent superoxide anion and hydroxyl radical scavenging activity in the concentration range of 50 to 500 μM. Therefore, it can be concluded that TCCE has a hepatoprotective effect, the mechanism of which is related to the protection of hepatic mitochondria and the scavenging of free radicals. For more complete data on interactions of ursolic acids (16 in total), please visit the HSDB record page.

[1]. Ursolic acid inhibited growth of hepatocellular carcinoma HepG2 cells through AMPKα-mediated reduction of DNA methyltransferase 1. Mol Cell Biochem. 2014 Dec 30.
[2]. 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]. Ursolic acid inhibits the invasive phenotype of SNU-484 human gastric cancer cells. Oncol Lett. 2015 Feb;9(2):897-902.
[4]. 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]. 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.

Therapeutic Uses
This study investigated the effects of the methanol extract (ME) and its n-butanol fraction of Alstonia macrophylla Wall ex A. DC leaves on the forward motility (FM) of mammalian sperm (goats and humans). Both 600 μg/mL ME and 100 μg/mL fraction B significantly inhibited FM in goat and human sperm… Treatment with 600 μg/mL ME and 100 μg/mL fraction B resulted in approximately 60-80% loss of FM in goat sperm. Fraction B at 100 μg/mL caused a 90% loss of FM in human sperm, while fraction B at 400 μg/mL completely inhibited sperm FM at 0 minutes. The inhibitory activity of fraction B increased in a dose-dependent manner with increasing concentration. … Component B (ursolic acid) is a pentacyclic triterpenoid with the potential to inhibit sperm motility and could be used as a local vaginal contraceptive. Both oleanolic acid and ursolic acid can effectively protect laboratory animals from chemically induced liver damage. Oleanolic acid is already marketed in China as an oral medication for the treatment of human liver diseases.

C30H48O3

456.7003

456.36

C, 78.90; H, 10.59; O, 10.51

77-52-1

64945

Platelets from alcohol
Large, lustrous prisms from absolute alcohol, fine hair-like needles from dilute alcohol

1.1±0.1 g/cm3

556.9±50.0 °C at 760 mmHg

292 °C (dec.)(lit.)

304.7±26.6 °C

0.0±3.4 mmHg at 25°C

1.555

9.01

2

3

1

33

874

10

O([H])[C@@]1([H])C([H])([H])C([H])([H])[C@@]2(C([H])([H])[H])[C@]([H])(C1(C([H])([H])[H])C([H])([H])[H])C([H])([H])C([H])([H])[C@@]1(C([H])([H])[H])[C@]3(C([H])([H])[H])C([H])([H])C([H])([H])[C@@]4(C(=O)O[H])C([H])([H])C([H])([H])[C@@]([H])(C([H])([H])[H])[C@]([H])(C([H])([H])[H])[C@@]4([H])C3=C([H])C([H])([H])[C@@]12[H]

WCGUUGGRBIKTOS-GPOJBZKASA-N

InChI=1S/C30H48O3/c1-18-10-15-30(25(32)33)17-16-28(6)20(24(30)19(18)2)8-9-22-27(5)13-12-23(31)26(3,4)21(27)11-14-29(22,28)7/h8,18-19,21-24,31H,9-17H2,1-7H3,(H,32,33)/t18-,19+,21+,22-,23+,24+,27+,28-,29-,30+/m1/s1

(1S,2R,4aS,6aR,6aS,6bR,8aR,10S,12aR,14bS)-10-hydroxy-1,2,6a,6b,9,9,12a-heptamethyl-2,3,4,5,6,6a,7,8,8a,10,11,12,13,14b-tetradecahydro-1H-picene-4a-carboxylic acid

Ursolic acid; 77-52-1; Prunol; Malol; Urson; 3beta-Hydroxyurs-12-en-28-oic acid; Micromerol; (3beta)-3-Hydroxyurs-12-en-28-oic acid;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~33.33 mg/mL (~72.98 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.47 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 2: 6.67 mg/mL (14.60 mM) in 50% HP-β-CD in Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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 (Please use freshly prepared in vivo formulations for optimal results.)