Oleanolic acid

1 Achyranthes sp. 2 Aerva sp. 3 Akebia sp. 4 Calendula sp. 5 Centaurium sp. 6 Corchorus sp. 7 Crataegus sp. 8 Eleutherococcus sp. 9 Epilobium sp. 10 Ficus sp. 11 Foeniculum sp. 12 Guaiacum sp. 13 Hedera sp. 14 Ilex sp. 15 Jacaranda sp. 16 Lavandula sp. 17 Luffa sp. 18 Maytenus sp. 19 Melissa sp. 20 Myrtillocactus sp. 21 Nardostachys sp. 22 Nerium sp. 23 Olea sp. 24 Passiflora sp. 25 Polygala sp. 26 Putranjiva sp. 27 Rhododendron sp. 28 Rosa sp. 29 Rosmarinus sp. 30 Salvia sp. 31 Sambucus sp. 32 Satureja sp. 33 Shorea sp. 34 Strychnos sp. 35 Syzygium sp. 36 Terminalia sp. 37 Thymus sp. 38 Urtica sp. 39 Vaccinium sp. 40 Viscum sp. 41 Vitis sp.

Oleanolic acid (Caryophyllin) is a natural compound from plants with anti-tumor activities. IC50 value: Target: in vitro: OA suppressed the proliferation of lung cancer cells in both dose- and time-dependent manners, along with an increase in miR-122 abundance. The suppression of miR-122 abolished the effect of OA on lung cancer cells. CCNG1 and MEF2D, two putative miR-122 targets, were found to be downregulated by OA treatment [1]. OA induced autophagy in normal tissue-derived cells without cytotoxicity. OA-induced autophagy was shown to decrease the proliferation of KRAS-transformed normal cells and to impair their invasion and anchorage-independent growth [2]. in vivo: Mouse model experiments also demonstrated that OA suppressed the growth of KRAS-transformed breast epithelial cell MCF10A-derived tumor xenograft by inducing autophagy [2]. activation of MAPK pathways, including p-38 MAPK, JNK and ERK, was triggered by OA in both a dose and time-dependent fashion in all the tested cancer cells. OA induced p38 MAPK activation promoted mitochondrial translocation of Bax and Bim, and inhibited Bcl-2 function by enhancing their phosphorylation. OA can induce reactive oxygen species (ROS)-dependent ASK1 activation, and this event was indispensable for p38 MAPK-dependent apoptosis in cancer cells [3]. in vivo: In vivo, p38 MAPK knockdown A549 tumors proved resistant to the growth-inhibitory effect of OA [3]. in OA-treated EAM mice the number of Treg cells and the production of IL-10 and IL-35 were markedly increased, while proinflammatory and profibrotic cytokines were significantly reduced [4].

References:
[1]. Zhao X, et al. Oleanolic acid suppresses the proliferation of lung carcinoma cells by miR-122/Cyclin G1/MEF2D axis. Mol Cell Biochem. 2015 Feb;400(1-2):1-7. [2]. Liu J, et al. Oleanolic acid inhibits proliferation and invasiveness of Kras-transformed cells via autophagy. J Nutr Biochem. 2014 Nov;25(11):1154-60. [3]. Liu J, et al. p38 MAPK signaling mediates mitochondrial apoptosis in cancer cells induced by oleanolic acid. Asian Pac J Cancer Prev. 2014;15(11):4519-25. [4]. Martín R, et al. Oleanolic acid modulates the immune-inflammatory response in mice with experimental autoimmune myocarditis and protects from cardiac injury. Therapeutic implications for the human disease. J Mol Cell Cardiol. 2014 Jul;72:250-62.

Semi-synthesis of nitrogen derivatives of oleanolic acid and effect on breast carcinoma MCF-7 cells.[Pubmed:25075040]

Anticancer Res. 2014 Aug;34(8):4135-9.

BACKGROUND: Oleanolic acid is a triterpenoid that has shown in vitro cytotoxic activity against human tumour cells and is known to be present in many higher plants. MATERIALS AND METHODS: Oleanolic acid is known to have some biological potential including anticancer property. Oleanolic acid was isolated from the ethyl acetate fraction of Syzygium aromaticum seed with an aim of dervitatising the functional group and evaluating the biological activities of the semi-synthesised compounds. Acylation of the alcohol functional group of the Oleanolic acid afforded the opportunity of hydrazine reaction to give 3-acetoleanolic hydrazide. Further reaction of 3-acetoleanolic hydrazide with benzyladehyde, glacial acetic acid and methanol resulted in the synthesis of the corresponding 3-acetoxyoleanolic hydrazone. RESULTS: The semi-synthetic Oleanolic acid derivatives did not exhibit enhanced cytotoxic activity over Oleanolic acid itself. CONCLUSION: 3-acetoxyoleanolic hydrazide has a potent anticancer activity.

BDNF-ERK-CREB signalling mediates the role of miR-132 in the regulation of the effects of oleanolic acid in male mice.[Pubmed:25079084]

J Psychiatry Neurosci. 2014 Sep;39(5):348-59.

BACKGROUND: Although previous study has demonstrated that brain-derived neurotrophic factor (BDNF) is involved in the antidepressant-like effect of Oleanolic acid, there is little information regarding the details of the molecular mechanism involved in this effect. METHODS: We used a chronic unpredictable mild stress (CUMS) model to test the antidepressant-like effect of Oleanolic acid on depressant-like behaviour, miR-132 expression and synaptic protein expression in the male mouse hippocampus. Furthermore, we explored the possible signalling pathways associated with miR-132 expression that mediate the effect of Oleanolic acid on neuronal proliferation. RESULTS: The results demonstrated that a 3-week treatment with Oleanolic acid ameliorated CUMS-induced anhedonic and anxiogenic behaviours. Furthermore, we found that Oleanolic acid led to the BDNF-related phosphorylation and activation of extracellular signal-regulated kinases (ERK) and cyclic adenosine monophosphate response element binding protein (CREB), which was associated with the upregulation of miR-132 and hippocampal neuronal proliferation. Moreover, experiments with an miR-132 antagomir revealed that targeting miR-132 led to inhibition of neuronal proliferation and the postsynaptic density protein 95, but did not affect presynaptic protein synapsin I. LIMITATIONS: Several other stimuli can also induce CREB phosphorylation in the hippocampus. Thus, regulation of miR-132 may not be restricted to neurotrophic signalling. CONCLUSION: Our results show that Oleanolic acid induces the upregulation of miR-132, which serves as an important regulator of neurotrophic actions, mainly through the activation of the hippocampal BDNF-ERK-CREB signalling pathways.

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.[Pubmed:24704288]

Toxicol Appl Pharmacol. 2014 Jun 1;277(2):155-63.

Oleanolic acid, a triterpenoid contained in more than 1620 plants including various fruits and foodstuffs, has numerous metabolic effects, such as hepatoprotection. However, its underlying mechanisms remain poorly understood. Adipose tissue insulin resistance (Adipo-IR) may contribute to the development and progress of metabolic abnormalities through release of excessive free fatty acids from adipose tissue. This study investigated the effect of Oleanolic acid on Adipo-IR. The results showed that supplement with Oleanolic acid (25 mg/kg, once daily, by oral gavage) over 10 weeks attenuated liquid fructose-induced increase in plasma insulin concentration and the homeostasis model assessment of insulin resistance (HOMA-IR) index in rats. Simultaneously, Oleanolic acid reversed the increase in the Adipo-IR index and plasma non-esterified fatty acid concentrations during the oral glucose tolerance test assessment. In white adipose tissue, Oleanolic acid enhanced mRNA expression of the genes encoding insulin receptor, insulin receptor substrate (IRS)-1 and phosphatidylinositol 3-kinase. At the protein level, Oleanolic acid upregulated total IRS-1 expression, suppressed the increased phosphorylated IRS-1 at serine-307, and restored the increased phosphorylated IRS-1 to total IRS-1 ratio. In contrast, phosphorylated Akt to total Akt ratio was increased. Furthermore, Oleanolic acid reversed fructose-induced decrease in phosphorylated-Akt/Akt protein to plasma insulin concentration ratio. However, Oleanolic acid did not affect IRS-2 mRNA expression. Therefore, these results suggest that Oleanolic acid supplement ameliorates fructose-induced Adipo-IR in rats via the IRS-1/phosphatidylinositol 3-kinase/Akt pathway. Our findings may provide new insights into the mechanisms of metabolic actions of Oleanolic acid.

Oleanolic acid analogs as NO, TNF-alpha and IL-1beta inhibitors: synthesis, biological evaluation and docking studies.[Pubmed:25113933]

Bioorg Med Chem Lett. 2014 Sep 1;24(17):4114-9.

A series of Oleanolic acid analogs, characterized by structural modifications at position C-3 and C-28 of oleanane skeleton were synthesized and assessed for antiinflammatory potential towards lipopolysaccharide (LPS) induced nitric oxide (NO) production in macrophages. Results revealed that all the synthesized analogs of Oleanolic acid inhibit NO production with an IC50 of 2.66-41.7 muM as compared to the specific nitric oxide synthase (NOS) inhibitor, L-NAME (IC50=69.21 and 73.18 muM on RAW 264.7 and J774A.1 cells, respectively) without affecting the cell viability when tested at their half maximal concentration. The most potent NO inhibitors (2, 8, 9 and 10) at a concentration of 20 mug/mL also demonstrated mild inhibition (27.9-51.9%) of LPS-induced tumor necrosis factor alpha (TNF-alpha) and weak inhibition (11.1-37.5%) towards interleukin 1-beta (IL-1beta) production in both the cells. The present study paves a direction that analogs of Oleanolic acid can be employed as a lead in the development of potent NO inhibitors. Molecular docking studies also showed that 10 (with top Goldscore docking pose 19.05) showed similar interaction as that of co-crystallized inhibitor and, thereby, helps to design the potent inhibitors of TNF-alpha.

Oleanolic acid.[Pubmed:22377690]

Phytochemistry. 2012 May;77:10-5.

Oleanolic acid (3beta-hydroxyolean-12-en-28-oic acid) is a pentacyclic triterpenoid compound with a widespread occurrence throughout the plant kingdom. In nature, the compound exists either as a free acid or as an aglycone precursor for triterpenoid saponins, in which it can be linked to one or more sugar chains. Oleanolic acid and its derivatives possess several promising pharmacological activities, such as hepatoprotective effects, and anti-inflammatory, antioxidant, or anticancer activities. With the recent elucidation of its biosynthesis and the imminent commercialization of the first Oleanolic acid-derived drug, the compound promises to remain important for various studies. In this review, the recent progress in understanding the Oleanolic acid biosynthesis and its pharmacology are discussed. Furthermore, the importance and potential application of synthetic Oleanolic acid derivatives are highlighted, and research perspectives on Oleanolic acid are given.

Oleanolic acid and ursolic acid: novel hepatitis C virus antivirals that inhibit NS5B activity.[Pubmed:23422646]

Antiviral Res. 2013 Apr;98(1):44-53.

Hepatitis C virus (HCV) infects up to 170 million people worldwide and causes significant morbidity and mortality. Unfortunately, current therapy is only curative in approximately 50% of HCV patients and has adverse side effects, which warrants the need to develop novel and effective antivirals against HCV. We have previously reported that the Chinese herb Fructus Ligustri Lucidi (FLL) directly inhibited HCV NS5B RNA-dependent RNA polymerase (RdRp) activity (Kong et al., 2007). In this study, we found that the FLL aqueous extract strongly suppressed HCV replication. Further high-performance liquid chromatography (HPLC) analysis combined with inhibitory assays indicates that Oleanolic acid and ursolic acid are two antiviral components within FLL aqueous extract that significantly suppressed the replication of HCV genotype 1b replicon and HCV genotype 2a JFH1 virus. Moreover, Oleanolic acid and ursolic acid exhibited anti-HCV activity at least partly through suppressing HCV NS5B RdRp activity as noncompetitive inhibitors. Therefore, our results for the first time demonstrated that natural products Oleanolic acid and ursolic acid could be used as potential HCV antivirals that can be applied to clinic trials either as monotherapy or in combination with other HCV antivirals.

Oleanolic acid suppresses the proliferation of human bladder cancer by Akt/mTOR/S6K and ERK1/2 signaling.[Pubmed:26823699]

Int J Clin Exp Pathol. 2015 Nov 1;8(11):13864-70. eCollection 2015.

Oleanolic acid has significant pharmacological activities, such as anti-tumor, regulating blood sugar level and liver protection, which are more effective compared with free aglyconeOleanolic acid. However, it is still unknown if Oleanolic acid affects the proliferation of human bladder cancer. We utilized T24 cells to study the effect of Oleanolic acid on the proliferation and apoptosis of human bladder cancer. In this study, we found that the anti-cancer effect of Oleanolic acid significantly suppressed cell proliferation and increased apoptosis and caspase-3 activity of T24 cells. Furthermore, Akt, mTOR and S6K protein expression was greatly inhibited in T24 cells under Oleanolic acid treatment. Meanwhile, ERK1/2 of phosphorylation protein expression was significantly promoted by Oleanolic acid treatment. Taken together, we provided evidences that Oleanolic acid was Akt/mTOR/S6K and ERK1/2 signaling-targeting anti-tumor agent. These findings represent new evidences that Oleanolic acid suppresses the proliferation of human bladder cancer by Akt/mTOR/S6K and ERK1/2 signaling, and Oleanolic acid may be used to prevent human bladder cancer.

Biochemical basis of the antidiabetic activity of oleanolic acid and related pentacyclic triterpenes.[Pubmed:23704520]

Diabetes. 2013 Jun;62(6):1791-9.

Oleanolic acid (OA), a natural component of many plant food and medicinal herbs, is endowed with a wide range of pharmacological properties whose therapeutic potential has only partly been exploited until now. Throughout complex and multifactorial mechanisms, OA exerts beneficial effects against diabetes and metabolic syndrome. It improves insulin response, preserves functionality and survival of beta-cells, and protects against diabetes complications. OA may directly modulate enzymes connected to insulin biosynthesis, secretion, and signaling. However, its major contributions appear to be derived from the interaction with important transduction pathways, and many of its effects are consistently related to activation of the transcription factor Nrf2. Doing that, OA induces the expression of antioxidant enzymes and phase II response genes, blocks NF-kappaB, and represses the polyol pathway, AGEs production, and hyperlipidemia. The management of type 2 diabetes requires an integrated approach, which includes the early intervention to prevent or delay the disease progression, and the use of therapies to control glycemia and lipidemia in its late stages. In this sense, the use of functional foods or drugs containing OA is, undoubtedly, an interesting path.

Structure-activity relationship study of betulinic acid, a novel and selective TGR5 agonist, and its synthetic derivatives: potential impact in diabetes.[Pubmed:19911773]

J Med Chem. 2010 Jan 14;53(1):178-90.

We describe here the biological screening of a collection of natural occurring triterpenoids against the G protein-coupled receptor TGR5, known to be activated by bile acids and which mediates some important cell functions. This work revealed that betulinic (1), oleanolic (2), and ursolic acid (3) exhibited TGR5 agonist activity in a selective manner compared to bile acids, which also activated FXR, the nuclear bile acid receptor. The most potent natural triterpenoid betulinic acid was chosen as a reference compound for an SAR study. Hemisyntheses were performed on the betulinic acid scaffold, and we focused on structural modifications of the C-3 alcohol, the C-17 carboxylic acid, and the C-20 alkene. In particular, structural variations around the C-3 position gave rise to major improvements of potency exemplified with derivatives 18 dia 2 (RG-239) and 19 dia 2. The best derivative was tested in vitro and in vivo, and its biological profile is discussed.

Oleanolic acid (Caryophyllin) is a natural compound from plants with anti-tumor activities.

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