Oleanolic Acid Buy
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Oleanolic acid (3β-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.
Structures of oleanolic acid and some of its derivatives (a) Oleanolic acid ] (b) CDDO (c) CDDO-Ma ] (d) CDDO-Me (e) CDDO-Im [17].
OA has also demonstrated its ability to inhibit gluconeogenesis and attenuate hepatic insulin resistance. Hepatic insulin resistance in obese condition is considered a major link between type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) [59,60]. Treatments of obese diabetic mice with 20 mg/kg/day for 14 days resulted in reduced body, liver and fat weights, enhanced insulin signaling and inhibited gluconeogenesis [7]. Similarly, one of the findings of our study on oleanolic acid indicates that early postnatal administration of OA is able to mitigate the development of NAFLD in fructose fed adult female rats [61]. This evidence also suggests the hepatoprotective potential of oleanolic acid.
Glycogen phosphorylase is an enzyme which catalyzes the breakdown of glycogen to release glucose into the bloodstream [62]. Its activity contributes to hepatic glucose production and hence, its inhibition is an important approach in the control of hyperglycemia in type 2 diabetes [62,63]. Zhang et al. [64] designed a series of novel derivatives of OA with long alkyl chains or aromatic rings at C3 position in order to enhance its hypoglycemic activity. One of the series synthesized, 3β-{2-[4-(2-naphthalen-1-yl) acetoxymethyl-1H-1,2,3-triazol-1-yl]acetoxy}olean-12-en-28-oic acid (Figure 2) showed the strongest activity in the inhibition of glycogen phosphorylase and enhancement of glucose consumption.
Tuberculosis (TB) is a potential chronic disease caused by the bacillus Mycobacterium tuberculosis and it is one of the leading causes of death in developing countries [76]. Drug resistance is a major threat to the control and management of TB and one of the strategies employed to overcome drug resistance is the use of combination therapy [77]. Jimenez-Arellanes et al. [78] combined OA with its isomer, ursolic acid (UA) to determine their synergistic antibacterial activity against Mycobacterium tuberculosis H37Rv and drug resistant clinical strain (MDR) of tuberculosis in macrophage cell lines and tuberculosis infested BALB/C mice. The study assessed the pulmonary bacilli loads and expression levels of interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α) and inducible nitric oxide synthase (iNOS). Although OA and UA singly showed antimycobacterial activity, there was also a synergistic intracellular activity of the mixture of both compounds against the tuberculosis strains in the macrophage cell lines. In the infected BALB/C mice, there was a significant reduction in the pulmonary bacilli loads upon treatment with both compounds. Furthermore, there was an increase in expression of iNOS and the cytokines; TNF-α and IFN-γ, which suggests that OA in combination with UA also have immunomodulatory effects that can be harnessed in the control of tuberculosis and possibly other diseases.
Modification of OA has resulted in compounds with biological activity, such as antidiabetic activity. Yolanda et al. synthesized analogues of OA (three ethers and four esters on hydroxyl C3 in ring A, three esters from the carboxyl group C-28, and corresponding primary alcohol), derived from the reduction of carboxylic acid with LiAlH4. Cinnamoyl ester (13) and ethyl ether (14) (Figure 5) were found to be the most PTP-1B inhibitors. The in vitro inhibitory effect of compound 13 was significant, and it substantially lowered blood glucose levels in vivo experiments when compared to OA. Compound 14 exhibited better inhibitory activity and selectivity over protein-tyrosine phosphatase 1B (PTP-1B), with advanced interaction with site B, in accordance with docking studies [53].
Oleanolic acid or oleanic acid is a naturally occurring pentacyclic triterpenoid related to betulinic acid. It is widely distributed in food and plants where it exists as a free acid or as an aglycone of triterpenoid saponins.[2]
Oleanolic acid can be found in olive oil, Phytolacca americana (American pokeweed), and Syzygium spp, garlic, etc. It was first studied and isolated from several plants, including Olea europaea[3] (leaves, fruit), Rosa woodsii (leaves), Prosopis glandulosa (leaves and twigs), Phoradendron juniperinum (whole plant), Syzygium claviflorum (leaves), Hyptis capitata (whole plant), Mirabilis jalapa[4] and Ternstroemia gymnanthera (aerial part). Other Syzygium species including java apple (Syzygium samarangense) and rose apples contain it, as does Ocimum tenuiflorum (holy basil).
Oleanolic acid biosynthesis starts with mevalonate to create squalene. Squalene monooxygenase in the next step oxidases the squalene and forms an epoxide resulting in 2,3-oxidosqualene.[5] Beta-amyrin synthase creates beta-amyrin by a ring formation cascade.[5][6] After the formation of beta amyrin, CYP716AATR2, also known as a cytochrome p450 enzyme, oxidizes carbon 28 turning it into alcohol.[6] CYP716AATR2 converts the alcohol to aldehyde and finally to a carboxylic acid forming oleanolic acid.[6]
Oleanolic acid is relatively non-toxic, hepatoprotective, and exhibits antitumor and antiviral properties.[7] Oleanolic acid was found to exhibit weak anti-HIV[8] and weak anti-HCV activities in vitro, but more potent synthetic analogs are being investigated as potential drugs.[9]
An extremely potent synthetic triterpenoid analog of oleanolic acid was found in 2005, that is a powerful inhibitor of cellular inflammatory processes. They work by the induction by IFN-γ of inducible nitric oxide synthase (iNOS) and of cyclooxygenase 2 in mouse macrophages. They are extremely potent inducers of the phase 2 response (e.g., elevation of NADH-quinone oxidoreductase and heme oxygenase 1), which is a major protector of cells against oxidative and electrophile stress.[10]
A 2002 study in Wistar rats found that oleanolic acid reduced sperm quality and motility, causing infertility. After withdrawing exposure, male rats regained fertility and successfully impregnated female rats.[11] Oleanolic acid is also used as standard for comparison of hyaluronidase, elastase and matrix-metalloproteinase-1 inhibition of other substances in primary research (similar to diclofenac sodium for comparison of analgesic activity).[12][13]
Oleanolic acid is a GPBA receptor (TGR5) partial agonist (EC50 = 2.25 μM; 72% efficacy). Displays no activity at FXR. Also inhibits protein phosphate 1B (PTP1B) and glycogen phosphorylase. Suppresses cell proliferation and increases apoptosis in T24 bladder cancer cells. Antidiabetic, antihyperglycaemic, antitumor and hepatoprotective.
Genet et al (2010) Structure-activity relationship study of betulinic acid, a novel and selective TGR5 agonist, and its synthetic derivatives: potential impact in diabetes. J.Med.Chem. 53 178 PMID: 19911773 Mu et al (2015) Oleanolic acid suppresses the proliferation of human bladder cancer by Akt/mTOR/S6K and ERK1/2 signaling. Int.J.Clin.Exp.Pathol. 8 13864 PMID: 26823699 Castellano et al (2013) Biochemical basis of the antidiabetic activity of oleanolic acid and related pentacyclic triterpenes. Diabetes 62 1791 PMID: 23704520 View Related Products by Target GPBA ReceptorsTransferasesPhosphorylasesApoptosisApoptosis InducersLipid Metabolism View Related Products by Product Action View all GPBA Receptor Agonists
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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 β-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-κB, 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. 59ce067264
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