Epigenetic modifications of triterpenoid ursolic acid in activating Nrf2 and blocking cellular transformation of mouse epidermal cells

Abstract

Ursolic acid (UA), a well-known natural triterpenoid found in abundance in blueberries, cranberries and apple peels, has been reported to possess many beneficial health effects. These effects include anti-cancer activity in various cancers, such as skin cancer. Skin cancer is the most common cancer in the world. Nuclear factor E2-related factor 2 (Nrf2) is a master regulator of anti-oxidative stress response with anti-carcinogenic activity against UV- and chemical-induced tumor formation in the skin. Recent studies show that epigenetic modifications of Nrf2 play an important role in cancer prevention. However the epigenetic impact of UA on Nrf2 signaling remains poorly understood in skin cancer. In this study, we investigated the epigenetic effects of UA on mouse epidermal JB6 P+ cells. UA inhibited cellular transformation by 12-O-tetradecanoylphorbol-13-acetate (TPA) at a concentration at which the cytotoxicity was no more than 25%. Under this condition, UA induced the expression of the Nrf2-mediated detoxifying/antioxidant enzymes heme oxygenase-1 (HO-1), NAD(P)H:quinone oxidoreductase 1 (NQO1), and UDP-glucuronosyltransferase 1A1 (UGT1A1). DNA methylation analysis revealed that UA demethylated the first 15 CpG sites of the Nrf2 promoter region, which correlated with the re-expression of Nrf2. Furthermore, UA reduced the expression of epigenetic modifying enzymes, including the DNA methyltransferases (DNMTs) DNMT1 and DNMT3a and the histone deacetylases (HDACs) HDAC1, 2, 3, and 8 (Class I) and HDAC6 and 7 (Class II), and HDAC activity. Taken together, these results suggest that the epigenetic effects of the triterpenoid UA could potentially contribute to its beneficial effects, including the prevention of skin cancer.

Pharmacokinetics and Pharmacodynamics of the Triterpenoid Ursolic Acid in Regulating the Antioxidant, Anti-inflammatory, and Epigenetic Gene Responses in Rat Leukocytes

“…Multiple levels of interactions between epigenetic regulation and oxidative stress/inflammation have been observed and documented in carcinogenesis 37, 38 . Indeed, the role of UA in the epigenetic regulation of gene expression has been recently shown 22 . In this study, we measured the mRNA levels of epigenetic modulators, including DNMTs and HDACs, and UA was found to decrease LPS-induced DNMT and HDAC expression.…”

“…Recent studies have indicated that UA exerts a cellular protective effect via the Nrf2 pathway in different experimental models 21, 22 . However, to date, no study has been conducted to link the pharmacokinetics (PK) and pharmacodynamics (PD) of UA in vivo .…”

Supercritical CO2 extraction of steroidal sapogenins from fenugreek (Trigonella foenum-graecum L.)seed

“…other steroidal sapogenins, namely sarsapogenin and protodioscin, detected in fenugreek possessed significant anticancer, hypocholesterolemic, and antidepressant activities [6][7][8][9][10][11][12], exhibited the beneficial effects on the cardiovascular system [10], and might take a part in the regulation of glycemia and high blood pressure [8][9]13]. Besides, oleanolic and ursolic acids are known for different biological activities, their ability to reduce blood pressure, to regulate cholesterol level, and to induce the apoptosis of cancer cells [14][15][16][17][18][19][20]. Interestingly, ursolic acid represents one of the most important constituents of fenugreek seed.…”

“…Interestingly, ursolic acid represents one of the most important constituents of fenugreek seed. In the literature so far, it was reported to be present only in its ethanol-aqueous extract [16][17][18][19][20][21][22]. The concurrent presence of oleanolic acid and ursolic acid, its isomer, in plant material might be responsible for their possible synergistic effect on several health impairments [23][24][25].…”

“…Because of the wide pharmacological properties useful in the treatment of many health disorders, obtaining fenugreek seed extracts rich in saponins attracted the attention of the scientific community [3][4]7,[9][10][11][12]17,20,[22][23][26][27]. Supercritical fluid extraction (SFE) was applied as one of the most promising extraction techniques, with the advantages in comparison to traditional techniques, being that obtained supercritical extract is free of organic solvents, the SFE extraction is much faster without the necessity to employ the steps of further purification, making the final product much more economical.…”