Compounds from Angelica keiskei with NQO1 induction, DPPH scavenging and α-glucosidase inhibitory activities
Highlights
► A LC–MS method was applied to reveal compounds with QR induction activity. ► Twenty three compounds, including two new ones were isolated from Angelica keiskei. ► Isolated compounds showed QR induction and α-glucosidase inhibiting activities. ► Isolated compounds could scavenge DPPH.
Introduction
NAD(P)H: quinone oxidoreductase 1 (NQO1) was proved to catalyse quinones such as menadione to hydroquinones, providing protection against quinone-mediated oxidative damage (Haan, Pot, Aarts, Rietjens, & Alink, 2006). As an obligated two-electron reductase, NQO1 is associated with chemoprotection and anticarcinogenic activity (Dinkova-Kostova & Talalay, 2010). Thereby, induction of NQO1 is expected to become a strategy for cytoprotection. NQO1 is regulated by the Keap1/Nrf2/ARE pathway in which Keap1 binding to transcription factor Nrf2 is involved in the ubiquitination and degradation of Nrf2. Electrophiles like chalcones (with α,β-unsaturated ketone moiety) binding to Keap1 in the thiol groups by Michael addition prevents the conjugation of Keap1 with Nrf2 and up-regulates the level of NQO1 as consequence (Dinkova-Kostova and Talalay, 2010, Rudolph and Freeman, 2009). Glutathione (GSH) is a small molecule also containing thiol groups. It is thought that compounds which can react with glutathione (GSH) by Michael addition present good NQO1 induction activity (Ma et al., 2009, Rudolph and Freeman, 2009).
Free radicals can lead to carcinogenesis, aging, inflammation and atherosclerosis through the reaction with cellular biological molecules. The reaction with DNA is just a kind of oxidative damage to DNA involved in carcinogenesis and aging (Maria, Fabiano, Ricardo, & de Brito, 2009). More and more interests in antioxidants from dietary food have been attracted.
α-Glucosidases are the key enzymes responsible for carbohydrate digestion and glucose release, which cause postprandial hyperglycaemia, implicated in the development of Type 2 diabetes. α-Glucosidase inhibitors were also reported to prevent dysfunction of β-cell insulin secretion in diabetic patients (Baron, 1998, Casirola and Ferraris, 2006). Therefore, α-glucosidase inhibitors may potentially suppress the progression of diabetes.
Angelica keiskei (AK), is a kind of herbaceous perennid belonging to the Umbelliferae plants. It is traditionally used as a health food, with the effects of diuretic, laxative, analeptic and galactagogue (Akihisa et al., 2006, Ogawa et al., 2005). The roots and the leaves of AK have been thought to have the benefit effects including antihypertension, antitumour, antithrombus (Kimura & Baba, 2003) and controlling the blood glucose (Enoki et al., 2007).
The preliminary bioassays showed the ethanol extract of AK had NQO1 induction, DPPH scavenging and α-glucosidase inhibition activities. A LC–MS method with GSH as the substrate was applied for the purpose of revealing the compounds with NQO1 induction activity and some proposed compounds were found to conjugate with GSH. In order to confirm the activities and structures of the compounds, 23 compounds were obtained from the 95% ethanol extract of AK, their bioassays of NQO1 induction, DPPH scavenging and α-glucosidase inhibition activities were also performed.
Section snippets
Chemicals and reagents
HPLC grade acetonitrile (CH3CN) and methanol (MeOH) were purchased from Merk Company (Darmstadt, Germany). Deionised water was purified using a Milli-Q system (Millipore, Bedford, MA, USA). Glutathione (reduced) was purchased from Bio Basic Inc (Amherst, USA). CDCl3-d1, MeOD-d4, DMSO-d6, Dimethyl sulfoxide (DMSO), maltase from yeast, 4-nitrophenyl α-d-glucopyranoside and thiazolyl blue (MTT) were obtained from Sigma–Aldrich Company (St. Louis, MO, USA). Minimum Essential Medium Alpha Medium
Bioactivities of the extract of AK
The 95% ethanol extract of AK had NQO1 induction activity, with an IR value (fold of NQO1 induction compared to negative levels) of 2.44 at the concentration of 25 μg/mL, while the IR values for the P.E. and CH2Cl2 extract were 2.61 at the concentration of 20 μg/mL. The 95% ethanol extract of AK inhibited α-glucosidase by 46.29% at the concentration of 50 μg/mL and it also could scavenge DPPH radical as well.
Identification of the isolated compounds from AK
Through the preparative reverse-phase HPLC, fraction E yielded pseudoisopsoralen (14) (tR =
Conclusion
The extract of A. keiskei was proved to have NQO1 induction, DPPH radical scavenging and α-glucosidase inhibition activities. The extraction and isolation of AK yielded two new compounds 4-hydroxy-3,5,5-trimethyl-4-(1,2,3-trihydroxybutyl)cyclohex-2-enone (18) and (Z)-2-(3-hydroxypent-1-ynyl)-3-(non-1-enyl)oxiran-2-ol (23). Further research showed that the chalcones isobavachalcone (1), xanthoangelol (2), 4-hydroxyderricin (3) and (E)-1-(3-((E
Acknowledgements
The work was financially supported by Zhejiang Key Science & Technological Program (2009C13028) and National Natural Science Foundation of China (81001371).
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