Effects of Different Dietary Flavonoids on Dipeptidyl Peptidase-IV Activity and Expression: Insights into Structure–Activity Relationship

Abstract

The inhibitory effects of 30 dietary flavonoids on dipeptidyl peptidase-IV (DPP-IV) were investigated to illustrate their quantitative structure−activity relationship (QSAR) and further explore their inhibition at the cellular level. Results of in vitro experiment show that isorhamnetin-3-O-glucoside (IC 50 , 6.53 ± 0.280 μM) had the strongest inhibition followed by cyanidin-3-Oglucoside (IC 50 , 8.26 ± 0.143 μM) and isorhamnetin-3-O-rutinoside (IC 50 , 8.57 ± 0.422 μM). A 3D QSAR model [comparative molecular field analysis, q 2 = 0.502, optimum number of components (ONC) = 3, R 2 = 0.983, F = 404.378, standard error of estimation (SEE) = 0.070, and two descriptors; comparative similarity index analysis, q 2 = 0.580, ONC = 10, R 2 = 0.999, F = 1617.594, SEE = 0.022, and four descriptors] indicates that the DPP-IV inhibition of flavonoid was facilitated by crucial structural factors. Position 3 of ring C favored bulky, hydrogen bond acceptors and hydrophilic and electron-donating substituents. The presence of minor and electron-withdrawing groups at position 4′ of ring B and positions 5 and 7 of ring A could improve DPP-IV inhibition. Moreover, the three flavonoids mentioned above could effectively suppress DPP-IV activity and expression in Caco-2 cells. This work may supply new insights into dietary flavonoids as DPP-IV inhibitors for controlling blood glucose.

Inhibition of Dipeptidyl Peptidase-4 by Flavonoids: Structure–Activity Relationship, Kinetics and Interaction Mechanism

“…The IC 50 values of these flavonoids were determined to be 138.79 ± 0.87 μM, 156.29 ± 1.18 μM, 166.52 ± 0.6 μM, 81.05 ± 4.14 μM, and 149.96 ± 0.58 μM, respectively. Gao et al ( 34 ) also reported a strong inhibitory activity of cyanidin 3-O-glucoside against DPP-4 with a IC 50 value of 8.26 μM in their experiments. The difference in the IC 50 value might be owing to the use of different DPP-IV inhibitor screening assay kit, in which the origin of DPP-4, concentration of the enzyme and substrate may be different from each other, and thus leading to differences in the obtained results among different researches.…”

“…These results also confirmed the importance of hydroxyl groups on DPP-4 inhibition of flavonoids and indicated that methylation of the hydroxyl groups on ring A and B is not favorable for the DPP-4 inhibition of flavonoids. Gao et al also found methylation of the hydroxyl group at position 4' of ring B led to weaker inhibitory activity against DPP-4 by comparing the inhibitory activity of eriodictyol and hesperitin ( 34 ). Nontheless, methylation of the hydroxyl group at position 3 of ring C tended to improve the inhibitory effect as evidenced by comparing the inhibitory activity of quercetin (E23) with 3-O-methylquercetin (E22).…”

“…Nontheless, methylation of the hydroxyl group at position 3 of ring C tended to improve the inhibitory effect as evidenced by comparing the inhibitory activity of quercetin (E23) with 3-O-methylquercetin (E22). This might be ascribed to the strong electron-donating capacity of methoxyl groups, according to the speculation that position 3 of ring C favored bulky and electron-donating substituents for DPP-4 inhibition ( 34 ).…”

“…The flavonoids in nature usually occur as glycosylated forms. The conjugation of bulky sugar groups to the core structure of flavonoids might decrease their binding affinity to DPP-4 due to steric hindrance, leading to lower inhibitory activity of flavonoid glycosides ( 34 , 35 ). In this sense, the glycosides of luteolin, including luteoloside (A10), luteolin 7-O-glucuronide (A9), orientin (A12), and isoorientin (A6), all showed lower inhibitory activity than luteolin (A8), and the inhibitory percentage of apigenin (A1) were also higher than those of its glycosides, which includes vitexin (A14), vitexin 4'-O-glucoside (A16), vitexin 2”-glucoside(A15), isovitexin (A7), and narirutin (A11).…”

Dietary Flavonoids Alleviate Inflammation and Vascular Endothelial Barrier Dysfunction Induced by Advanced Glycation End Products In Vitro

“…In our previous studies, we found that apigenin-7- O -glucoside (A7G), isorhamnetin-3- O -rutinoside (I3R), and cyanidin-3- O -glucoside (C3G) were the three most effective flavonoids for inhibiting the activities of α-glucosidase and dipeptidyl peptidase-IV and improving insulin resistance among more than 20 dietary flavonoids that may be beneficial for diabetic patients in controlling blood glucose [ 12 , 13 ]. However, information about the effects and mechanisms of the three flavonoids on AGEs-induced inflammation and vascular endothelial dysfunction remain unknown.…”