Anti-diabetic and anti-Alzheimer's disease activities of oligonol

Abstract

Oligonol is a low-molecular-weight form of polyphenol that is derived from lychee fruit extract containing catechin-type monomers and proanthocyanidin oligomers. Recently, oligonol has emerged as a rich source of naturally occurring therapeutic agent, is predicted to indicate favorable effects on numerous chronic diseases, including diabetics mellitus, oxidative stress, inflammation, obesity, and cancer. The detailed mechanisms by which oligonol may act as an anti-diabetic, moreover, anti-Alzheimer’s molecule haven't been determined. In this study, we investigate the anti-diabetic activities of oligonol via α-glucosidase and human recombinant protein tyrosine phosphatase 1B (PTP1B) assays and find out the possible mechanism of oligonol in insulin resistance HepG2 cells. This study additionally investigates the binding affinity of the constituents of oligonol on PTP1B, and t-BHP induced hepatoprotective effects by scavenging peroxynitrite as well as scavenging of total and intracellular ROS generation. Moreover, investigates anti-Alzheimer's disease activities, by evaluating the ability of this compound to inhibit acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1). Oligonol exhibited potent concentration-dependent anti-diabetic activities by inhibiting α-glucosidase and PTP1B with IC50 values of 23.14 ± 0.91 µg/mL and 1.02 ± 0.04 µg/mL, respectively. Moreover, a kinetics study revealed that oligonol inhibited α-glucosidase (Ki=22.36) and PTP1B (Ki=8.51) with characteristics typical of a mixed inhibitor. According to the cellular study, oligonol increased the insulin-provoked glucose uptake and decreased the expression of PTP1B in insulin-resistant HepG2 cells in a dose-dependent manner compared to the normal and insulin resistance group. The binding mode was determined using state-of-the-art of covalent docking and scoring methodology. The obtained data clearly demonstrated that the constituents of oligonol possess high inhibitory activity against PTP1B by bind with specific interacting residues (SER80), which shared among all of the oligonol constituents except procyanidin A1, and A2, involved in PTP1B inhibition. Further, oligonol activates the IRS-1 by decreasing the phosphorylation of IRS-1 (Ser 307) and increased the phosphorylation of Akt, PI3K, and ERK 1 significantly, as well as suppressed proinflammatory nuclear factor-kappa B (NF-κB) p65 and inhibit the caspase-3 activation significantly in insulin-resistant HepG2 cells compared to the control group. In addition, protective effects of oligonol against tertbutyl hydroperoxide (t-BHP) induced oxidative stress in HepG2 cells was determined, that showed significant hepatoprotective activity by decreasing intracellular and or total ROS (IC50= 2.30 ± 0.32 µg/mL) generation dose-dependently. Oligonol also displayed potent concentration-dependent inhibitory activity against AChE and BChE with IC50 values of 4.34 ± 0.06 µg/mL and 2.07 ± 0.53 µg/mL, respectively. However, oligonol exhibited only marginal concentration-dependent BACE1 inhibitory activity with an IC50 value 130.45 ± 1.49 µg/mL. A kinetic's study revealed mixed-type inhibition against AChE (Ki=4.65) and BACE1 (Ki=58.80), but noncompetitive-type inhibition against BChE (Ki=9.80). Furthermore, oligonol exhibited the dose-dependent scavenging activity of ONOO- with IC50 values of 17.98 ± 0.76 µg/mL, and inhibitory activity of peroxynitrite (ONOO-)-mediated protein tyrosine nitration. Therefore, the results of the present study clearly demonstrate the promising antidiabetic, hepatoprotective, as well as anti-AD potential of oligonol.