Anti-Inflammatory, Anti-Diabetic, and Anti-Alzheimer’s Effects of Prenylated Flavonoids from Okinawa Propolis: An Investigation by Experimental and Computational Studies

Md Shahinozzaman,Takahiro Ishii,Md Hossain,Mohammad Halim,Shinkichi Tawata,Nozomi Taira

doi:10.3390/molecules23102479

Abstract

Okinawa propolis (OP) and its major ingredients were reported to have anti-cancer effects and lifespan-extending effects on Caenorhabditis elegans through inactivation of the oncogenic kinase, p21-activated kinase 1 (PAK1). Herein, five prenylated flavonoids from OP, nymphaeol-A (NA), nymphaeol-B (NB), nymphaeol-C (NC), isonymphaeol-B (INB), and 3′-geranyl-naringenin (GN), were evaluated for their anti-inflammatory, anti-diabetic, and anti-Alzheimer’s effects using in vitro techniques. They showed significant anti-inflammatory effects through inhibition of albumin denaturation (half maximal inhibitory concentration (IC50) values of 0.26–1.02 µM), nitrite accumulation (IC50 values of 2.4–7.0 µM), and cyclooxygenase-2 (COX-2) activity (IC50 values of 11.74–24.03 µM). They also strongly suppressed in vitro α-glucosidase enzyme activity with IC50 values of 3.77–5.66 µM. However, only INB and NA inhibited acetylcholinesterase significantly compared to the standard drug donepezil, with IC50 values of 7.23 and 7.77 µM, respectively. Molecular docking results indicated that OP compounds have good binding affinity to the α-glucosidase and acetylcholinesterase proteins, making non-bonded interactions with their active residues and surrounding allosteric residues. In addition, none of the compounds violated Lipinski’s rule of five and showed notable toxicity parameters. Density functional theory (DFT)-based global reactivity descriptors demonstrated their high reactive nature along with the kinetic stability. In conclusion, this combined study suggests that OP components might be beneficial in the treatment of inflammation, type 2 diabetes mellitus, and Alzheimer’s disease.

Highlights

Acute inflammation is thought be a good defense strategy to remove injurious stimuli and to initiate the healing process in the body
Inflammatory responses contribute to type 2 diabetes (T2D) occurrence by causing insulin resistance, and, in turn, they are intensified in the presence of hyperglycemia and promote long-term diabetic complications [4]
Okinawa propolis (OP) compounds inhibited albumin denaturation in a dose-dependent manner. They all showed strong inhibitory effects, and the results were found to be significant compared to ketorolac, a non-steroidal anti-inflammatory drug (NSAID)

Summary

Introduction

Acute inflammation is thought be a good defense strategy to remove injurious stimuli and to initiate the healing process in the body. During CI, increasing numbers of macrophage cells at inflammatory sites play an important role in the defense system, but produce several toxins themselves including reactive oxygen or nitrogen species (ROS or RNS). Inflammatory responses contribute to type 2 diabetes (T2D) occurrence by causing insulin resistance, and, in turn, they are intensified in the presence of hyperglycemia and promote long-term diabetic complications [4]. Both inflammation and T2D trigger the age-related neurodegenerative disorder, Alzheimer’s disease (AD) [5,6], which is often termed as type 3 diabetes due to its pathophysiological similarities with T2D [7]. AD patients have elevated insulin levels, which play a vital role in developing neuropathological hallmarks of AD through increasing amyloid beta (Aβ) accumulation and tau phosphorylation in the brain [9,10,11]

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Results

Conclusion