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

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.

[1]  M. Hossain,et al.  Cytotoxic Desulfated Saponin from Holothuria atra Predicted to Have High Binding Affinity to the Oncogenic Kinase PAK1: A Combined In Vitro and In Silico Study. , 2018, Scientia pharmaceutica.

[2]  F. Azam,et al.  NSAIDs as potential treatment option for preventing amyloid β toxicity in Alzheimer’s disease: an investigation by docking, molecular dynamics, and DFT studies , 2018, Journal of biomolecular structure & dynamics.

[3]  M. Kamal,et al.  Flavonoids as acetylcholinesterase inhibitors: Current therapeutic standing and future prospects. , 2018, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[4]  S. Shah,et al.  Synthesis, α-glucosidase inhibition and molecular docking study of coumarin based derivatives. , 2018, Bioorganic chemistry.

[5]  M. Halim,et al.  Multiple receptor conformers based molecular docking study of fluorine enhanced ethionamide with mycobacterium enoyl ACP reductase (InhA). , 2017, Journal of molecular graphics & modelling.

[6]  J. Anireddy,et al.  Synthesis and α-glucosidase inhibition activity of dihydroxy pyrrolidines. , 2017, Bioorganic & medicinal chemistry letters.

[7]  S. Kumazawa,et al.  Frondoside A from sea cucumber and nymphaeols from Okinawa propolis: Natural anti-cancer agents that selectively inhibit PAK1 in vitro. , 2017, Drug discoveries & therapeutics.

[8]  Y. Uto,et al.  1,2,3-Triazolyl ester of Ketorolac: A "Click Chemistry"-based highly potent PAK1-blocking cancer-killer. , 2017, European journal of medicinal chemistry.

[9]  A. Awal,et al.  In vitro xanthine oxidase and albumin denaturation inhibition assay of Barringtonia racemosa L. and total phenolic content analysis for potential anti-infl ammatory use in gouty arthritis , 2016 .

[10]  S. Chander,et al.  Rational design, synthesis, anti-HIV-1 RT and antimicrobial activity of novel 3-(6-methoxy-3,4-dihydroquinolin-1(2H)-yl)-1-(piperazin-1-yl)propan-1-one derivatives. , 2016, Bioorganic chemistry.

[11]  Md. Asiful Islam,et al.  Type 2 Diabetes Mellitus and Alzheimer's Disease: Bridging the Pathophysiology and Management. , 2016, Current pharmaceutical design.

[12]  D. Holtzman,et al.  Changes in insulin and insulin signaling in Alzheimer’s disease: cause or consequence? , 2016, The Journal of experimental medicine.

[13]  S. Tawata,et al.  Effect of Okinawa Propolis on PAK1 Activity, Caenorhabditis elegans Longevity, Melanogenesis, and Growth of Cancer Cells. , 2016, Journal of agricultural and food chemistry.

[14]  D. Centeno,et al.  Evaluation of acetylcholinesterase inhibitory activity of Brazilian red macroalgae organic extracts , 2015 .

[15]  F. Azam,et al.  Molecular interaction studies of green tea catechins as multitarget drug candidates for the treatment of Parkinson’s disease: computational and structural insights , 2015, Network.

[16]  L. Misery,et al.  Antioxidant and anti-inflammatory effects of Ruta chalepensis L. extracts on LPS-stimulated RAW 264.7 cells , 2015, In Vitro Cellular & Developmental Biology - Animal.

[17]  A. Rauf,et al.  Cytotoxic, antitumour-promoting and inhibition of protein denaturation effects of flavonoids, isolated from Potentilla evestita Th. Wolf , 2015, Natural product research.

[18]  F. Azam,et al.  Ginger components as new leads for the design and development of novel multi-targeted anti-Alzheimer’s drugs: a computational investigation , 2014, Drug design, development and therapy.

[19]  H. Maruta Herbal Therapeutics that Block the Oncogenic Kinase PAK1: A Practical Approach towards PAK1‐dependent Diseases and Longevity , 2014, Phytotherapy research : PTR.

[20]  Andre Pascal Kengne,et al.  Diabetes Mellitus and Inflammation , 2013, Current Diabetes Reports.

[21]  Jie Shen,et al.  admetSAR: A Comprehensive Source and Free Tool for Assessment of Chemical ADMET Properties , 2012, J. Chem. Inf. Model..

[22]  R. Curi,et al.  Molecular Targets Related to Inflammation and Insulin Resistance and Potential Interventions , 2012, Journal of biomedicine & biotechnology.

[23]  P. Salehi,et al.  In vitro α-glucosidase inhibitory activity of phenolic constituents from aerial parts of Polygonum hyrcanicum , 2012, DARU Journal of Pharmaceutical Sciences.

[24]  B. Aggarwal,et al.  Upsides and downsides of reactive oxygen species for cancer: the roles of reactive oxygen species in tumorigenesis, prevention, and therapy. , 2012, Antioxidants & redox signaling.

[25]  H. Hanyu,et al.  Efficacy of PPAR-γ agonist pioglitazone in mild Alzheimer disease , 2011, Neurobiology of Aging.

[26]  Said Bellahcen,et al.  Antidiabetic medicinal plants as a source of alpha glucosidase inhibitors. , 2010, Current diabetes reviews.

[27]  J. van Staden,et al.  Anti-inflammatory, anticholinesterase, antioxidant and phytochemical properties of medicinal plants used for pain-related ailments in South Africa. , 2010, Journal of ethnopharmacology.

[28]  Zina Kroner,et al.  The relationship between Alzheimer's disease and diabetes: Type 3 diabetes? , 2009, Alternative medicine review : a journal of clinical therapeutic.

[29]  Arthur J. Olson,et al.  AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading , 2009, J. Comput. Chem..

[30]  Shabana I. Khan,et al.  Cyclooxygenase‐2 inhibitory and antioxidant compounds from the truffle Elaphomyces granulatus , 2009, Phytotherapy research : PTR.

[31]  R. Medzhitov Origin and physiological roles of inflammation , 2008, Nature.

[32]  K. Bae,et al.  Anti-inflammatory activity of 4-methoxyhonokiol is a function of the inhibition of iNOS and COX-2 expression in RAW 264.7 macrophages via NF-kappaB, JNK and p38 MAPK inactivation. , 2008, European journal of pharmacology.

[33]  A. Roses Commentary on “A roadmap for the prevention of dementia: The inaugural Leon Thal Symposium.” An impending prevention clinical trial for Alzheimer's disease: Roadmaps and realities , 2008, Alzheimer's & Dementia.

[34]  E. Siemers,et al.  Commentary on “A roadmap for the prevention of dementia: The inaugural Leon Thal Symposium” , 2008, Alzheimer's & Dementia.

[35]  P. Mehta,et al.  Intranasal insulin improves cognition and modulates β-amyloid in early AD , 2008, Neurology.

[36]  Tsutomu Nakayama,et al.  Antioxidant prenylated flavonoids from propolis collected in Okinawa, Japan. , 2007, Journal of agricultural and food chemistry.

[37]  A. Goldfine,et al.  Inflammation and insulin resistance. , 2006, The Journal of clinical investigation.

[38]  Christina A. Wilson,et al.  GSK-3α regulates production of Alzheimer's disease amyloid-β peptides , 2003, Nature.

[39]  Anne Hersey,et al.  Rate-Limited Steps of Human Oral Absorption and QSAR Studies , 2002, Pharmaceutical Research.

[40]  G. Folkers,et al.  Applications of density functional theory-based methods in medicinal chemistry , 2002 .

[41]  P. Greengard,et al.  Does insulin dysfunction play a role in Alzheimer's disease? , 2002, Trends in pharmacological sciences.

[42]  Stephen R. Johnson,et al.  Molecular properties that influence the oral bioavailability of drug candidates. , 2002, Journal of medicinal chemistry.

[43]  Y. Song,et al.  Caffeic acid phenethyl ester inhibits nitric oxide synthase gene expression and enzyme activity. , 2002, Cancer letters.

[44]  C. Plata-salamán,et al.  Inflammation and Alzheimer’s disease , 2000, Neurobiology of Aging.

[45]  F. Lombardo,et al.  Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings , 1997 .

[46]  R. Li,et al.  Use of dipole moment as a parameter in drug-receptor interaction and quantitative structure-activity relationship studies. , 1982, Journal of pharmaceutical sciences.

[47]  K. Courtney,et al.  A new and rapid colorimetric determination of acetylcholinesterase activity. , 1961, Biochemical pharmacology.

[48]  N. Momose,et al.  Analysis of antioxidant prenylflavonoids in different parts of Macaranga tanarius, the plant origin of Okinawan propolis. , 2014, Asian Pacific journal of tropical medicine.

[49]  P. Moreira Alzheimer's disease and diabetes: an integrative view of the role of mitochondria, oxidative stress, and insulin. , 2012, Journal of Alzheimer's disease : JAD.

[50]  M. Reger,et al.  Intranasal insulin improves cognition and modulates beta-amyloid in early AD. , 2008, Neurology.

[51]  Christina A. Wilson,et al.  GSK-3alpha regulates production of Alzheimer's disease amyloid-beta peptides. , 2003, Nature.