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      Molecular Insight into the Therapeutic Promise of Flavonoids against Alzheimer’s Disease

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          Abstract

          Alzheimer’s disease (AD) is one of the utmost chronic neurodegenerative disorders, which is characterized from a neuropathological point of view by the aggregates of amyloid beta (Aβ) peptides that are deposited as senile plaques and tau proteins which form neurofibrillary tangles (NFTs). Even though advancement has been observed in order to understand AD pathogenesis, currently available therapeutic methods can only deliver modest symptomatic relief. Interestingly, naturally occurring dietary flavonoids have gained substantial attention due to their antioxidative, anti-inflammatory, and anti-amyloidogenic properties as alternative candidates for AD therapy. Experimental proof provides support to the idea that some flavonoids might protect AD by interfering with the production and aggregation of Aβ peptides and/or decreasing the aggregation of tau. Flavonoids have the ability to promote clearance of Aβ peptides and inhibit tau phosphorylation by the mTOR/autophagy signaling pathway. Moreover, due to their cholinesterase inhibitory potential, flavonoids can represent promising symptomatic anti-Alzheimer agents. Several processes have been suggested for the aptitude of flavonoids to slow down the advancement or to avert the onset of Alzheimer’s pathogenesis. To enhance cognitive performance and to prevent the onset and progress of AD, the interaction of flavonoids with various signaling pathways is proposed to exert their therapeutic potential. Therefore, this review elaborates on the probable therapeutic approaches of flavonoids aimed at averting or slowing the progression of the AD pathogenesis.

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          Flavonoids as antioxidants.

          Flavonoids are phenolic substances isolated from a wide range of vascular plants, with over 8000 individual compounds known. They act in plants as antioxidants, antimicrobials, photoreceptors, visual attractors, feeding repellants, and for light screening. Many studies have suggested that flavonoids exhibit biological activities, including antiallergenic, antiviral, antiinflammatory, and vasodilating actions. However, most interest has been devoted to the antioxidant activity of flavonoids, which is due to their ability to reduce free radical formation and to scavenge free radicals. The capacity of flavonoids to act as antioxidants in vitro has been the subject of several studies in the past years, and important structure-activity relationships of the antioxidant activity have been established. The antioxidant efficacy of flavonoids in vivo is less documented, presumably because of the limited knowledge on their uptake in humans. Most ingested flavonoids are extensively degraded to various phenolic acids, some of which still possess a radical-scavenging ability. Both the absorbed flavonoids and their metabolites may display an in vivo antioxidant activity, which is evidenced experimentally by the increase of the plasma antioxidant status, the sparing effect on vitamin E of erythrocyte membranes and low-density lipoproteins, and the preservation of erythrocyte membrane polyunsaturated fatty acids. This review presents the current knowledge on structural aspects and in vitro antioxidant capacity of most common flavonoids as well as in vivo antioxidant activity and effects on endogenous antioxidants.
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            Neural mechanisms of ageing and cognitive decline.

            During the past century, treatments for the diseases of youth and middle age have helped raise life expectancy significantly. However, cognitive decline has emerged as one of the greatest health threats of old age, with nearly 50% of adults over the age of 85 afflicted with Alzheimer's disease. Developing therapeutic interventions for such conditions demands a greater understanding of the processes underlying normal and pathological brain ageing. Recent advances in the biology of ageing in model organisms, together with molecular and systems-level studies of the brain, are beginning to shed light on these mechanisms and their potential roles in cognitive decline.
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              Flavonoids: antioxidants or signalling molecules?

              Many studies are accumulating that report the neuroprotective, cardioprotective, and chemopreventive actions of dietary flavonoids. While there has been a major focus on the antioxidant properties, there is an emerging view that flavonoids, and their in vivo metabolites, do not act as conventional hydrogen-donating antioxidants but may exert modulatory actions in cells through actions at protein kinase and lipid kinase signalling pathways. Flavonoids, and more recently their metabolites, have been reported to act at phosphoinositide 3-kinase (PI 3-kinase), Akt/protein kinase B (Akt/PKB), tyrosine kinases, protein kinase C (PKC), and mitogen activated protein kinase (MAP kinase) signalling cascades. Inhibitory or stimulatory actions at these pathways are likely to affect cellular function profoundly by altering the phosphorylation state of target molecules and by modulating gene expression. A clear understanding of the mechanisms of action of flavonoids, either as antioxidants or modulators of cell signalling, and the influence of their metabolism on these properties are key to the evaluation of these potent biomolecules as anticancer agents, cardioprotectants, and inhibitors of neurodegeneration
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                Author and article information

                Journal
                Molecules
                Molecules
                molecules
                Molecules
                MDPI
                1420-3049
                11 March 2020
                March 2020
                : 25
                : 6
                : 1267
                Affiliations
                [1 ]Department of Pharmacy, Southeast University, Dhaka 1213, Bangladesh
                [2 ]Pharmakon Neuroscience Research Network, Dhaka 1207, Bangladesh
                [3 ]Department of Pharmacy, BRAC University, Dhaka 1212, Bangladesh
                [4 ]Department of Pharmacology and Toxicology, Faculty of Bio-Sciences, Cholistan University of Veterinary and Animal Sciences (CUVAS), Bahawalpur 63100, Pakistan
                [5 ]Research Unit, Induced Resistance and Plant Bioprotection, EA 4707, SFR Condorcet FR CNRS 3417, Faculty of Sciences, University of Reims Champagne-Ardenne, PO Box 1039, 51687 Reims CEDEX 2, France
                [6 ]Division of Drug Design and Medicinal Chemistry Research Lab, Department of Pharmaceutical Chemistry, Ahalia School of Pharmacy, Palakkad, Kerala 678557, India
                [7 ]Department of Chemistry, University of Swabi, Anbar 23561, Khyber Pakhtunkhwa, Pakistan
                [8 ]Department of Bioresources and Food Sciences, Konkuk University, Seoul 05029, Korea
                [9 ]Instituto de Investigación e Innovación en Salud, Facultad de Ciencias de la Salud, Universidad Central de Chile, Santiago 8330507, Chile
                [10 ]Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain
                [11 ]King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia
                [12 ]Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia
                [13 ]Chrono-Environnement Laboratory, UMR CNRS 6249, Bourgogne Franche-Comté University, F-25030 Besançon, France
                Author notes
                [* ]Correspondence: msu-neuropharma@ 123456hotmail.com or msu_neuropharma@ 123456hotmail.com (M.S.U.); philippe.jeandet@ 123456univ-reims.fr (P.J.); Tel.: +880-1710220110 (M.S.U.); +33-3-26913-341 (P.J.)
                Author information
                https://orcid.org/0000-0002-0805-7840
                https://orcid.org/0000-0002-6078-8587
                https://orcid.org/0000-0001-8670-4356
                https://orcid.org/0000-0003-3023-4871
                https://orcid.org/0000-0003-2429-5491
                https://orcid.org/0000-0002-2790-2544
                https://orcid.org/0000-0002-9820-2078
                Article
                molecules-25-01267
                10.3390/molecules25061267
                7143946
                32168835
                5fd24d99-8783-40b6-82c9-095af3897ca3
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 06 February 2020
                : 10 March 2020
                Categories
                Review

                alzheimer’s disease,flavonoids,amyloid plaque,neurofibrillary tangles,pi3k/akt signaling,mapk signaling,mtor

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