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      Flavonoids as Prospective Neuroprotectants and Their Therapeutic Propensity in Aging Associated Neurological Disorders

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          Abstract

          Modern research has revealed that dietary consumption of flavonoids and flavonoids-rich foods significantly improve cognitive capabilities, inhibit or delay the senescence process and related neurodegenerative disorders including Alzheimer’s disease (AD). The flavonoids rich foods such as green tea, cocoa, blue berry and other foods improve the various states of cognitive dysfunction, AD and dementia-like pathological alterations in different animal models. The mechanisms of flavonoids have been shown to be mediated through the inhibition of cholinesterases including acetylcholinesterase (AChE), and butyrylcholinesterase (BChE), β-secretase (BACE1), free radicals and modulation of signaling pathways, that are implicated in cognitive and neuroprotective functions. Flavonoids interact with various signaling protein pathways like ERK and PI3-kinase/Akt and modulate their actions, thereby leading to beneficial neuroprotective effects. Moreover, they enhance vascular blood flow and instigate neurogenesis particularly in the hippocampus. Flavonoids also hamper the progression of pathological symptoms of neurodegenerative diseases by inhibiting neuronal apoptosis induced by neurotoxic substances including free radicals and β-amyloid proteins (Aβ). All these protective mechanisms contribute to the maintenance of number, quality of neurons and their synaptic connectivity in the brain. Thus flavonoids can thwart the progression of age-related disorders and can be a potential source for the design and development of new drugs effective in cognitive disorders.

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          Most cited references153

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          Antimicrobial activity of flavonoids

          Flavonoids are ubiquitous in photosynthesising cells and are commonly found in fruit, vegetables, nuts, seeds, stems, flowers, tea, wine, propolis and honey. For centuries, preparations containing these compounds as the principal physiologically active constituents have been used to treat human diseases. Increasingly, this class of natural products is becoming the subject of anti-infective research, and many groups have isolated and identified the structures of flavonoids possessing antifungal, antiviral and antibacterial activity. Moreover, several groups have demonstrated synergy between active flavonoids as well as between flavonoids and existing chemotherapeutics. Reports of activity in the field of antibacterial flavonoid research are widely conflicting, probably owing to inter- and intra-assay variation in susceptibility testing. However, several high-quality investigations have examined the relationship between flavonoid structure and antibacterial activity and these are in close agreement. In addition, numerous research groups have sought to elucidate the antibacterial mechanisms of action of selected flavonoids. The activity of quercetin, for example, has been at least partially attributed to inhibition of DNA gyrase. It has also been proposed that sophoraflavone G and (−)-epigallocatechin gallate inhibit cytoplasmic membrane function, and that licochalcones A and C inhibit energy metabolism. Other flavonoids whose mechanisms of action have been investigated include robinetin, myricetin, apigenin, rutin, galangin, 2,4,2′-trihydroxy-5′-methylchalcone and lonchocarpol A. These compounds represent novel leads, and future studies may allow the development of a pharmacologically acceptable antimicrobial agent or class of agents.
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            The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer.

            Flavonoids are nearly ubiquitous in plants and are recognized as the pigments responsible for the colors of leaves, especially in autumn. They are rich in seeds, citrus fruits, olive oil, tea, and red wine. They are low molecular weight compounds composed of a three-ring structure with various substitutions. This basic structure is shared by tocopherols (vitamin E). Flavonoids can be subdivided according to the presence of an oxy group at position 4, a double bond between carbon atoms 2 and 3, or a hydroxyl group in position 3 of the C (middle) ring. These characteristics appear to also be required for best activity, especially antioxidant and antiproliferative, in the systems studied. The particular hydroxylation pattern of the B ring of the flavonoles increases their activities, especially in inhibition of mast cell secretion. Certain plants and spices containing flavonoids have been used for thousands of years in traditional Eastern medicine. In spite of the voluminous literature available, however, Western medicine has not yet used flavonoids therapeutically, even though their safety record is exceptional. Suggestions are made where such possibilities may be worth pursuing.
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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

                Contributors
                Journal
                Front Aging Neurosci
                Front Aging Neurosci
                Front. Aging Neurosci.
                Frontiers in Aging Neuroscience
                Frontiers Media S.A.
                1663-4365
                26 June 2019
                2019
                : 11
                : 155
                Affiliations
                [1] 1Department of Pharmacy, University of Malakand , Chakdara, Pakistan
                [2] 2Department of Pharmacy, University of Swabi , Swabi, Pakistan
                [3] 3University of Chinese Academy of Sciences , Beijing, China
                [4] 4Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology , Beijing, China
                [5] 5Suliman Bin Abdullah Aba-Alkhail Centre for Interdisciplinary Research in Basic Sciences, International Islamic University Islamabad , Islamabad, Pakistan
                [6] 6Institute of Basic Medical Sciences (IBMS), Khyber Medical University , Peshawar, Pakistan
                [7] 7Department of Pharmacy, Sarhad University of Science and Information Technology (SUIT) , Peshawar, Pakistan
                Author notes

                Edited by: Nibaldo C. Inestrosa, Pontifical Catholic University of Chile, Chile

                Reviewed by: Denis Gris, Université de Sherbrooke, Canada; Dong-Gyu Jo, Sungkyunkwan University, South Korea

                *Correspondence: Muhammad Ayaz ayazuop@ 123456gmail.com
                Article
                10.3389/fnagi.2019.00155
                6606780
                30740048
                8befb0ab-9f83-488f-b55c-5deae5cb15f4
                Copyright © 2019 Ayaz, Sadiq, Junaid, Ullah, Ovais, Ullah, Ahmed and Shahid.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 05 June 2018
                : 11 June 2019
                Page count
                Figures: 13, Tables: 1, Equations: 0, References: 171, Pages: 20, Words: 12647
                Categories
                Neuroscience
                Review

                Neurosciences
                alzheimer’s disease,polyphenols,amyloid beta,cholinesterases,antioxidant,signaling pathways and cognition

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