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      Potential Therapeutic Targets of Quercetin and Its Derivatives: Its Role in the Therapy of Cognitive Impairment

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          Abstract

          Quercetin (QC) is a flavonoid and crucial bioactive compound found in a variety of vegetables and fruits. In preclinical studies, QC has demonstrated broad activity against several diseases and disorders. According to recent investigations, QC is a potential therapeutic candidate for the treatment of nervous system illnesses because of its protective role against oxidative damage and neuroinflammation. QC acts on several molecular signals, including ion channels, neuroreceptors, and inflammatory receptor signaling, and it also regulates neurotrophic and anti-oxidative signaling molecules. While the study of QC in neurological disorders has focused on numerous target molecules, the role of QC on certain molecular targets such as G-protein coupled and nuclear receptors remains to be investigated. Our analysis presents several molecular targets of QC and its derivatives that demonstrate the pharmacological potential against cognitive impairment. Consequently, this article may guide future studies using QC and its analogs on specific signaling molecules. Finding new molecular targets of QC and its analogs may ultimately assist in the treatment of cognitive impairment.

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          Most cited references111

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          SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis.

          A progressive loss of neurons with age underlies a variety of debilitating neurological disorders, including Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), yet few effective treatments are currently available. The SIR2 gene promotes longevity in a variety of organisms and may underlie the health benefits of caloric restriction, a diet that delays aging and neurodegeneration in mammals. Here, we report that a human homologue of SIR2, SIRT1, is upregulated in mouse models for AD, ALS and in primary neurons challenged with neurotoxic insults. In cell-based models for AD/tauopathies and ALS, SIRT1 and resveratrol, a SIRT1-activating molecule, both promote neuronal survival. In the inducible p25 transgenic mouse, a model of AD and tauopathies, resveratrol reduced neurodegeneration in the hippocampus, prevented learning impairment, and decreased the acetylation of the known SIRT1 substrates PGC-1alpha and p53. Furthermore, injection of SIRT1 lentivirus in the hippocampus of p25 transgenic mice conferred significant protection against neurodegeneration. Thus, SIRT1 constitutes a unique molecular link between aging and human neurodegenerative disorders and provides a promising avenue for therapeutic intervention.
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            A critical review of the data related to the safety of quercetin and lack of evidence of in vivo toxicity, including lack of genotoxic/carcinogenic properties.

            Quercetin is a naturally-occurring flavonol (a member of the flavonoid family of compounds) that has a long history of consumption as part of the normal human diet. Because a number of biological properties of quercetin may be beneficial to human health, interest in the addition of this flavonol to various traditional food products has been increasing. Prior to the use of quercetin in food applications that would increase intake beyond that from naturally-occurring levels of the flavonol in the typical Western diet, its safety needs to be established or confirmed. This review provides a critical examination of the scientific literature associated with the safety of quercetin. Results of numerous genotoxicity and mutagenicity, short- and long-term animal, and human studies are reviewed in the context of quercetin exposure in vivo. To reconcile results of in vitro studies, which consistently demonstrated quercetin-related mutagenicity to the absence of carcinogenicity in vivo, the mechanisms that lead to the apparent in vitro mutagenicity, and those that ensure absence of quercetin toxicity in vivo are discussed. The weight of the available evidence supports the safety of quercetin for addition to food.
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              Mechanisms of Neuroprotection by Quercetin: Counteracting Oxidative Stress and More

              Increasing interest has recently focused on determining whether several natural compounds, collectively referred to as nutraceuticals, may exert neuroprotective actions in the developing, adult, and aging nervous system. Quercetin, a polyphenol widely present in nature, has received the most attention in this regard. Several studies in vitro, in experimental animals and in humans, have provided supportive evidence for neuroprotective effects of quercetin, either against neurotoxic chemicals or in various models of neuronal injury and neurodegenerative diseases. The exact mechanisms of such protective effects remain elusive, though many hypotheses have been formulated. In addition to a possible direct antioxidant effect, quercetin may also act by stimulating cellular defenses against oxidative stress. Two such pathways include the induction of Nrf2-ARE and induction of the antioxidant/anti-inflammatory enzyme paraoxonase 2 (PON2). In addition, quercetin has been shown to activate sirtuins (SIRT1), to induce autophagy, and to act as a phytoestrogen, all mechanisms by which quercetin may provide its neuroprotection.
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                Author and article information

                Journal
                J Clin Med
                J Clin Med
                jcm
                Journal of Clinical Medicine
                MDPI
                2077-0383
                25 October 2019
                November 2019
                : 8
                : 11
                : 1789
                Affiliations
                [1 ]Department of Applied Life Sciences and Integrated Bioscience, Graduate School, Konkuk University, Chungju 27478, Korea
                [2 ]The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3010, Australia
                [3 ]Department of Integrated Bioscience and Biotechnology, College of Biomedical and Health Sciences, and Research Institute of Inflammatory Diseases (RID), Konkuk University, Chungju 27478, Korea
                [4 ]Department of Anatomy, Dongguk University Graduate School of Medicine, Gyeongju 38066, Korea
                Author notes
                [* ]Correspondence: choidk@ 123456kku.ac.kr ; Tel.: +82-43-840-3610
                Author information
                https://orcid.org/0000-0001-8216-1171
                https://orcid.org/0000-0003-4707-3488
                https://orcid.org/0000-0003-4128-5308
                https://orcid.org/0000-0001-7041-1524
                Article
                jcm-08-01789
                10.3390/jcm8111789
                6912580
                31717708
                3574e5c4-11d9-4885-b1e1-931865a5700e
                © 2019 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
                : 16 September 2019
                : 21 October 2019
                Categories
                Review

                quercetin,nervous system,molecular signals,pharmacological potential,cognitive impairment

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