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      Potential Therapeutic Anti-Inflammatory and Immunomodulatory Effects of Dihydroflavones, Flavones, and Flavonols

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          Abstract

          Systemic inflammation, circulating immune cell activation, and endothelial cell damage play a critical role in vascular pathogenesis. Flavonoids have shown anti-inflammatory effects. In this study, we investigated the effects of different flavonoids on the production of pro-inflammatory interleukin (IL) 1β, 6, and 8, and tumor necrosis factor α (TNF-α), in peripheral blood cells. Methods: We studied the whole blood from 36 healthy donors. Lipopolysaccharide (LPS)-stimulated (0.5 μg/mL) whole-blood aliquots were incubated in the presence or absence of different concentrations of quercetin, rutin, naringenin, naringin, diosmetin, and diosmin for 6 h. Cultures were centrifuged and the supernatant was collected in order to measure IL-1β, TNF-α, IL-6, and IL-8 production using specific immunoassay techniques. This production was significantly inhibited by quercetin, naringenin, naringin, and diosmetin, but in no case by rutin or diosmin. Flavonoids exert different effects, maybe due to the differences between aglycons and glucosides present in their chemical structures. However, these studies suggest that quercetin, naringenin, naringin, and diosmetin could have a potential therapeutic effect in the inflammatory process of cardiovascular disease.

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          Most cited references45

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          Citrus flavonoids: Molecular structure, biological activity and nutritional properties: A review

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            Role of antioxidants in prophylaxis and therapy: A pharmaceutical perspective.

            Antioxidants are emerging as prophylactic and therapeutic agents. These are the agents, which scavenge free radicals otherwise reactive oxygen species and prevent the damage caused by them. Free radicals have been associated with pathogenesis of various disorders like cancer, diabetes, cardiovascular diseases, autoimmune diseases, neurodegenerative disorders and are implicated in aging. Several antioxidants like SOD, CAT, epigallocatechin-3-O-gallate, lycopene, ellagic acid, coenzyme Q10, indole-3-carbinol, genistein, quercetin, vitamin C and vitamin E have been found to be pharmacologically active as prophylactic and therapeutic agents for above mentioned diseases. Antioxidants are part of diet but their bioavailability through dietary supplementation depends on several factors. This major drawback of dietary agents may be due to one or many of the several factors like poor solubility, inefficient permeability, instability due to storage of food, first pass effect and GI degradation. Conventional dosage forms may not result in efficient formulation owing to their poor biopharmaceutical properties. Principles of novel drug delivery systems need to be applied to significantly improve the performance of antioxidants. Novel drug delivery systems (NDDS) would also help in delivery of these antioxidants by oral route, as this route is of prime importance when antioxidants are intended for prophylactic purpose. Implication of NDDS for the delivery of antioxidants is largely governed by physicochemical characteristics, biopharmaceutical properties and pharmacokinetic parameters of the antioxidant to be formulated. Recently, chemical modifications, coupling agents, liposomes, microparticles, nanoparticles and gel-based systems have been explored for the delivery of these difficult to deliver molecules. Results from several studies conducted across the globe are positive and provided us with new anticipation for the improvement of human healthcare.
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              The role of metabolism (and the microbiome) in defining the clinical efficacy of dietary flavonoids1

              At a population level, there is growing evidence of the beneficial effects of dietary flavonoids on health. However, there is extensive heterogeneity in the response to increased intake, which is likely mediated via wide interindividual variability in flavonoid absorption and metabolism. Flavonoids are extensively metabolized by phase I and phase II metabolism (which occur predominantly in the gastrointestinal tract and liver) and colonic microbial metabolism. A number of factors, including age, sex, and genotype, may affect these metabolic processes. In addition, food composition and flavonoid source are likely to affect bioavailability, and emerging data suggest a critical role for the microbiome. This review will focus on the current knowledge for the main subclasses of flavonoids, including anthocyanins, flavonols, flavan-3-ols, and flavanones, for which there is growing evidence from prospective studies of beneficial effects on health. The identification of key factors that govern metabolism and an understanding of how the differential capacity to metabolize these bioactive compounds affect health outcomes will help establish how to optimize intakes of flavonoids for health benefits and in specific subgroups. We identify research areas that need to be addressed to further understand important determinants of flavonoid bioavailability and metabolism and to advance the knowledge base that is required to move toward the development of dietary guidelines and recommendations for flavonoids and flavonoid-rich foods.
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                Author and article information

                Journal
                Molecules
                Molecules
                molecules
                Molecules
                MDPI
                1420-3049
                24 February 2020
                February 2020
                : 25
                : 4
                : 1017
                Affiliations
                [1 ]Biomedical Sciences Department, Pharmacology Unit, University of Alcalá, Alcalá de Henares, 28871 Madrid, Spain; lucinda.villaescusa@ 123456uah.es (L.V.); francisco.zaragoza@ 123456uah.es (F.Z.)
                [2 ]Laboratory of Immune System Diseases and Oncology, Department of Medicine and Medical Specialties, University of Alcalá, Alcala de Henares, 28871 Madrid, Spain; jorge.monserrat@ 123456uah.es (J.M.); mademons@ 123456gmail.com (M.Á.-M.)
                [3 ]Immune System Diseases and Oncology Service, University Hospital “Príncipe de Asturias”, Alcalá de Henares, 28871 Madrid, Spain
                [4 ]Biomedical Research Networking Center in Hepatic and Digestive Diseases (CIBERehd), 28871 Madrid, Spain
                [5 ]Ramón y Cajal Health Research Institute (IRYCIS), 28034 Madrid, Spain
                Author notes
                Author information
                https://orcid.org/0000-0003-1775-4645
                Article
                molecules-25-01017
                10.3390/molecules25041017
                7070238
                32102475
                6d153501-24d4-46f7-9ba6-440389ab1e46
                © 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
                : 21 January 2020
                : 22 February 2020
                Categories
                Article

                flavonoids,aglycons,glycosides,il-1β,tnf-α,il-6,il-8,pro-inflammatory cytokines

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