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      Flavonoids as Cytokine Modulators: A Possible Therapy for Inflammation-Related Diseases

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          Abstract

          High levels of cytokines, such as interleukin (IL)-1β, tumor necrosis factor (TNF)-α and IL-6, are associated with chronic diseases like rheumatoid arthritis, asthma, atherosclerosis, Alzheimer’s disease and cancer; therefore cytokine inhibition might be an important target for the treatment of these diseases. Most drugs used to alleviate some inflammation-related symptoms act by inhibiting cyclooxygenases activity or by blocking cytokine receptors. Nevertheless, these drugs have secondary effects when used on a long-term basis. It has been mentioned that flavonoids, namely quercetin, apigenin and luteolin, reduce cytokine expression and secretion. In this regard, flavonoids may have therapeutical potential in the treatment of inflammation-related diseases as cytokine modulators. This review is focused on current research about the effect of flavonoids on cytokine modulation and the description of the way these compounds exert their effect.

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          Origin and physiological roles of inflammation.

          Ruslan Medzhitov (2008)
          Inflammation underlies a wide variety of physiological and pathological processes. Although the pathological aspects of many types of inflammation are well appreciated, their physiological functions are mostly unknown. The classic instigators of inflammation - infection and tissue injury - are at one end of a large range of adverse conditions that induce inflammation, and they trigger the recruitment of leukocytes and plasma proteins to the affected tissue site. Tissue stress or malfunction similarly induces an adaptive response, which is referred to here as para-inflammation. This response relies mainly on tissue-resident macrophages and is intermediate between the basal homeostatic state and a classic inflammatory response. Para-inflammation is probably responsible for the chronic inflammatory conditions that are associated with modern human diseases.
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            The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer.

            E. Middleton, C. Kandaswami, T Theoharides (2000)
            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 as antioxidants in plants: location and functional significance.

              Giovanni Agati, Elisa Azzarello, Susanna Pollastri … (2012)
              Stress-responsive dihydroxy B-ring-substituted flavonoids have great potential to inhibit the generation of reactive oxygen species (ROS) and reduce the levels of ROS once they are formed, i.e., to perform antioxidant functions. These flavonoids are located within or in the proximity of centers of ROS generation in severely stressed plants. Efficient mechanisms have been recently identified for the transport of flavonoids from the endoplasmic reticulum, the site of their biosynthesis, to different cellular compartments. The mechanism underlying flavonoid-mediated ROS reduction in plants is still unclear. 'Antioxidant' flavonoids are found in the chloroplast, which suggests a role as scavengers of singlet oxygen and stabilizers of the chloroplast outer envelope membrane. Dihydroxy B-ring substituted flavonoids are present in the nucleus of mesophyll cells and may inhibit ROS-generation making complexes with Fe and Cu ions. The genes that govern the biosynthesis of antioxidant flavonoids are present in liverworts and mosses and are mostly up-regulated as a consequence of severe stress. This suggests that the antioxidant flavonoid metabolism is a robust trait of terrestrial plants. Vacuolar dihydroxy B-ring flavonoids have been reported to serve as co-substrates for vacuolar peroxidases to reduce H(2)O(2) escape from the chloroplast, following the depletion of ascorbate peroxidase activity. Antioxidant flavonoids may effectively control key steps of cell growth and differentiation, thus acting regulating the development of the whole plant and individual organs. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
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                Author and article information

                Contributors
                Antonio Segura-Carretero: Role: Academic Editor
                Ana Maria Gómez Caravaca: Role: Academic Editor
                Journal
                Journal ID (nlm-ta): Int J Mol Sci
                Journal ID (iso-abbrev): Int J Mol Sci
                Journal ID (publisher-id): ijms
                Title: International Journal of Molecular Sciences
                Publisher: MDPI
                ISSN (Electronic): 1422-0067
                Publication date (Electronic): 09 June 2016
                Publication date Collection: June 2016
                Volume: 17
                Issue: 6
                Electronic Location Identifier: 921
                Affiliations
                [1 ]Centro de Investigación en Alimentación y Desarrollo A.C., Carretera a Eldorado Km 5.5 Col. El Diez, 80110 Culiacán, Sinaloa, Mexico; nayely061005@ 123456gmail.com (N.L.-L.); erickpaulggrijalva@ 123456gmail.com (E.P.G.-G.)
                [2 ]Universidad Politécnica del Mar y la Sierra, Carretera a Potrerillos del Norote/La Cruz Km 3, La Cruz, 82740 Elota, Sinaloa, Mexico; dulceambriz@ 123456hotmail.com
                Author notes
                [* ]Correspondence: jbheredia@ 123456ciad.mx ; Tel.: +52-166-776-05536
                Article
                Publisher ID: ijms-17-00921
                DOI: 10.3390/ijms17060921
                PMC ID: 4926454
                PubMed ID: 27294919
                SO-VID: 47bd8cf5-c6af-4483-a02b-9c49a2005341
                Copyright © © 2016 by the authors; licensee MDPI, Basel, Switzerland.
                License:

                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
                Date received : 30 April 2016
                Date accepted : 03 June 2016
                Categories
                Subject: Review

                ScienceOpen disciplines: Molecular biology
                Keywords: flavonoids,anti-inflammatory effect,cytokine inhibition
                Data availability:
                ScienceOpen disciplines: Molecular biology
                Keywords: flavonoids, anti-inflammatory effect, cytokine inhibition

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