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      Quercetin Inhibits IL-1β-Induced Inflammation, Hyaluronan Production and Adipogenesis in Orbital Fibroblasts from Graves' Orbitopathy

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          Abstract

          Management of Graves' orbitopathy (GO) is challenging, as no reliable, specific, and safe medical therapeutic agents have yet been developed. We investigated the effect of quercetin in primary cultured orbital fibroblasts from GO, targeting pathways of inflammation, aberrant accumulation of extracellular matrix macromolecules, and adipose tissue expansion. Quercetin significantly attenuated intercellular adhesion molecule-1 (ICAM-1), interleukin (IL) -6, IL-8, and cyclooxygenase (COX) -2 mRNA expression, and inhibited IL-1β-induced increases in ICAM-1, IL-6, and IL-8 mRNA. Increased hyaluronan production induced by IL-1β or tumor necrosis factor-α was suppressed by quercetin in a dose- and time-dependent manner. Treatment with noncytotoxic doses of quercetin inhibited accumulation of intracytoplasmic lipid droplets and resulted in a dose-dependent decrease in expression of peroxisome proliferator-activated receptor γ, CCAAT/enhancer-binding protein (C/EBP) α, and C/EBPβ proteins. In conclusion, inhibition of inflammation, hyaluronan production, and adipogenesis by the natural plant product quercetin in vitro provides the basis for further study of its potential use in the treatment of GO.

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          An established preadipose cell line and its differentiation in culture. II. Factors affecting the adipose conversion.

          Howard Green, Olaniyi Kehinde (1975)
          When cells of the established preadipose line 3T3-L1 enter a resting state, they accumulate triglyceride and convert to adipose cells. The adipose conversion is brought about by a large increase in the rate of triglyceride synthesis, as measured by the incorporation rate of labeled palmitate, acetate, and glucose. In a resting 3T3 subline which dose not undergo the adipose conversion, the rate of triglyceride synthesis from these precursors is very low, and similar to that of growing 3T3-L1 cells, before their adipose conversion begins. If 3T3-L1 cells incorporate bromodeoxyuridine during growth, triglyceride synthesis does not increase when the cells reach a stationary state, and triglycerides do not accumulate. As would be expected from their known actions on tissue adipose cells, lipogenic and lipolytic hormones and drugs affect the rate of synthesis and accumulation of triglyceride by 3T3-L1 cells, but in contrast to bromodeoxyuridine, these modulating agents do not seem to affect the proportion of cells which undergoes the adipose conversion. Insulin markedly increases the rate of synthesis and accumulation of triglyceride by fatty 3T3-L1 cells, and produces a related increase in cell protein content. Of 20 randomly selected clones isolated from the original 3T3 stock, 19 are able to convert to adipose cells. The probability of such a conversion varies greatly among the different clones, in most cases being much lower than for 3T3-L1; but once the conversion takes place, the adipose cells produced from all of the 19 clones appear similar. The adipose conversion would seem to depend on an on-off switch, which is on with a different probability in different clones. This probability is quasistably inherited by the clonal progeny.
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            The anti-obesity effect of quercetin is mediated by the AMPK and MAPK signaling pathways.

            Hyunjung Lee, Suna Kim, Jiyun Ahn … (2008)
            Quercetin is the most abundant flavonoid and is assumed to have protective roles against the pathogenesis of multiple diseases associated with oxidative stress. In the present study, we investigated the molecular mechanisms by which quercetin affects adipogenesis and apoptosis in 3T3-L1 cells. The exposure of 3T3-L1 preadipocytes to quercetin resulted in attenuated adipogenesis and decreased expression of adipogenesis-related factors and enzymes. Moreover, quercetin exposure up-regulated the levels of phosphorylated adenosine monophosphate-activated protein kinase (AMPK) and its substrate, acetyl-CoA carboxylase (ACC). Treatment of 3T3-L1 adipocytes with quercetin resulted in the induction of apoptosis and a concomitant decrease in ERK and JNK phosphorylation. Taken together, these data indicate that quercetin exerts anti-adipogenesis activity by activating the AMPK signal pathway in 3T3-L1 preadipocytes, while the quercetin-induced apoptosis of mature adipocytes was mediated by modulation of the ERK and JNK pathways, which play pivotal roles during apoptosis.
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              Management of Graves' ophthalmopathy: reality and perspectives.

              L. Bartalena, Claudio Marcocci, A Pinchera (2000)
              Graves' ophthalmopathy is an debilitating disease impairing the quality of life of affected individuals. Despite recent progress in the understanding of its pathogenesis, treatment is often not satisfactory. In mild cases, local therapeutic measures (artificial tears and ointments, sunglasses, nocturnal taping of the eyes, prisms) can control symptoms and signs. In severe forms of the disease (3-5%), aggressive measures are required. If the disease is active, high-dose glucocorticoids and/or orbital radiotherapy, or orbital decompression represent the mainstay of treatment. If the disease is severe but inactive, orbital decompression is preferred. Novel treatments such as somatostatin analogs or intravenous immunoglobulins are under evaluation. Rehabilitative (extraocular muscle or eyelid) surgery is often needed after treatment and inactivation of eye disease. Correction of both hyper- and hypothyroidism is crucial for the ophthalmopathy. Antithyroid drugs and thyroidectomy do not influence the course of the ophthalmopathy, whereas radioiodine treatment may cause the progression of preexisting ophthalmopathy, especially in smokers. The exacerbation, however, is prevented by glucocorticoids. In addition, thyroid ablation may prove beneficial for the ophthalmopathy in view of the pathogenetic model relating eye disease to autoimmune reactions directed against antigens shared by the thyroid and the orbit.
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                Author and article information

                Contributors
                : Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2011
                Publication date (Electronic): 19 October 2011
                Volume: 6
                Issue: 10
                Electronic Location Identifier: e26261
                Affiliations
                [1 ]Institute of Vision Research, Department of Ophthalmology, Yonsei University College of Medicine, Seoul, Korea
                [2 ]Endocrinology, Brain Korea 21 Project for Medical Science, Institute of Endocrine Research, and Severance Integrative Research Institute for Cerebral & Cardiovascular Disease, Seoul, Korea
                [3 ]Department of Anatomy and Cell Biology, Cellular Dysfunction Research Center, University of Ulsan College of Medicine, Seoul, Korea
                [4 ]Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul, Korea
                University of Muenster, Germany
                Author notes

                Conceived and designed the experiments: JSY SYL EJL. Performed the experiments: HJL SHC E-JC. Analyzed the data: JSY. Contributed reagents/materials/analysis tools: JSY HJL. Wrote the paper: JSY. Revision and final approval: SYL EJL.

                ¶ These authors also contributed equally to this work.

                Article
                Publisher ID: PONE-D-11-06128
                DOI: 10.1371/journal.pone.0026261
                PMC ID: 3198474
                PubMed ID: 22039452
                SO-VID: 81456ecb-857a-47a5-aab6-3baa1e3c63bf
                Copyright © Yoon et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                Date received : 1 April 2011
                Date accepted : 23 September 2011
                Page count
                Pages: 10
                Categories
                Subject: Research Article
                Subject: Biology
                Subject: Anatomy and Physiology
                Subject: Immune Physiology
                Subject: Cytokines
                Subject: Immunology
                Subject: Immune System
                Subject: Cytokines
                Subject: Medicine
                Subject: Clinical Immunology
                Subject: Autoimmune Diseases
                Subject: Graves' Disease
                Subject: Immunity
                Subject: Inflammation
                Subject: Endocrinology
                Subject: Thyroid
                Subject: Graves' Disease

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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