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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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          Most cited references 30

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

          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.

            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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              Resveratrol induces apoptosis and inhibits adipogenesis in 3T3-L1 adipocytes.

              Resveratrol, a phytoallexin, has recently been reported to slow aging by acting as a sirtuin activator. Resveratrol also has a wide range of pharmacological effects on adipocytes. In this study, we investigated the effects of resveratrol on adipogenesis and apoptosis using 3T3-L1 cells. In mature adipocytes, 100 and 200 microM resveratrol decreased cell viability dose-dependently by 23 +/- 2.7%, and 75.3 +/- 2.8% (p < 0.0001), respectively, after 48 h treatment, and 100 microM resveratrol increased apoptosis by 76 +/- 8.7% (p < 0.0001). Resveratrol at 25 and 50 microM decreased lipid accumulation in maturing preadipocytes significantly by 43 +/- 1.27% and 94.3 +/- 0.3% (p < 0.0001) and decreased cell viability by 25 +/- 1.3% and 70.4 +/- 1.6% (p < 0.0001), respectively. In order to understand the anti-adipogenic effects of resveratrol, maturing 3T3-L1 preadipocytes were treated with 25 microM resveratrol and the change in the expression of several adipogenic transcription factors and enzymes was investigated using real-time RT-PCR. Resveratrol down-regulated the expression of PPAR gamma, C/EBP alpha, SREBP-1c, FAS, HSL, LPL and up-regulated the expression of genes regulating mitochondrial activity (SIRT3, UCP1 and Mfn2). These results indicate that resveratrol may alter fat mass by directly affecting cell viability and adipogenesis in maturing preadipocytes and inducing apoptosis in adipocytes and thus may have applications for the treatment of obesity. (c) 2008 John Wiley & Sons, Ltd.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2011
                19 October 2011
                : 6
                : 10
                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
                PONE-D-11-06128
                10.1371/journal.pone.0026261
                3198474
                22039452
                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.
                Page count
                Pages: 10
                Categories
                Research Article
                Biology
                Anatomy and Physiology
                Immune Physiology
                Cytokines
                Immunology
                Immune System
                Cytokines
                Medicine
                Clinical Immunology
                Autoimmune Diseases
                Graves' Disease
                Immunity
                Inflammation
                Endocrinology
                Thyroid
                Graves' Disease

                Uncategorized

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