Green Tea Polyphenol Epigallocatechin-3-Gallate Suppresses Collagen Production and Proliferation in Keloid Fibroblasts via Inhibition of the STAT3-Signaling Pathway

Park, Gyuman; Yoon, Byung Sun; Moon, Jung Hwan; Kim, Bona; Jun, Eun Kyoung; Oh, Sejong; Kim, Hyunggee; Song, Hea Joon; Noh, Joo Young; Oh, Cheol; You, Seungkwon

doi:10.1038/jid.2008.103

Cited by 114 publications

(110 citation statements)

References 47 publications

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“…This is in agreement with data published by Park et al 32 who reported that EGCG inhibited proliferation and migration of keloid and to lesser extent normal fibroblasts in vitro. We also demonstrated that at higher doses of EGCG (100 µg/ml and above) treated fibroblasts demonstrate a statistically significant (P<0.05) increase in the quantity of cells in G 0 /G 1 compared to controls indicating that a smaller fraction of cells were dividing.…”

Section: Discussionsupporting

confidence: 83%

“…13, [32][33][34] Furthermore, microorganisms with resistance to systemic antibiotics have increased resistance to many topical antimicrobial treatments currently in use. 35 There is a need to evaluate the efficacy of topical agents that can be used to supplement or enhance current systemic antimicrobial therapies.…”

Section: Discussionmentioning

confidence: 99%

“…33 Park et al examine keloid formation in vivo with and without EGCG. 32 These are very different wound healing models and while these data suggest an effect of EGCG at low doses, the studies involve the response of a diabetic pathology and not the direct effect of EGCG on normal wound healing. Our group examined the inflammatory infiltrate in EGCG and non-treated tissues and found no difference, indicating the observed differences were not due to alterations in inflammation.…”

Section: 36mentioning

confidence: 99%

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The Effects of (-)-Epigallocatechin-3-Galate on Wound Closure and Infections in Mice

Osterburg¹,

Yamaguchi²,

Robinson³

et al. 2015

Surg Res Open J

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In this study, we investigated the effects of (-)-epigallocatechin-3-gallate (EGCG) on wound healing both in vitro and in vivo with and without infection. EGCG has antimicrobial properties and could be useful as a topical agent to prevent and/or treat wound infections. Normal fibroblasts were isolated from the dermis of C57BL/6 mice and cultured with 0, 0.001 to 0.400 mg/ml of EGCG. In vitro assays demonstrated that migration, proliferation, and apoptosis were inhibited at EGCG concentrations of 0.100-0.400 mg/ml. Expression of α-smooth muscle actin (α-SMA) was also reduced. In vivo experiments measured closure/contraction of full-thickness dorsal wounds that were treated with 0, 0.3, 3.0, and 30.0 mg/ml of EGCG every 24 hours. Macrophages (F4/80), neutrophils (Ly-6G) and myofibroblasts (α-SMA) were assessed at 48 and 168 hours. By 168 hours there was a significant reduction in presence with the 30 mg/ml dose vs. 0.3 and 3.0 mg/ml (p<0.009, p<0.006, respectively). The percentage of wound closure at one week in EGCG treated wounds was 87.87% (0.03 mg), 85.23% (0.3 mg) and 40.06% (30 mg/ml) compared to controls. Reduced quantities of α-SMA myofibroblasts were observed in the 3 mg EGCG treatment group compared to controls at 168 hours. We previously demonstrated that EGCG has antimicrobial properties (MIC 50 ~0.3 mg/ml). This data suggests that EGCG could potentially be applied to the wound surface as an antimicrobial without negatively influencing healing. To this end we applied EGCG (10 mg/ml) to a model of an infected traumatic wound. EGCG treatment significantly reduced bacterial load after one and two dose regimens.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: 36mentioning

confidence: 99%

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The Effects of (-)-Epigallocatechin-3-Galate on Wound Closure and Infections in Mice

Osterburg¹,

Yamaguchi²,

Robinson³

et al. 2015

Surg Res Open J

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“…On one hand, STAT3 triggers a transduction signal that is required for the synthesis of the extracellular matrix and cellular proliferation of fibroblasts isolated from hypertrophic scars (36). In keloids, a fibrotic disease, STAT3 promotes collagen synthesis, proliferation, and migration of fibroblasts (37,38). Moreover, an aberrant activation of this pathway has also been reported in human sclerodermic skin and in a mouse model of SSc induced by bleomycin (19).…”

Section: Discussionmentioning

confidence: 99%

Niclosamide Prevents Systemic Sclerosis in a Reactive Oxygen Species–Induced Mouse Model

Morin

Kavian

Nicco

et al. 2016

The Journal of Immunology

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Systemic sclerosis (SSc) is a connective tissue disorder characterized by fibrosis of the skin and inner organs, vasculopathy, and immunological abnormalities. Recent insights on the implication of STAT3, AKT, and Wnt/β-catenin in fibrosis have prompted us to investigate, in a mouse model of ROS-induced SSc, the effects of niclosamide, an antihelmintic drug that inhibits both of these signaling pathways. SSc was induced in BALB/c mice by daily s.c. injections of hypochlorous acid (HOCl). Mice were treated or not every other day, 5 d a week, for 6 wk, by niclosamide. Skin and lung fibrosis as well as immunological features were studied. Mice exposed to HOCl developed a diffuse cutaneous SSc with pulmonary fibrosis and anti-DNA topoisomerase 1 autoantibodies. STAT3, AKT, and Wnt/β-catenin pathways were hyperactivated in the skin and the lungs of diseased mice. Niclosamide reversed fibrosis of the skin and the lungs. Beneficial immunological effects were also observed because niclosamide decreased the activation of CD4+ and CD8+ T cells, autoimmune B cell activation, as well as IL-4 and IL-13 production in the skin. The improvement permitted by niclosamide in the mouse model of HOCl-induced SSc as well as the well-documented safety profile of this drug provide a rationale for the evaluation of niclosamide in the management of patients affected by this disease.

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“…3 The lack of an animal model that can truly mimic human KD in vivo condition imposes limitations when investigating functional activities of potential therapeutic agents in treating KD. 4,5 However, these models have failed to provide the essential components of skin tissue that occur in vivo, such as mature ECM, blood vessels, inflammatory cells, and intrinsic and extrinsic biochemical interactions. Therefore, the ultimate aim of this study was to determine the applicability of recent research findings in existing in vitro keloid models to our recently developed keloid organ culture (OC) model.…”

mentioning

confidence: 99%

Ex vivo evaluation of antifibrotic compounds in skin scarring: EGCG and silencing of PAI-1 independently inhibit growth and induce keloid shrinkage

Syed

Bagabir

Paus

et al. 2013

Laboratory Investigation

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Keloid disease (KD) is a common fibroproliferative disorder of unknown etiopathogenesis. Its unique occurrence in human skin and lack of animal models pose challenges for KD research. The lack of a suitable model in KD and overreliance on cell culture has hampered the progress in developing new treatments. Therefore, we evaluated the effect of two promising candidate antifibrotic therapies: ( À )-epigallocatechin-3-gallate (EGCG) and plasminogen activator inhibitor-1 (PAI-1) silencing in a long-term human keloid organ culture (OC). Four millimeters of air-liquid interface (ALI) keloid explants on collagen gel matrix in serum-free medium (n ¼ 8 cases) were treated with different modalities (EGCG treatment; PAI-1 knockdown by short interfering RNA (siRNA) and application of dexamethasone (DEX) as control). Normal skin (n ¼ 6) was used as control (only for D0 keloid-untreated comparison). Besides routine histology and quantitative (immuno-) histomorphometry, the key phenotypic and growth parameters of KD were assessed. Results demonstrated that EGCG reduced keloid volume significantly (40% by week 4), increased apoptosis (Z40% from weeks 1 to 4), and decreased proliferation (r17% in week 2). EGCG induced epidermal shrinkage, reduced collagen-I and -III at mRNA and protein levels, depleted 98% of keloid-associated mast cells, and reduced the percentage of both cellularity and blood vessel count by week 4. Knockdown of PAI-1 significantly reduced keloid volume by 28% in week 4, respectively, and reduced collagen-I and -III at both mRNA and protein levels. As expected, DEX increased keloid apoptosis, decreased keloid proliferation, and collagen synthesis, but induced connective tissue growth factor overexpression. In conclusion, using keloid OC model, we provide the first functional evidence for testing candidate antifibrotic compounds in KD. We show that EGCG and PAI-1 silencing effectively inhibits growth and induces shrinkage of human keloid tissue in situ. Therefore, the application of EGCG, PAI-1 silencing, and other emerging compounds tested using this model may provide effective treatment and potentially aid in the prevention of recurrence of KD following surgery. Keloid disease (KD) is a benign hyperproliferative dermal disease of unknown etiopathogenesis with ill-defined treatment, 1 which is unique to humans. 2 KD can arise following an abnormal wound healing process in genetically susceptible individuals. 2 The hallmark of KD is excessive deposition of extracellular matrix (ECM) in the dermis. 3 The lack of an animal model that can truly mimic human KD in vivo condition imposes limitations when investigating functional activities of potential therapeutic agents in treating KD. 4,5 However, these models have failed to provide the essential components of skin tissue that occur in vivo, such as mature ECM, blood vessels, inflammatory cells, and intrinsic and extrinsic biochemical interactions. Therefore, the ultimate aim of this study was to determine the applicability of recent research findings in existing i...

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Green Tea Polyphenol Epigallocatechin-3-Gallate Suppresses Collagen Production and Proliferation in Keloid Fibroblasts via Inhibition of the STAT3-Signaling Pathway

Cited by 114 publications

References 47 publications

The Effects of (-)-Epigallocatechin-3-Galate on Wound Closure and Infections in Mice

The Effects of (-)-Epigallocatechin-3-Galate on Wound Closure and Infections in Mice

Niclosamide Prevents Systemic Sclerosis in a Reactive Oxygen Species–Induced Mouse Model

Ex vivo evaluation of antifibrotic compounds in skin scarring: EGCG and silencing of PAI-1 independently inhibit growth and induce keloid shrinkage

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