COA-Cl prevented TGF-β1-induced CTGF expression by Akt dephosphorylation in normal human dermal fibroblasts, and it attenuated skin fibrosis in mice models of systemic sclerosis

Nakai, Kozo; Karita, Sakiko; Igarashi, Jun–ichi; Tsukamoto, Ikuko; Hirano, Katsuya; Kubota, Yasuo

doi:10.1016/j.jdermsci.2019.02.003

Cited by 13 publications

(10 citation statements)

References 41 publications

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“…During this process, CTGF is activated because of a significant increase in TGF-β expression, regulation of related proteins, and massive proliferation of lung fibroblasts (Nakai et al, 2019). Collagen fibers are deposited in large amounts in the lung tissue, resulting in the substantialization of lung tissue.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, many studies have confirmed that connective tissue growth factor (CTGF) plays the role of a modulator of fibrosis progression induced by TGF-β. Dysregulation of CTGF has been linked to various fibrotic processes including the growth of fibroblasts and the secretion of ECM (Wuyts et al, 2013;Park et al, 2016), and this biological function was widespread in various fibrotic diseases, such as lung (Tzortzaki et al, 2007), liver (Arauz et al, 2013;Zhou et al, 2015;Han et al, 2019), kidney (Mao et al, 2020) and dermal fibrosis (Nakai et al, 2019). Among the CTGF signaling implicated in TGF-β responses, aberrant activation of the extracellular signal-regulated kinase (ERK) occurs and is phosphorylated to p-ERK (Kato et al, 2014;Chang et al, 2015), which further stimulates proliferation and collagen synthesis.…”

Section: Introductionmentioning

confidence: 99%

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Effects of Nervilia fordii Extract on Pulmonary Fibrosis Through TGF-β/Smad Signaling Pathway

Yao

Yuan

et al. 2021

Front. Pharmacol.

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Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible interstitial pulmonary disease with a poor prognosis. The extract of Nervilia fordii (NFE) has shown remarkable benefit in the treatment of acute lung injury, lung cancer, and severe acute respiratory syndrome (SARS). However, the potential mechanism and efficacy of NFE in the treatment of IPF remain unknown. In this study, a systematic network pharmacology analysis was used to predict the mechanism and efficacy of NFE in the treatment of IPF, based on the major components of NFE elucidated by UPLC-TOF-MS/MS. The potential molecular interactions between the compounds and potential targets were predicted using molecular docking. In vivo, rats with pulmonary fibrosis induced by a single intratracheal injection of bleomycin (BLM) were orally administered NFE for 14 days. Lung index and biochemical levels were determined, and histopathological analysis using hematoxylin and eosin (H&E) and Masson staining was performed. The effects of NFE on fibroblast proliferation in Lipopolysaccharide (LPS) and TGF-β1-induced mouse 3T6 fibroblasts were evaluated in vitro. In total, 20 components were identified in NFE, and 102 potential targets for IPF treatment were predicted. These targets potentially participate in processes regulated by transmembrane receptor protein tyrosine kinase, ERBB2, and et al. Molecular docking results predicted high affinity interactions between three components (rhamnazin, rhamnetin, and rhamnocitrin) and the potential targets, suggesting that TGF-β is the most important potential target of NFE in the treatment of pulmonary fibrosis. NFE significantly decreased the lung index and alleviated BLM-induced pulmonary fibrosis in rats. Histopathological observation of lung tissues showed that NFE alleviated inflammation and collagen deposition in BLM-induced rats. NFE inhibited the migration of LPS- and TGF-β1-induced 3T6 fibroblasts, reduced the contents of hydroxyproline and collagen, and contributed to anti-inflammation and anti-oxidation. With the intervention of NFE, the protein and RNA expression of TGF-β1, a-SMA, Smad3/4, p-Smad3/4, CTGF, and p-ERK1/2 were significantly downregulated, while Smad7 and ERK1/2 were upregulated significantly in vivo and in vitro. These findings indicated that NFE may exert therapeutic effects on pulmonary fibrosis by alleviating inflammation, oxidation, and collagen deposition. The mechanism related to the inhibition of the TGF-β/Smad signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effects of Nervilia fordii Extract on Pulmonary Fibrosis Through TGF-β/Smad Signaling Pathway

Yao

Yuan

et al. 2021

Front. Pharmacol.

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“…From the findings above, both CTGF and TGF-β1 expression levels were upregulated in scald tissue, accompanied with a downregulation of miR-133a-3p. CTGF has been reported to be a downstream mediator of TGF-β1 [ 38 , 39 ]. It is demonstrated that CTGF is required for TGF-β1-induced fibrosis [ 40 ].…”

Section: Disccusionmentioning

confidence: 99%

MiR-133a-3p inhibits scar formation in scalded mice and suppresses the proliferation and migration of scar derived-fibroblasts by targeting connective tissue growth factor

Hirman

Cheng

et al. 2021

Exp. Anim.

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Excessive scar formation post burn injury can cause great pain to the patients.MiR-133a-3p has been demonstrated to be anti-fibrotic in some fibrosis-related diseases. However, its possible role in scar formation has not been elucidated yet. In present study, the effect of miR-133a-3p on scar formation was investigated in a scalded model of mice. Moreover, the function of miR-133a-3p on proliferation and migration of scar-derived fibroblasts (SFs) was studied in vitro. It was found that miR-133a-3p was dramatically downregulated in scar tissue of scalded mice.Upregulation of miR-133a-3p by miR-133a-3p agomir obviously inhibited the scar formation in scalded mice. Histological staining showed that upregulation of miR-133a-3p attenuated the excessive deposition of collagen in scar tissue of scalded mice. In vitro study showed that upregulation of miR-133a-3p effectively suppressed the proliferation and migration of SFs. Besides, upregulation of miR-133a-3p attenuated the protein levels of α-smooth muscle actin (α-SMA) and collagen I, indicating that miR-133a-3p could suppress the activation of SFs. The expression of connective tissue growth factor (CTGF), a critical mediator in cell proliferation, migration and extracellular matrix (ECM) synthesis, was also downregulated by the upregulation of miR-133a-3p. Luciferase reporter assay validated that CTGF was directly targeted by miR-133a-3p. In addition, overexpression of CTGF abolished the effect of miR-133a-3p on inhibiting the proliferation, migration and activation of SFs, indicating that miR-133a-3p functioned by targeting CTGF. Therefore, miR-133a-3p might be a promising target for treating pathological scars.

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“…In murine full-thickness excisional wound model as well as human burn injuries, CTGF accumulated at the wound site from 0 to 7 days post injury [19]. It has been reported that exogenous CTGF facilitated brosis in diabetic wound healing [16,20,21]. Elevated level of CTGF was de ned in systemic sclerosis; however, inhibition of CTGF sharply reduced cutaneous brosis [16,20,21,22].…”

Section: Introductionmentioning

confidence: 99%

“…It has been reported that exogenous CTGF facilitated brosis in diabetic wound healing [16,20,21]. Elevated level of CTGF was de ned in systemic sclerosis; however, inhibition of CTGF sharply reduced cutaneous brosis [16,20,21,22].…”

Section: Introductionmentioning

confidence: 99%

M2-polarized macrophages mediate wound healing by regulating connective tissue growth factor via AKT, ERK1/2, and STAT3 signaling pathways

et al. 2021

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Background: Timely and su cient recruitment of M1 macrophages and M2 polarization are necessary for brous repair during cutaneous wound healing. The inherent mechanism of how M2 polarization mediate wound healing is worth exploring and illustrating. Abnormally up-regulated connective tissue growth factor (CTGF) is closely related with multiple organ brosis, including cardiac, pulmonary, hepatic, renal, and cutaneous brosis. Previous studies have reported that M2-polarized macrophages contribute to hepatic and renal brosis by secreting CTGF. It is worth discussing if M2 macrophages regulate brosis through secreting CTGF in cutaneous wound healing.Methods: We established the murine full-thickness excisional wound model and inhibited macrophages during proliferation phase (mainly M2 and M1-M2 polarization) with clodronate liposomes to analyze how M2 macrophages mediate wound healing rates, collagen deposition, collagen 1/3 expression, and Ki67 expression in vivo. Furthermore, M2 polarization was induced by IL-4 and in vitro. F4/80 + CD206 + M2 macrophages were measured by ow cytometry. The morphological characteristics were observed. Secretion of IL-6, TNF-α, IL-10, TGF-β1, and CTGF was tested by ELISA. CTGF gene of M2 was blocked using siCTGF. Effects of M2 on proliferation and migration of broblasts were detected by CCK8 and cellular wound healing assay. Protein level of AKT, ERK1/2, and STAT3 pathway were assessed by western blotting.Results: Depletion of macrophages at proliferation phase (mainly M2 and M1-M2 polarization) resulted in delayed cutaneous wound closure and down-regulation of wound healing rates, collagen deposition, collagen 1/3 expression, and Ki67 expression. M2 polarization was induced, which producing more CTGF, TGF-β1, and IL-6, as well as less TNF-α and IL-10. Blockade of CTGF in M2 macrophages deactivated broblast proliferation and migration. Addition of recombinant CTGF restored the promotional effects of M2 macrophages on broblast proliferation and migration. Blockade of CTGF in M2 mediate broblasts via down-regulating AKT, ERK1/2, and STAT3 signaling pathway. Conclusion:Our research, for the rst time, indicated that M2-polarized macrophages promoted cutaneous wound healing by secreting CTGF, which further mediating proliferation and migration of broblasts via AKT, ERK1/2, and STAT3 signaling pathway.

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COA-Cl prevented TGF-β1-induced CTGF expression by Akt dephosphorylation in normal human dermal fibroblasts, and it attenuated skin fibrosis in mice models of systemic sclerosis

Cited by 13 publications

References 41 publications

Effects of Nervilia fordii Extract on Pulmonary Fibrosis Through TGF-β/Smad Signaling Pathway

Effects of Nervilia fordii Extract on Pulmonary Fibrosis Through TGF-β/Smad Signaling Pathway

MiR-133a-3p inhibits scar formation in scalded mice and suppresses the proliferation and migration of scar derived-fibroblasts by targeting connective tissue growth factor

M2-polarized macrophages mediate wound healing by regulating connective tissue growth factor via AKT, ERK1/2, and STAT3 signaling pathways

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