Activation of transforming growth factor‐β1 by thrombin via integrins αvβ1, αvβ3, and αvβ5 in buccal fibroblasts: Suppression by epigallocatechin‐3‐gallate

Chang, Jenny Zwei-Chieng; Hsieh, Yi-Ping; Lin, W H; Chen, Hsin‐Ming; Kuo, Mark Yen‐Ping

doi:10.1002/hed.24791

Cited by 25 publications

(16 citation statements)

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“…One study demonstrated that EGCG attenuates fibroblast proliferation and excessive collagen production by interfering with TGF-β1 signaling ( 37 ). EGCG inhibits the expression of tumor necrosis factor receptor associated factor 6, inhibits the activation of TGF-b1 and regulates rheumatoid arthritis ( 38 ). The present study demonstrated that following EGCG treatment, TGF-β1 p-Smad3 expression levels were significantly increased in mouse models of heart failure.…”

Section: Discussionmentioning

confidence: 99%

Epigallocatechingallate attenuates myocardial injury in a mouse model of heart failure through TGF‑β1/Smad3 signaling pathway

Chen

Liu

et al. 2018

Mol Med Report

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The present study aimed to assess the protective effect of epigallocatechingallate (EGCG) against myocardial injury in a mouse model of heart failure and to determine the mechanism underlying regulation of the transforming growth factor-β1/mothers against decapentaplegic homolog 3 (TGF-β1/Smad3) signaling pathway. Mouse models of heart failure were established. Alterations in ejection fraction, left ventricular internal diastolic diameter (LVIDd) and left ventricular internal systolic diameter (LVIDs) were measured by echocardiography. Pathological alterations of myocardial tissue were determined by hematoxylin and eosin, and Masson staining. The levels of serum brain natriuretic peptide (BNP), N-terminal-proBNP, interleukin (IL)-1β, IL-6, tumor necrosis factor-α, malondialdehyde, superoxide dismutase and glutathione peroxidase were detected with ELISA. Expression of collagen I, collagen III were detected by western blotting and reverse transcription quantitative polymerase chain reaction. Transforming growth factor-β1 (TGF-β1), Smad3, phosphorylated (p)-Smad3, apoptosis regulator BAX (Bax), caspase-3 and apoptosis regulator Bcl2 in mouse cardiac tissue were measured by western blotting. P-smad3 and TGF-β1 were measured by immunofluorescence staining. EGCG reversed the alterations in LVIDd and LVIDs induced by establishment of the model of heart failure, increased ejection fraction, inhibited myocardial fibrosis, attenuated the oxidative stress, inflammatory and cardiomyocyte apoptosis and lowered the expression levels of collagen I and collagen III. Following treatment with TGF-β1 inhibitor, the protective effect of EGCG against heart failure was attenuated. The results of the present study demonstrated that EGCG can inhibit the progression and development of heart failure in mice through inhibition of myocardial fibrosis and reduction of ventricular collagen remodeling. This protective effect of EGCG is likely mediated through inhibition of TGF-β1/smad3 signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Epigallocatechingallate attenuates myocardial injury in a mouse model of heart failure through TGF‑β1/Smad3 signaling pathway

Chen

Liu

et al. 2018

Mol Med Report

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“…Although TGF-b from activated platelets generally exists in its latent form, activated platelets can convert this to an active form (37) ; thrombin can also activate TGF-b through cell surface integrin. (38) Our data revealed that TGF-b from activated platelet supernatant upregulates TF in MG63 cells, but further TGF-b activation then occurs in the tumor microenvironment. Next, we confirmed that platelets activated by osteosarcoma cells release both total and active TGF-b.…”

Section: Discussionmentioning

confidence: 60%

“…As expected, with thrombin stimulation, both total and active TGF‐β were found in activated platelet supernatant. Although TGF‐β from activated platelets generally exists in its latent form, activated platelets can convert this to an active form; thrombin can also activate TGF‐β through cell surface integrin . Our data revealed that TGF‐β from activated platelet supernatant upregulates TF in MG63 cells, but further TGF‐β activation then occurs in the tumor microenvironment.…”

Section: Discussionmentioning

confidence: 72%

Platelet-Derived TGF-β Induces Tissue Factor Expression via the Smad3 Pathway in Osteosarcoma Cells

Saito

Ichikawa

Ando

et al. 2018

Journal of Bone and Mineral Research

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Over the last three decades, the prognosis of osteosarcoma has remained unchanged; the prognosis for patients with lung metastasis is still poor, and the development of new treatments is urgently required. We previously showed that aggressive osteosarcoma cells express more tissue factor (TF) and demonstrate enhanced extrinsic pathway capacity. Furthermore, tumor growth can be suppressed with the anticoagulant low molecular weight heparin. However, the molecular mechanisms underlying TF regulation are still unclear. Here, we report that transforming growth factor-β (TGF-β) upregulates TF, which can occur via activated platelets. TF was found to be expressed on osteosarcoma cell surfaces, which mediated the production of Xa and thrombin. TF induction by TGF-β was observed in several osteosarcoma cells, and especially in MG 63 cells. Both TF expression by TGF-β and extrinsic pathway activity through TF were rapidly increased. This reaction was inhibited by a TGF-β type I receptor inhibitor and TGF-β neutralizing antibody. Although TGF-β was found to phosphorylate both Smad2 and Smad3, their roles were markedly disparate. Surprisingly, Smad2 knockdown resulted in no inhibitory effect, whereas Smad3 knockdown completely suppressed TGF-β-induced TF expression. Next, data suggested that platelets were the source of TGF-β. We confirmed that thrombin-activated platelets and osteosarcoma cells could release TGF-β, and that platelet-derived TGF-β could induce TF expression. These processes were also inhibited by a TGF-β type I receptor inhibitor and Smad3 knockdown. Moreover, CD42b, TF, TGF-β, Smad2/3, and p-Smad2/3 were also detected in a biopsy sample from an osteosarcoma patient. Collectively, these finding suggested that the interaction between osteosarcoma cells and platelets, via thrombin and TGF-β, results in a continuous cycle, and that anti-platelet or anti-TGF-β therapy could be a promising tool for disease treatment. © 2018 American Society for Bone and Mineral Research.

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“…Current evidence has suggested that TGF-β signaling is the key pathway to trigger the manifestation of OSF [7,8]. It has been shown that thrombin released from microtrauma during areca nut chewing was able to induce αvβ1, αvβ3, and αvβ5 integrins-mediated TGF-β1 activation, leading to production of connective tissue growth factor (CTGF) in human BMFs [26]. Arecoline-induced mitochondrial ROS also plays a pivotal role in the activation of latent TGFβ1 and the subsequent increase of CTGF and early growth response-1 in BMFs [27].…”

Section: Discussionmentioning

confidence: 99%

Arctigenin Reduces Myofibroblast Activities in Oral Submucous Fibrosis by LINC00974 Inhibition

Lin

Hsieh

Liao

et al. 2019

IJMS

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Oral submucous fibrosis (OSF) is an oral precancerous condition associated with the habit of areca nut chewing and the TGF-β pathway. Currently, there is no curative treatment to completely heal OSF, and it is imperative to alleviate patients’ symptoms and prevent it from undergoing malignant transformation. Arctigenin, a lignan extracted from Arctium lappa, has been reported to have a variety of pharmacological activities, including anti-fibrosis. In the present study, we examined the effect of arctigenin on the cell proliferation of buccal mucosal fibroblasts (BMFs) and fibrotic BMFs (fBMFs), followed by assessment of myofibroblast activities. We found that arctigenin was able to abolish the arecoline-induced collagen gel contractility, migration, invasion, and wound healing capacities of BMFs and downregulate the myofibroblast characteristics of fBMFs in a dose-dependent manner. Most importantly, the production of TGF-β in fBMFs was reduced after exposure to arctigenin, along with the suppression of p-Smad2, α-smooth muscle actin, and type I collagen A1. In addition, arctigenin was shown to diminish the expression of LINC00974, which has been proven to activate TGF-β/Smad signaling for oral fibrogenesis. Taken together, we demonstrated that arctigenin may act as a suitable adjunct therapy for OSF.

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Activation of transforming growth factor‐β1 by thrombin via integrins αvβ1, αvβ3, and αvβ5 in buccal fibroblasts: Suppression by epigallocatechin‐3‐gallate

Abstract: Thrombin induces αvβ1, αvβ3, and αvβ5 integrins-mediated TGF-β1 activations via ROCK signaling. EGCG inhibits thrombin-induced CCN2 synthesis in BMFs by suppressing latent TGF-β1 activation.

Cited by 25 publications

References 50 publications

Epigallocatechingallate attenuates myocardial injury in a mouse model of heart failure through TGF‑β1/Smad3 signaling pathway

Epigallocatechingallate attenuates myocardial injury in a mouse model of heart failure through TGF‑β1/Smad3 signaling pathway

Platelet-Derived TGF-β Induces Tissue Factor Expression via the Smad3 Pathway in Osteosarcoma Cells

Arctigenin Reduces Myofibroblast Activities in Oral Submucous Fibrosis by LINC00974 Inhibition

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