Astragaloside <scp>IV</scp> modulates <scp>TGF</scp>‐β1‐dependent epithelial‐mesenchymal transition in bleomycin‐induced pulmonary fibrosis

Qian, Weibin; Cai, Xinrui; Qian, Qi; Zhang, Wei; Wang, Dongli

doi:10.1111/jcmm.13725

Cited by 119 publications

(83 citation statements)

References 39 publications

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“…Human lung adenocarcinoma epithelial cells (A549 cells) damage caused by Nano NiO connected with oxidative stress . Other study demonstrated that bleomycin led to pulmonary fibrosis by triggering epithelial to mesenchymal transition (EMT) in rats and A549 cells . However, the mechanisms of Nano NiO‐induced pulmonary fibrosis remain unclear.…”

Section: Introductionmentioning

confidence: 99%

TGF‐β1 mediated MAPK signaling pathway promotes collagen formation induced by Nano NiO in A549 cells

Tian

Chang

Zhang

et al. 2019

Environmental Toxicology

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Nickel oxide nanoparticles (Nano NiO) could induce pulmonary fibrosis, however, the mechanisms are still unknown. The aim of the present study was to explore the roles of transforming growth factor‐β1 (TGF‐β1), mitogen‐activated protein kinase (MAPK) pathway and MMPs/TIMPs balance in Nano NiO‐induced pulmonary fibrosis. For that purpose, we first established Nano NiO‐induced human lung adenocarcinoma epithelial cells (A549 cells) model of collagen excessive formation through detecting the levels of hydroxyproline (Hyp) and type I collagen (Col‐I). Then the protein levels of TGF‐β1, MAPKs, and MMPs/TIMPs were assessed by Western blot. The results showed that Nano NiO resulted in the increased contents of Hyp, Col‐I, and TGF‐β1, the MAPK pathway activation and MMPs/TIMPs imbalance with a dose‐dependent manner. In addition, to investigate whether TGF‐β1 mediated MAPK signaling pathway, A549 cells were treated by 100 μg/mL Nano NiO combined with TGF‐β1, p38 MAPK, and ERK1/2 inhibitors (10 μM SB431542, 10 μM SB203580, and 10 μM U0126), respectively. We found that MAPK signal pathway was suppressed by TGF‐β1 inhibitor. Meanwhile, the increased contents of Hyp and Col‐I, and MMPs/TIMPs imbalance were alleviated by the p38 MAPK and ERK1/2 inhibitors, respectively. These findings indicated that the MAPK pathway and MMPs/TIMPs imbalance were involved in collagen excessive formation induced by Nano NiO.

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Section: Introductionmentioning

confidence: 99%

TGF‐β1 mediated MAPK signaling pathway promotes collagen formation induced by Nano NiO in A549 cells

Tian

Chang

Zhang

et al. 2019

Environmental Toxicology

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“…Of note, several studies supporting an association between EMT and lung fibrosis have been published. 25 – 30 …”

Section: Discussionmentioning

confidence: 99%

<p>Tranilast Inhibits Pulmonary Fibrosis by Suppressing TGFβ/SMAD2 Pathway</p>

Kato¹,

Takahashi²,

Satô³

et al. 2020

DDDT

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Purpose Idiopathic pulmonary fibrosis (IPF) is characterized by the accumulation of extracellular matrix (ECM) protein in the lungs. Transforming growth factor (TGF) β-induced ECM protein synthesis contributes to the development of IPF. Tranilast, an anti-allergy drug, suppresses TGFβ expression and inhibits interstitial renal fibrosis in animal models. However, the beneficial effects of tranilast or its mechanism as a therapy for pulmonary fibrosis have not been clarified. Methods We investigated the in vitro effect of tranilast on ECM production and TGFβ/SMAD2 pathway in TGFβ2-stimulated A549 human alveolar epithelial cells, using quantitative polymerase chain reaction, Western blotting, and immunofluorescence. In vitro observations were validated in the lungs of a murine pulmonary fibrosis model, which we developed by intravenous injection of bleomycin. Results Treatment with tranilast suppressed the expression of ECM proteins, such as fibronectin and type IV collagen, and attenuated SMAD2 phosphorylation in TGFβ2-stimulated A549 cells. In addition, based on a wound healing assay in these cells, tranilast significantly inhibited cell motility, with foci formation that comprised of ECM proteins. Histological analyses revealed that the administration of tranilast significantly attenuated lung fibrosis in mice. Furthermore, tranilast treatment significantly reduced levels of TGFβ, collagen, fibronectin, and phosphorylated SMAD2 in pulmonary fibrotic tissues in mice. Conclusion These findings suggest that tranilast inhibits pulmonary fibrosis by suppressing TGFβ/SMAD2-mediated ECM protein production, presenting tranilast as a promising and novel anti-fibrotic agent for the treatment of IPF.

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“…Previous studies have shown that several signaling pathways are involved in the protective effects of astragaloside IV in different cell types during fibrosis and under high glucose challenge. Astragaloside IV inhibits TGF-β1/PI3K/AKT-induced forehead box O3a hyper-phosphorylation and downregulation to reverse EMT during the progression of bleomycin-induced pulmonary fibrosis (62). Astragaloside IV has been reported to inhibit renal fibrosis and promote renal function in diabetic KK-Ay mice through inhibition of glucose-induced EMT in glomerular podocytes by activating autophagy and Sirtuin-1 expression, which results in decreased acetylation of NF-κB subunit p65 (63).…”

Section: Discussionmentioning

confidence: 99%

Effect of astragaloside IV and the role of nuclear receptor RXRα in human peritoneal mesothelial cells in high glucose‑based peritoneal dialysis fluids

et al. 2019

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Peritoneal fibrosis is a serious complication that can occur during peritoneal dialysis (PD), which is primarily caused by damage to peritoneal mesothelial cells (PMCs). The onset of peritoneal fibrosis is delayed or inhibited by promoting PMC survival and inhibiting PMC epithelial-to-mesenchymal transition (EMT). In the present study, the effect of astragaloside IV and the role of the nuclear receptor retinoid X receptor-α (RXRα) in PMCs in high glucose-based PD fluids was investigated. Human PMC HMrSV5 cells were transfected with RXRα short hairpin RNA (shRNA), or an empty vector, and then treated with PD fluids and astragaloside IV. Cell viability, apoptosis and EMT were examined using the Cell Counting Kit-8 assay and flow cytometry, and by determining the levels of caspase-3, E-cadherin and α-smooth muscle actin (α-SMA) via western blot analysis. Cell viability and apoptosis were increased, as were the levels of E-cadherin in HMrSV5 cells following treatment with PD fluid. The protein levels of α-SMA and caspase-3 were increased by treatment with PD fluid. Exposure to astragaloside IV inhibited these changes; however, astragaloside IV did not change cell viability, apoptosis, E-cadherin or α-SMA levels in HMrSV5 cells under normal conditions. Transfection of HMrSV5 cells with RXRα shRNA resulted in decreased viability and E-cadherin expression, and increased apoptosis and α-SMA levels, in HMrSV5 cells treated with PD fluids and co-treated with astragaloside IV or vehicle. These results suggested that astragaloside IV increased cell viability, and inhibited apoptosis and EMT in PMCs in PD fluids, but did not affect these properties of PMCs under normal condition. Thus, the present study suggested that RXRα is involved in maintaining viability, inhibiting apoptosis and reducing EMT of PMCs in PD fluid.

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Astragaloside IV modulates TGF‐β1‐dependent epithelial‐mesenchymal transition in bleomycin‐induced pulmonary fibrosis

Cited by 119 publications

References 39 publications

TGF‐β1 mediated MAPK signaling pathway promotes collagen formation induced by Nano NiO in A549 cells

TGF‐β1 mediated MAPK signaling pathway promotes collagen formation induced by Nano NiO in A549 cells

<p>Tranilast Inhibits Pulmonary Fibrosis by Suppressing TGFβ/SMAD2 Pathway</p>

Effect of astragaloside IV and the role of nuclear receptor RXRα in human peritoneal mesothelial cells in high glucose‑based peritoneal dialysis fluids

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