Emodin inhibiting neutrophil elastase‐induced epithelial‐mesenchymal transition through Notch1 signalling in alveolar epithelial cells

Zhou, Linshui; Gao, Rundi; Hong, Hui-Hua; Li, Xiaojuan; Yang, Jia; Shen, Wei; Wang, Zhen; Junchao, Yang

doi:10.1111/jcmm.15827

Cited by 17 publications

(15 citation statements)

References 38 publications

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“…Repeated damage to the alveolar epithelial cells induced by various harmful factors has been accepted as the first and foremost cause of pulmonary fibrosis and complex networks of cytokines are involved in this process, as well as the subsequent tissue repair and fibrosis [30]. Here, a well-validated model of EMT in the A549 human alveolar cell line was used to study the mechanism of pulmonary fibrosis, for which a suite of morphological, phenotypic and functional markers and outcomes have been well characterized [31][32][33]. BLM is widely used as an inducer of pulmonary fibrosis in animal models [34], and similar effects were validated in vitro experiments, and EMT characteristics were detected in BLM treated A549 cells [35,36].…”

Section: Discussionmentioning

confidence: 99%

Role of CXCL16 in BLM-induced epithelial–mesenchymal transition in human A549 cells

Bai

et al. 2021

Respir Res

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Alveolar epithelial cells play an essential role in the initiation and progression of pulmonary fibrosis, and the occurrence of epithelial–mesenchymal transition (EMT) may be the early events of pulmonary fibrosis. Recent studies have shown chemokines are involved in the complex process of EMT, and CXC chemokine ligand 16 (CXCL16) is also associated with many fibrosis-related diseases. However, whether CXCL16 is dysregulated in alveolar epithelial cells and the role of CXCL16 in modulating EMT in pulmonary fibrosis has not been reported. In this study, we found that CXCL16 and its receptor C-X-C motif chemokine receptor 6 (CXCR6) were upregulated in bleomycin induced EMT in human alveolar type II-like epithelial A549 cells. Synergistic effect of CXCL16 and bleomycin in promoting EMT occurrence, extracellular matrix (ECM) excretion, as well as the pro-inflammatory and pro-fibrotic cytokines productions in A549 cells were observed, and those biological functions were impaired by CXCL16 siRNA. We further confirmed that CXCL16 regulated EMT in A549 cells via the TGF-β1/Smad3 pathways. These results indicated that CXCL16 could promote pulmonary fibrosis by promoting the process of EMT via the TGF-β1/Smad3 signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Role of CXCL16 in BLM-induced epithelial–mesenchymal transition in human A549 cells

Bai

et al. 2021

Respir Res

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“…The transition of AECs into mesenchymal cells has been reported to cause and/or aggravate PF [ 6 ]. In this study, the direct effects of PTUPB on the TGF- β 1-induced EMT were investigated.…”

Section: Discussionmentioning

confidence: 99%

“…EMT is involved in wound healing, fibrosis, embryonic development, and cancer metastasis [ 5 ]. Most investigators concur that alveolar type II epithelial cells undergo EMT during PF development [ 6 , 7 ]. Studies have shown that pulmonary fibroblasts are derived from various routes, of which about one-third are derived from alveolar type II epithelial cells via EMT [ 8 ].…”

Section: Introductionmentioning

confidence: 98%

COX-2/sEH Dual Inhibitor PTUPB Attenuates Epithelial-Mesenchymal Transformation of Alveolar Epithelial Cells via Nrf2-Mediated Inhibition of TGF-β1/Smad Signaling

Zhang

Guan

Zhang

et al. 2022

Oxidative Medicine and Cellular Longevity

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Background. Arachidonic acid (ARA) metabolites are involved in the pathogenesis of epithelial-mesenchymal transformation (EMT). However, the role of ARA metabolism in the progression of EMT during pulmonary fibrosis (PF) has not been fully elucidated. The purpose of this study was to investigate the role of cytochrome P450 oxidase (CYP)/soluble epoxide hydrolase (sEH) and cyclooxygenase-2 (COX-2) metabolic disorders of ARA in EMT during PF. Methods. A signal intratracheal injection of bleomycin (BLM) was given to induce PF in C57BL/6 J mice. A COX-2/sEH dual inhibitor PTUPB was used to establish the function of CYPs/COX-2 dysregulation to EMT in PF mice. In vitro experiments, murine alveolar epithelial cells (MLE12) and human alveolar epithelial cells (A549) were used to explore the roles and mechanisms of PTUPB on transforming growth factor (TGF)-β1-induced EMT. Results. PTUPB treatment reversed the increase of mesenchymal marker molecule α-smooth muscle actin (α-SMA) and the loss of epithelial marker molecule E-cadherin in lung tissue of PF mice. In vitro, COX-2 and sEH protein levels were increased in TGF-β1-treated alveolar epithelial cells (AECs). PTUPB decreased the expression of α-SMA and restored the expression of E-cadherin in TGF-β1-treated AECs, accompanied by reduced migration and collagen synthesis. Moreover, PTUPB attenuated TGF-β1-Smad2/3 pathway activation in AECs via Nrf2 antioxidant cascade. Conclusion. PTUPB inhibits EMT in AECs via Nrf2-mediated inhibition of the TGF-β1-Smad2/3 pathway, which holds great promise for the clinical treatment of PF.

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“…Emodin at 10 μg/ml significantly inhibited the enzymatic activity of neutrophil elastase, which then inhibited nuclear notch-mediated EMT, and subsequently inhibited ECM production. These studies not only highlighted the critical roles of neutrophil infiltration and Notch1 signaling in IPF progression but also emphasized the plausible therapeutic effects of emodin for the treatment of IPF [ 81 ]. Furthermore, researchers also found that anti-fibrosis benefits of emodin (0.3 or 1 mg/kg) were related to down-regulation of SMAD ubiquitination regulatory factor 2 and up-regulation of Smad7 in surgery-induced renal fibrotic rats [ 82 ].…”

Section: Pharmacological Effects Of Emodinmentioning

confidence: 99%

Advances in the study of emodin: an update on pharmacological properties and mechanistic basis

Zheng

et al. 2021

Chin Med

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Rhei Radix et Rhizoma, also known as rhubarb or Da Huang, has been widely used as a spice and as traditional herbal medicine for centuries, and is currently marketed in China as the principal herbs in various prescriptions, such as Da-Huang-Zhe-Chong pills and Da-Huang-Qing-Wei pills. Emodin, a major bioactive anthraquinone derivative extracted from rhubarb, represents multiple health benefits in the treatment of a host of diseases, such as immune-inflammatory abnormality, tumor progression, bacterial or viral infections, and metabolic syndrome. Emerging evidence has made great strides in clarifying the multi-targeting therapeutic mechanisms underlying the efficacious therapeutic potential of emodin, including anti-inflammatory, immunomodulatory, anti-fibrosis, anti-tumor, anti-viral, anti-bacterial, and anti-diabetic properties. This comprehensive review aims to provide an updated summary of recent developments on these pharmacological efficacies and molecular mechanisms of emodin, with a focus on the underlying molecular targets and signaling networks. We also reviewed recent attempts to improve the pharmacokinetic properties and biological activities of emodin by structural modification and novel material-based targeted delivery. In conclusion, emodin still has great potential to become promising therapeutic options to immune and inflammation abnormality, organ fibrosis, common malignancy, pathogenic bacteria or virus infections, and endocrine disease or disorder. Scientifically addressing concerns regarding the poor bioavailability and vague molecular targets would significantly contribute to the widespread acceptance of rhubarb not only as a dietary supplement in food flavorings and colorings but also as a health-promoting TCM in the coming years.

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Emodin inhibiting neutrophil elastase‐induced epithelial‐mesenchymal transition through Notch1 signalling in alveolar epithelial cells

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 17 publications

References 38 publications

Role of CXCL16 in BLM-induced epithelial–mesenchymal transition in human A549 cells

Role of CXCL16 in BLM-induced epithelial–mesenchymal transition in human A549 cells

COX-2/sEH Dual Inhibitor PTUPB Attenuates Epithelial-Mesenchymal Transformation of Alveolar Epithelial Cells via Nrf2-Mediated Inhibition of TGF-β1/Smad Signaling

Advances in the study of emodin: an update on pharmacological properties and mechanistic basis

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