Catalpol Protects Against Pulmonary Fibrosis Through Inhibiting TGF-β1/Smad3 and Wnt/β-Catenin Signaling Pathways

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by fibroblast proliferation and extracellular matrix remodeling; however, the molecular mechanisms underlying its occurrence and development are not yet fully understood. Despite it having a variety of beneficial pharmacological activities, the effects of catalpol (CAT), which is extracted from Rehmannia glutinosa, in IPF are not known. In this study, the differentially expressed genes, proteins, and pathways of IPF in the Gene Expression Omnibus database were analyzed, and CAT was molecularly docked with the corresponding key proteins to screen its pharmacological targets, which were then verified using an animal model. The results show that collagen metabolism imbalance, inflammatory response, and epithelial-mesenchymal transition (EMT) are the core processes in IPF, and the TGF-β1/Smad3 and Wnt/β-catenin pathways are the key signaling pathways for the development of pulmonary fibrosis. Our results also suggest that CAT binds to TGF-βR1, Smad3, Wnt3a, and GSK-3β through hydrogen bonds, van der Waals bonds, and other interactions to downregulate the expression and phosphorylation of Smad3, Wnt3a, GSK-3β, and β-catenin, inhibit the expression of cytokines, and reduce the degree of oxidative stress in lung tissue. Furthermore, CAT can inhibit the EMT process and collagen remodeling by downregulating fibrotic biomarkers and promoting the expression of epithelial cadherin. This study elucidates several key processes and signaling pathways involved in the development of IPF, and suggests the potential value of CAT in the treatment of IPF.

Download Full-text

Downregulation of S100A2 alleviates pulmonary fibrosis through inhibiting wnt/β-catenin signaling pathway

10.21203/rs.3.rs-23375/v1 ◽

2020 ◽

Author(s):

Guichuan Huang ◽

Jing Zhang ◽

Gang Qing ◽

Daishun Liu ◽

Xin Wang ◽

...

Keyword(s):

Pulmonary Fibrosis ◽

Western Blot ◽

Molecular Mechanisms ◽

Transforming Growth Factor ◽

Epithelial Mesenchymal Transition ◽

A549 Cells ◽

Mesenchymal Transition ◽

Qrt Pcr ◽

Tgf Β1

Abstract Background：Pulmonary fibrosis (PF) is a progressive and lethal disease with poor prognosis. S100A2 plays an important role in the progression of cancer. However, the role of S100A2 in PF has not been reported yet. In this study, we explored the potential role of S100A2 in PF and its potential molecular mechanisms. Methods: First, we analyzed S100A2 expression of patients with PF by retrieving RNA-sequencing datasets from Gene Expression Omnibus (GEO) database. Next, we detected the expression of S100A2 in patients with PF using quantitative real time PCR (qRT-PCR). Then, S100A2 expression was determined with or without the treatment of transforming growth factor-β1 (TGF-β1) in A549 cells. Epithelial-mesenchymal transition (EMT) biomarkers, including E-cadherin，vimentin, and α smooth muscle actin (α-SMA), were identified using qRT-PCR and western blot. Finally, the relevant signalling pathway indicators were detected by western blot. Results: Increased expression of S100A2 was first observed in lung tissues of PF patients. Meanwhile, we found that downregulation of S100A2 inhibited the TGF-β1-induced EMT in A549 cells. Mechanically, TGF-β1 up-regulated β-catenin and phosphorylation of GSK-3β, which was blocked by silencing S100A2 in vitro. Conclusion: These findings demonstrate that downregulation of S100A2 alleviate pulmonary fibrosis via inhibiting EMT. S100A2 is a promising potential target for further understanding the mechanism and developing strategy for the treatment of PF and other EMT-associated disease.

Download Full-text

MiRNA, a New Treatment Strategy for Pulmonary Fibrosis

Current Drug Targets ◽

10.2174/1874609813666200928141822 ◽

2020 ◽

Vol 21 ◽

Author(s):

Yanhong Liu ◽

Hongguang Nie ◽

Yan Ding ◽

Yapeng Hou ◽

Kejun Mao ◽

...

Keyword(s):

Pulmonary Fibrosis ◽

Epithelial Mesenchymal Transition ◽

Alveolar Epithelial Cell ◽

The Elderly ◽

Matrix Remodeling ◽

Mesenchymal Transition ◽

Delay In Diagnosis ◽

Alveolar Epithelial ◽

Epithelial Cell Apoptosis ◽

New Treatment

: Pulmonary fibrosis (PF) is the most common chronic, progressive interstitial lung disease, mainly occurring in the elderly, with a median survival of 2-4 years after diagnosis. Its high mortality rate attributes to the delay in diagnosis due to its generic symptoms, and more importantly, to the lack of effective treatments. MicroRNAs (miRNAs) are a class of small non-coding RNAs that involve in many essential cellular processes, including extracellular matrix remodeling, alveolar epithelial cell apoptosis, epithelial-mesenchymal transition, etc. We summarized the dysregulated miRNAs in TGF-β signaling pathway-mediated PF in recent years with dual effects, such as anti-fibrotic let-7 family and pro-fibrotic miR-21 members. Therefore, this review will set out the latest application of miRNAs to provide a new direction for PF treatment.

Download Full-text

The Molecular Mechanism of Epithelial–Mesenchymal Transition for Breast Carcinogenesis

Biomolecules ◽

10.3390/biom9090476 ◽

2019 ◽

Vol 9 (9) ◽

pp. 476 ◽

Cited By ~ 4

Author(s):

Chia-Jung Li ◽

Pei-Yi Chu ◽

Giou-Teng Yiang ◽

Meng-Yu Wu

Keyword(s):

Epithelial Cells ◽

Tumor Progression ◽

Signaling Pathways ◽

Intracellular Signaling ◽

Molecular Mechanisms ◽

Transforming Growth Factor ◽

Epithelial Mesenchymal Transition ◽

Transforming Growth Factor Β ◽

Inhibition Of Proliferation ◽

Mesenchymal Transition

The transforming growth factor-β (TGF-β) signaling pathway plays multiple regulatory roles in the tumorigenesis and development of cancer. TGF-β can inhibit the growth and proliferation of epithelial cells and induce apoptosis, thereby playing a role in inhibiting breast cancer. Therefore, the loss of response in epithelial cells that leads to the inhibition of cell proliferation due to TGF-β is a landmark event in tumorigenesis. As tumors progress, TGF-β can promote tumor cell invasion, metastasis, and drug resistance. At present, the above-mentioned role of TGF-β is related to the interaction of multiple signaling pathways in the cell, which can attenuate or abolish the inhibition of proliferation and apoptosis-promoting effects of TGF-β and enhance its promotion of tumor progression. This article focuses on the molecular mechanisms through which TGF-β interacts with multiple intracellular signaling pathways in tumor progression and the effects of these interactions on tumorigenesis.

Download Full-text

MiR-149-3p promotes the cisplatin resistance and EMT in ovarian cancer through downregulating TIMP2 and CDKN1A

Journal of Ovarian Research ◽

10.1186/s13048-021-00919-5 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Jin Wang ◽

Lingxia Liu

Keyword(s):

Ovarian Cancer ◽

Molecular Mechanisms ◽

Cisplatin Resistance ◽

Epithelial Mesenchymal Transition ◽

Gynecological Cancer ◽

Gene Expression Omnibus ◽

Luciferase Assay ◽

Migration And Invasion ◽

Mesenchymal Transition

Abstract Background Ovarian cancer (OC), a kind of gynecological cancer, is characterized by high mortality rate, with microRNAs (miRNAs) playing essential roles in it. However, the clinical significance of miRNAs and their molecular mechanisms in OC are mostly unknown. Methods miR-149-3p expression was predicted through Gene Expression Omnibus (GEO) data in OC and confirmed by q-PCR in various OC cells and tissues from patients with different clinical characteristics. Moreover, its roles in terms of proliferation, migration and invasion were measured by CCK-8, colony formation, wound healing and transwell assays in OC cells including cisplatin-resistant and cisplatin-sensitive cells. And its effect on epithelial-mesenchymal transition was also assessed through detecting related protein expression. Additionally, its potential targets were verified by dual luciferase assay and Ago-RIP assay. Finally, its oncogenic functions were explored in vivo. Results In data from GSE79943, GSE131790, and TCGA, miR-149-3p was found to be highly expressed in OC tissues and associated with poor survival. In metastasis and chemoresistant tissues and cisplatin-resistant OC cells, its high expression was confirmed. In terms of tumorigenic effects, miR-149-3p knockdown in cisplatin-resistant OC cells inhibited its cisplatin resistance and other malignant phenotypes, while miR-149-3p overexpression in cisplatin-resistant OC cells led to contrary results. Mechanistically, miR-149-3p targeted 3’UTR of CDKN1A and TIMP2 to function as an oncogenic miRNA. Conclusion In brief, miR-149-3p promoted cisplatin resistance and EMT in OC by downregulating CDKN1A and TIMP2, which might provide a potential therapeutic target for OC treatment.

Download Full-text

Network Pharmacology and Experimental Assessment to Explore the Pharmacological Mechanism of Qimai Feiluoping Decoction Against Pulmonary Fibrosis

Frontiers in Pharmacology ◽

10.3389/fphar.2021.770197 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yingying Yang ◽

Lu Ding ◽

Tingting Bao ◽

Yaxin Li ◽

Jing Ma ◽

...

Keyword(s):

Pulmonary Fibrosis ◽

Epithelial Mesenchymal Transition ◽

Clinical Symptoms ◽

A549 Cells ◽

Network Pharmacology ◽

Active Components ◽

Mesenchymal Transition ◽

Pharmacological Mechanism ◽

Ecm Degradation ◽

Tgf Β1

Pulmonary fibrosis (PF) is one of the pathologic changes in COVID-19 patients in convalescence, and it is also a potential long-term sequela in severe COVID-19 patients. Qimai Feiluoping decoction (QM) is a traditional Chinese medicine formula recommended in the Chinese national medical program for COVID-19 convalescent patients, and PF is one of its indications. Through clinical observation, QM was found to improve the clinical symptoms and pulmonary function and reduce the degree of PF of COVID-19 convalescent patients. To further explore the pharmacological mechanisms and possible active components of QM in anti-PF effect, UHPLC/Q-TOF-MS was used to analyze the composition of the QM extract and the active components that can be absorbed into the blood, leading to the identification of 56 chemical compounds and 10 active components. Then, network pharmacology was used to predict the potential mechanisms and targets of QM; it predicted that QM exerts its anti-PF effects via the regulation of the epithelial–mesenchymal transition (EMT), extracellular matrix (ECM) degradation, and TGF-β signaling pathway. Finally, TGF-β1–induced A549 cells were used to verify and explore the pharmacological effects of QM and found that QM could inhibit the proliferation of TGF-β1–induced A549 cells, attenuate EMT, and promote ECM degradation by inhibiting the TGF-β/Smad3 pathway.

Download Full-text

FP080Epigallocatechin-3-gallate prevents TGF-β1-induced epithelial-mesenchymal transition and fibrotic changes of renal cells via GSK-3β/β-catenin/Snail1 and Nrf2 pathways

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfz106.fp080 ◽

2019 ◽

Vol 34 (Supplement_1) ◽

Author(s):

Rattiyaporn Kanlaya ◽

Paleerath Peerapen ◽

Angkhana Nilnumkhum ◽

Sirikanya Plumworasawat ◽

Kanyarat Sueksakit ◽

...

Keyword(s):

Epithelial Mesenchymal Transition ◽

Renal Cells ◽

Mesenchymal Transition ◽

Gsk 3Β ◽

Tgf Β1

Download Full-text

Epithelial-Mesenchymal Transition in Oral Squamous Cell Carcinoma

ISRN Oncology ◽

10.5402/2012/681469 ◽

2012 ◽

Vol 2012 ◽

pp. 1-10 ◽

Cited By ~ 21

Author(s):

Suttichai Krisanaprakornkit ◽

Anak Iamaroon

Keyword(s):

Squamous Cell Carcinoma ◽

Oral Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Signaling Pathways ◽

Squamous Cell ◽

Molecular Mechanisms ◽

Epithelial Mesenchymal Transition ◽

Large Body ◽

Invasion And Metastasis ◽

Mesenchymal Transition

Oral cancer is one of the drastic human cancers due to its aggressiveness and high mortality rate. Of all oral cancers, squamous cell carcinoma is the most common accounting for more than 90%. Epithelial-mesenchymal transition (EMT) is suggested to play an important role during cancer invasion and metastasis. Recently, emerging knowledge on EMT in carcinogenesis is explosive, tempting us to analyze previous studies on EMT in oral squamous cell carcinoma (OSCC). In this paper, we have first addressed the general molecular mechanisms of EMT, evidenced by alterations of cell morphology during EMT, the presence of cadherin switching, turning on and turning off of many specific genes, the activation of various signaling pathways, and so on. The remaining part of this paper will focus on recent findings of the investigations of EMT on OSCC. These include the evidence of EMT taking place in OSCC and the signaling pathways employed by OSCC cells during their invasion and metastasis. Collectively, with the large body of new knowledge on EMT in OSCC elaborated here, we are hopeful that targeting treatment for OSCC will be developed.

Download Full-text

N6-methyladenosine-mediated Nrf2 Regulates the Defense Mechanism Against PM2.5-induced Pulmonary Fibrosis

10.21203/rs.3.rs-631972/v1 ◽

2021 ◽

Author(s):

Ding Ji ◽

Chenxi Hu ◽

Jie Ning ◽

Xiaoling Ying ◽

Haiqing Zhang ◽

...

Keyword(s):

Pulmonary Fibrosis ◽

Molecular Mechanisms ◽

Defense Mechanism ◽

Epithelial Mesenchymal Transition ◽

Aerodynamic Diameter ◽

Mesenchymal Transition ◽

Single Base ◽

Qrt Pcr ◽

Rna Immunoprecipitation ◽

Pm2.5 Exposure

Abstract Background: It has been reported that particulate matter with an aerodynamic diameter of < 2.5 µm (PM2.5) could induce epithelial–mesenchymal transition (EMT)- and extracellular matrix (ECM)-related pulmonary fibrosis (PF). The transcription factor Nrf2 alleviated PM2.5-induced PF by antagonizing oxidative stress. The N6-methyladenosine (m6A) modifications play a significant role in the stress response. However, the effect of m6A modification on the mechanisms of Nrf2-mediated defense against PM2.5-induced PF remain unknown. Here, we investigated the role and the underlying molecular mechanisms of m6A methylation of Nrf2 mRNA in PM2.5-induced PF. Results: Male C57BL/6 mice were exposed to filtered air (FA), unfiltered air (UA) and concentrated air (CA)for 16 weeks. 16HBE cells were treated with 0, 50, or 100 µg/mL PM2.5 for 24 h. Our data showed that chronic PM2.5 exposure could induce fibrosis in lung and increase Nrf2 signals. In Nrf2 deficient cells, α-SMA expression was significantly upregulated whereas E-cadherin decreased compared with WT cells after PM2.5 treatment which implied the aggravated fibrosis. m6A methyltransferase METTL3 was upregulated after PM2.5 treatment. m6A-methylated RNA immunoprecipitation (MeRIP) and qRT-PCR results showed that METTL3 improved the m6A modification of Nrf2 mRNA in PM2.5-exposed 16HBE cells. MeRIP-Seq and single-base T3 ligase-based PCR results showed that the m6A-modified sites of Nrf2 mRNA were 1317, 1376, and 935 in lung of mice after PM2.5 exposure. RIP results suggested that the m6A binding proteins YTHDF1/IGF2BP1 promoted Nrf2 translation by binding to Nrf2 mRNA m6A residues.Conclusions: Our results revealed the mechanism by which m6A regulated the activities of the Nrf2-mediated signaling pathway against PM2.5-induced PF.

Download Full-text

Atractylodin Suppresses TGF-β-Mediated Epithelial-Mesenchymal Transition in Alveolar Epithelial Cells and Attenuates Bleomycin-Induced Pulmonary Fibrosis in Mice

International Journal of Molecular Sciences ◽

10.3390/ijms222011152 ◽

2021 ◽

Vol 22 (20) ◽

pp. 11152

Author(s):

Kai-Wei Chang ◽

Xiang Zhang ◽

Shih-Chao Lin ◽

Yu-Chao Lin ◽

Chia-Hsiang Li ◽

...

Keyword(s):

Epithelial Cells ◽

Pulmonary Fibrosis ◽

Lung Injury ◽

Epithelial Mesenchymal Transition ◽

A549 Cells ◽

Alveolar Epithelial Cells ◽

Collagen Deposition ◽

Mesenchymal Transition ◽

Alveolar Epithelial ◽

Tgf Β1

Idiopathic pulmonary fibrosis (IPF) is characterized by fibrotic change in alveolar epithelial cells and leads to the irreversible deterioration of pulmonary function. Transforming growth factor-beta 1 (TGF-β1)-induced epithelial-mesenchymal transition (EMT) in type 2 lung epithelial cells contributes to excessive collagen deposition and plays an important role in IPF. Atractylodin (ATL) is a kind of herbal medicine that has been proven to protect intestinal inflammation and attenuate acute lung injury. Our study aimed to determine whether EMT played a crucial role in the pathogenesis of pulmonary fibrosis and whether EMT can be utilized as a therapeutic target by ATL treatment to mitigate IPF. To address this topic, we took two steps to investigate: 1. Utilization of anin vitro EMT model by treating alveolar epithelial cells (A549 cells) with TGF-β1 followed by ATL treatment for elucidating the underlying pathways, including Smad2/3 hyperphosphorylation, mitogen-activated protein kinase (MAPK) pathway overexpression, Snail and Slug upregulation, and loss of E-cadherin. Utilization of an in vivo lung injury model by treating bleomycin on mice followed by ATL treatment to demonstrate the therapeutic effectiveness, such as, less collagen deposition and lower E-cadherin expression. In conclusion, ATL attenuates TGF-β1-induced EMT in A549 cells and bleomycin-induced pulmonary fibrosis in mice.

Download Full-text

Bleomycin induces epithelial-to-mesenchymal transition via bFGF/PI3K/ESRP1 signaling in pulmonary fibrosis

Bioscience Reports ◽

10.1042/bsr20190756 ◽

2020 ◽

Vol 40 (1) ◽

Cited By ~ 1

Author(s):

Chang-Mei Weng ◽

Qing Li ◽

Kui-Jun Chen ◽

Cheng-Xiong Xu ◽

Meng-Sheng Deng ◽

...

Keyword(s):

Pulmonary Fibrosis ◽

Epithelial Mesenchymal Transition ◽

Regulatory Protein ◽

A549 Cells ◽

Akt Signaling ◽

High Rate ◽

Akt Inhibitor ◽

Mesenchymal Transition ◽

Tgf Β1

Abstract Idiopathic pulmonary fibrosis (IPF) is a fatal and chronic disease with a high rate of infection and mortality; however, its etiology and pathogenesis remain unclear. Studies have revealed that epithelial–mesenchymal transition (EMT) is a crucial cellular event in IPF. Here, we identified that the pulmonary fibrosis inducer bleomycin simultaneously increased the expression of bFGF and TGF-β1 and inhibited epithelial-specific regulatory protein (ESRP1) expression in vivo and in vitro. In addition, in vitro experiments showed that bFGF and TGF-β1 down-regulated the expression of ESRP1 and that silencing ESRP1 promoted EMT in A549 cells. Notably, we determined that bFGF activates PI3K/Akt signaling, and treatment with the PI3K/Akt inhibitor LY294002 inhibited bleomycin-induced cell morphology changes and EMT. In addition, the effects of LY294002 on bleomycin-induced EMT were inhibited by ESRP1 silencing in A549 cells. Taken together, these findings suggest that bleomycin induced EMT through down-regulating ESRP1 by simultaneously increasing bFGF and TGF-β1 in pulmonary fibrosis. Additionally, our findings indicated that bFGF inhibits ESRP1 by activating PI3K/Akt signaling.

Download Full-text