<scp>HIF</scp>‐1α regulates <scp>EMT </scp><i>via</i> the Snail and β‐catenin pathways in paraquat poisoning‐induced early pulmonary fibrosis

Zhu, Yong; Tan, Jing‐Yu; Xie, Hui; Wang, Jinfeng; Meng, Xiaoxiao; Wang, Ruilan

doi:10.1111/jcmm.12769

Cited by 99 publications

(78 citation statements)

References 56 publications

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“…Lysyl oxidase may promote EMT during PQ-induced pulmonar y fibrosis (17). In PQ poisoning-induced early pulmonary fibrosis, hypoxia-inducible factor-1α enhanced Snail and β-catenin and promoted EMT (18). The results of the present study demonstrated that PQ significantly upregulated the expression levels of Wnt1, LRP5, LRP6 and β-catenin.…”

Section: Discussionsupporting

confidence: 50%

Rapamycin protects against paraquat‑induced pulmonary epithelial‑mesenchymal transition via the Wnt/β‑catenin signaling pathway

et al. 2018

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Abstract. Paraquat (PQ) is a herbicide that is widely used in developing countries, and pulmonary fibrosisis one of the most typical features of PQ poisoning. The molecular mechanism underlying PQ toxicity is largely unknown, which makes it difficult to treat. In the present study, western blot analysis, reverse transcription-quantitative polymerase chain reaction and fluorescent immunostaining were used to analyze the effects of rapamycin on PQ-induced epithelial-mesenchymal transition (EMT) in A549 and MRC-5 cells. It was revealed that rapamycin significantly downregulated the mesenchymal cell marker, α-smooth muscle actin, and significantly upregulated the epithelial cell marker, E-cadherin, at mRNA and protein expression levels compared with the PQ group. Treatment with PQ significantly increased Wnt1, low-density lipoprotein receptor-related protein (LRP)5, LRP6 and β-catenin expression levels in A549 cells, while rapamycin significantly inhibited these effects of PQ. Activation of the Wnt signaling pathway using lithium chloride attenuated the inhibitory effects of rapamycin on PQ-induced EMT. In conclusion, rapamycin protects against PQ-induced pulmonary EMT via the Wnt/β-catenin signaling pathway. IntroductionParaquat (PQ; 1,1'-dimethyl-4,4'-bipyridinium) is a herbicide that is widely used in developing countries worldwide, which may cause severe toxicity in animals and humans (1). PQ poisoning was reported to account for up to a third of all suicides around the world (2). PQ poisoning may cause patients to develop acute multi-organ failure, pulmonary fibrosis and finally mortality due to respiratory failure (3). Pulmonary fibrosis is a typical feature of PQ poisoning, the onset of which may be several days or weeks following ingestion of PQ (4). Although PQ-induced pulmonary fibrosis has a high mortality rate, the molecular mechanisms underlying its toxicity are largely unknown, which makes it particularly hard to treat.Epithelial-mesenchymal transition (EMT) has been reported to be associated with pulmonary fibrosis following PQ exposure (3). It has also been reported that factors, including epithelial growth factor, transforming growth factor-β1 (TGF-β1), insulin-like growth factor and interleukin-17, may induce EMT (5). Myofibroblasts are key mediators in fibrosis. In murine models of hepatic and renal fibrosis, ~40% of α-smooth muscle actin (SMA)-positive myofibroblasts were derived from epithelial cells via EMT (6). However, to the best of our knowledge, the roles and mechanisms of rapamycin in the EMT process of A549 and MRC-5 cells remain unknown.In the present study, the roles and mechanisms of rapamycin on PQ-induced pulmonary fibrosis were investigated. It was revealed that rapamycin alleviated PQ-induced EMT in A549 and MRC-5 cells, and PQ activated the Wnt signaling pathway. Rapamycin inhibited the effects of PQ, and the activation of the Wnt signaling pathway attenuated the inhibitory effects of rapamycin on PQ-induced EMT. Materials and methodsReagents. PQ, rapamycin and lithium chloride (...

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Section: Discussionsupporting

confidence: 50%

Rapamycin protects against paraquat‑induced pulmonary epithelial‑mesenchymal transition via the Wnt/β‑catenin signaling pathway

et al. 2018

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“…Many research groups around the globe are working on PQ acute poisoning to clear the molecular pathways and cellular mechanisms involved in this popular intoxication. Recently it has been clarified that HIF-1␣ and TGF-1␤ are the crucial player in the PQ-induced lethal fibrosis Zhu et al, 2016). Considering the respiratory system as the main target of PQ poisoning and lack of any confirmed specific antidote for acute PQ poisoning, suggesting any alternative in vitro models for further clarification in molecular pathways, which may highlight reasonable therapeutic approaches.…”

Section: Discussionmentioning

confidence: 99%

Atorvastatin protected from paraquat-induced cytotoxicity in alveolar macrophages via down-regulation of TLR-4

Alizadeh-Tabrizi

Malekinejad

Varasteh

et al. 2017

Environmental Toxicology and Pharmacology

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a b s t r a c tThe current study designed to clarify the mechanism of paraquat-induced cytotoxicity and protective effects of Atorvastatin on freshly isolated alveolar macrophages (AMs). AMs were collected via bronchoalveolar lavage and exposed to various concentrations of paraquat in the presence and absence of atorvastatin for 24 h. Cell viability, myeloperoxidase activity; nitric oxide generation and total antioxidant capacity were assessed. Expression of TLR-4 at mRNA and protein levels were studied by using PCR and western blot methods Atorvastatin enhanced the paraquat-reduced cell viability and reduced the paraquat-induced myeloperoxidase activity and nitric oxide production. Moreover, atorvastatin downregulated by 60% the paraquat up-regulated expression of TLR-4 at protein and mRNA level. Our results suggest that, AMs in vitro model could be a novel cytological tool for studies on paraquat poisoning and therapy regimens. Additionally, atorvastatin cytoprotective effects on paraquat-induced cytotoxicity partly attribute to its anti-myeloperoxidase, antioxidant properties, which might be regulated via TLR-4 expression.

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“…Conversely, the mesenchymal-epithelial transition (MET) describes the reverse process. Transcriptional factors such as Twist1, ZEB2, Snail and FOXC2 can directly or indirectly trigger the EMT [9]. However, the molecular mechanisms by which EMT and MET occur during cancer progression are still unclear [10].…”

Section: Introductionmentioning

confidence: 99%

Silencing of Prrx2 Inhibits the Invasion and Metastasis of Breast Cancer both In Vitro and In Vivo by Reversing Epithelial-Mesenchymal Transition

Lv¹,

Wang

Liu

et al. 2017

Cell Physiol Biochem

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Background/Aims: Epithelial-mesenchymal transition (EMT) is recognized as a crucial mechanism in breast cancer progression and metastasis. Paired-related homeobox 2 (Prrx2) has been identified as a new EMT inducer in cancer, but the underlying mechanisms are still poorly understood. Methods: The expression of Prrx2 was assessed by immunohistochemistry in breast cancer tissues to evaluate the clinicopathological significance of Prrx2, as well as the correlation between Prrx2 and EMT. Short hairpin RNA knockdown of Prrx2 was used to examine cellular effects of Prrx2, detecte the expression of Wnt/β-catenin signaling and EMT-associated proteins, and observe cell proliferation, invasion and migration abilities in vitro and in vivo. Results: Clinical association studies showed that Prrx2 expression was related to tumor size, lymph node metastasis, tumor node metastasis stages, EMT and poor survival. Results also showed that knockdown of Prrx2 could alter cell morphology, suppressed the abilities of cell proliferation, invasion and migration in breast cancer. Moreover, silencing of Prrx2 induced the mesenchymal-epithelial transition and prevented nuclear translocation of β-catenin, inhibited wnt/β-catenin signaling pathway. Conclusion: Our study indicated that Prrx2 may be an important activator of EMT in human breast cancer and it can serve as a molecular target of therapeutic interventions for breast cancer.

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HIF‐1α regulates EMT via the Snail and β‐catenin pathways in paraquat poisoning‐induced early pulmonary fibrosis

Cited by 99 publications

References 56 publications

Rapamycin protects against paraquat‑induced pulmonary epithelial‑mesenchymal transition via the Wnt/β‑catenin signaling pathway

Rapamycin protects against paraquat‑induced pulmonary epithelial‑mesenchymal transition via the Wnt/β‑catenin signaling pathway

Atorvastatin protected from paraquat-induced cytotoxicity in alveolar macrophages via down-regulation of TLR-4

Silencing of Prrx2 Inhibits the Invasion and Metastasis of Breast Cancer both In Vitro and In Vivo by Reversing Epithelial-Mesenchymal Transition

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