1. PKM2/Hif-1α signal suppression involved in therapeutics of pulmonary fibrosis with microcystin-RR but not with pirfenidone.
- Author
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Ren, Yan, Wang, Jie, Guo, Wen-wen, Chen, Jing-wen, Xu, Li-zhi, Wu, Zhi-wei, and Wang, Ya-ping
- Subjects
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PULMONARY fibrosis , *FIBROBLAST growth factor receptors , *IDIOPATHIC pulmonary fibrosis , *PYRUVATE kinase , *LUNG diseases - Abstract
To date there are only pirfenidone (PFD) and nintedanib to be given conditional recommendation in idiopathic pulmonary fibrosis (IPF) therapies with slowing disease progression, but neither has prospectively shown a reduced mortality. It is one of the urgent topics to find effective drugs for pulmonary fibrosis in medicine. Previous studies have demonstrated that microcystin-RR (MC-RR) effectively alleviates bleomycin-induced pulmonary fibrosis, but the mechanism has not been fully elucidated yet. We further conducted a comparison of therapeutic effect on the model animals of pulmonary fibrosis between MC-RR and PFD with histopathology and the expression of the molecular markers involved in differentiation, proliferation and metabolism of myofibroblasts, a major effector cell of tissue fibrosis. The levels of the enzyme molecules for maintaining the stability of interstitial structure were also evaluated. Our results showed that MC-RR and PFD effectively alleviated pulmonary fibrosis in model mice with a decreased signaling and marker molecules associated with myofibroblast differentiation and lung fibrotic lesion. In the meantime, both MC-RR and PFD treatment are beneficial to restore molecular dynamics of interstitial tissue and maintain the stability of interstitial architecture. Unexpectedly, MC-RR, rather than PFD, showed a significant effect on inhibiting PKM2-HIF-1α signaling and reducing the level of p-STAT3. Additionally, MC-RR showed a better inhibition effect on FGFR1 expression. Given that PKM2-HIF-1α and activated STAT3 molecular present a critical role in promoting the proliferation of myofibroblasts, MC-RR as a new strategy for IPF treatment has potential advantage over PFD. [Display omitted] • Low toxicity microcystin-RR effectively alleviates pulmonary fibrosis as pirfenidone. • The medicinal application of microcystin-RR in pulmonary fibrosis could have better safety. • Microcystin-RR suppresses pyruvate kinase M2 signaling but pirfenidone does not. • Microcystin-RR impedes markedly the augment of fibroblast growth factor receptor 1. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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