The Function And Regulation Mechanisms Of Formononetin-7-sal In Pulmonary Fibrosis

Objective:Pulmonary fibrosis(pulmonary fibrosis,PF)is a progressive disorder with poor prognosis and limited treatment options.Until now there has been high mortality and no effective treatment.Therefore,novel therapeutic drugs should be developed in preclinical studies.In the process of extracting astragalus and salvia,the project team produce a new compound named formononetin-7-sal ester(FS)by natural medicine chemistry technology.Compared with formononetin and danshensu,the water-solubility and the stability are all improved.Pharmacological activity shows that the compound has a strong effect of anti-pulmonary fibrosis,and its mechanism of action relates to the inhibition of muscle fibroblast proliferation.The data shows that the long chain of non-coding ITPF might be involved in its mechanism of anti-pulmonary fibrosis.The project aims to study the effect of FS in anti-pulmonary fibrosis and the regulative mechanism of LncITPF,and provide the data for developing new drugs and gene therapy for pulmonary fibrosis.Methods:The FS stability and pharmacological activity after synthesis were significantly better than that of the monomer.FS treatment can improve the lung function of mice,reduce extracellular matrix deposition and destruction of alveolar structure;it can inhibit the activation,migration,and collagen synthesis of myofibroblasts.FS can significantly inhibit the transcriptional activity of the transcription factor MEF2c.It was also found that hnRNP L mediates lncITPF regulation of MEF2c expression,and IncITPF may be a potential therapeutic target.Resoults:The FS stability and pharmacological activity were significantly better than that of the monomer after synthesis.FS can improve the lung function of mice,reduce extracellular matrix deposition and destruction of alveolar structure;it can inhibit the activation,migration,and collagen synthesis of myofibroblasts.FS can significantly inhibit the transcriptional activity of the transcription factor MEF2c.It was also found that hnRNP L mediates lncITPF regulation of MEF2c expression,and lncITPF may be a potential therapeutic target.Conclusion:FS prevents experimental pulmonary fibrosis dependent on MEF2c signal pathway,mediate the EMT phenomenon and enhance myofibroblast migration ability,thus promote the development of IPF.