engeletin and Pulmonary-Fibrosis

Pulmonary fibrosis is a common pulmonary interstitial disease of pathogenesis without effective drugs for treatment. Therefore, discovering new and effective drugs is urgently needed. In the present study, we prepared a novel compound named acetyl oxygen benzoate engeletin ester (AOBEE), investigated its effect on experimental pulmonary fibrosis, and proposed a long non-coding RNA (lncRNA)-mediated mechanism of its action. Bleomycin-induced pulmonary fibrosis in mice exhibited that AOBEE improved forced vital capacity (FVC) and alveolar structure and inhibited α-SMA, vimentin, and collagen expression. TGFβ1-stimulated fibroblast L929 cells showed that AOBEE reduced these fibrotic proteins expression and inhibited the activated-fibroblast proliferation and migration. Whole transcriptome sequencing was performed to screen out lncRNA-lnc865 and lnc556 with high expression under bleomycin treatment, but AOBEE caused a considerable decrease in lnc865 and lnc556. Mechanistic study elucidated that AOBEE alleviated pulmonary fibrosis through lnc865- and lnc556-mediated mechanism, in which both lnc865 and lnc556 sponged miR-29b-2-5p to target signal transducer and activator of transcription 3 (STAT3). Further signal pathway inhibitors and the Cignal Finder 45-pathway reporter array illustrated that the up- and downstream pathways were TGFβ1-smad2/3 and p38MAPK, and Krüppel-like factor 4 (KLF4), respectively. In conclusion, AOBEE promoted KLF4 degradation leading to the attenuation of pulmonary fibrosis by inhibiting TGFβ1-smad/p38MAPK-lnc865/lnc556-miR-29b-2-5p-STAT3 signal pathway. We hope this work will provide valuable information to design new drugs and therapeutic targets of lncRNAs for pulmonary fibrosis treatment.

Topics: Animals; Cell Death; Cell Line; Flavonols; Glycosides; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Mice, Inbred C57BL; MicroRNAs; Models, Biological; p38 Mitogen-Activated Protein Kinases; Proteolysis; Pulmonary Fibrosis; RNA, Long Noncoding; Signal Transduction; Smad Proteins; STAT3 Transcription Factor; Transforming Growth Factor beta1

Pulmonary fibrosis (PF) is a highly heterogeneous and lethal pathological process having no effective drug. Engeletin exerts multiple biological activities including anti-inflammatory and lung repair. Whether engeletin has therapeutic effects on PF remains unclear.. Examining effect and mechanism of engeletin on PF. We reported gene expression profiling of engeletin through RNA-seq; and identified lnc949-mediated TGF-β1-Smad2/3 and JNK were upstream signalling pathways of ER stress induced by engeletin. Our results showed engeletin remedies pulmonary fibrogenesis and may be a new drug candidate.

Topics: Animals; Bleomycin; Cell Line; Endoplasmic Reticulum Stress; Flavonols; Gene Knockdown Techniques; Glycosides; Male; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Pulmonary Fibrosis; RNA, Long Noncoding; Smad2 Protein; Smad3 Protein; Transforming Growth Factor beta1