ABSTRACT
ABSTRACT: Dihydroartemisinin (DHA) is an active form of artemisinin extracted from the traditional Chinese medicine Artemisia annua , which is used to treat malaria. Previous studies have shown that DHA has a therapeutic effect on pulmonary hypertension (PH), but its specific mechanism has not been fully elucidated. In this study, a hypoxia-induced PH mouse model was established and DHA was administered as a therapeutic intervention. We measured hemodynamics and right ventricular hypertrophy and observed hematoxylin and eosin staining of lung tissue sections, proving the therapeutic effect of DHA on PH. Furthermore, cell counting kit-8 and 5-ethynyl-2'-deoxyuridine (EdU) cell proliferation assay kit were performed to examine cell proliferation of pulmonary artery smooth muscle cells cultured in hypoxia or in normoxia. Transwell migration chamber assay was performed to examine cell migration of the same cell model. Consistent with the therapeutic effect in vivo, DHA inhibited hypoxia-induced cell proliferation and migration. Through high-throughput sequencing of mouse lung tissue, we screened embryonic lethal abnormal vision-like 2 (ELAVL2) as a key RNA binding protein in PH. Mechanistically, DHA inhibited the proliferation and migration of pulmonary artery smooth muscle cells by promoting the expression of ELAVL2 and regulating the miR-503/PI3K/AKT pathway. The binding relationship between ELAVL2 and pre-miR-503 was verified by RNA binding protein immunoprecipitation assay. In conclusion, we first propose that DHA alleviates PH through the ELAVL2/miR-503/PI3K/AKT pathway, which may provide a basis for new therapeutic strategies of PH.
Subject(s)
Artemisinins , Hypertension, Pulmonary , MicroRNAs , Animals , Artemisinins/pharmacology , Cell Proliferation , Cells, Cultured , ELAV-Like Protein 2/metabolism , Hypertension, Pulmonary/drug therapy , Hypertension, Pulmonary/etiology , Hypertension, Pulmonary/prevention & control , Hypoxia/complications , Hypoxia/drug therapy , Hypoxia/metabolism , Mice , MicroRNAs/metabolism , Myocytes, Smooth Muscle/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Pulmonary ArteryABSTRACT
BACKGROUND AND OBJECTIVE: Qishen Yiqi formula (QSYQ) is used to treat cardiovascular disease in the clinical practice of traditional Chinese medicine. However, few studies have explored whether QSYQ affects pulmonary arterial hypertension (PAH), and the mechanisms of action and molecular targets of QSYQ for the treatment of PAH are unclear. A bioinformatics/network topology-based strategy was used to identify the bioactive ingredients, putative targets, and molecular mechanisms of QSYQ in PAH. METHODS: A network pharmacology-based strategy was employed by integrating active component gathering, target prediction, PAH gene collection, network topology, and gene enrichment analysis to systematically explore the multicomponent synergistic mechanisms. RESULTS: In total, 107 bioactive ingredients of QSYQ and 228 ingredient targets were identified. Moreover, 234 PAH-related differentially expressed genes with a |fold change| >2 and an adjusted P value < 0.005 were identified between the PAH patient and control groups, and 266 therapeutic targets were identified. The pathway enrichment analysis indicated that 85 pathways, including the PI3K-Akt, MAPK, and HIF-1 signaling pathways, were significantly enriched. TP53 was the core target gene, and 7 other top genes (MAPK1, RELA, NFKB1, CDKN1A, AKT1, MYC, and MDM2) were the key genes in the gene-pathway network based on the effects of QSYQ on PAH. CONCLUSION: An integrative investigation based on network pharmacology may elucidate the multicomponent synergistic mechanisms of QSYQ in PAH and lay a foundation for further animal experiments, human clinical trials and rational clinical applications of QSYQ.
Subject(s)
Computational Biology , Drugs, Chinese Herbal/pharmacology , Gene Regulatory Networks/drug effects , Pulmonary Arterial Hypertension/drug therapy , Drugs, Chinese Herbal/chemistry , Humans , Medicine, Chinese Traditional , Pulmonary Arterial Hypertension/geneticsABSTRACT
Idiopathic Pulmonary fibrosis(PF)is a chronic progressive disease, which is a lack of effective treatment,and the pathogenesis of IPF is not fully elucidated. Asiaticoside(AS) is isolated from Centella asiatica and has the effect of promoting scar healing and reducing scar formation. However,its possible role in idiopathic pulmonary fibrosis remains unclear. Adenosine A2A receptor (A2AR) is reported a protective factor in pulmonary fibrosis, and the bone morphogenetic protein 7 (BMP7) signaling pathway plays a crucial role in fibrosis in multiple organs. But the impact of A2AR on the BMP7 pathway has not yet been reported. Therefore, we hypothesized AS may promote the expression of A2AR, and then influence the BMP7/Smad1/5 pathway to alleviate pulmonary fibrosis. A2AR-/- mice and wild-type (WT) mice were administered bleomycin (BLM) by intratracheal injection. AS (50 mg/kg/d) was given daily for 28 days. AS reduced collagen deposition in lung tissue, interstitial lung inflammation. Furthermore, AS promoted A2AR expression and BMP7 pathway. Collectively, AS may attenuate BLM-induced pulmonary fibrosis by upregulating the BMP7 signaling pathway through A2AR.