S1PR1 serves as a viable drug target against pulmonary fibrosis by increasing the integrity of the endothelial barrier of the lung

Idiopathic pulmonary fibrosis(IPF)is a progressive lung disease with unclear etiology and limited treatment options.The median survival time for IPF patients is approximately 2–3 years and there is no effective intervention to treat IPF other than lung transplantation.As important components of lung tissue,endothelial cells(ECs)are associated with pulmonary diseases.However,the role of endothelial dysfunction in pulmonary fibrosis(PF)is incompletely understood.Sphingosine-1-phosphate receptor 1(S1PR1)is a G protein-coupled receptor highly expressed in lung ECs.Its expression is markedly reduced in patients with IPF.Herein,we generated an endothelial-conditional S1pr1 knockout mouse model which exhibited inflammation and fibrosis with or without bleomycin(BLM)challenge.Selective activation of S1PR1 with an S1PR1 agonist,IMMH002,exerted a potent therapeutic effect in mice with bleomycin-induced fibrosis by protecting the integrity of the endothelial barrier.These results suggest that S1PR1 might be a promising drug target for IPF therapy.

Self-assembly of metal-cholesterol oxidase hybrid nanostructures and application in bioconversion of steroids derivatives

A cholesterol oxidase(COD)was hybridized with Ca^(2+),Zn^(2+),Al^(3+),Fe^(2+) and Mn^(2+).After precipitation with PO_(4)^(3-) at 4℃ for 72 h,the resulting pellets were freeze-dried.In scanning electron microscopy assays,the metal-COD complexes revealed flower-like or granular structures after hybridization.Fourier transform infrared spectroscopy assay revealed the characteristic peaks of both the enzyme and metal materials.X-ray diffraction analysis indicated that COD was encapsulated in CaHPO_(4)·2H_(2)O-,Zn_(3)(PO_(4))_(2)·4H_(2)O-,AlPO_(4-),FeP_(4-) and Mn_(3)(PO_(4))_(2)·3H_(2)O-based nanostructures,respectively.Differential scanning calorimetry assay indicated significant increases in thermo-denaturation temperatures from 60.5℃ to 167.02℃,167.02℃,137.70℃,172.85℃ and 160.99℃,respectively.Using steroid derivatives as substrates,this enzyme could convert cholesterol,pregnenolone,dehydroepiandrosterone,ergosterol,b-sitosterol and stigmasterol to related single products.Hybridization in metal-based nanostructures could significantly enhance the initial conversion ratio and reaction stability of the enzyme.In addition,substrate selectivity could be affected by various metal materials.Briefly,using Ca^(2+),Zn^(2+),Al^(3+),Fe^(2+) and Mn^(2+) as hybrid raw materials could help to encapsulate COD in related metal-enzyme nanostructures,and could help to promote the stability and tolerant properties of the enzyme,while also enhancing its catalytic characteristics.