Disrupted bone morphogenetic protein type 2 receptor (BMPR2) signaling in endothelial cells drives pulmonary arterial hypertension (PAH). However, targeted recovery of this signaling pathway by lipid nanoparticles (LNPs) has not been explored as a therapy. Here, we employed Design of Experiments to optimize the delivery efficiency of LNPs targeting pulmonary endothelial cells developed by our laboratory, resulting in a remarkable 35-fold increase in a simplified three-component formulation without helper lipids. Administration of BMPR2 mRNA LNPs effectively reversed established PAH in two experimental rat models (monocrotaline or SU5416-hypoxia) by reversing pulmonary vascular remodeling. Specifically, BMPR2 mRNA LNPs replenished the expression of BMPR2 protein and subsequently activated downstream pathways, as confirmed by elevated levels of p-SMAD1/5/9 and ID1 proteins. The relief of pulmonary arterial occlusion was demonstrated by thinned pulmonary arterial media and decreased proportion of full muscularized vessels. Alleviation of right ventricular hypertrophy was indicated by declined Fulton index, the cross-sectional area of right ventricular cardiomyocytes as well as collagen deposition. Effective recovery of right ventricular function was evidenced by increased pulmonary artery flow acceleration time/pulmonary artery flow ejection time ratio. These findings underscore the potential of restoring BMPR2 signaling through pulmonary endothelial cell-specific LNPs for treating PAH.

A matrix solid phase dispersion ( MSPD) method was developed for the simultaneous preparation of samples of 15 mycotoxin biomarkers including deoxynivalenol, aflatoxins and zearalenone from eggs, which were subsequently determined by liquid chromatography-electrospray ionization tandem mass spectrometry ( LC-ESI-MS/MS) under the multiple reaction monitoring ( MRM) mode. For the analysis, the samples were first mixed with C18 particles and loaded into an empty column, then 20 mL of acetonitrile/methanol (1:1, V/V) containing 1 mmol/L ammonium formate was used to elute the sample. The eluent was then dried with nitrogen flow and redissolved into the mobile phase. After filtration, samples were brought into vials and used for analysis. Different from other methods, no extra complicated purification and centrifugation steps were required in the procedure of MSPD. This method had good linearity in the range of 0. 2-100 ng/mL, with the correlation coefficient (r2) greater than 0. 9931. The limits of detection (LODs, S/N=3) and limits of quantification ( LOQs, S/N=3 ) of this method were 0. 05-2 μg/kg and 0. 2-4 μg/kg respectively. Comprehensive extraction recoveries of the 15 compounds ranged from 61% to 90%.

Objective Previous studies have shown that genetic variants in the interferons regulatory factor 5 (IRF5) gene are associated with rheumatoid arthritis (RA) in European and Japanese, but not found in Han Chinese. We conducted this study to investigate whether genetic variants in the IRF5 gene are associated with RA in ShaanXi Han Chinese population. Methods This study was collected 576 RA patients and 768 normal controls. Six IRF5 gene polymorphisms (rs729302, rs2004640, rs752637, rs3807306, rs10954213 and rs2280714) were genotyped by the SNaPshot method. T-test and χ2 test were used for statistic analysis. The genotype and allele frequencies were evaluated using the chi square tests. Genotyping data were adjusted by Logistic regression method by age and gender. The linkage disequilibrium (LD) block structure was examined using Hapview 4.2 software. Results Six SNPs inspected complied with Hardy-weinberg equilibrium (P>0.05). Two SNPs were significantly associated with RA: rs729302 A risk allele [OR=1.29, 95%CI (1.10, 1.50), P=5.57×10-3];dominant model [OR=1.58, 95%CI (1.10, 2.27), P=0.024], recessive model [OR=1.31, 95%CI (1.17, 1.64), P=0.028]. rs2004640 T risk allele [OR=1.28, 95%CI (1.08, 1.54), P=0.039]; dominant model [OR=1.27, 95%CI (1.03, 1.58), P=0.036]. In addition, there was no significant difference in rs752637, rs3807306, rs10954213 and rs2280714 SNPs between RA group and control and genotyped polymorphisms were significantly associated with RA susceptibility. Conclusion The present study confirm that rs729302 and rs2004640 in the IRF5 gene is significantly associated with increased risk of RA in ShaanXi Han Chinese population.