No abstract

Janus tyrosine kinase 3 (JAK3) is expressed in lymphoid cells and is involved in the signalling of T cell functions. The development of a selective JAK3 inhibitor has been shown to have a potential benefit in the treatment of autoimmune disorders. In this article, we developed the 4-aminopiperidine-based compound RB1, which was highly selective for JAK3 inhibition, with an IC50 of value of 40 nM, but did not inhibit JAK1, JAK2 or tyrosine kinase 2 (TYK2) at concentrations up to 5 µM. Furthermore, RB1 also exhibited favourable selectivity against a panel of representative kinases. In a battery of cytokine-stimulated cell-based assays, this potent inhibitor of JAK3 activity with good selectivity against other kinases could potently inhibit JAK3 activity over the activity of JAK1 or JAK2 (over at least 100-fold). A combination of liquid chromatography-mass spectrometry (LC-MS) experiments validated that RB1 covalently modified the unique cysteine 909 residue in JAK3. In vivo, RB1 exerted significantly improved pathology in the joints of a collagen-induced arthritis mouse model. The reasonable pharmacokinetics properties (F = 72.52%, T1/2 = 14.6 h) and favourable results of toxicology experiments (LD50 > 2 g/kg) suggest that RB1 has the potential to be an efficacious treatment for RA.

Purpose Schisandrin B (Sch B) is clinically applied for the treatment of hepatitis and ischemic disease. However, its clinical efficacy is limited due to the poor solubility and low bioavailability. This study aimed to develop matrix metalloproteinase (MMP)-sensitive peptide-modified, polyethylene glycol (PEG)-modified (PEGylated) solid lipid nanoparticles (SLNs) for loading Sch B (MMP-Sch B SLNs), and to evaluate the therapeutic effect in the myocardial infarction model. Methods PEG lipid and MMP-targeting peptide conjugate were synthesized. MMP-Sch B SLNs were prepared by solvent displacement technique. The physicochemical properties and pharmacokinetics of SLNs were investigated. In vivo effects on infarct size was evaluated in rats. Results The successful synthesis of lipid-peptide conjugate was confirmed. MMP-Sch B SLNs had a particle size of 130 nm, a zeta potential of 18.3 mV, and a sustained-release behavior. Higher heart drug concentration and longer blood circulation times were achieved by Sch B loaded SLNs than the drug solution according to the pharmacokinetic and biodistribution results. The best therapeutic efficacy was exhibited by MMP-Sch B SLNs by reducing the infarction size to the greatest extent. Conclusion The modified SLNs may be a good choice for delivery of Sch B for the treatment of myocardial infarction.

Background: lncRNA-SNHG16 was identified as an oncogene in many cancers, but its involvement in prostate carcinoma is unknown. Material and Method: Expression of lncRNA-SNHG16 and glucose transporter 1 (GLUT-1) in 52 prostate carcinoma tissues and 36 normal prostate tissues was analyzed by RT-qPCR. Transfections were performed to analyze gene interactions. Cell proliferation was analyzed by cell proliferation assay. Results: Overexpression of lncRNA-SNHG16 effectively distinguished prostate carcinoma patients from normal ones. Expression levels of lncRNA-SNHG16 and GLUT-1 mRNA were significantly and positively correlated across prostate carcinoma tissues. In vitro cancer cell experiments revealed that lncRNA-SNHG16 siRNA silencing downregulated the expressions of GLUT-1 and reduced glucose uptake. lncRNA-SNHG16 siRNA silencing also significantly inhibited prostate carcinoma cell proliferation. However, lncRNA-SNHG16 siRNA silencing did not affect the normal prostate. Conclusion: In conclusion, lncRNA-SNHG16 might be a possible treatment target for prostate cancer.