Accumulating evidence suggests that the non-receptor tyrosine kinase c-Abl plays an important role in the progression of Parkinson’s disease (PD) and c-Abl inhibition could be neuroprotective in PD and related α-synucleinopathies. Nilotinib, a c-Abl inhibitor, has shown improved motor and cognitive symptoms in PD patients. However, issues concerning blood–brain barrier (BBB) penetration, lack of selectivity and safety still remain. Radotinib HCl is a selective Bcr-Abl kinase inhibitor that not only effectively access the brain, but also exhibits greater pharmacokinetic properties and safety profiles compared to Nilotinib and other c-Abl inhibitors. Here, we show the neuroprotective efficacy of Radotinib HCl, a brain penetrant c-Abl inhibitor, in a pre-clinical model of PD. Importantly, in vitro studies demonstrate that the treatment of Radotinib HCl protects the α-synuclein preformed fibrils (PFF)-induced neuronal toxicity, reduces the α-synuclein PFF-induced Lewy bodies (LB)/Lewy neurites (LN)-like pathology and inhibits the α-synuclein PFF-induced c-Abl activation in primary cortical neurons. Furthermore, administration of Radotinib HCl inhibits c-Abl activation and prevents dopaminergic neuron loss, neuroinflammation and behavioral deficits following α-synuclein PFF-induced toxicity in vivo. Taken together, our findings indicate that Radotinib HCl has beneficial neuroprotective effects in PD and provides an evidence that selective and brain permeable c-Abl inhibitors can be potential therapeutic agents for the treatment of PD and related α-synucleinopathies.

ABSTRACTradotinib in Philadelphia chromosome-positive chronic phase-CML patients with resistance and/or intolerance to prior BCR-ABL1 tyrosine kinase inhibitors. (clinicaltrials.gov identifier: 01602952) MethodsAdditional details of the study design and methods can be found in the Online Supplementary Appendix.

A two-dimensional molybdenum disulfide (MoS2)-based gas sensor was decorated with Pt nanoparticles (NPs) for high sensitivity and low limit of detection (LOD) for specific gases (NH3 and H2S). The two-dimensional MoS2 film was grown at 400°C using metal organic gas vapour deposition. To fabricate the MoS2 gas sensor, an interdigitated Au/Ti electrode was deposited using the electron beam (e-beam) evaporation method with a stencil mask. The MoS2 gas sensor without metal decoration sensitively detects NH3 and H2S gas down to 2.5 and 30 ppm, respectively, at room temperature (RT). However, for improved detection of NH3 and H2S gas, we investigated the functionalization strategy using metal decoration. Pt NP decoration modulated the electronic properties of MoS2, significantly improving the sensitivity of NH3 and H2S gas by 5.58× and 4.25×, respectively, compared with the undecorated MoS2 gas sensor under concentrations of 70 ppm. Furthermore, the Pt NP-decorated MoS2 sensor had lower LODs for NH3 and H2S gas of 130 ppb and 5 ppm, respectively, at RT.

This paper presents experimental results on sulfur bonding to etched GaAs surfaces which have an As/Ga ratio ranging from 0.6 to 6.0. The source of the sulfur was either a liquid solution of Na2S or (NH4)2S, or gaseous H2S applied in a N2 purged glove box. Angle resolved x-ray photoelectron spectroscopy (XPS) spectra was obtained from ∼40 different samples in order to determine the concentration of the various surface chemical species and their bonding state. Most of the experiments were conducted with H2S exposed samples at substrate temperatures from 30 to 350 °C. Sulfur is shown to bond to both Ga and As. The amount of bonding to each depends on the As/Ga ratio. This is true for both H2S and the liquid S solutions. Only one S–As bonding state was observed, independent of the S treatment process. S was observed to bond to elemental As and substrate As with the same binding energy and concentration. H2S exposed surfaces had a higher concentration of S than did those that were treated with Na2S or the (NH4)2S.

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It is well known that the CYP2C19 genetic polymorphism influences the pharmacokinetics and pharmacodynamics of proton pump inhibitors (PPIs), but no report has addressed the effects on ilaprazole, a newly developed PPI. To investigate the effects of the CYP2C19 genetic polymorphism on the disposition and pharmacodynamics of ilaprazole, multiple doses of once-daily 10 mg ilaprazole were repeatedly administered for 7 days to 27 healthy Korean participants, comprising 9 homozygous CYP2C19 extensive metabolizers (homo EMs), 10 heterozygous EMs (hetero EMs), and 8 homozygous poor metabolizers (PMs). The plasma concentration and pharmacodynamic response were measured in the last dose interval. Each genotype group was matched for gender and thus was composed of 4 male and 4 female participants when the analysis was conducted. The pharmacokinetic parameters estimated from the plasma concentrations of ilaprazole and its metabolite ilaprazole sulfone, the serum gastrin level, and the 24-hour intragastric pH were compared among the CYP2C19 genotype groups. No statistically significant differences in the maximum plasma concentration at steady state(C(ss,max)) and the area under the concentration-time curve from zero to 24 hours (AUC(τ)) of ilaprazole and ilaprazole sulfone were observed among the homo EM, hetero EM, and PM CYP2C19 genotypes. In addition, the mean 24-hour intragastric pH, the percentage of time at pH >4, and the AUC(τ) of serum gastrin showed no significant differences among the CYP2C19 genotype groups. The data suggests that the pharmacokinetics and pharmacodynamics of ilaprazole are not significantly influenced by the CYP2C19 genetic polymorphism in healthy participants.

Thiazolidinedione. -A variety of novel pyrimidine derivatives having a thiazolidinedione moiety [cf. (X), (XI)] is synthesized and evaluated for their antidiabetic activity. Derivatives (Xc) and (Xd) exhibit considerably more potent biological activities than the reference compounds rosiglitazone and pioglitazone. -(LEE, H. W.; KIM, B. Y.; AHN, J. B.; KANG, S. K.; LEE, J. H.; SHIN, J. S.; AHN, S. K.; LEE, S. J.; YOON, S. S.; Eur.

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