QbD driven targeted pulmonary delivery of dexamethasone-loaded chitosan microspheres: Biodistribution and pharmacokinetic study.

Inhaling drugs, on the other hand, is limited mainly by the natural mechanisms of the respiratory system, which push drug particles out of the lungs or make them inefficient once they are there. Because of this, many ways have been found to work around the problems with drug transport through the lungs. Researchers have made polymeric microparticles (MP) and nanoparticles as a possible way to get drugs into the lungs. They showed that the drug could be trapped in large amounts and retained in the lungs for a long time, with as little contact as possible with the bloodstream. MP were formulated in this study to get dexamethasone (DMC) into the pulmonary area. The Box-Behnken design optimized microspheres preparation to meet the pulmonary delivery prerequisites. Optimized formulation was figured out based on the desirability approach. The mass median aerodynamic diameter (MMAD) of the optimized formula (O-DMC-MP) was 8.46 ± 1.45 µm, and the fine particle fraction (FPF) was 77.69 ± 1.26%. This showed that it made suitable drug delivery system, which could make it possible for MP to settle deeply in the lung space after being breathed in. With the first burst of drug release, it was seen that drug release could last up to 16 h. Also, there was no clear sign that the optimized formulation was toxic to the alveoli basal epithelial cells in the lungs, as supported by cytotoxic studies in HUVEC, A549, and H1299 cell lines. Most importantly, loading DMC inside MP cuts the amount of drug into the bloodstream compared to plain DMC, as evident from biodistribution studies. Stability tests have shown that the product can stay the same over time at both the storage conditions. Using chitosan DMC-MP can be a better therapeutic formulation to treat acute respiratory distress syndrome (ARDS).

Drosophila MOF regulates DIAP1 and induces apoptosis in a JNK dependent pathway.

Histone modulations have been implicated in various cellular and developmental processes where in Drosophila Mof is involved in acetylation of H4K16. Reduction in the size of larval imaginal discs is observed in the null mutants of mof with increased apoptosis. Deficiency involving Hid, Reaper and Grim [H99] alleviated mof (RNAi) induced apoptosis in the eye discs. mof (RNAi) induced apoptosis leads to activation of caspases which is suppressed by over expression of caspase inhibitors like P35 and Diap1 clearly depicting the role of caspases in programmed cell death. Also apoptosis induced by knockdown of mof is rescued by JNK mutants of bsk and tak1 indicating the role of JNK in mof (RNAi) induced apoptosis. The adult eye ablation phenotype produced by ectopic expression of Hid, Rpr and Grim, was restored by over expression of Mof. Accumulation of Mof at the Diap1 promoter 800 bp upstream of the transcription start site in wild type larvae is significantly higher (up to twofolds) compared to mof (1) mutants. This enrichment coincides with modification of histone H4K16Ac indicating an induction of direct transcriptional up regulation of Diap1 by Mof. Based on these results we propose that apoptosis triggered by mof (RNAi) proceeds through a caspase-dependent and JNK mediated pathway.

Anthranilamide-pyrazolo[1,5-a]pyrimidine conjugates as p53 activators in cervical cancer cells.

A library of new anthranilamide-pyrazolo[1,5-a]pyrimidine conjugates were designed, synthesized, and evaluated for their anticancer activity in cervical cancer cells such as HeLa and SiHa that possess low levels of p53. All 24 conjugates showed antiproliferative activity, while some of them exhibit significant cytotoxicity. In assays related to cell-cycle distribution, these conjugates induced G(2) /M arrest in HeLa cells and G(1) cell-cycle arrest in SiHa cells. Immunocytochemistry assays revealed that these compounds cause nuclear translocation of p53, thereby indicating the activation of p53. In cervical cancer cells, the p53 protein is degraded by E6 oncoprotein. Immunoblot and RT-PCR analyses proved the presence of mitochondria-mediated apoptosis with involvement p53 target genes such as BAX, Bcl2, and p21 (CDKI). Moreover, these compounds increased the phosphorylated forms of p53 and provide signals for apoptosis induction. Interestingly, one of the conjugates, (2-phenyl-7-(3,4,5-trimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-5-yl)(4-(2-(thiophen-2-ylmethylamino)benzoyl)piperazin-1-yl)methanone, is the most promising candidate in this series and has the potential to be taken up for further detailed studies.