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“2-Aminothiazoles are a new class of small molecules with antiprion activity in prion-infected neuroblastoma cell lines (J. Virol. 2010, 84, 3408). We report here structure-activity studies undertaken to improve the potency and physiochemical properties of 2-aminothiazoles, with a particular emphasis on achieving and sustaining
high drug concentrations in the brain. The results of this effort include the generation of informative structure-activity relationships (SAR) and SNX-5422 inhibitor the identification of lead compounds that are orally absorbed and achieve high brain concentrations in animals. The new aminothiazole analogue (5-methylpyridin-2-yl)-[4-(3-phenylisoxazol-5-yl)-thiazol-2-yl]-amine (27), for example, exhibited an EC(50) of 0.94 mu M in prion-infected neuroblastoma AL3818 cells (ScN2a-cl3)
and reached a concentration of similar to 25 mu M in the brains of mice following three days of oral administration in a rodent liquid diet. The studies described herein suggest 2-aminothiazoles as promising new leads in the search for effective therapeutics for prion diseases.”
“Background. Peritonitis is a common cause of surgical sepsis. The failure of the host to mount an appropriate immune response contributes to persistence of the infection. We investigated the role microRNAs may play in this failed immune response.\n\nMethods. Klebsiella pneumoniae was injected intraperitoneally in mice. Weight loss was used to predict clinical outcome. Peritoneal exudate cells (PECs) and supernatant were collected. RNA from PECs was run on screening microRNA array cards to determine
gene expression, and validated by single assay analysis. Cytokine levels in supernatant were assayed by enzyme-linked immunosorbent assay.\n\nResults. Despite similar bacterial levels, Selleck GW786034 PEG counts were higher in the predicted death group. The predicted deaths had higher levels of proinflammatory tumor necrosis factor-alpha/IL-6 and significantly lower levels of interleukin-10. MiR-221 was up-regulated in both the predicted death and predicted survivor groups. Five miRNAs were up-regulated in the predicted survivor group compared with normal controls.\n\nConclusion. Higher PEG counts and proinflammatory cytokines in the predicted death group indicates an exaggerated inflammatory response, with lower IL-10 levels despite similar bacterial counts. There were two dysregulated miRNAs with transcriptional targets that may explain our results. A more balanced immune response with an appropriate counter inflammatory response may be important for improving survival.