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eased collagen and IVS thickening in heart development.Identifying the metabolites of a drug has become an indispensable task in the development of new drugs. Dipfluzine (Dip) is a promising candidate for the treatment of cerebral vascular diseases and has 5 metabolites (M1∼M5) in rat urine and liver microsomes, but their biological activity is still unknown. Because selective cerebral vasodilation is a main role of Dip, we investigated the vasodilation of Dip and its 5 metabolites in isolated Sprague-Dawley (SD) male rat basilar arteries preconstricted with high-K+ or 5-HT. The results showed that only M1 possessed concentration-dependent inhibitory activity on the vasoconstriction of arteries with or without the endothelium, and M1 has a more potent vasodilatory effect than Dip on both contraction models. Like Dip, the vasodilatory mechanisms of M1 may be not only related to receptor-operated and voltage-dependent calcium ion channels of smooth muscle cells but also to the release of NO and EDHF from endothelial cells and the opening of Ca2+-activated K+ channels and ATP-sensitive potassium ion channels. Unlike Dip, the vasodilation mechanism of M1 is also related to the opening of voltage-sensitive K+ channel. Together with more selectivity to non-VDCC than Dip, this may partially explain why M1 has stronger vasodilatory effects than Dip. The mechanisms of vasodilation of Dip and M1 may result from the combined action of these or other factors, especially blocking non-endothelium dependent non-VDCC and endothelium dependent IKCa channels. These results point to the possibility that M1 provides synergism for the clinical use of Dip, which may inform the synthesis of new drugs.The organic selenium compound diphenyl diselenide (DD) has been recognized as an antioxidant and neuroprotective agent, exerting an anti-hyperglycemic effect in experimental models of diabetes. However, the precise mechanisms involved in the protection are unclear. Using the zebrafish (Danio rerio) as a model organism, here we investigated biomarkers underlying the protective effects of DD against hyperglycemia, targeting in a transcriptional approach the redox and insulin-signaling pathway. Fish were fed on a diet containing DD (3 mg/kg) for 74 days. In the last 14 days, they were exposed to a 111 mM glucose solution to induce a hyperglycemic state. DD reduced blood glucose levels as well as normalized the brain mRNA transcription of four insulin receptors-coding genes (Insra1, Insra2, Insrb1, Insrb2), which were down-regulated by glucose. DD alone caused an up-regulation of relative mRNA transcription in both Insra receptors and glucose transporter 3 genes. DD counteracted hyperglycemia-induced lipid peroxidation, protein and thiol depletion. Along with the decreased activity of antioxidant enzymes SOD and GPx, the brain of hyperglycemic fish presented a reduction in mRNA transcription of FoxO3A, FoxO3B, Nrf2, GPx3A, SOD1, and SOD2 genes. Besides normalizing the transcriptional levels, DD caused an up-regulation of relative mRNAs that encode Nrf2, FoxO1A, FOXO3A, GPx4A, PTP1B, AKT and SelP. Collectively, our findings suggest that the antioxidant and anti-hyperglycemic actions of DD in a zebrafish diabetes model are likely associated with the regulation of the oxidative stress resistance and the insulin-signaling pathway and that could be related to the modulation at mRNA level of two important transcription factors, Nrf2 and FoxO.Background Preoperative planning with commercially available imaging software in shoulder arthroplasty may allow for improved decision making and more accurate placement of the glenoid component. Methods 81 consecutive shoulder computed tomography (CT) scans obtained for preoperative planning purposes for shoulder arthroplasty were analyzed by commercially available software from four companies (Blueprint - Wright Medical, Memphis, TN; GPS - Exactech, Gainesville, FL, USA; Materialise - DJO, Vista, CA, USA; and VIP - Arthrex, Naples, FL, USA), and by 5 fellowship trained sports medicine/shoulder surgeons. Inclination, version and subluxation of the humerus were measured in a blinded fashion on axial and coronal sequences at the mid-glenoid. Surgeon measurements were analyzed for agreement, and were compared to the 4 commercial programs. Results Surgeon reliability was acceptable for version (intraclass correlation coefficient (ICC) 0.876), inclination (ICC0.84), and subluxation (ICC 0.523). Significant differences were found between surgeon and commercial software measurements in version (p=0.03), inclination (p=0.023) and subluxation (p less then 0.001). Software measurements tended to be more superiorly inclined (average -2° to 2° greater), more retroverted (average 2°-5° greater) and more posteriorly subluxed (average 7°-10° greater) than surgeon measurements. In comparing imaging software measurements only Blueprint produced significantly different version measurements than surgeon measurements (p=0.02). Conclusion Preoperative planning software for shoulder arthroplasty has limited agreement in measures of version, inclination and subluxation measurements while surgeons have high inter-reliability. Surgeons should be cautious when using commercial software planning systems and when comparing publications that use different planning systems to determine preoperative glenoid deformity measurements.The use of genomic approaches in toxicological studies has greatly increased our ability to define the molecular profiles of environmental chemicals associated with developmental neurotoxicity (DNT). Integration of these approaches with adverse outcome pathways (AOPs), a framework that translates environmental exposures to adverse developmental phenotypes, can potentially inform DNT testing strategies. Here, using retinoic acid (RA) as a case example, we demonstrate that the integration of toxicogenomic profiles into the AOP framework can be used to establish a paradigm for chemical testing. ZD1839 mouse RA is a critical regulatory signaling molecule involved in multiple aspects of mammalian central nervous system (CNS) development, including hindbrain formation/patterning and neuronal differentiation, and imbalances in RA signaling pathways are linked with DNT. While the mechanisms remain unresolved, environmental chemicals can cause DNT by disrupting the RA signaling pathway. First, we reviewed literature evidence of RA and other retinoid exposures and DNT to define a provisional AOP related to imbalances in RA embryonic bioavailability and hindbrain development. link2 Next, by integrating toxicogenomic datasets, we defined a relevant transcriptomic signature associated with RA-induced developmental neurotoxicity (RA-DNT) in human and rodent models that was tested against zebrafish model data, demonstrating potential for integration into an AOP framework. Finally, we demonstrated how these approaches may be systematically utilized to identify chemical hazards by testing the RA-DNT signature against azoles, a proposed class of compounds that alters RA-signaling. The provisional AOP from this study can be expanded in the future to better define DNT biomarkers relevant to RA signaling and toxicity.Quinolone-based Schiff base zirconium(IV) complex was studied as potential bacterial inhibitor against Gram-positive Staphylococcus aureus and Gram-negative Salmonella typhi growth, showing that the interaction of the complex with L-glutamine which presents in the membrane of wall leads cell death, and the mode of bacterial interaction was analyzed theoretically by DFT. Furthermore, the interaction of different amino acid residues L-alanine, D-alanine, L-lysine and D-glutamine with the metal complex through UV-vis docking studies was conducted observing that D-glutamine interacts efficiently among other amino acid residues. This observation is consistent with the interaction of the metal complex that was effective when participating in an insight of the peptidoglycan cell wall since the binding nature of glutamine potentially inhibits these microorganisms.Lennox-Gastaut Syndrome (LGS) is a rare form of childhood epilepsy. Rufinamide is an orphan drug indicated for the treatment of LGS. Three-Dimensional Printing (3DP) is a process in which solid objects are created based on a digital file by adding materials layer by layer. Fused deposition modelling (FDM) is a 3DP technique with the advantages of solid dispersion systems and the ability to use various pharmaceutical excipients in small scales, which makes this technology favorable for the production of orphan drugs. Rufinamide is a water-insoluble lipophilic compound which can exist in different polymorphic forms. The therapeutic dose is 3200 mg/day, at which rufinamide exhibits nonlinear pharmacokinetics, which may be attributed to its limited solubility. The main purpose of this paper is to improve the dissolution of rufinamide through the use of 3DP technology. For this purpose, optimum 3DP tablets were developed based on 3DP manufacturability and dissolution behaviors. The findings suggest that a mixture of hydroxypropyl methylcellulose (HPMC), Soluplus®, Kollidon® VA64, Gelucire® 48/16 and Triacetin are suitable excipients for FDM-3DP technology that can improve the dissolution of rufinamide. The optimum 3DP tablet shows significantly higher dissolution than Inovelon® at the therapeutic dose due to its improved wdissolution.Ethnopharmacological relevance Yuk-Mi-Jihwang-Tang (YJT) has been popularly prescribed to treat aging related disorders over than hundreds of years in East Asia countries. link3 Aim of the study To investigate possible modulatory actions of YJT on chronic restraint stress (CRS)-induced neurodegeneration on hippocampus neuronal injuries. Materials and methods Mice were orally administered with YJT (100, 200, or 400 mg/kg) or ascorbic acid (100 mg/kg) before 4 h of stress for 28 days. Morris water maze task was completed from day 24th to 28th, and stress hormones and biochemical analyzes were measured. Results Four weeks of the CRS abnormally affected memory impairments by measurement of escape latency and time spent in the target quadrant. Additionally, neurotransmitters were also drastically altered in serum or hippocampus protein levels by CRS. Gene expressions for 5-hydroxytryptamine (5-HT) receptor, 5-HT-transport, and tryptophan hydroxylase were also altered, whereas YJT led to normalize the above alterations. Additionally, YJT also beneficially worked on endogenous redox system as well as inflammatory reactions in the hippocampal neurons. We observed that hippocampal excitotoxicity was induced by CRS which were evidenced by depletion of phosphor-cAMP response element-binding protein, brain-derived neurotrophic factor, nuclear factor erythroid-2-related factor 2, heme oxygenase-1 and abnormally increases of acetylcholine esterase activities in hippocampus protein levels; however, YJT considerably improved the above pathological conditions. Conclusions Our findings supported YJT enhance memory function via regulation of hippocampal excitotoxicity-derived memory impairment, stress hormone, and endogenous redox, respectively.Nuclear egress is a rate-limiting step of herpesviral replication, restricting the nucleocytoplasmic transport of viral capsids. The process is regulated by two viral nuclear egress proteins (core NEC pUL50-pUL53), which recruit additional cellular and viral proteins. The multicomponent NEC mediates disassembly of the nuclear lamina barrier and the docking of nuclear capsids. The quantitation of nuclear egress has been accomplished by electron microscopic analysis, but is generally hampered by the low number of detectable cytoplasmic capsids. A newly established method for the quantitation of viral nuclear egress improves the characterization of viral mutants, host cell permissiveness and antiviral drug efficacy. In this study, various strains of human cytomegalovirus (HCMV) were used to measure the replication efficiencies in primary human fibroblasts, applying methods of cell fractionation, DNase digestion, sucrose cushions and quantitative PCR. Several stages of optimization led to a reliable quantitative assay that allowed the characterization of viral nuclear egress efficacy.