Notes

3D-reconstructions associated with Bast's Control device and also Membranous Labyrinth: Information with regard to Vestibular Implantation and also Meniere's Illness.
Silver nanoparticles (AgNPs) are widely incorporated into different hygiene, personal care, and healthcare products. However, few studies have been undertaken to determine the effects of biogenic AgNPs on human health. The effect of biosynthesized AgNPs using the fungus Aspergillus tubingensis culture was evaluated on human umbilical vein endothelial cells (HUVECs), normal human fibroblasts (FN1), human hepatoma cells (HEPG2) and a Galleria mellonella model. HUVECs were more susceptible to biogenic AgNPs than normal fibroblasts FN1 and intense cytotoxicity was observed only for very high concentrations at and above 2.5 μM for both cells. Normal human fibroblasts FN1 exposed to AgNPs for 24 h showed viability of 98.83 ± 8.40% and 94.86 ± 5.50% for 1.25 and 2.5 μM, respectively. At 5 and 10 μM, related to the control, an increase in cell viability was observed being 112.66 ± 9.94% and 117.86 ± 8.86%, respectively. Similar results were obtained for treatment for 48 and 72 h. At 1.25, 2.5, 5 and 10 μM of AgNPs, at 24 h, HUVECs showed 51.34 ± 7.47%, 27.01 ± 5.77%, 26.00 ± 3.03% and 27.64 ± 5.85% of viability, respectively. No alteration in cell distribution among different cycle phases was observed after HUVEC and normal fibroblast FN1 exposure to AgNPs from 0.01 to 1 μM for 24, 48 and 72 h. Based on the clonogenic assay, nanoparticles successfully inhibited HEPG2 cell proliferation when exposed to concentrations up to 1 μM. In addition to that, AgNPs did not induce senescence and no morphological alteration was observed by scanning electron microscopy on the endothelial cells. In the larvae of the wax moth, Galleria mellonella, a model for toxicity, AgNPs showed no significant effects, which corroborates to the safety of their use in mammalian cells. These results demonstrate that the use of A. tubingensis AgNPs is a promising biotechnological approach and these AgNPs can be applied in several biomedical situations. check details This journal is © The Royal Society of Chemistry 2019.Data show that toxicity to the central nervous system (CNS) is the most frequent cause of safety failures during the clinical phase of drug development. CNS endpoints such as seizure pose a safety risk to patients and volunteers and can lead to a loss of competitiveness, delays, and increased costs. Current methods rely on detection in the nonclinical rodent and non-rodent studies required to support clinical trials. There are two main issues with this approach; seizure may be missed in the animal studies and, even if seizure is detected, significant resource has already been invested in the project by this stage. Thus, there is a need to develop improved screening methods that can be used earlier in drug discovery to predict seizure. Advances in stem cell biology coupled with an increased understanding of the role of ion channels in seizure offer an opportunity for a new paradigm in screening. Human derived induced pluripotent stem cells (hiPSCs) representative of almost all cellular subtypes present in the brain can be incorporated into physiologically relevant in vitro models that can be used to determine seizure risk using high-throughput methods. Akin to the success of screening against a panel of ion channels such as hERG to reduce cardiovascular safety liability, the involvement of ion channels in seizure suggests that a similar approach to early seizure detection is valid. Profiling of the ion channels expressed in hiPSC models showing the seizurogenic phenotype coupled with electrophysiological assessment of ion channel function could translate into an ion channel seizure panel for rapid and reliable in vitro detection of seizure. The mechanistic information gathered would support optimal drug design early in development before resources, animals and time have been wasted. This journal is © The Royal Society of Chemistry 2019.Background Induction of biliary epithelial cell apoptosis by toxic bile acids is involved in the development of cholestatic disease, but the underlying molecular mechanism is not clear. The purpose of this study was to investigate the molecular mechanisms involved in Sirt6 protection against the apoptosis of human intrahepatic biliary epithelial cells (HiBEC) induced by the bile acid glycochenodeoxycholate (GCDC). Results Sirt6 was either overexpressed or knocked down in HiBEC, with or without GCDC pretreatment. The CCK-8 assay was used to assess cell viability and, Hoechst 33258 staining was used to determine apoptotic rate. Mitochondrial DNA (mtDNA) copy number, malondialdehyde (MDA) and reactive oxygen species (ROS) production were detected to evaluate the severity of the mitochondrial dysfunction and oxidative stress. The mRNA and protein levels of PGC-1α, Nrf1, and Nrf2 were analyzed using RT-qPCR and western blot assay. The results showed that Sirt6 opposed GCDC-induced apoptosis in HiBEC via up-regulating PGC-1α expression and stabilizing mtDNA. We used agonists and inhibitors of AMPK to demonstrate that Sirt6 increased PGC-1α expression through the AMPK pathway whereas GCDC had the opposite effect. Finally, western blot, luciferase assay, and co-immunoprecipitation were used to describe a direct interaction and acetylation modification of PGC-1α by Sirt6. Conclusion Our data illuminated that Sirt6 ameliorated GCDC-induced HiBEC apoptosis by upregulating PGC-1α expression through the AMPK pathway and its deacetylation effect. © The Author(s) 2020.Background Microglia-mediated neuroinflammation is associated with epilepsy. Switching microglial polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype represents a novel therapeutic strategy for mitigating epileptogenesis. We previously found that dynorphins protected against epilepsy via activation of kappa opioid receptor (KOR). Here, this study aims to investigate the role and the mechanism of dynorphin in regulating microglial polarization. Methods A pilocarpine-induced rat model of epilepsy was established and lipopolysaccharide (LPS)-activated BV-2 microglial cells were used as an inflammatory model to explore the mechanism of dynorphin regulating microglial polarization. Results Overexpression of the dynorphin precursor protein prodynorphin (PDYN) alleviated the pilocarpine-induced neuronal apoptosis, promoted microglial polarization to the M2 phenotype, and inhibited pilocarpine-induced Toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) pathway in the hippocampi of epileptic rats.
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