Current Issue : January - March Volume : 2020 Issue Number : 1 Articles : 5 Articles
Inflammatory activation of astroglia adds to the pathology of various neurological\ndiseases. Astrocytes respond to microglia-derived cytokines such as interleukin-1alpha (IL-1alpha)\nwith enhanced inflammatory signaling.This provokes pro-inflammatory gene expression\nof, among others, the eicosanoid-generating enzyme prostaglandin endoperoxide synthase 2\n(Ptgs2). Whereas metabolic regulation of innate immune cell inflammatory responses is intensely\nstudied, pathways related to how metabolism modulates inflammatory signaling in astrocytes\nare underexplored. Here, we examined how mitochondrial oxidative phosphorylation affects\ninflammatory responses towards IL-1alpha and tumor necrosis factor alpha in neonatal rat astrocytes.\nBlocking respiratory complex I and III or adenosine triphosphate (ATP) synthase did not affect\nactivation of inflammatory signaling by IL-1alpha, but did elicit differential effects on inflammatory gene\nmRNA expression. Remarkably, mRNA and protein expression of Ptgs2 by IL-1alpha was consistently\nup-regulated when oxidative phosphorylation was inhibited. The increase of Ptgs2 resulted\nfrom mRNA stabilization. Mitochondrial inhibitors also increased IL-1alpha-triggered secretion of\neicosanoids, such as prostaglandin E2, prostaglandin F2alpha, and 6-keto-prostaglandin F1alpha, as assessed\nby liquid chromatography/mass spectrometry. Mechanistically, attenuating oxidative phosphorylation\nelevated adenosine monophosphate (AMP) and activated AMP-activated protein kinase (AMPK).\nAMPK silencing prevented Ptgs2 up-regulation by mitochondrial inhibitors, while AMPK activators\nrecapitulated Ptgs2 mRNA stability regulation. Our data indicate modulation of astrocyte\ninflammatory responses by oxidative metabolism, with relevance towards eicosanoid production....
Drug metabolic enzymes and transporters are responsible for an important variability\nin drug disposition. The cocktail approach is a sound strategy for the simultaneous evaluation\nof several enzyme and transporter activities for a personalized dosage of medications. Recently,\nwe have demonstrated the reliability of the Geneva cocktail, combining the use of dried blood spots\n(DBS) and reduced dose of phenotyping drugs for the evaluation of the activity of six cytochromes\nand P-glycoprotein (P-gp). As part of a study evaluating potential drugâ??drug interactions between\nprobe drugs of the Geneva cocktail, the present paper focuses on the impact of cytochromes (CYP)\nprobe drugs on the disposition of fexofenadine, a P-gp test drug. In a randomized four-way\nLatin-square crossover study, 30 healthy volunteers (15 men and 15 women) received caffeine 50 mg,\nbupropion 20 mg, flurbiprofen 10 mg, omeprazole 10 mg, dextromethorphan 10 mg, midazolam 1 mg,\nand fexofenadine 25 mg alone (or as part of a previously validated combination) and all together\n(Geneva cocktail). The determination of drug concentrations was performed in DBS samples and\npharmacokinetic parameters were calculated. Fexofenadine AUC0â??8 h and Cmax decreased by 43%\n(geometric mean ratio: 0.57; CI 90: 0.50â??0.65; p < 0.001) and 49% (geometric mean ratio: 0.51; CI\n90: 0.44â??0.59; p < 0.001), respectively, when fexofenadine was administered as part of the Geneva\ncocktail in comparison to fexofenadine alone. Consequently, the apparent oral clearance (Cl/F)\nincreased 1.7-fold (CI 90: 1.49â??1.93; p < 0.001). There was no interaction between the remaining\nprobes. In conclusion, an unexpected interaction occurred between fexofenadine and one or several\nof the following substances: caffeine, bupropion, flurbiprofen, omeprazole, dextromethorphan,\nand midazolam. Further studies are necessary to elucidate the mechanism of this interaction....
Lurasidone is an atypical mood-stabilizing antipsychotic agent with unique receptorbinding\nprofile, including 5-HT7 receptor (5-HT7R) antagonism. Effects of 5-HT7R antagonism on\ntransmitter systems of schizophrenia and mood disorders, however, have not been well clarified.\nThus, this study examined the mechanisms underlying the clinical effects of lurasidone by\nmeasuring mesocortical serotonergic transmission. Following systemic and local administrations of\nlurasidone, MK801 and 5-HT receptor modulators, we determined releases of 5-HT in dorsal raphe\nnucleus (DRN), mediodorsal thalamic nucleus (MDTN) and medial prefrontal cortex (mPFC) and\nGamma-aminobutyric acid (GABA) in DRN using multiprobe microdialysis with ultra-high-performance\nliquid chromatography (UHPLC). Serotonergic and GABAergic neurons in the DRN are\npredominantly regulated by inhibitory 5-HT1A receptor (5-HT1AR) and excitatory 5-HT7R,\nrespectively. Lurasidone acutely generates GABAergic disinhibition by 5-HT7R antagonism, but\nconcomitant its 5-HT1AR agonism prevents serotonergic hyperactivation induced by 5-HT7R\ninhibition. During treatments with 5-HT1AR antagonist in DRN, lurasidone dose-dependently\nincreased 5-HT release in the DRN, MDTN and mPFC. Contrary, lurasidone chronically enhanced\nserotonergic transmission and GABAergic disinhibition in the DRN by desensitizing both 5-HT1AR\nand 5-HT7R. These effects of lurasidone acutely prevented MK801-evoked 5-HT release by\nGABAergic disinhibition via N-methyl-D-aspartate (NMDA)/glutamate receptor (NMDA-R)-\nmediated inhibition of 5-HT1AR function, but enhanced MK801-induced 5-HT release by\ndesensitizing 5-HT1AR and 5-HT7R. These results indicate that acutely lurasidone fails to affect 5-\nHT release, but chronically enhances serotonergic transmission by desensitizing both 5-HT1AR and\n5-HT7R. These unique properties of lurasidone ameliorate the dysfunctions of NMDA-R and\naugment antidepressive effects....
Tamoxifen (TAM) is an estrogen-receptor antagonist, widely used in the\nadjuvant treatment of early stage estrogen-sensitive breast cancer. Several studies have revealed\nnew biological targets of TAM that mediate the estrogen receptor independent activities of the drug.\nRecently, the antiviral activity of TAM on replication of human immunodeficiency virus (HIV),\nhepatitis C virus (HCV) and Herpes simplex virus (HSV-1) in vitro was described. In the current\nstudy, we aimed to investigate the effect of TAM on infection with vesicular stomatitis virus (VSV).\nMethods: Vero cells were treated with different concentrations of TAM for 24 h and then infected\nwith VSV. Additionally, C57BL/6 mice were pretreated with 4 mg TAM, one day and three days before\ninfection with VSV. Results: Treatment of Vero cells with TAM suppressed the viral replication of VSV\nin vitro and in vivo. The inhibitory effect of TAM on VSV replication correlated with an enhanced\ninterferon-I response and stimulation of macrophages. Conclusions: TAM was identified as being\ncapable to protect from VSV infection in vitro and in vivo. Consequently, this antiviral function (as\nan advantageous side-effect of TAM) might give rise to new clinical applications, such as treatment of\nresistant virus infections, or serve as an add-on to standard antiviral therapy....
Scope: Peptides containing tryptophanâ??tyrosine sequences, including the lacto-tetrapeptide\nglycineâ??threonineâ??tryptophanâ??tyrosine (GTWY) and Beta-lactolin, from Beta-lactoglobulin in whey\nenzymatic digestion, enhance hippocampus-dependent memory functions, which are blocked\nby the systemic administration of dopamine D1-like antagonist. In this study, we investigated the\nrole of the hippocampal dopaminergic system in the memory-enhancing effect of Beta-lactolin. Methods\nand Results: The results of in vivo microdialysis revealed that oral administration of Beta-lactolin\nincreased the extracellular concentration of dopamine in the hippocampus and enhanced both spatial\nworking memory, as measured in the Y-maze test, and spatial reference memory, as measured in\nthe novel object location test. These memory-enhancing effects of Beta-lactolin, but not the baseline\nmemory functions, were impaired by the knockdown of the dopamine D1 receptor subtype in the\nhippocampus. Beta-Lactolin also enhanced object memory, as measured by the novel object recognition\ntest. However, D1 knockdown in the hippocampus spared this memory function either with or without\nthe administration of Beta-lactolin. Conclusions: The present results indicate that oral administration\nof Beta-lactolin increases dopamine release and D1 receptor signaling in the hippocampus, thereby\nenhancing spatial memory, but it may improve object memory via a separate mechanism....
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