ABSTRACTNatural glucocorticoids, a class of cholesterol-derived hormones, modulate an array of metabolic, anti-inflammatory, immunosuppressive and cognitive signaling. The synthesis of natural glucocorticoids, largely cortisol in humans, is regulated by the hypothalamic-pituitary-adrenal (HPA) axis and exhibits pronounced circadian variation. Considering the central regulatory function of endogenous glucocorticoids, maintenance of the circadian activity of the HPA axis is essential to host survival and chronic disruption of such activity leads to systemic complications. There is a great deal of interest in synthetic glucocorticoids due to the immunosuppressive and anti-inflammatory properties and the development of novel dosing regimens that can minimize the disruption of endogenous activity, while still maintaining the pharmacological benefits of long-term synthetic glucocorticoid therapy. Synthetic glucocorticoids are associated with an increased risk of developing the pathological disorders related to chronic suppression of cortisol rhythmicity as a result of the potent negative feedback by synthetic glucocorticoids on the HPA axis precursors. In this study, a mathematical model was developed to explore the influence of chronopharmacological dosing of exogenous glucocorticoids on the endogenous cortisol rhythm considering intra-venous and oral dosing. Chronic daily dosing resulted in modification of the circadian rhythmicity of endogenous cortisol with the amplitude and acrophase of the altered rhythm dependent on the administration time. Simulations revealed that the circadian features of the endogenous cortisol rhythm can be preserved by proper timing of administration. The response following a single dose was not indicative of the response following long-term, repeated chronopharmacological dosing of synthetic glucocorticoids. Furthermore, simulations revealed the inductive influence of long-term treatment was only associated with low to moderate doses, while high doses generally led to suppression of endogenous activity regardless of the chronopharmacological dose. Finally, chronic daily dosing was found to alter the responsiveness of the HPA axis, such that a decrease in the amplitude of the cortisol rhythm resulted in a partial loss in the time-of-day dependent response to CRH stimulation, while an increase in the amplitude was associated with a more pronounced time-of-day dependence of the response. 相似文献
Virologica Sinica - The World Health Organization (WHO) has declared coronavirus disease 2019 (COVID-19) is the first pandemic caused by coronavirus named severe acute respiratory syndrome... 相似文献
Since the publication, in 1997, of the CPMP (Committee for Proprietary Medicinal Products) Points to Consider document on "The assessment of potential for QT prolongation by non-cardiovascular medicinal products," both regulatory bodies and the pharmaceutical industry have paid increasing attention to the conduct of careful preclinical studies on the subject. Regulatory attention has focused on the drafting of Safety Pharmacology guidelines through the ICH (International Conference on Harmonization) process, which resulted in approval by the ICH and acceptance by the three main regions (USA, Europe, and Japan) of the ICH S7A guideline. The guideline does not deal only with cardiovascular studies and does not provide guidance on QT investigations. This part has been deferred to a second guideline (ICH S7B). Nevertheless, pharmaceutical companies have implemented screening strategies aimed at selecting compounds that do not present QT liabilities. These strategies can differ according to the pharmaceutical class, while experimental models differ according to the stage of development of the compound. Several in vitro models are employed in discovery (radioligand binding, high-throughput patch clamp, efflux, and fluorescence assays). These models, coupled with in silico methods, allow companies to screen a high number of compounds. Other in vitro models, applied later in the R&D process (action potential duration, APD, in Purkinje fibers or papillary muscle and the isolated heart) are useful in better describing the activity of compounds on cardiac ion channels. The most robust and accepted in vivo test is represented by telemetry studies in conscious non-rodents. 相似文献
In this study, colorectal cancer (CRC)-diseased targets and resveratrol (Res)-associated targets were combined and constructed by the use of grouped databases for identification of the predicted targets. After production of target-functional protein interaction network of Res anti-CRC, the topological analysis was used to create the core targets of Res anti-CRC. All core targets performed the analyses of biological function and pathway enrichment to optimize the biological processes and key signaling pathways of Res anti-CRC. The resultant five core therapeutic targets of Res anti-CRC were identified as protein kinase B1 (AKT1), interleukin 6 (IL6), Tumor protein p53 (TP53), vascular endothelial growth factor, and mitogen-activated protein kinase 1, respectively. Biological processes of Res anti-CRC were predominantly associated with regulating apoptosis, immune response, cellular communication, signal transduction, and metabolism of the nuclide. In addition, the top 10 key signaling pathways were identified, respectively. In human CRC sample assays, CRC histologic sections showed elevated expression of AKT1 and IL6 proteins, accompanied with abnormal changes in blood molecules. In pharmacological experiments of Res anti-CRC in vitro, Res-treated HCT116 cells showed inhibited cell growth, induced cell death. In addition, downregulation of intracellular AKT1 and IL6 expression were checked in Res-treated HCT116 cells. Taken together, these bioinformatic findings and preliminary validated data uncovered pharmacological molecular mechanisms associated with Res anti-CRC, and further identified top five core therapeutic targets. Beneficially, these five predicted targets might serve as potential biomolecules for anti-CRC treatment. 相似文献
Farnesoid X receptor α (FXRα) as a bile acid sensor plays potent roles in multiple metabolic processes, and its antagonist has recently revealed special interests in the treatment of metabolic disorders, although the underlying mechanisms still remain unclear. Here, we identified that the small molecule N-benzyl-N-(3-(tert-butyl)-4-hydroxyphenyl)-2,6-dichloro-4-(dimethylamino) benzamide (NDB) functioned as a selective antagonist of human FXRα (hFXRα), and the crystal structure of hFXRα ligand binding domain (hFXRα-LBD) in complex with NDB was analyzed. It was unexpectedly discovered that NDB induced rearrangements of helix 11 (H11) and helix 12 (H12, AF-2) by forming a homodimer of hFXRα-LBD, totally different from the active conformation in monomer state, and the binding details were further supported by the mutation analysis. Moreover, functional studies demonstrated that NDB effectively antagonized the GW4064-stimulated FXR/RXR interaction and FXRα target gene expression in primary mouse hepatocytes, including the small heterodimer partner (SHP) and bile-salt export pump (BSEP); meanwhile, administration of NDB to db/db mice efficiently decreased the gene expressions of phosphoenolpyruvate carboxykinase (PEPCK), glucose 6-phosphatase (G6-pase), small heterodimer partner, and BSEP. It is expected that our first analyzed crystal structure of hFXRα-LBD·NDB will help expound the antagonistic mechanism of the receptor, and NDB may find its potential as a lead compound in anti-diabetes research. 相似文献
The biogenic amine serotonin ( 5‐hydroxytryptamine, 5‐HT) is a neurotransmitter in vertebrates and invertebrates. It acts in regulation and modulation of many physiological and behavioral processes through G‐protein‐coupled receptors. Five 5‐HT receptor subtypes have been reported in Drosophila that share high similarity with mammalian 5‐HT1A, 5‐HT1B, 5‐HT2A, 5‐HT2B, and 5‐HT7 receptors. We isolated a cDNA (Pr5‐HT8) from larval Pieris rapae, which shares relatively low similarity to the known 5‐HT receptor classes. After heterologous expression in HEK293 cells, Pr5‐HT8 mediated increased [Ca2+]i in response to low concentrations (< 10 nM) of 5‐HT. The receptor did not affect [cAMP]i even at high concentrations (> 10 μM) of 5‐HT. Dopamine, octopamine, and tyramine did not influence receptor signaling. Pr5‐HT8 was also activated by various 5‐HT receptor agonists including 5‐methoxytryptamine, (±)‐8‐Hydroxy‐2‐(dipropylamino) tetralin, and 5‐carboxamidotryptamine. Methiothepin, a non‐selective 5‐HT receptor antagonist, activated Pr5‐HT8. WAY 10635, a 5‐HT1A antagonist, but not SB‐269970, SB‐216641, or RS‐127445, inhibited 5‐HT‐induced [Ca2+]i increases. We infer that Pr5‐HT8 represents the first recognized member of a novel 5‐HT receptor class with a unique pharmacological profile. We found orthologs of Pr5‐HT8 in some insect pests and vectors such as beetles and mosquitoes, but not in the genomes of honeybee or parasitoid wasps. This is likely to be an invertebrate‐specific receptor because there were no similar receptors in mammals.