1,656 research outputs found

    The Concise Guide to PHARMACOLOGY 2023/24:Nuclear hormone receptors

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    The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and nearly 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (https://www.guidetopharmacology.org/), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.16179. Nuclear hormone receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein-coupled receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.</p

    Relacorilant, a Selective Glucocorticoid Receptor Modulator in Development for the Treatment of Patients With Cushing Syndrome, Does Not Cause Prolongation of the Cardiac QT Interval

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    Objective: To assess the effect of relacorilant, a selective glucocorticoid receptor modulator under investigation for the treatment of patients with endogenous hypercortisolism (Cushing syndrome [CS]), on the heart rate–corrected QT interval (QTc). Methods: Three clinical studies of relacorilant were included: (1) a first-in-human, randomized, placebo-controlled, ascending-dose (up to 500 mg of relacorilant) study in healthy volunteers; (2) a phase 1 placebo- and positive-controlled thorough QTc (TQT) study of 400 and 800 mg of relacorilant in healthy volunteers; and (3) a phase 2, open-label study of up to 400 mg of relacorilant administered daily for up to 16 weeks in patients with CS. Electrocardiogram recordings were taken, and QTc change from baseline (ΔQTc) was calculated. The association of plasma relacorilant concentration with the effect on QTc in healthy volunteers was assessed using linear mixed-effects modeling. Results: Across all studies, no notable changes in the electrocardiogram parameters were observed. At all time points and with all doses of relacorilant, including supratherapeutic doses, ΔQTc was small, generally negative, and, in the placebo-controlled studies, similar to placebo. In the TQT study, placebo-corrected ΔQTc with relacorilant was small and negative, whereas placebo-corrected ΔQTc with moxifloxacin positive control showed rapid QTc prolongation. These results constituted a negative TQT study. The model-estimated slopes of the concentration-QTc relationship were slightly negative, excluding an association of relacorilant with prolonged QTc. Conclusion: At all doses studied, relacorilant consistently demonstrated a lack of QTc prolongation in healthy volunteers and patients with CS, including in the TQT study. Ongoing phase 3 studies will help further establish the overall benefit-risk profile of relacorilant.</p

    In-cell analysis of FK506 binding protein 51-glucocorticoid receptor-heat shock protein 90 interaction at single residue resolution

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    The large immunophilins FKBP51 and FKBP52 play key roles in the Hsp90-mediated maturation of steroid hormone receptors, which is crucial for stress-related disorders and correct sexual embryonic development, respectively. A prominent regulatory target is the glucocorticoid receptor (GR), whose activation is repressed by FKBP51 and facilitated by FKBP52. Despite their vital roles, the molecular modes of action of FKBP51 and FKBP52 are poorly understood since the transient key states of FKBP-mediated GR-regulation have remained experimentally elusive. This work presents a systematic incorporation of a photoreactive amino acid inside human cells that allows capture of the transient FKBP51-GR-Hsp90 interactions. A photoreactive, unnatural amino acid is site specifically incorporated by amber suppression and acts as a proximity sensor to map the interaction at single residue resolution. This is first established for FKBP51, where the FKBP51-Hsp90 interaction interface is explored well beyond the known FKBP51-TPR-domain mediated interaction including both the FK1- and FK2-domain of FKBP51. Additionally, the Hsp90 cochaperone p23 is identified as a direct interaction partner of FKBP51 suggesting that a multi-protein complex is needed for a functional Hsp90 machinery. Creating a suitable, high-throughput analysis for mapping protein interaction via ELISA allows the elucidation of the GR-FKBP51 interaction interface in great detail. The identified crosslinking sites all depend on a functional Hsp90 chaperone cycle, are disrupted by GR activation, and cluster in characteristic patterns, defining the relative orientation and contact surfaces within the FKBP51/p23-apoGR complexes. Moreover, the developed ELISA enables quantification of in-cell activation of the GR by its synthetic agonist dexamethasone. GR-->FKBP52 crosslinks were found to be 5-fold more sensitive to GR activation compared to GR-->FKBP51 crosslinks. The ELISA data show that GR activation is facilitated in the context of a FKBP52-Hsp90-GR complex compared to GR in a FKBP51-Hsp90-GR complex. This in accordance with the well-documented GR-facilitating effect of FKBP52 and the GR-repressing effect of FKBP51. Taken together, this work presents the architecture and functional annotation of FKBP51-, and p23-containing Hsp90-apoGR pre-activation complexes, trapped by large scale in-cell photocrosslinking

    Maternal-Fetal Circadian Communication during Pregnancy

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    Circadian rhythms in gene expression and hormones are ubiquitous across species and across cell types. Circadian rhythms depend on a transcription-translation negative feedback loop that drives many daily rhythms in behavior and physiological processes. Circadian rhythms regulate many aspects of reproduction, such as fetal development and birth timing. Mammalian pregnancy presents a unique situation with circadian rhythms in the mom and, eventually, in the fetus. Prior studies showed that circadian rhythms develop in utero and that maternal signals, such as glucocorticoids, may act to entrain or drive daily rhythms in the fetus. However, there remains considerable debate about when and where these daily molecular oscillations first arise in development and which signals may be involved. We hypothesized that fetal circadian rhythms arise during pregnancy and synchronize to the mother prior to birth via maternal-to-fetal circadian communication. We monitored fetal clock gene expression in utero and found that fetal daily rhythms arise by E9. Our results indicate rhythms develop much earlier in the fetus than previously thought. We also found fetal rhythms synchronize to the mother by E16. Furthermore, mistimed daily glucocorticoids disrupt this synchrony. Additionally, we showed that the placenta exhibits intrinsic circadian rhythms beginning as early as E9 and blocking glucocorticoid signaling disrupted synchrony within the placenta. We conclude that fetal and placental circadian rhythms arise early in pregnancy and glucocorticoids may act as important entraining signals for these tissues. We also wanted to better understand the role of circadian rhythms in birth timing. Previous research indicated that circadian rhythms ensured birth occurred at a specific time of day, depending on the species. We hypothesized that mutations in clock genes would alter birth timing and gestation length. To test this, we examined gestation length, birth timing, and fetal development from multiple circadian mutant mouse lines. We found that Period1 performs a necessary role in the circadian gating of birth as loss of Period1 caused mice to give birth at random times of day. On the contrary, Period2 modifies the time of day of birth as mutations in this gene led to a ~6-hour shift in the timing of birth. Secondarily, our results demonstrate the importance of the Period2 gene in regulating gestation length. We conclude that the Period genes act as important regulators of labor. Taken together, these results highlight the complex role circadian rhythms have in regulating reproduction and development

    Glucocorticoid-based pharmacotherapies preventing PTSD

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    Altres ajuts: Swiss National Science Foundation (SNSF) [NCCR Synapsy grant: 51NF40-158776 and − 185897]Posttraumatic stress disorder (PTSD) is a highly disabling psychiatric condition that may arise after exposure to acute and severe trauma. It is a highly prevalent mental disorder worldwide, and the current treatment options for these patients remain limited due to low effectiveness. The time window right after traumatic events provides clinicians with a unique opportunity for preventive interventions against potential deleterious alterations in brain function that lead to PTSD. Some studies pointed out that PTSD patients present an abnormal function of the hypothalamic-pituitary-adrenal axis that may contribute to a vulnerability toward PTSD. Moreover, glucocorticoids have arisen as a promising option for preventing the disorder's development when administered in the aftermath of trauma. The present work compiles the recent findings of glucocorticoid administration for the prevention of a PTSD phenotype, from human studies to animal models of PTSD. Overall, glucocorticoid-based therapies for preventing PTSD demonstrated moderate evidence in terms of efficacy in both clinical and preclinical studies. Although clinical studies point out that glucocorticoids may not be effective for all patients' subpopulations, those with adequate traits might greatly benefit from them. Preclinical studies provide precise insight into the mechanisms mediating this preventive effect, showing glucocorticoid-based prevention to reduce long-lasting behavioral and neurobiological abnormalities caused by traumatic stress. However, further research is needed to delineate the precise mechanisms and the extent to which these interventions can translate into lower PTSD rates and morbidity

    Peripheral glucocorticoid receptor antagonism by relacorilant with modest HPA axis disinhibition

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    Glucocorticoid stress hormones are produced in response to hypothalamic-pituitary-adrenal (HPA) axis activation. Glucocorticoids are essential for physiology and exert numerous actions via binding to the glucocorticoid receptor (GR). Relacorilant is a highly selective GR antagonist currently undergoing a phase 3 clinical evaluation for the treatment of endogenous Cushing's syndrome. It was found that increases in serum adrenocorticotropic hormone (ACTH) and cortisol concentrations after relacorilant treatment were substantially less than the increases typically observed with mifepristone, but it is unclear what underlies these differences. In this study, we set out to further preclinically characterize relacorilant in comparison to the classical but non-selective GR antagonist mifepristone. In human HEK-293 cells, relacorilant potently antagonized dexamethasone- and cortisol-induced GR signaling, and in human peripheral blood mononuclear cells, relacorilant largely prevented the anti-inflammatory effects of dexamethasone. In mice, relacorilant treatment prevented hyperinsulinemia and immunosuppression caused by increased corticosterone exposure. Relacorilant treatment reduced the expression of classical GR target genes in peripheral tissues but not in the brain. In mice, relacorilant induced a modest disinhibition of the HPA axis as compared to mifepristone. In line with this, in mouse pituitary cells, relacorilant was generally less potent than mifepristone in regulating Pomc mRNA and ACTH release. This contrast between relacorilant and mifepristone is possibly due to the distinct transcriptional coregulator recruitment by the GR. In conclusion, relacorilant is thus an efficacious peripheral GR antagonist in mice with only modest disinhibition of the HPA axis, and the distinct properties of relacorilant endorse the potential of selective GR antagonist treatment for endogenous Cushing's syndrome
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