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#34890638   2021/12/08 To Up

Effects of tyrosine kinase inhibitors on androgen, estrogen α, glucocorticoid and thyroid receptors.

Modern anticancer therapies favor a targeted approach. Tyrosine kinase inhibitors (TKIs) are drugs that target molecular pathways involved in various types of malignancies. Although TKIs are safe and well tolerated, they remain not completely selective; e.g., endocrine-mediated adverse events have been observed with their use. In the present study, the effects of seven TKIs were determined on the activities of androgen receptor, estrogen receptor α (ERα), glucocorticoid receptor and thyroid receptor in vitro using stably transfected cell lines expressing firefly luciferase reporter gene: AR-EcoScreen, hERα-HeLa9903, MDA-kb2, and GH3.TRE-Luc cells, respectively. Antiandrogenic activity was seen for erlotinib, estrogenic activity for imatinib, antiestrogenic activity for dasatinib, erlotinib, nilotinib, regorafenib and sorafenib, glucocorticoid activity for erlotinib and ibrutinib, antiglucocorticoid activity for regorafenib and sorafenib, and antithyroid activity for ibrutinib. Additionally, synergism was seen for 1-5 μM dasatinib and 500 nM hydrocortisone combination for glucocorticoid activity in MDA-kb2 cells. The estrogenic activity of imatinib was confirmed as mediated through ERα, and interference of the TKIs with the reporter gene assays was ruled out in a cell-lysate-based firefly luciferase enzyme inhibition assay. Imatinib in combination with 4-hydroxytamoxifen showed concentration-dependent effects on the metabolic activity of ERα-expressing AN3CA, MCF-7, and SKOV3 cells, and on cell proliferation and adhesion of MCF-7 cells. These findings contribute to the understanding of the endocrine effects of TKIs, in terms of toxicity and effectiveness, and define the need to further evaluate the endocrine disrupting activities of TKIs to safeguard human and environmental health.
Maša Kenda, Damjan Avsec, Taja Zore, Eva Kogovšek, Urša Pečar Fonović, Janko Kos, Krištof Bozovičar, Tomaž Bratkovič, Nataša Karas Kuželički, Bojana Žegura, Metka Filipič, Marija Sollner Dolenc

1715 related Products with: Effects of tyrosine kinase inhibitors on androgen, estrogen α, glucocorticoid and thyroid receptors.

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#34789240   2021/11/17 To Up

Anticancer effects of mifepristone on human uveal melanoma cells.

Uveal melanoma (UM), the most prevalent intraocular tumor in adults, is a highly metastatic and drug resistant lesion. Recent studies have demonstrated cytotoxic and anti-metastatic effects of the antiprogestin and antiglucocorticoid mifepristone (MF) in vitro and in clinical trials involving meningioma, colon, breast, and ovarian cancers. Drug repurposing is a cost-effective approach to bring approved drugs with good safety profiles to the clinic. This current study assessed the cytotoxic effects of MF in human UM cell lines of different genetic backgrounds.
Prisca Bustamante Alvarez, Alexander Laskaris, Alicia A Goyeneche, Yunxi Chen, Carlos M Telleria, Julia V Burnier

1334 related Products with: Anticancer effects of mifepristone on human uveal melanoma cells.

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#34566653   2021/09/10 To Up

Efficacy of Treatments Targeting Hypothalamic-Pituitary-Adrenal Systems for Major Depressive Disorder: A Meta-Analysis.

Abnormal hypothalamic-pituitary-adrenal (HPA) axis has been implicated in major depressive disorder (MDD). A number of studies have attempted to use HPA-modulating medications to treat depression. However, their results are inconsistent. The efficacy of these drugs for MDD remains uncertain. The aims of this meta-analysis were to determine the effect and safety profile of HPA-targeting medications for MDD. World of Science and PubMed databases were comprehensively searched up to March 2021. All randomized controlled trials (RCTs) and open-label trials exploring antiglucocorticoid and related medications in patients with depression were included. Standardized mean differences (SMDs) and risk ratios (RRs) with 95% confidence intervals (CIs) were calculated for continuous or dichotomous outcomes, respectively. In the meta-analysis, we identified 16 RCTs and seven open-label studies that included 2972 subjects. Pooling the change data that assessed the efficacy across all included HPA-targeting medications for depression showed a significant difference between interventions and controls with very small heterogeneity after influence analysis (SMD = 0.138, 95%CI = 0.052, 0.224, p = 0.002; I = 20.7%, p = 0.212). No obvious publication bias was observed (p = 0.127). Effectiveness remained significant in patients with MDD (SMD = 0.136, 95%CI = 0.049, 0.223, p = 0.002). Subgroup analysis showed a significant difference favoring mifepristone and vasopressin 1B (V) receptor antagonist treatment. Adverse events were reported by 14 studies and our analysis of high-quality studies showed a significant difference in favor of controls (RR = 1.283, 95%CI = 1.134, 1.452, p = 0). Our study suggested that patients with MDD may benefit from mifepristone and V receptor antagonist treatments that have tolerable side effects. HPA-based medications are promising for depression treatment. However, additional high-quality RCTs, including head-to-head trials, are needed. https://www.crd.york.ac.uk/PROSPERO/, identifier registration number: CRD42021247279.
Yudan Ding, Zirou Wei, Haohao Yan, Wenbin Guo

1461 related Products with: Efficacy of Treatments Targeting Hypothalamic-Pituitary-Adrenal Systems for Major Depressive Disorder: A Meta-Analysis.

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#32365199   // To Up

Selective Progesterone Receptor Modulators-Mechanisms and Therapeutic Utility.

Selective progesterone receptor modulators (SPRMs) are a new class of compounds developed to target the progesterone receptor (PR) with a mix of agonist and antagonist properties. These compounds have been introduced for the treatment of several gynecological conditions based on the critical role of progesterone in reproduction and reproductive tissues. In patients with uterine fibroids, mifepristone and ulipristal acetate have consistently demonstrated efficacy, and vilaprisan is currently under investigation, while studies of asoprisnil and telapristone were halted for safety concerns. Mifepristone demonstrated utility for the management of endometriosis, while data are limited regarding the efficacy of asoprisnil, ulipristal acetate, telapristone, and vilaprisan for this condition. Currently, none of the SPRMs have shown therapeutic success in treating endometrial cancer. Multiple SPRMs have been assessed for efficacy in treating PR-positive recurrent breast cancer, with in vivo studies suggesting a benefit of mifepristone, and multiple in vitro models suggesting the efficacy of ulipristal acetate and telapristone. Mifepristone, ulipristal acetate, vilaprisan, and asoprisnil effectively treated heavy menstrual bleeding (HBM) in patients with uterine fibroids, but limited data exist regarding the efficacy of SPRMs for HMB outside this context. A notable class effect of SPRMs are benign, PR modulator-associated endometrial changes (PAECs) due to the actions of the compounds on the endometrium. Both mifepristone and ulipristal acetate are effective for emergency contraception, and mifepristone was approved by the US Food and Drug Administration (FDA) in 2012 for the treatment of Cushing's syndrome due to its additional antiglucocorticoid effect. Based on current evidence, SPRMs show considerable promise for treatment of several gynecologic conditions.
Md Soriful Islam, Sadia Afrin, Sara Isabel Jones, James Segars

1049 related Products with: Selective Progesterone Receptor Modulators-Mechanisms and Therapeutic Utility.

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#31499391   2019/08/23 To Up

Baseline cortisol and the efficacy of antiglucocorticoid treatment in mood disorders: A meta-analysis.

Hyperactivity of the Hypothalamic-Pituitary-Adrenal (HPA) axis and high cortisol levels have been widely reported in patients with mood disorders but previous clinical trials investigating the efficacy of antiglucocorticoid treatment in this population have reported inconsistent findings. The inconsistencies among these studies may be because not all patients with mood disorders have increased HPA axis activity and therefore might not benefit from antiglucocorticoid treatment. The aim of this meta-analysis was to investigate whether baseline cortisol levels influence the efficacy of antiglucocorticoid drugs in patients with mood disorders.
Giulia Lombardo, Daniela Enache, Laura Gianotti, Alan F Schatzberg, Allan H Young, Carmine M Pariante, Valeria Mondelli

2476 related Products with: Baseline cortisol and the efficacy of antiglucocorticoid treatment in mood disorders: A meta-analysis.

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#31075898   2019/05/09 To Up

Steroid Metabolites Support Evidence of Autism as a Spectrum.

: It is common nowadays to refer to autism as a spectrum. Increased evidence of the involvement of steroid metabolites has been shown by the presence of stronger alterations in Kanner's syndrome compared with Asperger syndrome. : 24 h urine samples were collected from 20 boys with Asperger syndrome, 21 boys with Kanner's syndrome, and identically sized control groups, each matched for age, weight, and height for comprehensive steroid hormone metabolite analysis via gas chromatography-mass spectrometry. : Higher levels of most steroid metabolites were detected in boys with Kanner's syndrome and Asperger syndrome compared to their matched controls. These differences were more pronounced in affected individuals with Kanner's syndrome versus Asperger syndrome. Furthermore, a specific and unique pattern of alteration of androsterone, etiocholanolone, progesterone, tetrahydrocortisone, and tetrahydrocortisol was identified in boys with Kanner's syndrome and Asperger syndrome. Interestingly, in both matched samples, only androsterone, etiocholanolone, progesterone, tetrahydrocortisone, tetrahydrocortisol, and 5a-tetrahydrocortisol groups were positively correlated. In the Asperger syndrome group, all metabolites showed a positive correlation. In the Kanner's syndrome group, 5-a tetrahydrocortisol with androsterone showed a positive correlation. : Due to differences in the level of alteration, the premise that Asperger syndrome is on the mild side of the autism spectrum and that Kanner's syndrome is on the severe side is supported, but alteration patterns yield different phenotypic expressions.
Benedikt Andreas Gasser, Johann Kurz, Bernhard Dick, Markus Georg Mohaupt

1111 related Products with: Steroid Metabolites Support Evidence of Autism as a Spectrum.

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#30231371   // To Up

Emerging Strategies in Systemic Therapy for the Treatment of Melanoma.

Recent years have seen major improvements in survival of patients with advanced melanoma with the advent of various novel systemic immunotherapies and targeted therapies. As our understanding of these agents and their various mechanisms of action improves, even more impressive outcomes are being achieved through use of various combination strategies, including the combining of different immunotherapies with one another as well as with other modalities. However, despite the improved outcomes that have been achieved in advanced melanoma, responses to treatment are heterogeneous and may not always be durable. Additional advances in therapy are required, and several emerging strategies are a focus of interest. These include the investigation of several new immunotherapy and/or targeted therapy combinations, such as checkpoint inhibitors (anti-PD-1/anti-CTLA-4) with other immunotherapies (e.g., indoleamine 2,3 dioxygenase [IDO] inhibitors, antilymphocyte activation 3 [anti-LAG-3], histone deacetylase [HDAC] inhibitors, Toll-like receptor 9 [TLR-9] agonists, antiglucocorticoid-induced tumor necrosis factor receptor [anti-GITR], pegylated interleukin-2 [IL-2]), combined targeted therapies (e.g., MEK and CDK4/6 coinhibition), and combined immunotherapy and targeted therapy (e.g., the triplet combination of BRAF/MEK inhibition with anti-PD-1s). The identification of novel therapeutic targets in the MAP kinase pathway also offers opportunities to improve outcomes by overcoming de novo and acquired resistance to BRAF/MEK inhibition (e.g., the development of ERK inhibitors). In addition, adoptive cell transfer, the infusion of large numbers of activated autologous lymphocytes, may have a potential role in patients whose disease has progressed after immunotherapy. Taken together, these new approaches offer further potential to increase systemic treatment options and improve long-term outcomes for patients with advanced melanoma.
Paolo A Ascierto, Keith Flaherty, Stephanie Goff

2039 related Products with: Emerging Strategies in Systemic Therapy for the Treatment of Melanoma.

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#30029724   2018/03/09 To Up

DHEA Modulates Immune Function: A Review of Evidence.

DHEA and DHEA-S have numerous associations with multiple aspects of immune function and are often characterized as beneficial and supportive of immunocompetence. However, closer inspection of these studies reveals confusion regarding the immunological components modified, the mechanisms of action, and degree of impact, and even whether these hormones even have direct action or are mediated by metabolites and interactions with other hormones and hormone receptors. Additionally, much of the research is conducted on rodent models using very high concentrations of hormone supplements, which may not be representative of the effects of these hormones in natural circulating concentrations, or may not translate to human physiology in a meaningful way. Here, we review the effects of DHEA and DHEA-S on immune function and examine the potential roles these hormones play on specific components of immune function. Drawing from the literature on hormone supplementation, as well as studies examining the natural circulating levels of DHEA and DHEA-S on specific immunological components and disease processes, we argue that DHEA has differential actions on human immune function, and that its effects are further shaped by concentrations of other hormones. Of particular interest is the role of DHEA as an antiglucocorticoid, and for its actions on both androgen and estrogen receptors. With additional research, DHEA may be useful as a therapeutic, particularly in diseases with high levels of inflammation, or where adrenal production is altered. The convoluted nature of DHEA-immune interactions makes direct effects difficult to interpret, and future research needs to consider direct, intracrine, and downstream effects of these hormones.
Sean P Prall, Michael P Muehlenbein

2131 related Products with: DHEA Modulates Immune Function: A Review of Evidence.

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#30025313   2018/07/10 To Up

Cognitive effects of mifepristone in overweight, euthymic adults with depressive disorders.

Previous studies have shown that individuals with mood disorders have a higher prevalence of both hypercortisolemia and insulin resistance. Insulin resistance is posited to contribute to the cognitive deficits observed in individuals who have depression. However, the mechanistic relationship between cortisol and insulin within the central nervous system remains to be further elucidated. This study aimed to evaluate the effects of the antiglucocorticoid agent, mifepristone, on metabolic function and cognitive performance in individuals receiving treatment for depressive disorders who were euthymic at baseline.
S Roat-Shumway, T E Wroolie, K Watson, A F Schatzberg, N L Rasgon

2164 related Products with: Cognitive effects of mifepristone in overweight, euthymic adults with depressive disorders.

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#29941978   2018/06/04 To Up

Peripubertal stress-induced heightened aggression: modulation of the glucocorticoid receptor in the central amygdala and normalization by mifepristone treatment.

Despite the enormous negative impact of excessive aggression for individuals and societies, there is a paucity of treatments. Here, using a peripubertal stress model of heightened aggression in rats, we investigated the involvement of the glucocorticoid system and tested the effectiveness of antiglucocorticoid treatment to normalize behavior. We assessed peripubertal stress-induced changes in glucocorticoid (GR) and mineralocorticoid (MR) gene expression in different amygdala nuclei and hippocampus, and report a specific increase in GR mRNA expression in the central amygdala (CeA). Administration of mifepristone (10 mg/kg), a GR antagonist, before stressor exposure at peripuberty prevented the habituation of plasma corticosterone responses observed throughout the stress protocol. This treatment also prevented the increase in aggression and GR expression in the CeA observed in peripubertally stressed rats at adulthood. Viral downregulation of CeA GR expression at adulthood led to reduced aggression. Subsequently, we showed that a brief, 3-day, treatment with mifepristone at adulthood was effective to normalize the abnormal aggression phenotype in peripubertally stressed rats. Our results support a key role for GR actions during peripubertal stress for the long-term programming of heightened aggression. Strikingly, they also support the translational interest of testing the effectiveness of mifepristone treatment to diminish reactive aggression in early adversity-related human psychopathologies.
Aurelie Papilloud, Vandana Veenit, Stamatina Tzanoulinou, Orbicia Riccio, Olivia Zanoletti, Isabelle Guillot de Suduiraut, Jocelyn Grosse, Carmen Sandi

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