scholarly journals Novel 2-(Adamantan-1-ylamino)Thiazol-4(5H)-One Derivatives and Their Inhibitory Activity towards 11β-HSD1—Synthesis, Molecular Docking and In Vitro Studies

2021 ◽  
Vol 22 (16) ◽  
pp. 8609
Author(s):  
Renata Studzińska ◽  
Daria Kupczyk ◽  
Wojciech Płaziński ◽  
Szymon Baumgart ◽  
Rafał Bilski ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Cushing’S Syndrome ◽  
Metabolic Diseases ◽  
Active Form ◽  
Cushing's Syndrome ◽  
Binding Energies ◽  
Common Mechanism ◽  
Thiazole Ring ◽  
Docking Simulations

A common mechanism in which glucocorticoids participate is suggested in the pathogenesis of such metabolic diseases as obesity, metabolic syndrome, or Cushing’s syndrome. The enzyme involved in the control of the availability of cortisol, the active form of the glucocorticoid for the glucocorticoid receptor, is 11β-HSD1. Inhibition of 11β-HSD1 activity may bring beneficial results for the alleviation of the course of metabolic diseases such as metabolic syndrome, Cushing’s syndrome or type 2 diabetes. In this work, we obtained 10 novel 2-(adamantan-1-ylamino)thiazol-4(5H)-one derivatives containing different substituents at C-5 of thiazole ring and tested their activity towards inhibition of two 11β-HSD isoforms. For most of them, over 50% inhibition of 11β-HSD1 and less than 45% inhibition of 11β-HSD2 activity at the concentration of 10 µM was observed. The binding energies found during docking simulations for 11β-HSD1 correctly reproduced the experimental IC50 values for analyzed compounds. The most active compound 2-(adamantan-1-ylamino)-1-thia-3-azaspiro[4.5]dec-2-en-4-one (3i) inhibits the activity of isoform 1 by 82.82%. This value is comparable to the known inhibitor-carbenoxolone. The IC50 value is twice the value determined by us for carbenoxolone, however inhibition of the enzyme isoform 2 to a lesser extent makes it an excellent material for further tests.

scholarly journals Metabolic Syndrome in Cushing’s Syndrome

2010 ◽  
Vol 92 (1) ◽  
pp. 96-101 ◽  
Author(s):  
Philippe Chanson ◽  
Sylvie Salenave
Keyword(s):  
Metabolic Syndrome ◽  
Cushing’S Syndrome ◽  
Cushing's Syndrome

scholarly journals Cellular and molecular abnormalities of a macronodular adrenal hyperplasia causing beta-blocker-sensitive Cushing's syndrome

2007 ◽  
Vol 51 (9) ◽  
pp. 1452-1462 ◽  
Author(s):  
Tânia L. Mazzuco ◽  
Michaël Thomas ◽  
Monique Martinie ◽  
Nadia Cherradi ◽  
Nathalie Sturm ◽  
...  
Keyword(s):  
Cushing’S Syndrome ◽  
Cultured Cells ◽  
Cushing's Syndrome ◽  
Screening Tests ◽  
Adrenal Hyperplasia ◽  
Hormone Production ◽  
Autocrine Loop ◽  
Molecular Alterations ◽  
Molecular Abnormalities

Cushing's syndrome due to ACTH-independent macronodular adrenal hyperplasia (AIMAH) can be associated with abnormal responses of aberrantly expressed adrenocortical receptors. This study aimed to characterize in vitro the pathophysiology of hypercortisolism in a b-blocker-sensitive Cushing's syndrome due to AIMAH. Cortisol secretion profile under aberrant receptors stimulation revealed hyperresponsiveness to salbutamol (beta2-adrenoceptor agonist), cisapride (5-HT4 receptor agonist), and vasopressin in AIMAH cultured cells, but not in normal adrenocortical cells. By RT-PCR, AIMAH tissues revealed beta2-adrenoceptor overexpression rather than ectopical expression. MC2R expression was similar in both AIMAH and normal adrenocortical tissues. Curiously, cortisol levels of AIMAH cells under basal condition were 15-fold higher than those of control cells and were not responsive to ACTH. Analysis of culture medium from AIMAH cells could detect the presence of ACTH, which was immunohistochemically confirmed. Finally, the present study of AIMAH cells has identified: a) cortisol hyperresponsiveness to catecholamines, 5-HT4 and vasopressin in vitro, in agreement with clinical screening tests; b) abnormal expression of beta2-adrenoceptors in some areas of the hyperplastic adrenal tissue; c) autocrine loop of ACTH production. Altogether, the demonstration of aberrant responses to hormonal receptors and autocrine hormone production in the same tissue supports the assumption of multiple molecular alterations in adrenal macronodular hyperplasia.

scholarly journals Elucidation of the Interaction between Flavan-3-ols and Bovine Serum Albumin and Its Effect on Their In-Vitro Cytotoxicity

Molecules ◽  
2019 ◽  
Vol 24 (20) ◽  
pp. 3667
Author(s):  
Yasuyuki Fujii ◽  
Yoshitomo Suhara ◽  
Yusuke Sukikara ◽  
Tomohiro Teshima ◽  
Yoshihisa Hirota ◽  
...  
Keyword(s):  
Cell Culture ◽  
Bovine Serum Albumin ◽  
Serum Albumin ◽  
Bovine Serum ◽  
Fetal Bovine Serum ◽  
In Vitro Cytotoxicity ◽  
Binding Energies ◽  
Docking Simulations ◽  
Fetal Bovine

Flavan-3-ols (FLs), specifically catechin and its oligomer B-type procyanidins, are suggested to potently bind to bovine serum albumin (BSA). We examined the interaction between BSA and FLs by fluorescence quenching and found the following order of binding activities to BSA: cinnamtannin A2 (A2; tetramer) > procyanidin C1 (C1; trimer) ≈ procyanidin B2 (B2, dimer) > (−)epicatechin (EC, monomer). Docking simulations between BSA and each compound at the binding site showed that the calculated binding energies were consistent with the results of our experimental assay. FLs exerted cytotoxicity at 1000 μg/mL in F11 cell culture with fetal bovine serum containing BSA. In culture containing serum-free medium, FLs exhibited significant cell proliferation at 10−4 μg/mL and cytotoxicity was observed at concentrations greater than 10 μg/mL. Results of this study suggest that interactions between polyphenols and BSA should be taken into account when evaluating procyanidin in an in vitro cell culture system.

STUDIES ON THE IN VITRO PRODUCTION OF CORTICOSTEROIDS BY ADRENAL GLANDS FROM NORMOTENSIVE INDIVIDUALS AND HYPERTENSIVE PATIENTS

1962 ◽  
Vol 40 (1) ◽  
pp. 285-301 ◽  
Author(s):  
Jean Davignon ◽  
Erich Koiw ◽  
Wojciech Nowaczynski ◽  
Gilles Tremblay ◽  
Jacques Genest
Keyword(s):  
Cushing’S Syndrome ◽  
Adrenal Glands ◽  
Cushing's Syndrome ◽  
The Other ◽  
Malignant Hypertension ◽  
Unit Weight ◽  
Chromatographic Technique ◽  
Acth Stimulation ◽  
The Mean

The production of aldosterone and other corticosteroids by adrenal glands surgically removed from 5 normotensive subjects with renal disease of various types, 11 patients with arterial hypertension, and 2 with Cushing's syndrome was investigated in vitro by the incubation chromatographic technique. The rate of steroid formation per unit weight of tissue was markedly lower in severe and malignant hypertension and slightly higher in benign hypertension as compared with the rate in normotensive controls. The amount of steroid released varied widely from one gland to the other and showed marked overlapping between the various groups; these variations were most prominent in benign hypertension, less in the normotensive group, and least evident in severe and malignant hypertension. The response of steroidogenesis to ACTH stimulation in vitro was slightly reduced in severe and malignant hypertension. The mean output of aldosterone by adrenal glands from hypertensives was slightly above the mean value obtained with normotensive control glands. The percentage of aldosterone formation in respect to total steroid production was roughly correlated with the severity of hypertension. In four hyperplastic adrenals obtained from two cases of Cushing's syndrome, the in vitro formation of steroids per unit weight of tissue and the response to ACTH did not differ significantly from that found in glands obtained from the other patients under study. The value of in vitro studies for the assessment of the functional capacity of the adrenal cortex is discussed.

scholarly journals TXNIP is highly regulated in bone biopsies from patients with endogenous Cushing's syndrome and related to bone turnover

2012 ◽  
Vol 166 (6) ◽  
pp. 1039-1048 ◽  
Author(s):  
Tove Lekva ◽  
Thor Ueland ◽  
Hege Bøyum ◽  
Johan Arild Evang ◽  
Kristin Godang ◽  
...  
Keyword(s):  
Surgical Treatment ◽  
Cushing’S Syndrome ◽  
Bone Cells ◽  
Cushing's Syndrome ◽  
Gene Encoding ◽  
Osteoclast Activity ◽  
Bone Biopsies ◽  
Before And After

ObjectivePatients with endogenous Cushing's Syndrome (CS), as long-time treated patients with exogenous glucocorticoids (GCs), have severe systemic manifestations including secondary osteoporosis and low-energy fractures. The aim of the present study was to investigate the functional role ofTXNIPin bone with focus on osteoblast (OB) differentiation and OB-mediated osteoclast activity and functionin vitro.Design and methodsNine bone biopsies from CS before and after surgical treatment were screened for expressional candidate genes. Microarray analyses revealed that the gene encodingTXNIPranked among the most upregulated genes. Subsequentin vitroandin vivostudies were performed.ResultsWe found thatTXNIPgene in bone is downregulated in CS following surgical treatment. Furthermore, ourin vivodata indicate novel associations between thioredoxin andTXNIP. Ourin vitrostudies showed that silencingTXNIPin OBs was followed by increased differentiation and expression and secretion of osteocalcin as well as enhanced activity of alkaline phosphatase. Moreover, treating osteoclasts with silenced TXNIP OB media showed an increased osteoclast activity.ConclusionsTXNIPexpression in bone is highly regulated during the treatment of active CS, and by GC in bone cellsin vitro. Our data indicate that TXNIP may mediate some of the detrimental effects of GC on OB function as well as modulate OB-mediated osteoclastogenesis by regulating the OPG/RANKL ratio.

scholarly journals cAMP signaling in cortisol-producing adrenal adenoma

2015 ◽  
Vol 173 (4) ◽  
pp. M99-M106 ◽  
Author(s):  
Davide Calebiro ◽  
Guido Di Dalmazi ◽  
Kerstin Bathon ◽  
Cristina L Ronchi ◽  
Felix Beuschlein
Keyword(s):  
Signaling Pathway ◽  
Cushing’S Syndrome ◽  
Cell Function ◽  
Adrenal Adenoma ◽  
Cushing's Syndrome ◽  
Camp Signaling ◽  
Common Finding ◽  
Adrenocortical Adenomas ◽  
Camp Signaling Pathway

The cAMP signaling pathway is one of the major players in the regulation of growth and hormonal secretion in adrenocortical cells. Although its role in the pathogenesis of adrenocortical hyperplasia associated with Cushing's syndrome has been clarified, a clear involvement of the cAMP signaling pathway and of one of its major downstream effectors, the protein kinase A (PKA), in sporadic adrenocortical adenomas remained elusive until recently. During the last year, a report by our group and three additional independent groups showed that somatic mutations of PRKACA, the gene coding for the catalytic subunit α of PKA, are a common genetic alteration in patients with Cushing's syndrome due to adrenal adenomas, occurring in 35–65% of the patients. In vitro studies revealed that those mutations are able to disrupt the association between catalytic and regulatory subunits of PKA, leading to a cAMP-independent activity of the enzyme. Despite somatic PRKACA mutations being a common finding in patients with clinically manifest Cushing's syndrome, the pathogenesis of adrenocortical adenomas associated with subclinical hypercortisolism seems to rely on a different molecular background. In this review, the role of cAMP/PKA signaling in the regulation of adrenocortical cell function and its alterations in cortisol-producing adrenocortical adenomas will be summarized, with particular focus on recent developments.

scholarly journals The Niemann-Pick C1 Like 1 (NPC1L1) Inhibitor Ezetimibe Improves Metabolic Disease Via Decreased Liver X Receptor (LXR) Activity in Liver of Obese Male Mice

Endocrinology ◽  
2014 ◽  
Vol 155 (8) ◽  
pp. 2810-2819 ◽  
Author(s):  
Taichi Sugizaki ◽  
Mitsuhiro Watanabe ◽  
Yasushi Horai ◽  
Nao Kaneko-Iwasaki ◽  
Eri Arita ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Metabolic Syndrome ◽  
Insulin Signaling ◽  
Metabolic Diseases ◽  
In Vitro Study ◽  
Liver X Receptor ◽  
Gene Expressions ◽  
The Metabolic Syndrome ◽  
Increased Risk

Dyslipidemic patients with diabetes mellitus, including metabolic syndrome, are at increased risk of coronary heart disease. It has been reported that ezetimibe, a cholesterol absorption inhibitor, improves metabolic diseases in mice and humans. However, the underlying mechanism has been unclear. Here we explored the effects of ezetimibe on lipid and glucose homeostasis. Male KK-Ay mice were fed a high-fat diet, which is the mouse model of metabolic syndrome, with or without ezetimibe for 14 weeks. Ezetimibe improved dyslipidemia, steatosis, and insulin resistance. Ezetimibe decreased hepatic oxysterols, which are endogenous agonists of liver X receptor (LXR), to decrease hepatic lipogenic gene expressions, especially in stearoyl-CoA desaturase-1 (SCD1), leading to a remarkable reduction of hepatic oleate content that would contribute to the improvement of steatosis by reducing triglycerides and cholesterol esters. Simultaneously, hepatic β-oxidation, NADPH oxidase and cytochrome P450 2E1 (CYP2E1) were reduced, and thus reactive oxygen species (ROS) and inflammatory cytokines were also decreased. Consistent with these changes, ezetimibe diminished c-Jun N-terminal kinase (JNK) phosphorylation and improved insulin signaling in the liver. In vitro study using primary hepatocytes obtained from male SD rats, treated with oleate and LXR agonist, showed excess lipid accumulation, increased oxidative stress and impaired insulin signaling. Therefore, in obese subjects, ezetimibe reduces hepatic LXR activity by reducing hepatic oxysterols to lower hepatic oleate content. This improves steatosis and reduces oxidative stress, and this reduction improves insulin signaling in the liver. These results provide insight into pathogenesis and strategies for treatment of the metabolic syndrome.

Levoketoconazole, the 2S,4R Enantiomer of Ketoconazole, a New Steroidogenesis Inhibitor for Cushing’s Syndrome Treatment

2021 ◽  
Author(s):  
Sara G Creemers ◽  
Richard A Feelders ◽  
Frank H de Jong ◽  
Gaston J H Franssen ◽  
Yolanda B de Rijke ◽  
...  
Keyword(s):  
Pituitary Adenoma ◽  
Cushing’S Syndrome ◽  
Cell Number ◽  
Cushing's Syndrome ◽  
Variable Degree ◽  
Acth Secretion ◽  
Adrenal Steroid ◽  
Liquid Chromatography Tandem Mass ◽  
Ic50 Values

Abstract Introduction Racemic ketoconazole (RK) is a steroidogenesis inhibitor used for treatment of Cushing’s syndrome. Levoketoconazole (COR-003), the pure 2S,4R enantiomer, is potentially more potent and safe compared to RK. We compared in vitro effects of levoketoconazole and RK on adrenocortical and pituitary adenoma cells. Materials and methods HAC15 cells and 15 primary human neoplastic adrenocortical cultures (+/- ACTH), and murine (AtT20) and human corticotroph adenoma cultures were incubated with levoketoconazole or RK (0.01-10µM). Cortisol and ACTH were measured using a chemiluminescence immunoassay system, and steroid profiles by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results In HAC15, levoketoconazole inhibited cortisol at lower concentrations (IC50: 0.300µM) compared to RK (0.611µM; P<0.0001). IC50 values of levoketoconazole for basal cortisol production in primary adrenocortical cultures varied over a 24-fold range (0.00578µM to 0.140µM), with in two patients a higher sensitivity of levoketoconazole versus RK (2.1- and 3.7-fold). LC-MS/MS analysis in selected cases revealed more potent inhibition of cortisol and other steroid profile components by levoketoconazole versus RK. In AtT20, levoketoconazole inhibited cell growth and ACTH secretion (10µM: -54% and -38%, respectively), and levoketoconazole inhibited cell number in one of two primary human corticotroph pituitary adenoma cultures (-44%, P<0.001). Conclusion Levoketoconazole potently inhibits cortisol production in adrenocortical cells, with a variable degree of suppression between specimens. Levoketoconazole inhibits adrenal steroid production more potently compared to RK and might also inhibit ACTH secretion and growth of pituitary adenoma cells. Together with previously reported potential advantages, this indicates that levoketoconazole is a promising novel pharmacotherapy for Cushing’s syndrome.

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