Journal of Steroid Biochemistry and Molecular Biology最新文献

{"title":"Synthesis and characterization of targeted 17β-hydroxysteroid dehydrogenase type 7 inhibitors.","authors":"Jean-Yves Sancéau, René Maltais, Ming Zhou, Sheng-Xiang Lin, Donald Poirier","doi":"10.1016/j.jsbmb.2024.106544","DOIUrl":"10.1016/j.jsbmb.2024.106544","url":null,"abstract":"<p><p>Sex steroid hormones such as estrogen estradiol (E2) and androgen dihydrotestosterone (DHT) are involved in the development of hormone-dependent cancers. Blockade of 17β-hydroxysteroid dehydrogenase type 7 (17β-HSD7), a member of the short chain dehydrogenase/reductase superfamily, is thought to decrease E2 levels while increasing those of DHT. Therefore, its unique double action makes this enzyme as an interesting drug target for treatment of breast cancer. The chemical synthesis, molecular characterization, and preliminary biological evaluation as 17β-HSD7 inhibitors of novel carbamate derivatives 3 and 4 are described. Like previous 17β-HSD7 inhibitors 1 and 2, compounds 3 and 4 bear a hydrophobic nonyl side chain at the C-17β position of a 4-aza-5α-androstane nucleus, but compound 3 has an oxygen atom replacing the CH₂ in the steroid A-ring C-2 position, while compound 4 has a C17-spiranic E-ring containing a carbamate function. They both inhibited the in vitro transformation of estrone (E1) into E2 by 17β-HSD7, but the introduction of a (17 R)-spirocarbamate is preferable to replacing C-2 methylene with an oxygen atom since compound 4 (IC₅₀ = 63 nM) is an inhibitor 14 times more powerful than compound 3 (IC₅₀ = 900 nM). Furthermore, when compared to the reference inhibitor 1 (IC₅₀ = 111 nM), the use of a C17-spiranic E-ring made it possible to introduce differently the hydrophobic nonyl side chain, without reducing the inhibitory activity.</p>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140960802","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Latent Class Analysis Reveals, in patient profiles, COVID-19–related better prognosis by calcifediol treatment than glucocorticoids","authors":"Marta Entrenas-Castillo ,&nbsp;Luis Manuel Entrenas-Costa ,&nbsp;María P. Pata ,&nbsp;Bernabe Jurado Gamez ,&nbsp;Cristina Muñoz-Corroto ,&nbsp;Cristina Gómez-Rebollo ,&nbsp;Estefanía Mira-Padilla ,&nbsp;Roger Bouillon ,&nbsp;Jose Manuel Quesada-Gomez","doi":"10.1016/j.jsbmb.2024.106609","DOIUrl":"10.1016/j.jsbmb.2024.106609","url":null,"abstract":"<div><div>Calcifediol and glucocorticoids have been repositioned for the treatment of COVID-19 and may reduce severity, the need for intensive care unit admission and death.</div></div><div><h3>Objective</h3><div>to identify class or profiles of patients hospitalized and treated with COVID-19 pneumonia using latent class clustering methods to assess the clinical and prognostic relevance of the resulting patients’ profiles. Poor prognosis was defined as death or need for ICU admission, good prognosis, the opposite. With special interest in differential responses to calcifediol.</div></div><div><h3>Setting</h3><div>Reina Sofia University Hospital, Córdoba Spain.</div></div><div><h3>Patients</h3><div>Retrospective observational cohort study of patients admitted for COVID-19. ClinicalTrials.gov public database (NCT05819918). Inclusion criteria: (i) Age ≥ 18 and ≤ 90 years, (ii) Pneumonia characterized by the presence of infiltrates on chest X-ray or CT scan, (iii) SARS-CoV-2 infection, confirmed, and (iv) CURB Scale 65 &gt;1.</div></div><div><h3>Design</h3><div>Latent class analysis, for obtaining homogeneous clusters, without specifying a priori the belonging group, and selecting the optimal number of clusters by minimizing information criteria. Evaluating the differences between groups for each variable by means of chi-square, Fisher's exact test and Kruskal-Wallis test.</div></div><div><h3>Results</h3><div>707 patients hospitalized from 10 March 2020 until 4 March 2022 were included. For the treatment variable, differences were found between class 3 (60 % treated with calcifediol only) and classes 1 (less than 1 % calcifediol only vs. 82 % treated with both), 2 (less than 1 % calcifediol only vs. 82 % treated with both) and 4 (1 % calcifediol only vs. 84 % treated with both). Class 3, (60 % with calcifediol), had a significantly better prognosis compared to patients treated with glucocorticoids alone (OR: 15.2, 95 % CI: [3.73–142], p&lt;0.001) or no treatment (OR: 7.38, 95 % CI: [2.63–30.2], p&lt;0.001).</div></div><div><h3>Conclusions</h3><div>our real-life study shows that calcifediol treatment significantly reduces the need for ICU admission and improved prognosis in patients hospitalized for COVID-19 pneumonia, especially in the profile of patients receiving it without glucocorticoids<del>.</del></div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142114493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fast and reliable quantification of aldosterone, cortisol and cortisone via LC-MS/MS to study 11β-hydroxysteroid dehydrogenase activities in primary cell cultures","authors":"Sonja Kunz ,&nbsp;Yao Meng ,&nbsp;Holger Schneider ,&nbsp;Laura Brunnenkant ,&nbsp;Michaela Höhne ,&nbsp;Tim Kühnle ,&nbsp;Martin Reincke ,&nbsp;Marily Theodoropoulou ,&nbsp;Martin Bidlingmaier","doi":"10.1016/j.jsbmb.2024.106610","DOIUrl":"10.1016/j.jsbmb.2024.106610","url":null,"abstract":"<div><p>Cell culture experiments can support characterization of enzymatic activities in healthy and tumorous human tissues. Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) enables simultaneous measurement of several steroids from a single sample, facilitating analysis of molecular pathways involved in steroid biosynthesis. We developed a reliable but fast method for quantification of cortisol, cortisone and aldosterone in cell culture supernatant. Validation, including investigation of matrix-matched calibration, was performed for two different cell types. Utility of the method was demonstrated in the study of 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) activity under conditions of glucocorticoid and mineralocorticoid excess in different cell types. Aldosterone, cortisol and cortisone were extracted by liquid-liquid extraction (LLE) with methyl <em>tert</em>-butyl ether from 1 mL of cell culture supernatant. Steroids were separated on a Kinetex biphenyl column (50 ×2.1 mm, 2.6 µm) with gradient elution of water and methanol containing 2 mM ammonium format and analysed in multiple reaction monitoring mode after positive electrospray ionization. Application of the method included cell culture experiments with two different primary cell types, human coronary artery smooth muscle cells (HCSMC) and human coronary artery endothelial cells (EC). Cells were treated with different concentrations of cortisol, aldosterone and mifepristone, a glucocorticoid receptor antagonist and quantitative PCR was performed. The method exhibits high precision (CV ≤ 6 %) and accuracy (deviation from nominal concentration ≤ 6 %) for concentrations above the limit of quantification (LoQ) which is 0.11, 0.56 and 0.69 nmol/L for aldosterone, cortisone and cortisol, respectively. Calibration curves did not differ when prepared in media or solvent. The method enabled us to confirm activity of HSD11B2 and concentration dependent conversion of cortisol to cortisone in HCSMC (median conversion ratio at 140 nM cortisol = 1.46 %). In contrast we did not observe any HSD11B2 activity in EC. Neither addition of high aldosterone, nor addition of 1 µM mifepristone had impact on glucocorticoid concentrations. Quantitative PCR revealed expression of <em>HSD11B1</em> and <em>HSD11B2</em> in HCSMC but not in EC. We present a fast and reliable method for quantification of cortisol, cortisone and aldosterone in cell culture supernatants. The method enabled us to study HSD11B2 activity in two different cell types and will support future experiments investigating mechanisms of target organ damage in conditions of glucocorticoid and mineralocorticoid excess.</p></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0960076024001584/pdfft?md5=300ef982d4c5616a5ed3c033a7f48aae&pid=1-s2.0-S0960076024001584-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142114492","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Steroids and Mass Spectrometry: A Personal Story.","authors":"Cedric H L Shackleton","doi":"10.1016/j.jsbmb.2024.106608","DOIUrl":"10.1016/j.jsbmb.2024.106608","url":null,"abstract":"","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142094055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GPER expression prevents estrogen-induced urinary retention in obese mice","authors":"Donna F. Kusewitt ,&nbsp;Geetanjali Sharma ,&nbsp;Christine D. Woods ,&nbsp;Emmanuel Rosas ,&nbsp;Helen J. Hathaway ,&nbsp;Eric R. Prossnitz","doi":"10.1016/j.jsbmb.2024.106607","DOIUrl":"10.1016/j.jsbmb.2024.106607","url":null,"abstract":"<div><p>Long-term administration of exogenous estrogen is known to cause urinary retention and marked, often fatal, bladder distention in both male and female mice. Estrogen-treated mice have increased bladder pressure and decreased urine flow, suggesting that urinary retention in estrogen-treated mice is due to infravesicular obstruction to urine outflow. Thus, the condition is commonly referred to as bladder outlet obstruction (BOO). Obesity can also lead to urinary retention. As the effects of estrogen are mediated by multiple receptors, including estrogen receptors ERα and ERβ and the G protein-coupled estrogen receptor (GPER), we sought to determine whether GPER plays a role in estrogen-induced BOO, particularly in the context of obesity. Wild type and GPER knockout (KO) mice fed a high-fat diet were ovariectomized or left ovary-intact (sham surgery) and supplemented with slow-release estrogen or vehicle-only pellets. Supplementing both GPER KO and wild type obese mice with estrogen for 8 weeks resulted in weight loss, splenic enlargement, and thymic atrophy, as expected. However, estrogen-treated obese GPER KO mice developed abdominal distension, debilitation, and ulceration of the skin surrounding the urogenital opening. At necropsy, these mice had prominently distended bladders and hydronephrosis. In contrast, estrogen-treated obese wild type mice only rarely displayed these signs. Our results suggest that, under conditions of obesity, estrogen induces BOO as a result of ERα-driven pathways and that GPER expression is protective against BOO.</p></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142094054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex hormone-binding globulin and its critical role in prostate cancer: A comprehensive review","authors":"Anirban Goutam Mukherjee,&nbsp;Abilash V G","doi":"10.1016/j.jsbmb.2024.106606","DOIUrl":"10.1016/j.jsbmb.2024.106606","url":null,"abstract":"<div><p>Prostate cancer (PC) is a common and widespread cancer that affects men globally. A complicated interaction of hormonal variables influences its development. Sex hormone-binding globulin (SHBG) is a crucial element in controlling the availability of sex hormones, especially androgens, which have a notable impact on the development and progression of PC. SHBG controls the levels of free, active androgens in the body, which helps regulate androgen-dependent processes associated with PC. The equilibrium between SHBG and androgens plays a critical role in maintaining the stability of the prostate. When this balance is disrupted, it is associated with the development and advancement of PC. The processes responsible for SHBG's role in PC are complex and have multiple aspects. SHBG primarily binds to androgens, preventing them from interacting with androgen receptors (ARs) in prostate cells. It reduces the activation of androgen signaling pathways essential for tumor development and survival. In addition, SHBG can directly affect prostate cells by interacting with specific receptors on the cell surface. This review thoroughly examines the role of SHBG in PC, including its physiological activities, methods of action, and clinical consequences.</p></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142057259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"OBHSA, a novel selective estrogen receptor degrader, overcomes tamoxifen resistance through cell cycle arrest and unfolded protein response-mediated apoptosis in breast cancer","authors":"Rong Shen ,&nbsp;Jiawei Zhou ,&nbsp;Lilan Xin ,&nbsp;Hai-Bing Zhou ,&nbsp;Jian Huang","doi":"10.1016/j.jsbmb.2024.106599","DOIUrl":"10.1016/j.jsbmb.2024.106599","url":null,"abstract":"<div><p>Breast cancer (BC) is a highly heterogeneous tumor that has surpassed lung cancer as the most frequently diagnosed cancer in women. In clinical practice,the primary approach for treating estrogen receptor alpha (ERα)-positive BC is through endocrine therapy, which involves targeting the ERα using medications like tamoxifen and fulvestrant. However, the problem of de novo or acquired resistance poses a significant clinical challenge, emphasizing the critical need for the development of novel therapeutic strategies. In this regard, we have successfully designed and developed a novel selective estrogen receptor degrader (SERD) called OBHSA, which specifically targets and degrades ERα, demonstrating remarkable efficacy. Our findings revealed the effectiveness of OBHSA in inhibiting the proliferation of various BC cells, including both tamoxifen-sensitive and tamoxifen-resistant BC cells, indicating its great potential to overcome endocrine resistance. In terms of mechanism, we discovered that OBHSA overcame tamoxifen resistance through two distinct pathways. Firstly, OBHSA degraded cyclin D1 in an ERα-dependent manner, thereby blocking the cell cycle. Secondly, OBHSA induced an elevation in intracellular reactive oxygen species, triggering an excessive activation of the unfolded protein response (UPR) and ultimately leading to apoptotic cell death. In summary, our finding demonstrated that OBHSA exerts anti-tumor effects by inducing cell cycle arrest and UPR-mediated apoptosis. These findings hold promise for the development of novel therapeutic drugs targeting endocrine-resistant BC.</p></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141989416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In memory of V. Craig Jordan (1947–2024): “Father of tamoxifen” and discoverer of SERMs","authors":"Philipp Y. Maximov","doi":"10.1016/j.jsbmb.2024.106598","DOIUrl":"10.1016/j.jsbmb.2024.106598","url":null,"abstract":"","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141918004","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Secosteroid diacylhydrazines as novel effective agents against hormone-dependent breast cancer cells","authors":"Alexey I. Ilovaisky ,&nbsp;Alexander M. Scherbakov ,&nbsp;Elena I. Chernoburova ,&nbsp;Marina A. Shchetinina ,&nbsp;Valentina M. Merkulova ,&nbsp;Fedor B. Bogdanov ,&nbsp;Danila V. Sorokin ,&nbsp;Diana I. Salnikova ,&nbsp;Eugene I. Bozhenko ,&nbsp;Igor V. Zavarzin ,&nbsp;Alexander O. Terent’ev","doi":"10.1016/j.jsbmb.2024.106597","DOIUrl":"10.1016/j.jsbmb.2024.106597","url":null,"abstract":"<div><p>This research aimed to develop novel selective secosteroids that are highly active against hormone-dependent breast cancer. A simple and convenient approach to N′-acylated 13,17-secoestra-1,3,5(10)-trien-17-oic acid hydrazides was disclosed and these novel types of secosteroids were screened for cytotoxicity against the hormone-dependent human breast cancer cell line MCF7. Most secosteroid N′-benzoyl hydrazides have demonstrated high cytotoxicity against MCF7 cells with IC₅₀ values below 5 μM, which are superior to that of the reference drug cisplatin. Hit compounds <strong>2c</strong>, <strong>2e</strong> and <strong>2i</strong> were characterized by high cytotoxicity (IC₅₀ = 1.6–1.9 μM) and very good selectivity towards MCF7 breast cancer cells. The lead secosteroids <strong>2c</strong>, <strong>2e</strong> and <strong>2i</strong> also exhibit antiestrogenic effects and alter the expression of cell cycle regulating proteins. The effect of selected compounds on PARP (poly(ADP-ribose) polymerase) and Bcl-2 (B-cell CLL/lymphoma 2) indicates their proapoptotic potential. The synthesized secosteroids may be considered as new promising anti-breast cancer agents targeting ERα and apoptosis pathways.</p></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141914509","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cross-sex hormonal replacement: Some effects over mitochondria","authors":"Montserrat Cardenas ,&nbsp;Fabián Alvarez ,&nbsp;Alfredo Cabrera-Orefice ,&nbsp;Cristina Paredes-Carbajal ,&nbsp;Alejandro Silva-Palacios ,&nbsp;Salvador Uribe-Carvajal ,&nbsp;José J. García – Trejo ,&nbsp;Natalia Pavón","doi":"10.1016/j.jsbmb.2024.106595","DOIUrl":"10.1016/j.jsbmb.2024.106595","url":null,"abstract":"<div><p>Transgender is a term for people whose gender identity or expression differs from their natal sex. These individuals often seek cross-hormonal therapy to simulate the individual´s desired gender. However, the use of estrogens and testosterone has side effects such as a higher propensity to cancer, weight changes and cardiovascular diseases. Testosterone has also been linked with hypertension. Still, little is known about the outcomes and prevalence of metabolic perturbations in the trans community. Here we aim to analyze if cross-administering sexual hormones affects heart mitochondrial function. Mitochondria produces the ATP needed for heart function. In fact, different studies show that mitochondrial dysfunction precedes cardiac damage. In this work we used either female rats castrated and injected with testosterone or male rats castrated and injected with estrogens for 4 months. We performed an electrocardiogram, and then we isolated heart mitochondria to measure the rate of oxygen consumption, calcium fluxes, membrane potential, superoxide dismutase activity, lipoperoxidation and cytokines. We detected wide modifications in all parameters associated to cross-hormonal administration.</p></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141903479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}