{"title":"Cortisol-to-cortisone and testosterone-to-androstenedione concentration ratios in nails: Their determination methods based on LC/MS/MS and differences from the serum concentration ratios in the literature","authors":"Himena Ishikawa, Sakurako Tanaka, Kenjiro Shibata, Tatsuya Higashi","doi":"10.1016/j.steroids.2025.109707","DOIUrl":"10.1016/j.steroids.2025.109707","url":null,"abstract":"<div><div>A fingernail clipping is expected to be a specimen suited for the detection of the medium-to-long term abnormal production of steroids. There are reports demonstrating that the concentration ratios of cortisol (F) to cortisone (E) and testosterone (T) to androstenedione (AD) in nails are significantly different from those in serum. However, the concentration ratios in the nails were determined with a small number of samples in some instances and differed from study to study, in addition to which, their gender differences remain poorly understood. Determining the differences in the concentration ratios between the nails and serum with a sufficient number of samples by gender and discussing a factor causing these differences will help for an accurate interpretation of the results in the nail-based steroid tests. In this study, we first developed and validated liquid chromatography/electrospray ionization-tandem mass spectrometry methods for determining the F/E and T/AD ratios in thumbnail clippings, then demonstrated that the F/E (in both sexes) and T/AD (in male) ratios in the nails were significantly lower than those in the serum reported in the literature. We found that steroids which are present at the higher concentrations in the nail than expected from their serum concentrations, such as E and AD, are bound to albumin at a high rate in the serum. As the affinities of corticoids and androgens to albumin are low (<em>Ka</em>, 10<sup>3</sup>–10<sup>4</sup> M<sup>−1</sup>), we concluded that the albumin-bound fractions can be the sources of the nail-incorporated steroids as well as the free fractions.</div></div>","PeriodicalId":21997,"journal":{"name":"Steroids","volume":"225 ","pages":"Article 109707"},"PeriodicalIF":2.3,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145442332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
SteroidsPub Date : 2026-01-01Epub Date: 2025-11-14DOI: 10.1016/j.steroids.2025.109717
Mercedes Perusquía
{"title":"Dehydroepiandrosterone impact on smooth muscle contractile activity by a nongenomic action","authors":"Mercedes Perusquía","doi":"10.1016/j.steroids.2025.109717","DOIUrl":"10.1016/j.steroids.2025.109717","url":null,"abstract":"<div><div>Dehydroepiandrosterone (DHEA) is the most abundant steroid hormone in primates; however, its levels decline with age in both men and women. Numerous studies have documented diverse biological activities of DHEA. This article reviews the current understanding of how DHEA regulates the contractile function of vascular and nonvascular smooth muscle (SM), specifically examining its relaxant properties mediated through nongenomic mechanisms. It summarizes both older and recent findings on DHEA and its role in regulating SM contractile activity. Moreover, it also discusses the potential mechanisms underlying its relaxation effects, including the structural–functional differences in the DHEA molecule and its ability to induce relaxation in various types of SM. Overall, DHEA introduces a novel aspect to the regulation of functional processes involved in SM contractile activity.</div></div>","PeriodicalId":21997,"journal":{"name":"Steroids","volume":"225 ","pages":"Article 109717"},"PeriodicalIF":2.3,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145518585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
SteroidsPub Date : 2026-01-01Epub Date: 2025-11-23DOI: 10.1016/j.steroids.2025.109723
Bilge Debelec-Butuner , Mert Burak Ozturk , Ozgur Tag , Ismail Hakki Akgun , Erdal Bedir
{"title":"Semi-synthetic sapogenin derivatives inhibit inflammation-induced tumorigenic signaling alterations in prostate carcinogenesis","authors":"Bilge Debelec-Butuner , Mert Burak Ozturk , Ozgur Tag , Ismail Hakki Akgun , Erdal Bedir","doi":"10.1016/j.steroids.2025.109723","DOIUrl":"10.1016/j.steroids.2025.109723","url":null,"abstract":"<div><div>Prostatic inflammation plays a pivotal role in prostate cancer development and progression via altering key cellular mechanisms, including proliferation, metastasis, and angiogenesis. Therefore, the use of anti-inflammatory drugs could provide a valid contribution to PCa prevention and treatment. In our research, we explored semi-synthetic derivatives of cycloastragenol (<strong>CA</strong>) and astragenol (<strong>AG</strong>) to assess their potential to inhibit inflammation-mediated tumorigenic signaling.</div><div>Building on our previous findings, which demonstrated their inhibitory activity on NFκB, we discovered that these molecules also suppress inflammation-induced cell proliferation and migration through distinct mechanisms. They effectively alleviated inflammation by reducing levels of ROS, NO, and VEGF expression. Furthermore, these molecules partially restored the expression of AR and the tumor suppressor NKX3.1, both of which are critical in prostate tumorigenesis within an inflammatory microenvironment. They also reversed inflammation-induced activation of Akt and β-catenin signaling, suggesting their potential to inhibit inflammation-related prostate tumorigenesis. Our study further demonstrated that these molecules exhibited dose-dependent effects on inducing cell cycle arrest and apoptosis, as evidenced by increased p21 and decreased BCL-2 protein levels, leading to activated cell death and suppressed cellular migration.</div><div>In conclusion, these semi-synthetic sapogenol derivatives demonstrate significant potential as anti-inflammatory and anticancer agents, offering a promising approach for targeting prostatic inflammation and inflammation-driven prostate carcinogenesis.</div></div>","PeriodicalId":21997,"journal":{"name":"Steroids","volume":"225 ","pages":"Article 109723"},"PeriodicalIF":2.3,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145605725","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
SteroidsPub Date : 2026-01-01Epub Date: 2025-11-19DOI: 10.1016/j.steroids.2025.109721
Swati Mummidivarpu , Utkarsh J. Dang , Michael Ziemba , Yetrib Hathout , Paula R. Clemens , Jesse Damsker , Laura Hagerty , William J. Jusko , Edward C. Smith , Jean K. Mah , Michela Guglieri , Yoram Nevo , Nancy Kuntz , Craig M. McDonald , Monique M. Ryan , Diana Castro , Richard S. Finkel , Laurie S. Conklin , John M. McCall , Kanneboyina Nagaraju , Eric P. Hoffman
{"title":"Exposure-response of serum biomarkers to vamorolone, a dissociative corticosteroidal anti-inflammatory drug, in 4- to <7-year children","authors":"Swati Mummidivarpu , Utkarsh J. Dang , Michael Ziemba , Yetrib Hathout , Paula R. Clemens , Jesse Damsker , Laura Hagerty , William J. Jusko , Edward C. Smith , Jean K. Mah , Michela Guglieri , Yoram Nevo , Nancy Kuntz , Craig M. McDonald , Monique M. Ryan , Diana Castro , Richard S. Finkel , Laurie S. Conklin , John M. McCall , Kanneboyina Nagaraju , Eric P. Hoffman","doi":"10.1016/j.steroids.2025.109721","DOIUrl":"10.1016/j.steroids.2025.109721","url":null,"abstract":"<div><h3>Objectives</h3><div>Corticosteroid agonists of the glucocorticoid receptor are a mainstay of therapeutics for pro-inflammatory conditions. Vamorolone is a novel partial agonist that is differentiated from the other members of the corticosteroid class by non-metabolism by 11β-hydroxysteroid dehydrogenases, antagonism of the mineralocorticoid receptor, and differential co-factor binding. Our objective was to define the pharmacodynamic response of serum proteins to vamorolone.</div></div><div><h3>Methods</h3><div>Clinical trial participants with Duchenne muscular dystrophy (4 to <7 yr; n = 39; mean [SD] age = 5.3 [1.0]) enrolled in a multiple ascending dose study of vamorolone were studied (24-fold dose range). Dose-response and exposure–response of 1,305 serum proteins were defined by intra-subject longitudinal changes (baseline vs. Day 14).</div></div><div><h3>Results</h3><div>Dose-response analysis identified 159 of 1,305 serum proteins as dose-responsive to vamorolone (12 % of proteins tested; 20 % increased, 80 % decreased). Two inflammatory networks showed drug-responsive suppression. One centered on extracellular serine proteases and lymphotoxins (PI3, KLK7, KLK8, KLK11, lymphotoxins A, B) converging on NFκB. The second centered on cytokines (CCL22/MDC, CCL21, CCL14, CXCL12) and IL23 signaling. In the IL23 network, acutely responsive anti-inflammatory proteins included increases of an inhibitor of IL17 signaling (IL17RC) and decreases of IL23 (IL12B:IL23A). A protein associated with resistance to environmental microbes, PTP1C, showed strong induction and is a novel candidate for aspects of corticosteroid efficacy. Two networks of cell-associated proteins were identified as drug responsive that may represent muscle tissue response (efficacy): connective tissue remodeling upstream of Notch signaling, and plasma membrane proteins impinging on AKT1 signaling.</div></div><div><h3>Conclusion</h3><div>The serum proteome pharmacodynamics of the response to vamorolone was defined.</div></div>","PeriodicalId":21997,"journal":{"name":"Steroids","volume":"225 ","pages":"Article 109721"},"PeriodicalIF":2.3,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145565177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
SteroidsPub Date : 2026-01-01Epub Date: 2025-11-19DOI: 10.1016/j.steroids.2025.109719
Hongling Wang , Yanming Zhang , Chunyang Lou , Xuliang Chang , Hang Yang , Daozuan Zhang , Haijun Ma , Zhenyuan Miao
{"title":"Discovery of dihydrobetulinic acid as a potent small molecule CD73 inhibitor","authors":"Hongling Wang , Yanming Zhang , Chunyang Lou , Xuliang Chang , Hang Yang , Daozuan Zhang , Haijun Ma , Zhenyuan Miao","doi":"10.1016/j.steroids.2025.109719","DOIUrl":"10.1016/j.steroids.2025.109719","url":null,"abstract":"<div><div>Betulinic acid (BA) is a pentacyclic triterpene compound with various biological activities. Herein, we designed and synthesized a series of dihydrobetulinic acid (DHBA) and its derivatives for the discovery of potent ecto-5′-nucleotidase (CD73) inhibitors. Biological evaluation of DHBA and its derivatives led to the disclosure of three active compounds DHBA, <strong>ZM792</strong> and <strong>ZM905</strong>. Further investigation of antitumor immunity revealed that DHBA could effectively restore the function of CD4<sup>+</sup> T cells. These results provide novel insights for future endeavors in developing novel agents derived from natural product targeting CD73 enzyme.</div></div>","PeriodicalId":21997,"journal":{"name":"Steroids","volume":"225 ","pages":"Article 109719"},"PeriodicalIF":2.3,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145565144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
SteroidsPub Date : 2026-01-01Epub Date: 2025-11-17DOI: 10.1016/j.steroids.2025.109718
Amal A. Mohamed , Wael Hafez , Said El-Feky , Mona G. Khalil , Amina S. Soliman , Karima Nasraldin , Ingy M. Ibrahim , Hanan A. Hegazy , Weam Shaheen , Abbas M. Abbas , Hager Shaheen , Marian FL. Abdelmalak , Hany N. Azzam , Omnia Ezzat , Noheir Ashraf Ibrahem Fathy Hassan , Omer Al Dulaimi , Naglaa K. Madkour
{"title":"Protective effect of vitamin D on high-fat-diet-induced metabolic dysfunction-associated steatotic liver disease in mice","authors":"Amal A. Mohamed , Wael Hafez , Said El-Feky , Mona G. Khalil , Amina S. Soliman , Karima Nasraldin , Ingy M. Ibrahim , Hanan A. Hegazy , Weam Shaheen , Abbas M. Abbas , Hager Shaheen , Marian FL. Abdelmalak , Hany N. Azzam , Omnia Ezzat , Noheir Ashraf Ibrahem Fathy Hassan , Omer Al Dulaimi , Naglaa K. Madkour","doi":"10.1016/j.steroids.2025.109718","DOIUrl":"10.1016/j.steroids.2025.109718","url":null,"abstract":"<div><h3>Background</h3><div>Genetics, inflammation, and nutrition contribute to the pathogenesis of metabolic dysfunction–associated steatotic liver disease (MASLD).</div></div><div><h3>Aim</h3><div>This preclinical study evaluated the protective effect of vitamin D supplementation against high-fat-diet–induced MASLD in a mouse model and compared physiological, inflammatory, and molecular responses across high-fat and low-fat dietary regimens, with and without vitamin D co-administration.</div></div><div><h3>Methods</h3><div>Forty-five healthy male albino Swiss mice (aged 6 weeks; 30 ± 10 g) were randomly assigned to five groups (n = 9 each): control (standard diet), HFD (high-fat diet), HFD + vitamin D, LFD (low-fat diet), and LFD + vitamin D. Vitamin D (20 000 IU/kg/week) was administered via drinking water for 12 weeks. Body weight, visceral adiposity, and liver indices were recorded, while serum biochemical markers, inflammatory cytokines, and expression of Toll-like receptor 7 (TLR7) and microRNA-155 (miR-155) were analyzed at endpoint.</div></div><div><h3>Results</h3><div>HFD-fed mice exhibited marked increases in ALT (51.44 ± 9.68 U/L), AST (56.67 ± 13.29 U/L), ALP (135.01 ± 16.19 U/L), AFP (28.56 ± 5.31 ng/mL), CRP (20.87 ± 5.56 mg/L), total cholesterol (225.00 ± 27.16 mg/dL), LDL (137.56 ± 28.66 mg/dL), and triglycerides (210.56 ± 28.71 mg/dL), accompanied by reduced HDL (30.24 ± 9.86 mg/dL) compared with controls. Pro-inflammatory cytokines TNF-α (28.33 ± 2.96 pg/mL), IL-6 (121.78 ± 8.98 pg/mL), and the expression of TLR7 (2.92 ± 0.83) and miR-155 (2.75 ± 0.77) were significantly elevated relative to normal-fed mice (miR-155: 0.84 ± 0.26). Vitamin D supplementation significantly ameliorated these metabolic and inflammatory disturbances.</div></div><div><h3>Conclusions</h3><div>Vitamin D supplementation mitigated HFD-induced hepatic injury, dyslipidemia, and inflammatory activation by modulating the miR-155/TLR7 axis. These findings highlight vitamin D as a potential adjunctive strategy for preventing or attenuating MASLD progression under high-fat dietary conditions.</div></div>","PeriodicalId":21997,"journal":{"name":"Steroids","volume":"225 ","pages":"Article 109718"},"PeriodicalIF":2.3,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145557784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Nutrient manipulation regulates growth and steroidal alkaloid production in plant cultures of Solanum viarum Dunal","authors":"Archana Prasad , Preeti Patel , Abhishek Niranjan , Gauri Saxena , Debasis Chakrabarty","doi":"10.1016/j.steroids.2025.109700","DOIUrl":"10.1016/j.steroids.2025.109700","url":null,"abstract":"<div><div><em>Solanum viarum</em> is a valuable medicinal plant native to India and widely distributed throughout Asia. It serves as a commercially viable raw source for the steroidal drug industry, being the richest natural source of an important steroidal alkaloid- solasodine. Enhancement of solasodine content in <em>in vitro</em> plant cultures is always a keen interest for tissue culturists for the research and development in pharmaceutical industries. In the present study, a multiple linear regression (MLR) model was employed to investigate the synergistic effects of key nutrient components in the growth medium (Mg, Ca, Fe, N, and sucrose) for optimized growth and solasodine production in <em>in vitro</em> plant cultures of <em>S. viarum</em>. All the cultures were harvested after 35, 45, and 55 days of the culture cycle. The three models were designed to predict growth index, solasodine content, and solasodine yield in the plant cultures. The designed model was further evaluated by performing a validation experiment using ten different experimental setups, which showed a greater similarity between the predicted and experimental datasets. The results of the model-based experimental set showed that 1.4 mM Mg, 2.9 mM Ca, 1.9 µM Fe, 41.9 mM Nitrogen, and 4 % (w/v) sucrose resulted in achieving maximum solasodine yield (108.82 mg/g DW) in the plant culture of <em>S. viarum</em> after 54 days of harvest<em>.</em> The proposed MLR model offers a robust and reliable approach for predicting the optimal concentrations of micro- and macronutrients to maximize growth and solasodine accumulation in <em>in vitro</em> cultures of <em>Solanum viarum</em>. This study establishes a strategic framework that can be leveraged to enhance biomass production and secondary metabolite yield, contributing significantly to the large-scale cultivation and pharmaceutical exploitation of this valuable medicinal plant.</div></div>","PeriodicalId":21997,"journal":{"name":"Steroids","volume":"224 ","pages":"Article 109700"},"PeriodicalIF":2.3,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145313632","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Soy isoflavone Daidzein resembling the vertebrate steroid structure exhibits neuroprotection via mitochondrial biogenesis in rotenone induced Parkinson’s disease in preclinical model","authors":"Vaibhavi Peshattiwar , Suraj Muke , Aakruti Kaikini , Sneha Bagle , Vikas Dighe , Sadhana Sathaye","doi":"10.1016/j.steroids.2025.109703","DOIUrl":"10.1016/j.steroids.2025.109703","url":null,"abstract":"<div><div>Parkinson’s disease (PD) ranks as the second most prevalent neurodegenerative disorder but is still devoid of neuroprotective treatment. Although approaches with disease modifying ability along with symptomatic relief has become an utmost necessity, the multifactorial nature of PD presents challenges for efficacy evaluation of potential test compound. This study attempts to address these issues by employing a rotenone induced PD model involving intranigral rotenone injection for evaluation of the neuroprotective efficacy of Daidzein (DZ) a soy isoflavone and a phytoestrogen. In this study, male Sprague Dawley rats after bilateral intranigral rotenone (12 μg) injection, were treated with DZ at a dose of 5, 10 and 20 mg/kg for 30 days. The neurobehavioral evaluation comprised of Rota-rod, Open field and Barnes maze test. The biochemical analysis constituting oxidative stress (Reduced glutathione, superoxide dismutase, catalase and lipid peroxidation), inflammation (TNF-α), mitochondrial alteration (complex I activity and biogenesis) was conducted on mid-brain tissue after 30 days of treatment. The Substantia nigra and striatum were subjected to immunohistochemical analysis (IHC) for TH positive neurons and Glial Fibrillary Acidic Protein. The analysis revealed significant improvement by daidzein in motor co-ordination and attenuation in cognitive deficits due to rotenone. The biochemical assessment exhibited significant decrement in oxidative stress as well as inflammation. DZ treatment also prevented complex I inhibition and promoted mitochondrial biogenesis eventually contributing to the neuroprotection apparent in IHC. Thus, the results strongly corroborate the neuroprotective potential of DZ against rotenone induced model of PD.</div></div>","PeriodicalId":21997,"journal":{"name":"Steroids","volume":"224 ","pages":"Article 109703"},"PeriodicalIF":2.3,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145337455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
SteroidsPub Date : 2025-12-01Epub Date: 2025-11-03DOI: 10.1016/j.steroids.2025.109684
Trevor M. Penning (Editor-in-Chief STEROIDS)
{"title":"Etienne Baulieu – In Memorial (1927–2025)","authors":"Trevor M. Penning (Editor-in-Chief STEROIDS)","doi":"10.1016/j.steroids.2025.109684","DOIUrl":"10.1016/j.steroids.2025.109684","url":null,"abstract":"","PeriodicalId":21997,"journal":{"name":"Steroids","volume":"224 ","pages":"Article 109684"},"PeriodicalIF":2.3,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145517276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
SteroidsPub Date : 2025-12-01Epub Date: 2025-10-04DOI: 10.1016/j.steroids.2025.109693
Anna Xie , Libo Wang , Yu Zhang, Sunzhengyuan Zhang, Jinlong Cao, Chenglong Wang, Hongjin Wu, Weiwei Dai
{"title":"Beta-Ecdysone protects osteocytes from excess glucocorticoids via Akt1-mediated regulation of Connexin43","authors":"Anna Xie , Libo Wang , Yu Zhang, Sunzhengyuan Zhang, Jinlong Cao, Chenglong Wang, Hongjin Wu, Weiwei Dai","doi":"10.1016/j.steroids.2025.109693","DOIUrl":"10.1016/j.steroids.2025.109693","url":null,"abstract":"<div><div>Glucocorticoid-induced osteoporosis (GIOP) is a leading cause of secondary osteoporosis (OP). β-Ecdysone (βEcd), a naturally occurring estrogen analog, was evaluated for its ability to mitigate the effects of glucocorticoids (GCs) on osteocytes, the crucial cells in bone remodeling. In GIOP mouse model induced by dexamethasone (Dex), micro-CT, biomechanical testing, silver nitrate staining, and hematoxylin-eosin (HE) staining were employed, demonstrating that βEcd effectively attenuated Dex-induced decreases in bone mass and strength, and alleviated Dex induced reduction in osteocyte dendrite and viability. Network pharmacology analysis predicted that the therapeutic efficacy of βEcd against GIOP is mediated through the crucial targets such as protein kinase B (Akt1), with significant enrichment in pathways including apoptosis and phosphoinositide 3-kinase (PI3K)-Akt signaling. In vitro, the osteocyte-like MLO-Y4 cells were treated with 10 μM Dex for 48 h in the presence or absence of βEcd or the PI3K inhibitor LY294002 (LY). Crystal violet staining and connexin43 (CX43) immunofluorescence (IF) staining were employed, and western blot was used to assess the levels of Akt1, phospho (p)-Akt, CX43, p-CX43, and apoptosis-related factors. Hoechst staining and annexin V/PI apoptosis assays were also used to evaluate apoptosis. The results demonstrated that βEcd counteracted Dex-induced apoptosis by modulating Akt1 and CX43 expression in MLO-Y4 cells, while inhibition of Akt activity reversed these effects, suggesting that βEcd targets the Akt1 gene. The findings indicate that βEcd protects osteocytes from GC-induced apoptosis through Akt-mediated regulation of CX43, highlighting its potential as a therapeutic approach for the prevention and treatment of GIOP.</div></div>","PeriodicalId":21997,"journal":{"name":"Steroids","volume":"224 ","pages":"Article 109693"},"PeriodicalIF":2.3,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145239818","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}