Journal of Steroid Biochemistry and Molecular Biology最新文献

{"title":"Bis(monoacylglycero)phosphate protects murine RAW 264.7 macrophages against 7-Ketocholesterol-induced apoptosis and impaired autophagy","authors":"Remi Lambert ,&nbsp;Sherine Montillet ,&nbsp;Clara Hennot ,&nbsp;Agathe Diaz-Gonzalez ,&nbsp;Marion Guichard ,&nbsp;Emeline Cros-Perrial ,&nbsp;Lars Petter Jordheim ,&nbsp;Karen Gaget ,&nbsp;Federica Calevro ,&nbsp;Celine Luquain-Costaz ,&nbsp;Isabelle Delton","doi":"10.1016/j.jsbmb.2026.106955","DOIUrl":"10.1016/j.jsbmb.2026.106955","url":null,"abstract":"<div><div>Atherosclerosis, a leading cause of cardiovascular disease, is driven by the accumulation of oxidized low-density lipoproteins (oxLDL) in arterial walls. 7-Ketocholesterol (7KC), a major oxysterol found in oxLDL and atherosclerotic plaques, triggers multiple cell injuries including loss of lysosomal integrity, oxidative stress, apoptosis, and impaired autophagy in vascular cells. Bis(monoacylglycero)phosphate (BMP), also known as lysobisphosphatidic acid, is a unique phospholipid concentrated in the endolysosomal compartment, known to regulate vesicle dynamics, lysosomal enzyme activities, intracellular cholesterol trafficking and its oxidative metabolism. Using a validated model of BMP enrichment in murine RAW 264.7 macrophages, we investigated whether BMP could exert protective activity against 7KC-induced damage. Our findings revealed that BMP enrichment provides comprehensive protection against 7KC at the cellular level by preserving cell viability, morphology, and neutral lipid balance. Mechanistically, BMP enrichment prevented apoptosis by maintaining mitochondrial integrity and blocking caspase activation. This was demonstrated by normalized BAX/BCL2 ratios, preserved pro-Caspase-3 levels, and reduced PARP cleavage. Remarkably, BMP enrichment also restored autophagic flux, thereby preventing the pathological accumulation of LC3-II and p62 that characterizes autophagy dysfunction. Enhanced colocalization between LC3 and BMP suggests direct functional interactions in the stress response. Gene expression analysis confirmed that BMP enrichment normalized the transcriptional dysregulation of key autophagy regulators, including <em>Sqstm1</em>, <em>Becn1</em>, and <em>Pink1</em>. Taken together, these results suggest that BMP is an endogenous protective factor that counteracts 7KC-induced cellular damage at multiple steps by regulating cell death and autophagy pathways in a coordinated manner.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"259 ","pages":"Article 106955"},"PeriodicalIF":2.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146182883","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":"Fenchone alleviates 7-ketocholesterol-induced oxiapoptophagy through activation of KLF4-PPARγ-Arg1-mediated M2 macrophage signalling","authors":"Sangeetha Ravi ,&nbsp;Livya Catherene Martin ,&nbsp;Manikandan Kumaresan ,&nbsp;Jaya Suriya Mani ,&nbsp;Beulaja Manikandan ,&nbsp;Manikandan Ramar","doi":"10.1016/j.jsbmb.2026.106951","DOIUrl":"10.1016/j.jsbmb.2026.106951","url":null,"abstract":"<div><div>7-ketocholesterol (7KCh), a cytotoxic oxysterol enriched in atherosclerotic plaques, provokes macrophage dysfunction through oxiapoptophagy, a linked process of oxidative stress, apoptosis and autophagy culminating in pro-inflammatory M1 polarization. Targeting this process could mitigate oxysterol-driven vascular inflammation. In this study, murine IC-21 macrophages were induced with 7KCh and co-exposed to fenchone, a bicyclic monoterpene with known anti-inflammatory properties. Cellular oxidative stress, apoptosis and autophagy were assessed by spectrofluorometric and cytometric assays. Expression of key mediators (iNOS, COX2, HO1, Casp3, Bcl2, LC3B, PARP1, Arg1, KLF4 and PPARγ) was quantified by RT-qPCR and western blotting. Molecular docking was used to identify interactions of fenchone with KLF4 and PPARγ. The results showed that 7KCh significantly increased ROS and NO production, disrupted mitochondrial membrane potential and induced apoptosis and autophagy in macrophages. Fenchone co-treatment counteracted these effects, restoring redox balance and membrane integrity. Molecular analyses revealed downregulation of iNOS, COX2, Casp3 and PARP1, alongside upregulation of HO1, Arg1, KLF4 and PPARγ. Docking analysis confirmed strong binding of fenchone to KLF4 and PPARγ, suggesting transcriptional regulation of macrophage polarization via the KLF4-PPARγ-Arg1 axis. These findings suggest that fenchone mitigates 7KCh-induced oxiapoptophagy and reprograms macrophages toward an anti-inflammatory M2 phenotype through modulation of KLF4/PPARγ signalling, positioning fenchone as a potential immunomodulatory candidate for combating oxysterol-mediated vascular inflammation.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"259 ","pages":"Article 106951"},"PeriodicalIF":2.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146133531","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":"What can we learn from the history of steroid metabolites and the ongoing identification of novel biologically active steroid metabolites?","authors":"Alex Odermatt ,&nbsp;David J. Morris","doi":"10.1016/j.jsbmb.2026.106954","DOIUrl":"10.1016/j.jsbmb.2026.106954","url":null,"abstract":"<div><div>Historically, it was thought that primary steroids released from endocrine glands exert their hormonal effects through corresponding receptors in peripheral tissues, and that their metabolism then inactivates them, followed by excretion. However, the metabolism of primary steroids is not just a way of inactivating and excreting them, but generates a variety of metabolites with different biological properties. In this review, we outline how various active steroid metabolites were discovered, describe some of the ways they are generated, and how they can in a non-classical way act on receptors or alter the activity of steroid metabolizing enzymes, thereby indirectly affecting receptor activities. Examples include the 5α-reduced ring-A metabolites of 11-deoxycorticosterone (DOC) and progesterone that are formed in the brain, act as neurosteroids and exert effects through the GABA-A membrane receptor. Another example is 11-ketoprogesterone that potently activates mineralocorticoid receptors (MR), but not glucocorticoid receptors (GR), and is more potent than its 11β-hydroxylated form, in contrast to glucocorticoids. Moreover, we discuss the microbiome as important source of bioactive metabolites, exemplified by the 11β-hydroxylated 5α-reduced ring-A corticosteroid and progesterone metabolites that were shown as potent 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2) inhibitors. 11β-HSD2 inhibition results in cortisol-induced MR activation, sodium retention and hypertension. Furthermore, microbial 17,20-desmolase activity can convert glucocorticoids to androgens, potentially influencing diseases and therapeutic outcomes. There are still many knowledge gaps regarding bioactive steroid metabolites. Identifying additional bioactive steroid metabolites and characterizing their genomic and non-genomic effects should help uncovering their cell-specific functions and contributions to the maintenance of homeostatic regulation.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"259 ","pages":"Article 106954"},"PeriodicalIF":2.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146182826","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":"Interleukin-2 receptor γ blocks the development of Leydig cells from stem/progenitor cells in male rats via JAK1-STAT3 pathway and GSDMD-mediated pyroptosis","authors":"Jingyi Zheng ,&nbsp;Qingyuan Wang ,&nbsp;Huiqian Zhang ,&nbsp;Yubin Xu ,&nbsp;Feilu Wang ,&nbsp;Yiyan Wang ,&nbsp;Xiaoheng Li ,&nbsp;Ren-Shan Ge","doi":"10.1016/j.jsbmb.2026.106953","DOIUrl":"10.1016/j.jsbmb.2026.106953","url":null,"abstract":"<div><div>Interleukin-2 (IL-2) receptor γ (IL2RG) is present in the Leydig cell lineage, but its functional role remains elusive. To investigate how IL2RG impacts Leydig cell development from stem cells and elucidate the underlying mechanisms, we used a rat model of ethane dimethanesulfonate (EDS)-induced cell depletion in Wild-type (WT) and <em>Il2rg</em> knockout (KO) mice. WT and KO male rats received intratesticular IL-2 injections (1 and 10 ng/testis) from day 7 to day 21 post-EDS. Stem Leydig cells around tubules and isolated progenitor Leydig cells were cultured with IL-2 (1 and 10 ng/mL) with/without STAT3 inhibitor. Hormone levels, cell counts, gene/protein expression, and signaling pathways were analyzed. The results revealed that IL-2 significantly reduced serum testosterone levels in WT rats but had no effects in KO rats, without altering luteinizing hormone and follicle-stimulating hormone levels. Furthermore, IL-2 lowered Leydig cell numbers and the labeling index of PCNA in CYP11A1⁺ Leydig cells at 10 ng/testis, and downregulated the expression of SCARB1, HSD3B1, CYP17A1, SRD5A1, and NR5A1, as well as their corresponding mRNA levels in WT rats with no effect observed in KO rats. IL-2 also inhibited the incorporation of 5-ethynyl-2′-deoxyuridine (EdU) into stem Leydig cells in WT rats and [³H] thymidine incorporation into progenitor Leydig cells, as well as their differentiation. Importantly, the effects of IL-2 were reversed by the STAT3 inhibitor. Signaling pathway analysis showed that IL-2 exerted effects via increasing JAK1, STAT5, and STAT3 phosphorylation. This study provides insights into the inhibitory effects of IL2RG on Leydig cell development and highlights the involvement of the JAK-STAT pathway, offering potential targets for further exploration in the context of Leydig cell biology and male reproductive health.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"259 ","pages":"Article 106953"},"PeriodicalIF":2.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146151290","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":"Integrative metabolomics and network pharmacology reveal the therapeutic mechanisms of Inonotus hispidus (Bull.) P. Karst. extract against primary dysmenorrhea","authors":"Qingchun Wang ,&nbsp;Haiying Bao ,&nbsp;Jingjing Zhao ,&nbsp;Hailong Liang","doi":"10.1016/j.jsbmb.2026.106957","DOIUrl":"10.1016/j.jsbmb.2026.106957","url":null,"abstract":"<div><div>Primary dysmenorrhea (PD) is a common gynecological disorder characterized by uterine hypercontraction and inflammation. This study employed an integrated strategy combining serum metabolomics, network pharmacology, and experimental validation to investigate the therapeutic potential of different extracts of <em>Inonotus hispidus</em>. In a rat PD model induced by estradiol benzoate and oxytocin, petroleum ether extracts of <em>I. hispidus</em> (MP) significantly alleviated writhing responses, attenuated uterine tissue injury, and corrected key biochemical imbalances, including the pivotal PGF₂α/PGE₂ ratio and levels of inflammatory cytokines (TNF-α, IL-6, IL-1β). Serum metabolomics analysis revealed that the therapeutic effect of MP was fundamentally linked to the systemic rectification of dysregulated arachidonic acid (AA) metabolism. Network pharmacology and subsequent experimental validation identified that MP concurrently modulates several interconnected signaling pathways. Crucially, MP activated PPARγ by promoting its dephosphorylation, which in turn potently suppressed the NLRP3 inflammasome. Concurrently, it regulated the PI3K/Akt/NF-κB survival-inflammatory axis and inhibited the RhoA/ROCK-mediated contractile pathway, reducing phosphorylation of downstream effectors MYPT1 and MLC. In vitro, the medicated serum (MP-S), containing systemically absorbed bioactive compounds, demonstrated superior and more comprehensive cytoprotection against oxytocin-induced oxidative stress, mitochondrial dysfunction, and apoptosis in rat uterine smooth muscle cells (RUSMCs) than the single compound ergosterone, underscoring the principle of multi-component synergy. Collectively, this work delineates a multi-target mechanism for MP against PD, involving the correction of AA metabolic dysregulation, activation of the PPARγ-NLRP3 axis to suppress inflammation, and inhibition of pathways driving smooth muscle hypercontraction, providing a solid scientific foundation for its development as a modern, multi-targeted therapeutic agent.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"259 ","pages":"Article 106957"},"PeriodicalIF":2.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146182873","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":"E3 ubiquitin ligase PELI1 promotes ferroptosis in granulosa cells in PCOS by degrading Fth1","authors":"Xiaomeng Zha ,&nbsp;Liang Chen ,&nbsp;Zhaoping Tan ,&nbsp;Tiancheng Wu ,&nbsp;Qiaohua Xiong ,&nbsp;Haihua Wang ,&nbsp;Yuanyuan Kuang ,&nbsp;Fei Xing ,&nbsp;Aihua Lu ,&nbsp;Lili Sun ,&nbsp;Yuanzhen Zhang","doi":"10.1016/j.jsbmb.2026.106948","DOIUrl":"10.1016/j.jsbmb.2026.106948","url":null,"abstract":"<div><div>Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disease in women of reproductive age, characterized by hyperandrogenemia and obstruction of ovulation. However, the underlying mechanisms of ovarian abnormalities in PCOS remain to be investigated. In this study, we first identified altered levels of ovarian ferroptosis in the PCOS population by screening a web-based database. Further, we established a prasterone-exposed PCOS mouse model and a granulosa cell model to confirm that hyperandrogenism can lead to the development of ferroptosis in ovarian granulosa cells. The transcriptome sequencing and cellular experiments were conducted to explore the possible mechanisms. It was found that the ubiquitination pathway and P53 pathway are significantly enriched in the prasterone-exposed granulosa cells. The E3 ubiquitin ligase PELI1 gene is significantly highly expressed in PCOS ovaries and may contribute to ferroptosis by degrading FTH1. In addition, high expression of the P53 gene was associated with alterations in PELI1/FTH1. This study confirmed that hyperandrogenism can mediate the development of ovarian ferroptosis via the P53/PELI1/FTH1 pathway and the E3 ubiquitin ligase PELI1 plays an important regulatory role. In vivo, the iron death inhibitor deferoxamine mesylate could alleviate ferroptosis and follicular development disorder in the ovaries of PCOS mice. This study provides new insights into the pathological changes of PCOS ovaries and possible interventions for the treatment of PCOS.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"259 ","pages":"Article 106948"},"PeriodicalIF":2.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146097526","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":"Dehydroepiandrosterone alleviates pulmonary fibrosis by modulating the TLR4/NF-κB/NLRP3 signaling cascade in macrophages.","authors":"Qingqing Xie, Xu Zhao, Yiwei Lu, Shiquan Shuai","doi":"10.1016/j.jsbmb.2026.107028","DOIUrl":"https://doi.org/10.1016/j.jsbmb.2026.107028","url":null,"abstract":"<p><p>Idiopathic pulmonary fibrosis (IPF) is a severe progressive lung disease with limited treatment options. Dehydroepiandrosterone (DHEA), an endogenous steroid hormone, possesses anti-inflammatory and anti-fibrotic properties, but its mechanism of action in pulmonary fibrosis (PF) remains incompletely understood. This study aimed to investigate whether DHEA alleviates PF by modulating macrophage-driven inflammatory responses. An in vitro model of PF was established using conditioned medium from LPS-stimulated, PMA-differentiated THP-1 macrophages to treat MRC-5 pulmonary fibroblasts. DHEA pretreatment (5-20μM) was applied to macrophages, and the TLR4-specific inhibitor TAK-242 was used for mechanistic validation. Inflammatory cytokines were measured by ELISA, protein expression of TLR4/NF-κB/NLRP3 cascade components and extracellular matrix markers (α-SMA, Collagen I) by Western blotting, and cell proliferation by CCK-8 and flow cytometry. DHEA significantly reduced LPS-induced secretion of TNF-α, IL-6, IL-1β, and IL-18 from macrophages. It downregulated TLR4 expression, inhibited NF-κB phosphorylation, and suppressed NLRP3 inflammasome activation (NLRP3, ASC, Caspase-1). Furthermore, DHEA treatment of macrophages prevented their conditioned medium from inducing abnormal proliferation of MRC-5 cells and reduced α-SMA and Collagen I expression in these fibroblasts, similar to the effects of TAK-242. In conclusion, DHEA alleviates inflammatory responses and in vitro pulmonary fibrosis by blocking the TLR4/NF-κB/NLRP3 signaling cascade in macrophages, providing a new mechanistic basis for its potential therapeutic application in PF.</p>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":" ","pages":"107028"},"PeriodicalIF":2.5,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147788617","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":"Exploring the feature prioritization and data sampling of PCOS diagnosis via densely connected attention based squeeze deep learning detection model","authors":"Siji Jose Pulluparambil ,&nbsp;Subrahmanya Bhat","doi":"10.1016/j.jsbmb.2025.106933","DOIUrl":"10.1016/j.jsbmb.2025.106933","url":null,"abstract":"<div><div>Accurate and timely diagnosis remains a challenge due to the complexity of Polycystic Ovary Syndrome (PCOS) symptoms and data imbalance issues in the existing datasets. This research aims to develop a robust PCOS detection model that addresses these challenges by introducing a novel hybrid methodology with effective feature prioritization while handling data balancing issues. The research involves three major phases: pre-processing, feature selection, and PCOS detection. In the pre-processing stage, dataset balancing is emphasized by the combination of Synthetic Minority Oversampling Techniques (SMOTE) and Edited Nearest Neighbor (ENN). Under this stage, replacing null values, balancing the dataset, and dropping unnecessary columns are accomplished to increase PCOS detection accuracy. The second stage is feature selection, where a distinct hybrid bionic strategy named the Gorilla Salp Swarm Troop Model (GS2TM) is proposed to pick the optimal set of dominant features. The GS2TM algorithm reduces the feature set by 51.1 %, retaining only 23 features while achieving a state-of-the-art accuracy of 98.7 %. In addition, the Densely Connected Attention-Based Squeeze Convolutional Detection Model (DASCD) is proposed for the prediction of PCOS, in which multiple layers are adjusted in a feed-forward manner. The novelty of this work lies in the unified pipeline that simultaneously addresses three major challenges in PCOS detection, such as dataset imbalance (SMOTE-ENN), feature redundancy (GS2TM), and overfitting (DASCD with attention), providing both high accuracy and enhanced interpretability. As a result, the proposed detection model greatly improves accuracy compared to other existing ML-based strategies. Specifically, by utilizing 23 characteristics with GS2TM, the proposed model outperforms with an accuracy of 98.7 % in categorizing PCOS and non-PCOS.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"258 ","pages":"Article 106933"},"PeriodicalIF":2.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145893463","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":"Androgen production in adrenocortical H295R cells is regulated by thyroid hormone T3 without reciprocal thyroid axis modulation in pediatric CAH","authors":"Philipp Augsburger ,&nbsp;Therina du Toit ,&nbsp;Emre Murat Altinkiliç ,&nbsp;Sabine Hannema ,&nbsp;Christiaan de Bruin ,&nbsp;Evangelia Charmandari ,&nbsp;Erica L.T. van den Akker ,&nbsp;Christa E. Flück","doi":"10.1016/j.jsbmb.2026.106939","DOIUrl":"10.1016/j.jsbmb.2026.106939","url":null,"abstract":"<div><div>Thyroid hormones (THs) are critical regulators of human development, cellular differentiation, and metabolism. While their systemic effects are well established, their role in adrenal androgen production remains poorly defined. Moreover, potential feedback regulation of the hypothalamic–pituitary–thyroid (HPT) axis by adrenal androgens has not been thoroughly investigated. This study aimed to clarify the regulatory effects of THs on adrenal androgens and to investigate potential feedback mechanisms in patients with congenital adrenal hyperplasia (CAH). In an in-vitro experiment, treatment with 3,3′,5-triiodo-<span>L</span>-thyronine (T3) on adrenocortical carcinoma H295R cells significantly reduced dehydroepiandrosterone (DHEA) and DHEA-sulfate production while modestly increasing testosterone (T) and androstenedione (A4). These changes were associated with an increase in expression of <em>HSD3B2</em> and <em>AKR1C3</em>, and a decrease of <em>CYP17A1</em>. Transcriptomic analysis additionally revealed enrichment of pathways related to steroidogenesis and adrenal development through T3 treatment. In the clinical part of the study, hormone levels in pediatric CAH patients were analyzed. Serum free thyroxine (fT4) and thyroid-stimulating hormone (TSH) showed weak negative correlations with the adrenal androgens DHEA and A4. However, no differences in fT4 or TSH concentrations were observed between well-controlled and hyperandrogenic patients, suggesting a lack of feedback regulation by adrenal androgens on the HPT axis. In conclusion, these findings suggest that THs regulate adrenal androgen production by modulating the activity of key steroidogenic enzymes. This relationship appears to be predominantly unidirectional, with THs influencing adrenal steroidogenesis but adrenal androgens not altering HPT axis function.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"258 ","pages":"Article 106939"},"PeriodicalIF":2.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145981245","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":"Targeting cholinesterases with steroid hormone derivatives: Insights from In Vitro assays and molecular modeling","authors":"Jovana J. Ajduković ,&nbsp;Ana Matošević ,&nbsp;Anita Bosak ,&nbsp;Strahinja Kovačević ,&nbsp;Milica Karadžić Banjac ,&nbsp;Ivana Z. Kuzminac ,&nbsp;Andrea R. Nikolić ,&nbsp;Marina P. Savić","doi":"10.1016/j.jsbmb.2026.106950","DOIUrl":"10.1016/j.jsbmb.2026.106950","url":null,"abstract":"<div><div>Steroids represent a large family of organic compounds that, as signaling molecules, play important role in variety of physiological processes as control of metabolic pathways, inflammation processes, immune response, and growth, development and reproduction. Modifying the steroid core has allowed the creation of novel synthetic derivatives, which can offer significant benefits in medicine for treating a wide range of pathological conditions. Quite a number of natural steroids have been identified as effective inhibitors of cholinesterases, pointing them out as potential therapeutic alternatives in the application in Alzheimer’s disease (AD). Nevertheless, only a limited number of synthetic steroids have so far been studied as cholinesterase inhibitors, highlighting an opportunity for the development of new therapeutic agents derived from natural steroidal frameworks. In this study, we selected a set of structurally diverse steroid hormone derivatives and evaluated <em>in vitro</em> their inhibitory activity against human AChE and BChE. IC₅₀ values were estimated for several of the most active compounds, with pyridine-containing hydroxy derivative <strong>8</strong> exhibiting affinity toward BChE (IC₅₀ 2.76 µM), similar to that for clinically used cholinesterase inhibitors. <em>In silico</em> analyses suggest that hydrophobic interactions with key amino-acid residues predominantly govern the binding of these compounds within the enzyme’s active site.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"258 ","pages":"Article 106950"},"PeriodicalIF":2.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146108279","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}