The Journal Of Steroid Biochemistry And Molecular Biology[JOURNAL]
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200 papers
The Microbiome-Gut-Gonad Axis: How Microbial Metabolites Orchestrate Reproductive Physiology, Pathology, and Therapy.
El-Sehrawy AAMA, Oriquat G, Rizaev J … +5 more , Yuldasheva S, Shakhmurova G, Abdul NH, Singh R, Bainsal N
J Steroid Biochem Mol Biol · 2026 Jul · PMID 42401402 · Publisher ↗
The human microbiome, a dynamic endocrine organ, exerts profound systemic influence through the production of bioactive metabolites. While the microbiome-gut-brain axis is well-established, the direct conduit between the...
The human microbiome, a dynamic endocrine organ, exerts profound systemic influence through the production of bioactive metabolites. While the microbiome-gut-brain axis is well-established, the direct conduit between the gut microbiota and the reproductive system, the Microbiome-Gut-Gonad Axis, remains an emerging paradigm. This review explored cutting-edge evidence to construct a comprehensive model of the Microbiome-Gut-Gonad axis, focusing on the mechanistic roles of specific microbial metabolites in both physiological reproductive function and the pathogenesis of endocrine disorders. We move beyond mere correlation to elucidate how gut-derived molecules, such as short-chain fatty acids (SCFAs), secondary bile acids, and indole derivatives, directly and indirectly modulate the hypothalamic-pituitary-gonadal (HPG) axis by modulating the production of neuropeptides and hormones (Gonadotropin-releasing hormone (GnRH)) that regulate reproductive functions and also steroidogenesis and gametogenesis. We examine novel mechanisms including: the epigenetic regulation of steroidogenic enzymes by butyrate; the modulation of enterohepatic circulation of estrogens by β-glucuronidase-producing bacteria; and the role of tryptophan metabolites as ligands for aryl hydrocarbon receptor (AhR) in ovarian and testicular function. Furthermore, we critically appraise the disruptive potential of dysbiosis-driven metabolite shifts in PCOS, endometriosis, and male infertility, highlighting microbial metabolite signatures as promising exploratory biomarkers that require standardized, multi-center clinical validation before diagnostic use. At present, these signatures should be considered candidate biomarkers only, because external validation cohorts, assay reproducibility, and clinically meaningful estimates of sensitivity, specificity, predictive values, and clinical utility have not yet been established. Therapeutically, we evaluate innovative interventions, including precision probiotics, postbiotics, and dietary strategies targeting specific bacterial guilds, but these approaches remain investigational because current human evidence is still limited and heterogeneous. Finally, by integrating microbial endocrinology into reproductive medicine, this review establishes a new framework for understanding the etiology of reproductive endocrine disorders and paves the way for microbiome-targeted therapeutic avenues. Importantly, the evidence base is tiered: mechanistic statements in this review are drawn primarily from in vitro and animal studies, human disease links are described separately as observational evidence, and interventional claims are limited to early clinical studies and randomized trial summaries.
L-arginine improves prenatal and pre-pubertal codeine-induced steroidogenesis deregulation by suppressing oxidative stress-dependent signaling in male wistar rats.
Akhigbe RE, Afolabi OA, Ajayi AF
J Steroid Biochem Mol Biol · 2026 Jul · PMID 42392414 · Publisher ↗
This study investigated the impact of prepubertal L-arginine on prepubertal and maternal codeine-induced testicular toxicity in F1 male offspring. Forty female rats were randomized at weaning into either vehicle-treated...
This study investigated the impact of prepubertal L-arginine on prepubertal and maternal codeine-induced testicular toxicity in F1 male offspring. Forty female rats were randomized at weaning into either vehicle-treated control or codeine-treated groups (n = 20 rats/group). After 8 weeks of treatment, the animals were matched with healthy, sexually developed male rats. During pregnancy and lactation, the female rats continued their pre-pregnancy treatments. The female rats delivered at term and 20 male FI offspring from each group (the control and codeine-treated groups) were divided into four groups by randomization after weaning: the control, codeine-treated, L-arginine-treated, and codeine + L-arginine-treated groups (n = 10 rats per group). Prepubertal codeine use significantly reduced testicular weight and gamma-glutamyl transferase and sorbitol dehydrogenase activities, increased testicular injury markers (lactate dehydrogenase and lactate), and distorted testicular histoarchitecture. These findings were associated with decreased activities of steroidogenic proteins (StAR, 3β-HSD, and 17β-HSD) and male reproductive hormones (LH, FSH, and testosterone). More so, codeine increased pro-inflammatory (myeloperoxidase, TNF-α, IL-1β) and pro-apoptotic (Bax and caspase 3 activity) genes and proteins, and reduced antioxidant cytoprotective genes and proteins. These negative effects were associated with the modulation of transcription factors (Nrf2 and NF-kB) and were more profound in animals whose dams were also exposed to codeine compared with those whose dams were not exposed to codeine. Nonetheless, codeine-induced perturbations were attenuated by prepubertal L-arginine administration. Our results revealed that L-arginine protected the testis and preserved testicular steroidogenesis in codeine-exposed rats by suppressing oxidative stress, inflammation, and apoptosis.
Discovery of 17-imidazo[1,2-a]pyridinyl-3α-hydroxy-5α-androstanes (17IPAs) as novel potent positive allosteric modulators of the GABA receptor: Synthesis, in vitro and in silico studies.
Volkova YA, Birukova VE, Kolbaev SN … +6 more , Bukanova JV, Kondrakhin EA, Kovalev GI, Zavarzin IV, Sharonova IN, Rossokhin AV
J Steroid Biochem Mol Biol · 2026 Jul · PMID 42392413 · Publisher ↗
Neuroactive steroids (NASs) have attracted considerable interest as novel treatments for various central nervous system (CNS) disorders and as new intravenous general anesthetics. Herein, we report the synthesis, biologi...
Neuroactive steroids (NASs) have attracted considerable interest as novel treatments for various central nervous system (CNS) disorders and as new intravenous general anesthetics. Herein, we report the synthesis, biological evaluation, and in silico studies of a series of promising NASs, 17-imidazo[1,2-a]pyridinyl-3α-hydroxy-5α-androstanes (17IPAs). It was shown that 17IPAs can be synthesized by the condensation of 21-bromo-3α-hydroxy-5α-androstan-20-one with substituted 2-aminopyridines under mild conditions. A representative series of 17IPAs was evaluated for their ability to alter the amplitude of currents evoked by 1µM γ-aminobutyric acid (GABA) in isolated rat cerebellar Purkinje neurons. The compounds were found to be potent and efficacious positive allosteric modulators of GABA type A receptors (GABARs), with EC values ranging from 0.34 to 3.2µM. Interactions of the most potent compound (EC = 0.34 ± 0.1µM) with the GABAR were investigated using molecular docking calculations. Our model predicts that the imidazo[1,2-a]pyridine moiety at the C17 position of the 5α-androstan-3α-ol core does not prevent the binding of the compound to the neurosteroid site at the β(+)/α(-) intersubunit interfaces. We conclude that 17IPAs retain their ability to potentiate α1β2γ2 GABARs despite the changes in the profile of interacting residues. Experiments with [H]flunitrazepam displacement in rat cortical membranes excluded any possible competitive binding of 17IPAs to the benzodiazepine binding site of GABAR. Overall, 17-imidazo[1,2-a]pyridinyl-5α-androstanes may serve as the starting point for the rational design of novel selective NASs for CNS indications and anesthesia.
Androgen receptor as therapeutic indicator for LAR-positive triple-negative breast cancer: Preclinical and clinical assessment.
Shukla N, Sharma D, Rathore D … +4 more , Dharwal N, Vora H, Shah J, Dave H
J Steroid Biochem Mol Biol · 2026 Jun · PMID 42373057 · Publisher ↗
Triple-negative breast cancer (TNBC) is an aggressive disease with limited treatment options, where the luminal androgen receptor (LAR+) subtype presents a promising target for AR-directed therapy. However, the impact of...
Triple-negative breast cancer (TNBC) is an aggressive disease with limited treatment options, where the luminal androgen receptor (LAR+) subtype presents a promising target for AR-directed therapy. However, the impact of AR splice-variants on responses to bicalutamide (Bica) and enzalutamide (Enza) is not well understood across various breast cancer forms. This study investigated Bica and Enza in the LAR + TNBC (MDA-MB-453), the AR-low TNBC (MDA-MB-231), and the ER + luminal (MCF-7) cells, using both 2D monolayer and 3D spheroid cultures. It examined AR splice-variant expression, cell-cycle progression, viability, and nuclear AR immunohistochemistry in TNBC patient samples from India. In 2D cultures, these drugs showed subtype-specific effects: in MDA-MB-453, both reduced AR-V7 and caused G1 arrest, with Bica exerting a stronger effect; in MDA-MB-231, Bica and Enza differentially regulated AR-V1, AR-V4, AR-V5, and AR-V6 without significant cell-cycle alterations. In MCF-7, Enza induced G1 arrest alongside changes in AR variants. In 3D spheroids, drug responses differed markedly from 2D conditions, and co-treatment with dihydrotestosterone (DHT) emphasized context-dependent AR signaling. Nuclear AR was detected in 30% of Indian TNBC samples. Overall, the findings reveal that AR splice variants vary in expression and regulation across breast cancer subtypes, and that treatment effectiveness is influenced by the splice-variant profile, ER-AR interactions, and the tumor environment. Total AR protein alone is insufficient for patient stratification. These insights support the inclusion of AR splice-variant analysis in biomarker-based strategies to enable precise AR-targeted therapies in breast cancer.
The 24,25(OH)D-TLCD3B signaling complex and reproductive function in mice and men.
Kooij I, Mitrofanov K, Rehfeld A … +6 more , Andreassen CH, Kyhn Madsen S, Janssen AM, St-Arnaud R, Jørgensen A, Blomberg Jensen M
J Steroid Biochem Mol Biol · 2026 Jun · PMID 42365880 · Publisher ↗
Vitamin D influences male reproductive function, and the expression of the vitamin D-inactivating enzyme CYP24A1 in spermatozoa has consistently been shown to be positively correlated with semen quality. The predominant...
Vitamin D influences male reproductive function, and the expression of the vitamin D-inactivating enzyme CYP24A1 in spermatozoa has consistently been shown to be positively correlated with semen quality. The predominant CYP24A1-generated metabolite, 24,25(OH)D, previously considered to be inactive, has recently been shown to bind and activate TRAM-LAG1-CLN8 domain 3B (TLCD3B). Here, we demonstrate that TLCD3B is expressed in mouse and human testis, and in the midpiece of human spermatozoa. Short-term treatment of male mice with 24,25(OH)D increased serum levels of LH and inhibin B. However, global and germ cell-specific TLCD3B-deficient mice showed no major changes in reproductive function. Conversely, in female global TLCD3B-deficient mice, serum levels of 1,25(OH)D were elevated, accompanied by reduced ovarian Cyp24a1 expression, but no major changes in reproductive function were observed. In human spermatozoa, high concentrations of 24,25(OH)D-treatment elicited a rapid Ca²⁺ increase, but this was likely mediated via the vitamin D receptor. Our findings demonstrate that 24,25(OH)D-TLCD3B signaling is dispensable for reproductive function in mice and exerts limited effects in human spermatozoa. Our study highlights the complexity of vitamin D signaling and shows that 24,25(OH)D-TLCD3B has limited importance for male reproductive function in reproductively competent young adult mice.
Testosterone and epitestosterone differentially regulate UDP-glucuronosyltransferases (UGT) activity.
Xiao L, Qi J, Zhang Y … +3 more , Li W, Zhu L, Liang S
J Steroid Biochem Mol Biol · 2026 Jun · PMID 42303060 · Publisher ↗
Despite being constantly exposed to endogenous substrates, the effects of these substrates on UDP-glucuronosyltransferase (UGT) activity remain poorly understood. This study investigated the effects of testosterone (T) a...
Despite being constantly exposed to endogenous substrates, the effects of these substrates on UDP-glucuronosyltransferase (UGT) activity remain poorly understood. This study investigated the effects of testosterone (T) and its 17-epimer epitestosterone (epiT) on UGTs using in vitro and in silico approaches. T competitively inhibited UGT2B7 with K values ranging from 11.4 to 30.2 μM, while displaying mixed-type inhibition towards UGT2B15 with a K of 7.74 μM. In contrast, epiT showed substantially stronger competitive inhibition against both UGT2B7 and -2B15, with K values of 1.06-2.12 μM and 2.75 μM, respectively. Both T and epiT activated UGT2B17 via a two-site kinetic model, with activator binding constants of 8.30 μM (T) and 9.52 μM (epiT). Androgen binding similarly enhanced substrate affinity, but epiT increased the turnover number more (β = 4.01) than T (β = 2.34). Molecular docking revealed that epiT binds more tightly to UGT2B7 and -2B15 (binding energies: -9.1 and -7.51 kcal/mol) than T (-8.4 and -6.98 kcal/mol), owing to additional hydrogen bonds formed by its 17α-hydroxyl group. In summary, this study reveals that a single stereochemical inversion dramatically enhances UGT modulation, positioning epiT as an important endogenous modulator of glucuronidation in androgen-rich tissues.
Interferon-gamma-inducible protein-10 is associated to increased primary bile acids and fibrosis in primary sclerosing cholangitis.
Langhans B, Dold L, Zhou T … +6 more , Trägner JS, Friedrichs S, Stellaard F, Lütjohann D, Strassburg CP, Kalthoff S
J Steroid Biochem Mol Biol · 2026 Jun · PMID 42303059 · Publisher ↗
Primary sclerosing cholangitis (PSC) is a chronic, progressive cholestatic liver disease characterized by inflammation and fibrosis of the bile ducts. Altered bile acid (BA) profile was shown to trigger immune responses...
Primary sclerosing cholangitis (PSC) is a chronic, progressive cholestatic liver disease characterized by inflammation and fibrosis of the bile ducts. Altered bile acid (BA) profile was shown to trigger immune responses in the liver, contributing to inflammation and liver fibrosis. Here, we analyzed BAs, their precursors (oxysterols), surrogate markers of cholesterol synthesis as well as of absorption, and studied their association with clinical/ immunological parameters in PSC. We analyzed concentrations of BAs (cholic acid, CA; chenodeoxycholic acid, CDCA; deoxycholic acid, DCA; lithocholic acid, LCA; ursodeoxycholic acid, UDCA), their precursors (7α-, 24-, 27-hydroxycholesterol, 7αOH-Chol, 24OH-Chol, 27OH-Chol), cholesterol synthesis marker lathosterol and cholesterol absorption markers (5α-cholestanol, sitosterol, campesterol) in serum from patients with PSC (n = 33) in comparison to healthy blood donors (n = 30). Inflammatory cytokines in serum were measured using flow-cytometry-based bead array. While serum concentrations of cholesterol and its precursor lathosterol were comparable between patients with PSC and healthy individuals, serum concentrations of CA and CDCA were statistically significant increased in PSC. Furthermore, we observed elevated concentrations of cholesterol absorption markers in PSC. Association with clinical parameters revealed a statistically significant correlation of CA, CDCA, and cholesterol absorption markers with AP, bilirubin, AST, and ALT. In addition, pro-inflammatory IP-10 (interferon-gamma-inducible protein-10) was increased in serum of PSC patients and associated with primary BAs and liver fibrosis. Our findings reveal a distinct metabolic signature in PSC characterized by increased primary BAs and cholesterol absorption markers in serum. The correlations between IP-10, BAs, and fibrosis suggest a bile acid-driven pro-inflammatory circuit potentially contributing to disease progression.
Testosterone increases clonogenicity and self-renewal capacity of human glioblastoma cells.
Quintero JC, Alemán OR, Hernández-Lúa LN … +3 more , Robles-Flores M, Díaz NF, Camacho-Arroyo I
J Steroid Biochem Mol Biol · 2026 Jun · PMID 42264401 · Publisher ↗
Glioblastoma is the most common and aggressive malignant brain tumor in adults, characterized by rapid progression and limited therapeutic response. The presence of glioma stem cells contributes to high recurrence and tr...
Glioblastoma is the most common and aggressive malignant brain tumor in adults, characterized by rapid progression and limited therapeutic response. The presence of glioma stem cells contributes to high recurrence and treatment resistance. Epidemiological data indicate a higher incidence of glioblastoma in men than in women, suggesting a potential role for sex hormones in disease progression. To evaluate the influence of testosterone on glioblastoma stemness-associated characteristics, male human glioblastoma-derived cell lines were analyzed for androgen receptor (AR) regulation and responses to testosterone exposure. AR protein levels were quantified, and functional assays were performed to assess clonogenicity, neurospheres formation, and stemness-associated gene expression. T98G and U251 human glioblastoma cell lines expressed AR. Notably, neurospheres exhibited a higher AR expression than cells in monolayer cultures, and testosterone further increased its expression. In suspension cultures, testosterone significantly enhanced clonogenic potential, as evidenced by increased numbers and sizes of primary and secondary neurospheres. Testosterone upregulated the expression of stemness-associated genes (PROM1, SOX2, and NES) and, in differentiation assays, elevated the number of Sox2-positive cells. Overall, these findings suggest that testosterone increases clonogenicity and self-renewal capacity of human glioblastoma cells, highlighting androgen signaling as a critical regulator of tumor resilience and a promising therapeutic target to disrupt the maintenance of glioblastoma stem-like cells.
Role of 5α-reductase inhibitors in Parkinson's disease: Gambling or not?
Hussein NR, Al-Kuraishy HM, Fahad EH … +4 more , Sulaiman GM, Mohammed HA, Al-Gareeb AI, Albuhadily AK
J Steroid Biochem Mol Biol · 2026 Jun · PMID 42264400 · Publisher ↗
Parkinson's disease (PD) is a progressive neurodegenerative disease due to degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The fundamental cause of PD is not completely confirmed. Howev...
Parkinson's disease (PD) is a progressive neurodegenerative disease due to degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The fundamental cause of PD is not completely confirmed. However, genetic, epigenetic, and environmental factors are intricate in the progressive accumulation of mutant α-synuclein (α-Syn) in the dopaminergic neurons of the SNpc. PD is frequently linked with other age-related diseases such as benign prostatic hypertrophy, which is treated by the 5α-reductase inhibitor finasteride. Particularly, 5α-reductase, which is expressed in the prostate, is also expressed in the brain for the biosynthesis of the neuroprotective neurosteroids. Thus, 5α-reductase inhibitors such as finasteride may adversely affect the pathogenesis of PD. Nevertheless, numerous preclinical and clinical investigations highlight that finasteride may have a neuroprotective effect against the development and progression of PD. Despite this effect of finasteride, prolonged use of a 5α-reductase inhibitor is associated with the development of dementia in the initial periods after starting treatment. However, reducing the magnitude of the association over time suggested that the risk may be completely or in part due to increased dementia detection among patients with benign prostate enlargement. The fundamental mechanism by which 5α-reductase inhibitors are related to cognitive impairment is indistinct. Therefore, the possible role of finasteride in PD is not completely clarified. Consequently, the objective of the present review was to explain and discuss the precise role of finasteride in PD.
Evolutionary divergence and expression dynamics of the progestin receptor system: Sex-specific responses to exogenous progestin in Spinibarbus hollandi.
Zhou J, Yang W, Huang W … +5 more , Zhang M, Zhan L, Han C, Li Q, Huang J
J Steroid Biochem Mol Biol · 2026 Jun · PMID 42248218 · Publisher ↗
Progestin signaling in teleosts is mediated by a diverse receptor repertoire that has been further expanded after genome duplication. However, how these receptors are organized and respond to exogenous stimulation within...
Progestin signaling in teleosts is mediated by a diverse receptor repertoire that has been further expanded after genome duplication. However, how these receptors are organized and respond to exogenous stimulation within a single species remains poorly understood. Here, we characterized the progestin receptor system (PRS) in Spinibarbus hollandi through genome-wide identification, evolutionary analysis, basal expression profiling, molecular docking, and levonorgestrel (LNG) treatment experiments. We identified 14 PRS genes, including lineage-specific loss of paqr5b and retention of duplicated paqr6, indicating uneven post-duplication trajectories within this receptor family. Basal expression profiling further revealed tissue-specific patterns of PRS components across the gonad, liver, and brain. Under LNG treatment, somatic growth remained largely stable, whereas gonadal development showed clear sex-biased responses. Females exhibited ovarian regression and reduced gonadosomatic index across all treatment groups, whereas males retained active spermatogenesis at low and medium concentrations and developed degenerative lesions mainly at the highest concentration. These phenotypic differences were accompanied by tissue-specific shifts in the overall PRS expression landscape and by non-uniform transcriptional responses among selected PRS members, including shared downregulation of paqr7a, a female-specific decline but relative male stability of paqr7b, inducible hepatic expression of pgr1, and brain upregulation of pgrmc1. Together, these findings indicate that the PRS of S. hollandi has diverged at both the repertoire and expression levels and responds to exogenous progestin treatment in a tissue- and sex-dependent manner.
miR-148a-3p is elevated in serum of PCOS women and modulates ALDH1A3-retinoic acid signaling to reduce estrogen synthesis in granulosa-like cells.
Altinkilic EM, Sauter KS, du Toit T … +4 more , Nicholson P, Sakin Ö, Attar R, Flück CE
J Steroid Biochem Mol Biol · 2026 Jun · PMID 42242562 · Publisher ↗
Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder with substantial reproductive and metabolic consequences, yet its molecular mechanisms remain incompletely understood. This study investigated circul...
Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder with substantial reproductive and metabolic consequences, yet its molecular mechanisms remain incompletely understood. This study investigated circulating microRNAs (miRNAs) as potential regulators of ovarian steroidogenesis contributing to PCOS pathophysiology. Serum samples from 42 Turkish non-diabetic women with PCOS and 42 age-matched healthy controls were analyzed in a case-control design integrating small RNA sequencing with subgrouping based on steroidogenic characteristics. Differentially expressed miRNAs were subsequently examined in adrenal and ovarian cell models, including HGL5, OVCAR-3, and KGN granulosa cells, using miRNA mimics to assess transcriptional effects and estradiol synthesis in vitro. Serum profiling identified miR-148a-3p as significantly upregulated in hyperandrogenic PCOS. Functional assays demonstrated that miR-148a-3p enhances expression of aldehyde dehydrogenase 1A3 (ALDH1A3), promoting retinoic acid synthesis and suppressing estradiol production in granulosa cells. Luciferase reporter studies confirmed transcriptional activation of ALDH1A3 by miR-148a-3p. These findings position miR-148a-3p as a possible regulator of ovarian steroidogenesis in PCOS. By driving ALDH1A3-mediated retinoic acid production and reducing estrogen synthesis, miR-148a-3p may contribute to the hyperandrogenic phenotype. The miR-148a-3p-ALDH1A3 axis offers a promising avenue for biomarker development and therapeutic targeting in PCOS.
Ameliorative effects and mechanisms of Inonotus hispidus on PCOS via regulation of gut microbiota-ovarian metabolism axis and ferroptosis inhibition.
Zhao J, Hu D, Bao H … +2 more , Wang C, Wang Q
J Steroid Biochem Mol Biol · 2026 Jun · PMID 42235858 · Publisher ↗
Polycystic ovary syndrome (PCOS) is a prevalent endocrine metabolic disorder with limited therapeutic options. This study investigated the ameliorative effects and underlying mechanisms of the water extract of Inonotus h...
Polycystic ovary syndrome (PCOS) is a prevalent endocrine metabolic disorder with limited therapeutic options. This study investigated the ameliorative effects and underlying mechanisms of the water extract of Inonotus hispidus (WE) on PCOS in a testosterone propionate induced rat model. The results of this study indicate that WE significantly reduced abnormal body weight gain, restored disrupted estrous cycles, and ameliorated ovarian cystic degeneration, interstitial fibrosis, and hepatic steatosis in PCOS rats. It also down-regulated serum estradiol, testosterone, luteinizing hormone levels and the LH/FSH ratio, and normalized amino acid metabolism related enzyme activity. Metabolomic analysis revealed WE reversed ovarian metabolic dysregulation, enriching pathways like amino acid and bile acid metabolism. 16S rRNA sequencing showed WE reshaped gut microbiota dysbiosis, restoring α/β diversity and correcting the Firmicutes/Bacteroidetes ratio. Western blot analysis confirmed that WE inhibited ovarian cell ferroptosis by downregulating ACSL4, HIF-1α, and TFRC expression, while upregulating GPX4, and normalized the expression of amino acid metabolism-related proteins. This study demonstrates that WE improves ovarian function in rats by inhibiting ferroptosis, regulating ovarian amino acid/bile acid metabolism, and reshaping the gut microbiota, thereby exerting therapeutic effects on PCOS. This study provides a theoretical basis for the preclinical research and future clinical translation of Inonotus hispidus.
Characterization of a novel synthetic constitutive-active glucocorticoid receptor.
Lu H, Fahy C, Wang G
J Steroid Biochem Mol Biol · 2026 Jun · PMID 42235857 · Publisher ↗
Glucocorticoids (GCs), acting via the glucocorticoid receptor (GR), are the only available drugs for severe alcoholic hepatitis (AH). Additionally, GCs are important drugs for various lung diseases. However, GCs lack lon...
Glucocorticoids (GCs), acting via the glucocorticoid receptor (GR), are the only available drugs for severe alcoholic hepatitis (AH). Additionally, GCs are important drugs for various lung diseases. However, GCs lack long-term benefits and are avoided in AH with active infection or gastrointestinal bleeding. Recently, we engineered "superGR", a constitutive-active synthetic GR fragment with modifications. The purpose of this study was to characterize this "superGR" using human hepatoma and lung epithelial cells. Results of dual-luciferase reporter assays showed that in human hepatoma HepG2 cells, "superGR" potently and ligand-independently, activated the promoter of many human genes markedly down-regulated in AH including those important for cytoprotection, lipid catabolism, and anti-inflammation. Interestingly, some of these genes are not usually activated by wildtype GR, with "superGR" even activating protective genes down-regulated by the wildtype GR. Moreover, "superGR" exhibited strong repressive effects on key proinflammatory genes induced in AH. Deletion and mutation analyses indicated that inhibitory regions in the N- and C-terminal domains contribute to the inability of wildtype GR to activate certain genes. qPCR analysis revealed that lipid nanoparticle-mediated delivery of "superGR" mRNAs to human hepatoma HepG2 cells and lung epithelial H441 cells potently upregulated these cytoprotective genes and down-regulated pro-inflammatory genes, with better efficacy than Dexamethasone treatment. Additionally, "superGR" synergized with interleukin-22 to induce cytoprotective and immunomodulatory genes in HepG2 cells. Future in vivo studies on tissue-specific delivery of "superGR" on expression of key genes for cytoprotection, lipid catabolism, and anti-inflammation in models of liver and lung diseases are warranted for further evaluation.
A nuclear delivery strategy for curative treatment of COPD using 1α,25-dihydroxyvitamin D3 and lipid nanoparticles.
Akita T, Nemoto W, Kawai T … +1 more , Yamashita C
J Steroid Biochem Mol Biol · 2026 Sep · PMID 42219118 · Publisher ↗
Chronic obstructive pulmonary disease (COPD) presents with obstructive ventilation disorders. Because no drugs can regenerate destroyed alveoli, there is an urgent need for new treatments that repair alveolar damage. We...
Chronic obstructive pulmonary disease (COPD) presents with obstructive ventilation disorders. Because no drugs can regenerate destroyed alveoli, there is an urgent need for new treatments that repair alveolar damage. We previously reported revealed that 1α,25-dihydroxyvitamin D3 (1,25(OH)D) showed emphysema-improving effects in COPD model mice. However, because 1,25(OH)D carries a risk of serious adverse effects such as hypercalcemia, strategies to reduce the risk are needed to allow further dose reduction. To solve this problem and achieve efficient intracellular drug delivery, we focused on SS-cleavable proton-activated lipid-like material O-Phentyl-P4C2 (COATSOMESS-OP; hereafter "SS-OP") and helper lipid as the components of lipid nanoparticles. In this study, we investigated intracellular drug delivery, emphysema-improving effect, and reduction of adverse effect risk by 1,25(OH)D-encapsulated SS-OP lipid nanoparticle (SLPs) prepared using either of two helper lipids: 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) or 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE). Only 1,25(OH)D-encapsulated SLPs prepared using DOPE achieved efficient drug delivery, increased nuclear translocation relative to Free 1,25(OH)D, and successfully induced lung cell differentiation and improvement of the respiratory function at a lower dose. Moreover, the use of DOPE-based 1,25(OH)D-encapsulated SLPs, reduced elevated serum Ca levels, and these formulations are expected to be a therapeutic candidate for COPD.
Antiplatelet activity of novel aminoestrogens: R-β-mefenetame as a candidate for safer estrogen-based therapies.
García-Flores E, Cazarín-Santos BG, Hernández-Ortega S … +8 more , Fernández-G JM, León-Martínez M, Flores-García M, Mejía-Domínguez AM, Uribe-Carvajal S, Estrada-Juárez H, Trueba-Gómez R, de la Peña-Díaz A
J Steroid Biochem Mol Biol · 2026 May · PMID 42217759 · Publisher ↗
Hormone replacement therapy (HRT) relieves menopausal symptoms and improves quality of life. Also, estrogen-based regimens are needed for feminizing gender-affirming hormone therapy (GAHT). However, estrogen therapies ma...
Hormone replacement therapy (HRT) relieves menopausal symptoms and improves quality of life. Also, estrogen-based regimens are needed for feminizing gender-affirming hormone therapy (GAHT). However, estrogen therapies may evoke thrombotic complications, and thus, modified estrogens that preserve desirable estrogenic actions, while minimizing thrombogenic liability are needed. We synthesized two aminoestrogen enantiomers, R-β-Mefenetame and S-β-Mefenetame. Their structures were confirmed by elemental analysis, mass spectrometry, 1 H nuclear magnetic resonance, infrared spectroscopy, and single-crystal X-ray diffraction. Antiaggregant activity was evaluated in a murine model measuring whole-blood clotting time and whole-blood platelet impedance aggregometry. R-β-Mefenetame increased whole-blood clotting time further than S-β-Mefenetame. Both enantiomers decreased collagen-induced platelet aggregation by roughly 30% and did not modify ADP-induced aggregation under the conditions tested. Enantioselective activity differences prompted molecular docking analyses on the G protein-coupled estrogen receptor (GPER1), where higher selectivity of R-β-Mefenetame than S-β-Mefenetame was observed, offering a plausible mechanism for differences in hemostatic activity. Data also include silico ADME and toxicology profiling, identifying high lipophilicity, high plasma protein binding, predicted CYP2D6/CYP3A4 inhibition, and a potential hERG liability that should be addressed in future optimization. R-β-Mefenetame is a promising aminoestrogen that should be further evaluated for antiaggregant activity and hemostatic effects in more comprehensive thrombosis models.
Photoperiodic regulation of genes involved in steroidogenesis in adult tree sparrows (Passer montanus).
Yatung S, Ralte L, Trivedi AK
J Steroid Biochem Mol Biol · 2026 Sep · PMID 42178032 · Publisher ↗
Light serves as the primary environmental cue for timing life-history stages in a seasonal breeder. This study examines the effects of photoperiod, intensity, and spectrum on reproductive processes, particularly steroido...
Light serves as the primary environmental cue for timing life-history stages in a seasonal breeder. This study examines the effects of photoperiod, intensity, and spectrum on reproductive processes, particularly steroidogenesis, in adult tree sparrows. Three experiments were conducted over 30 days (n = 5 per sex/group). In Experiment 1, birds were exposed to short (8 L:16D), vernal equinox (12 L:12D), or long (16 L:8D) photoperiods. Experiment 2 examined light intensities of 10, 50, and 100 lux under a 16 L:8D photoperiod. Experiment 3 tested red (650 nm), blue (450 nm), green (520 nm), and white light (control) at 0.78 W/m² under a 16 L:8D photoperiod. All treatments were given for 30 days. Body mass, bill color, and gonad size were measured. The hypothalamus and gonads were analyzed for gene expression. Sampling was done in the middle of the light phases. In Experiment 1, bill color slightly darkened in the 16 L:8D group. Higher expressions of hypothalamic Tshβ, Dio2, and GnRH were observed in the 16 L:8D group, while hypothalamic Dio3 and GnIH were elevated in 8 L:16D. Steroidogenic gene (StAR, Nr4a1, Er, Scp2, Cyp17a1, Cyp11a1, Hsd11b2, Cyp11b, Srd5a1, Vdac1, Foxl2, and Cyp19a1) expression was highest in 16 L:8D. In Experiment 2, at the end, bill color slightly darkened, and gonadal growth, reproductive/steroidogenic gene expression were highest at 100 lux. In Experiment 3, red light enhanced gonadal growth and reproductive/steroidogenic gene expression compared to blue light; body mass and bill color remained unaffected. Overall, long photoperiods and higher intensities (100 lux) stimulate gonadal growth and steroidogenic processes, with red light promoting and blue light inhibiting photoperiodic responses in tree sparrows.
The Co-occurrence of Iron and vitamin D deficiency in the middle east: A regional review with a focus on Saudi Arabia as a case study for integrated public health strategies.
Essawi K
J Steroid Biochem Mol Biol · 2026 Sep · PMID 42178031 · Publisher ↗
Iron deficiency (ID) and vitamin D deficiency (VDD) often occur together in Saudi Arabia and across the Middle East, influenced by shared cultural, dietary, and environmental factors. This narrative review compiles evide...
Iron deficiency (ID) and vitamin D deficiency (VDD) often occur together in Saudi Arabia and across the Middle East, influenced by shared cultural, dietary, and environmental factors. This narrative review compiles evidence on this dual issue, exploring epidemiology, mechanisms, clinical effects, and public health strategies. Data confirm significant overlap: VDD affects 60-88% of Saudi adults and 60-81% of children, while ID impacts 23-36% of adults and 20-49% of children. Throughout this review, vitamin D deficiency (VDD) is defined per original study criteria, most commonly as 25-hydroxyvitamin D [25(OH)D] < 20 ng/mL (<50 nmol/L), consistent with pre-2024 Endocrine Society guidelines. We acknowledge the 2024 Endocrine Society revised guideline, which defines deficiency as < 12 ng/mL (<30 nmol/L) and eliminates the 'insufficiency' category; prevalence estimates would be substantially lower under this newer threshold. Their co-occurrence may be linked through common inflammatory pathways affecting hepcidin regulation and vitamin D activation, although human data are inconsistent. Combined deficiencies worsen health outcomes, including impaired growth, neurocognitive issues, immune problems, and adverse effects on maternal and child health. Diagnosis is difficult due to nonspecific symptoms and biomarker limitations during inflammation. Current interventions such as food fortification and supplementation, are hampered by isolated approaches and a lack of nationally representative combined prevalence data. The top priority is conducting a national survey to measure the prevalence of concurrent ID and VDD. Once this data is available, integrated strategies such as dual fortification, combined supplementation protocols, and culturally-sensitive public health campaigns can be effectively implemented. This framework offers an evidence-based approach to translating epidemiological and mechanistic insights into measurable public health improvements in Saudi Arabia and the wider Middle East.
Transcriptomic profiling of oocyte maturation in allotetraploid hybrid fish and identification of HSD17b12 mediating DHP synthesis.
Liao S, Diao D, Miao Y … +9 more , Liang H, Song G, Liu J, Zhang M, E Z, Lu D, Lin H, Li S, Zhang Y
J Steroid Biochem Mol Biol · 2026 Sep · PMID 42176960 · Publisher ↗
To reveal the molecular regulatory mechanism underlying oocyte development and maturation in an allotetraploid hybrid of Pengze crucian carp (♀) × Xingguo red carp (♂), the oocyte growth stage (PG, PV, EV, MV, LV and FG)...
To reveal the molecular regulatory mechanism underlying oocyte development and maturation in an allotetraploid hybrid of Pengze crucian carp (♀) × Xingguo red carp (♂), the oocyte growth stage (PG, PV, EV, MV, LV and FG) and maturation stage (FG, S1, S2 and S3) were classified based on morphological characteristics and germinal vesicle dynamics. Transcriptomic analysis identified stage-specific differentially expressed genes (DEGs), among which DEGs from C. auratus subgenome exhibited a dosage advantage in core regulation. KEGG analysis of DEGs screened via trend analysis revealed that DEGs from C. carpio subgenome were enriched in fatty acid metabolism and oocyte meiosis, while DEGs from C. auratus subgenome were enriched in the thyroid hormone and ErbB signaling pathways. Furthermore, 17β-Hydroxysteroid dehydrogenase type 12 (HSD17b12), the core gene mediating 17α,20β-dihydroxy-4-pregnen-3-one (DHP) synthesis, was identified in the allotetraploid hybrid, whose expression pattern was consistent with the dynamic changes in serum DHP levels and functional validation in HEK293T cells further confirmed its DHP-producing capacity. This study clarifies the subgenomic functional divergence during ovulation and identifies HSD17b12 as the core gene for DHP synthesis in allotetraploid hybrids, providing a theoretical basis for reproductive regulation and genetic breeding of polyploid fish.
Steroids in organ transplantation: Immunosuppression and tolerance.
Jyoti, Singh G, Bishnoi M … +7 more , Kaur R, Sethi SK, Hemlata, Paliwal D, Minhas R, Akash MB, Gulati HK
J Steroid Biochem Mol Biol · 2026 Sep · PMID 42173202 · Publisher ↗
Organ transplantation has evolved significantly since the first successful kidney transplant in the 1950s, but corticosteroids remain a mainstay of immunosuppressive therapy. This review addresses the emerging and expand...
Organ transplantation has evolved significantly since the first successful kidney transplant in the 1950s, but corticosteroids remain a mainstay of immunosuppressive therapy. This review addresses the emerging and expanding role of corticosteroids as adjunct therapeutic agents in transplantation with particular emphasis on their immunosuppressive and tolerance inducing properties. The progression of current immunosuppressive strategies, including the combined use of steroids, calcineurin inhibitors, and mTOR inhibitors have also been discussed. The review highlights the mechanisms underlying glucocorticoid activity, including receptor interactions, gene regulation, and modulation of inflammatory responses. The clinical significance of corticosteroids is discussed across different stages of transplant therapy, including induction, long-term maintenance, and management of acute rejection episodes. Special attention is given to their ability to promote immune tolerance by enhancing regulatory T-cell activity, thereby contributing to immune homeostasis and graft survival. Finally, review addresses future perspectives focused on minimizing steroid exposure through more individualized immunosuppressive approaches while evaluating the continuing central role of corticosteroids in the induction of transplant tolerance.
Importance of oxysterols in nutrition, cancer and other degenerative diseases.
Poirot M, de Médina P, Silvente-Poirot S
J Steroid Biochem Mol Biol · 2026 Sep · PMID 42167453 · Publisher ↗
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