The Journal Of Steroid Biochemistry And Molecular Biology[JOURNAL]
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200 papers
Why did we end up having so few vitamin D answers and what can we do about it? A provocative and narrative review.
Jorde R
J Steroid Biochem Mol Biol · 2026 Feb · PMID 41218688 · Publisher ↗
In spite of numerous vitamin D publications, including thousands of RCTs, meta-analyses, review papers and editorials, we still do not have answers to the most basic vitamin D questions. The recommendations for vitamin D...
In spite of numerous vitamin D publications, including thousands of RCTs, meta-analyses, review papers and editorials, we still do not have answers to the most basic vitamin D questions. The recommendations for vitamin D intake are based on a few and questionable studies, and according to the latest Endocrine Society Guidelines from 2024, there is no clinical trial evidence for establishing serum 25-hydroxyvitamin D (25OHD) thresholds to define vitamin D deficiency. Furthermore, large and impressive vitamin D RCTs, some with more than 20,000 participants, have failed to show significant effects on disease prevention. However, there are indications that vitamin D may have a small preventive effect on type 2 diabetes and auto-immune diseases, and vitamin D may also improve cancer survival. In general, the RCTs have been under-powered, and most subjects included were already vitamin D sufficient. The time for new vitamin D mega trials is probably over, and in the future, we have to design our RCTs smarter. One should mainly include subjects with low serum 25OHD levels, use individual dosing to reach a preset 25OHD level [treat-to-target), use realistic power calculations, and we should use similar study designs to facilitate individual patient data meta-analyses. We must be willing to realize that we have failed, we must be willing to change, and we must be willing to pull our forces together. A vitamin D consensus conference is highly needed. We cannot accept that in 2025 we do not know what is a sufficient serum 25OHD level.
Integrative bioinformatics and transcriptomic analysis identifies biomarkers in Polycystic Ovary Syndrome through machine learning approach.
Senthilkumar H, Arumugam M
J Steroid Biochem Mol Biol · 2026 Jan · PMID 41192647 · Publisher ↗
Polycystic Ovary Syndrome (PCOS) is a common endocrine condition that affects women of reproductive age. The study used high-throughput sequencing to profile gene expression in PCOS and control samples. The sequenced rea...
Polycystic Ovary Syndrome (PCOS) is a common endocrine condition that affects women of reproductive age. The study used high-throughput sequencing to profile gene expression in PCOS and control samples. The sequenced reads were quality assessed and aligned to the human reference genome hg38 using FastQC and the Hisat2 aligner. The R software "DESeq2" identified 1193 differentially expressed genes (DEGs) in SRP224633 and 82 DEGs in SRP353681. Notably, 8 DEGs were shared by the two datasets, and a total of 1267 DEGs were found. GO analysis revealed that DEGs in SRP224633 were enriched in biological processes related to immune response and cell activation, whereas DEGs in SRP353681 were associated with response to external stimuli and immune processes. Pathway analysis highlighted the involvement of chemokine signaling receptor, and cytokine-cytokine receptor interaction pathways in both datasets. The STRING database was used to evaluate protein-protein interaction (PPI) networks. Hub genes like IL1B, PTPRC, ITGAM, TYROBP, ITGB2, FCGR3A, CCR7, SYK, TLR2, FCGR3B were identified as crucial nodes using Cytohubba plugins in Cytoscape, highlighting their potential role in PCOS pathogenesis. Regulatory networks discovered miRNAs such as has-mir-34a-5p, hsa-miR-26a-5p, has-let-7b-5p and transcription factors such as SP1, RUNX1, ER as possible regulators of target genes implicated in PCOS pathogenesis. LASSO regression and ROC analysis indicated certain hub genes, such as IL1B, PTPRC, ITGB2, FCGR3A, CCR7, FCGR3B as relevant biomarkers due to their high coefficients, emphasizing their significance in PCOS. CCR7, FCGR3A, FCGR3B, and ITGB2 have been discovered as novel genes with significant potential as PCOS biomarkers. Our research adds to a deeper knowledge of PCOS at the molecular level by offering an extensive understanding of the etiological reasons and molecular mechanisms. The discovered DEGs, pathways, and regulatory networks and novel biomarker are promising targets for future studies and treatments in PCOS management.
Hyperforin as a non-steroidal modulator of the PXR-CYP3A4 regulatory axis: Mechanistic and computational insights into xenobiotic metabolism.
Sabarathinam S, Ganamurali N
J Steroid Biochem Mol Biol · 2026 Feb · PMID 41192646 · Publisher ↗
Hyperforin, a phloroglucinol derivative from Hypericum perforatum (St. John's Wort), exhibits antidepressant activity but poses significant herb-drug interaction risks through pregnane X receptor (PXR) activation and CYP...
Hyperforin, a phloroglucinol derivative from Hypericum perforatum (St. John's Wort), exhibits antidepressant activity but poses significant herb-drug interaction risks through pregnane X receptor (PXR) activation and CYP3A4 induction. Through integrated in silico analyses ADMET modeling, molecular target profiling, and SMARTCyp metabolism mapping hyperforin was identified as both a substrate and inducer of CYP3A4. Its physicochemical and metabolic properties converge on a common mechanism: PXR-mediated transcriptional upregulation of CYP3A4 that accelerates its own clearance and alters xenobiotic metabolism. These insights position hyperforin as a model of non-steroidal PXR agonist with implications for drug safety, regulatory evaluation, and rational use of phytochemical supplements.
Esaxerenone attenuates high salt-induced hypertension and renal damage via CD8T cell- associated NCC activation in aldosterone treated rats.
Xu C, Zhai N, Wang H … +6 more , Fang F, An J, Liu F, Zhong Y, Wang Z, Wang X
J Steroid Biochem Mol Biol · 2026 Jan · PMID 41177339 · Publisher ↗
Salt-water retention plays key roles in chronic kidney disease (CKD) and hypertension. The mineralocorticoid receptor (MR) blocker esaxerenone could attenuate hypertension and renal injury; however, the mechanism is only...
Salt-water retention plays key roles in chronic kidney disease (CKD) and hypertension. The mineralocorticoid receptor (MR) blocker esaxerenone could attenuate hypertension and renal injury; however, the mechanism is only partially understood. In this study, we used rats that were fed 8 % high-salt diet or/and infused with aldosterone to explore the possible mechanism of salt-water retention in CKD and hypertension, and the protective effect of esaxerenone. The blood pressure and renal injury were observed. Moreover, salt- water retention, CD8T cells infiltration and MR activation were detected. After treatment with high-salt diet plus aldosterone, the blood pressure level was significantly increased, and renal injury was more obvious than with the high-salt diet or aldosterone alone. The expression levels of the sodium transporter, as well as the mineralocorticoid receptor (NR3C2), were significantly upregulated in the ALD+HS group. Furthermore, the infiltration of CD3 and CD8 T cells were increased in the ALD+HS group. Besides, our results proved that esaxerenone could alleviate high-salt diet plus aldosterone-induced salt-water retention and renal injury. In conclusion, aldosterone plus high salt diet enhances renal infiltration of CD8T cells and upregulates NCC expression and phosphorylation, resulting in hypertension and kidney injury. Esaxerenone antagonizes the activation of mineralocorticoid receptors to decrease the infiltration of CD8T cells and the phosphorylation level of NCC, thereby alleviating salt-water retention and kidney injury.
Zingerone supplementation affects proliferation, apoptosis, antioxidant, GLUT4 and insulin receptor expression in uterus of mice.
Dutta A, Gurusubramanian G, Roy VK
J Steroid Biochem Mol Biol · 2026 Jan · PMID 41176169 · Publisher ↗
Zingerone has various biological properties with a modulatory role in ovarian activity. Despite its biological property, its effect has not been investigated on the uterus. Therefore, the present study has investigated t...
Zingerone has various biological properties with a modulatory role in ovarian activity. Despite its biological property, its effect has not been investigated on the uterus. Therefore, the present study has investigated the effects of zingerone supplementation on uterus of mice. Female Swiss albino mice were randomly divided into four groups: control, Z10, Z25, and Z50, where zingerone was orally given for 28 days. Zingerone treatment at 25 and 50 mg/kg increased the number of uterine glands. Immunolocalization of PCNA was decreased in the in vivo study, while in vitro BrdU incorporation was stimulated by the zingerone. Zingerone treatment increased apoptosis at a 25 mg/kg dose; however, zingerone at a 50 mg/kg dose decreased uterine apoptosis. In vitro study also showed zingerone down-regulates BCL2 expression and up-regulates active caspase expression. These findings suggest modulatory effects of zingerone on uterine proliferation and apoptosis. The pro-inflammatory TNFα showed the lowest expression in 50 mg/kg zingerone-treated mice uterus. In vitro findings also showed that zingerone decreased expression of TNFα. Furthermore, an in vivo study has also shown zingerone down-regulates INSR and GLUT4 without affecting uterine glucose concentration. In addition, an in vitro study has also shown that zingerone down-regulates INSR. Zingerone treatment showed elevated MDA levels and GPX enzyme activity. However, SOD activity was suppressed in 25 and 50 mg/kg groups. Furthermore, catalase activity was highest in the 50 mg/kg zingerone-treated group. Thus, these results showed the modulatory role of zingerone on apoptosis, glucose metabolism, and antioxidant status in uterus. The functional significance of zingerone-mediated parameters on uterine functions remains to be investigated.
Synergistic effects of sericin and mulberry leaf alkaloid combination therapy on type 2 diabetes via gut microbiota modulation.
Yufan Z, Aihua X, Yulong H … +5 more , Wei F, Xue Y, Changhao L, Shengran W, Jisheng L
J Steroid Biochem Mol Biol · 2026 Jan · PMID 41167312 · Publisher ↗
This study investigated the hypoglycemic efficacy and mechanism of action (with a focus on gut microbiota) of combined sericin-mulberry leaf alkaloid (MLA) therapy in type 2 diabetic mice, comparing it with monotherapy r...
This study investigated the hypoglycemic efficacy and mechanism of action (with a focus on gut microbiota) of combined sericin-mulberry leaf alkaloid (MLA) therapy in type 2 diabetic mice, comparing it with monotherapy regimens. Male diabetic (DB/DB) and non-diabetic (DB/m) mice were used, with five treatment groups designed: Diabetic Model (diabetic + saline), Ser (diabetic + 2.4 g/kg/day sericin), MLE (diabetic + 200 mg/kg/day MLA), Ser+MLE (diabetic + 1.2 g/kg/day sericin + 100 mg/kg/day MLA), and Control (DB/m + saline). Treatment lasted 35 days. Body weight and fasting blood glucose (FBG) were measured before and after treatment. Venous serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) were detected using an automated biochemical analyzer. Histological evaluation included liver and kidney morphology (HE staining), hepatic glycogen (PAS staining), and hepatic α-smooth muscle actin (α-SMA, immunohistochemical staining). Fecal samples underwent 16S rRNA gut microbiota analysis. Experimental results showed that compared with the control group, diabetic mice exhibited increased body weight (↑20.8 %, P < 0.05), elevated fasting blood glucose (↑434 %, P < 0.05), and significantly increased serum liver enzyme levels (ALT↑387 %, AST↑91.4 %, ALP↑56.9 %, all P < 0.05), accompanied by significant gut dysbiosis in the Diabetic Model group. After treatment, all groups exhibited significant reductions in weight gain, fasting blood glucose, and liver enzyme levels (all P < 0.05); sericin, MLE, and the sericin+MLE combination also modulated functional abundance of gut microbiota. In summary, the combined treatment of sericin and MLA demonstrated superior hypoglycemic and organ-protective effects compared to monotherapy, potentially achieved through restoration of gut microbiota homeostasis and enhanced metabolism.
Unveiling the mechanisms of Inonotus hispidus against polycystic ovary syndrome: An integrated metabolomics and network pharmacology approach in vivo and vitro.
Zhao J, Khadbaatar S, Bao H … +3 more , Liang H, Hu D, Tu Q
J Steroid Biochem Mol Biol · 2026 Jan · PMID 41161612 · Publisher ↗
Polycystic Ovary Syndrome (PCOS) is a prevalent endocrine disorder characterized by metabolic dysfunction. The research is the first to investigate the therapeutic effect of I. hispidus on polycystic ovarian syndrome (PC...
Polycystic Ovary Syndrome (PCOS) is a prevalent endocrine disorder characterized by metabolic dysfunction. The research is the first to investigate the therapeutic effect of I. hispidus on polycystic ovarian syndrome (PCOS) based on non-targeted metabolomics and network pharmacology in vivo and vitro. The induction of the rat PCOS model was achieved using testosterone propionate (TP) to evaluate the therapeutic effects of I. hispidus. Firstly, in vivo experiments showed that water extracts from I. hispidus (WE) significantly alleviated ovarian damage in PCOS rats and regulated serum hormone levels. Subsequently, untargeted metabolomics research found that WE may alter the serum metabolome of rats by affecting the metabolism of arginine and proline. Network pharmacology screened multiple chemical components and selected one of the key active ingredient, coniferaldehyde (CON), for validation in vitro cell experiments. Furthermore, treatment with WE, CON and the WE medicated serum (WMS) significantly promoted cell proliferation， and diminished both the levels of reactive oxygen species (ROS) and the apoptosis of KGN cells triggered by testosterone. Meanwhile, all drug interventions significantly regulate the expression of multiple target proteins. However, WMS has the most significant effect. These findings systematically reveal that I. hispidus exerts effects in ameliorating PCOS through multiple targets and multiple components, providing new insights into the mechanism of action of I. hispidus in treating PCOS. In summary, this study accentuates the potential of I. hispidus as a therapeutic agent for PCOS, elucidates a multitarget pharmacological mechanism, provides an experimental basis for subsequent preclinical exploration of Inonotus hispidus in PCOS intervention.
Corrigendum to "Low-fat diets and testosterone in men: Systematic review and meta-analysis of intervention studies" [Journal of Steroid Biochemistry and Molecular Biology, 210 (2021) 105878].
Whittaker J, Wu K
J Steroid Biochem Mol Biol · 2026 Jan · PMID 41139558 · Publisher ↗
Abstract loading — click title to view on PubMed.
Urine sterols metabolomics study during summer training of winter paralympic snowboarders.
Jin S, Wu J, Zhang Y … +7 more , Gao Y, Shen W, Cheng Z, Qi Y, Wu X, Yu X, Zuo Q
J Steroid Biochem Mol Biol · 2026 Jan · PMID 41138861 · Publisher ↗
This study used targeted metabolomics approach to explore the effects of strength training on sterol metabolism in Paralympic snowboarders. Sixteen national para-snowboard athletes (12 male, 4 female) were assessed durin...
This study used targeted metabolomics approach to explore the effects of strength training on sterol metabolism in Paralympic snowboarders. Sixteen national para-snowboard athletes (12 male, 4 female) were assessed during summer strength training phase. Blood and urine samples were collected during adaptation, maximal strength, and rapid strength training phases. We found that serum 25(OH)D levels improved from deficiency to insufficiency after training. Triglyceride and low-density lipoprotein cholesterol (LDL-C) levels decreased significantly after maximal and rapid strength training. Compared to the adaptation stage, 13 and 12 urinary metabolites were identified in male and female athletes, respectively, during the maximal strength phase, while 9 and 8 metabolites showed differences during the rapid strength phase. A total of 13 and 6 differential metabolites were identified in male and female athletes, respectively, when comparing the rapid strength training phase to the maximal strength training phase. Following cycle strength training, the biosynthesis of steroid hormones as well as the metabolic pathways of androgens and estrogens was activated. After the summer strength training period, urinary differential metabolites in male athletes showed a significant association with LDL-C and serum vitamin D levels. In contrast, among female athletes, urinary dihydroprogesterone levels were significantly correlated with 25(OH)D concentrations. In general, strength training improves blood lipids and serum vitamin D levels, with the most pronounced improvement in vitamin D occurring during the maximal strength phase. Steroid hormone biosynthesis, androgen and estrogen metabolic pathways, and metabolism are affected by exercise training, including bile acid metabolism in males.
Vitamin D pathway as a multi-level predictor of COVID-19 severity and mortality: Integrating serum levels, FokI (rs2228570) VDR polymorphism, and lung tissue expression.
Awla HK, Othman BA, Rafeeq DD … +6 more , Smail SW, Yashooa RK, Ghareeb AA, Salih RH, Omar SA, Janson C
J Steroid Biochem Mol Biol · 2026 Jan · PMID 41135833 · Publisher ↗
BACKGROUND: Vitamin D is a known immunomodulator, but its predictive value in COVID-19 remains incompletely understood. This study investigates the role of vitamin D across molecular, biochemical, and histopathological l...
BACKGROUND: Vitamin D is a known immunomodulator, but its predictive value in COVID-19 remains incompletely understood. This study investigates the role of vitamin D across molecular, biochemical, and histopathological levels to evaluate its association with COVID-19 severity and mortality. METHODS: A prospective case-control study was conducted in the Kurdistan Region of Iraq from May to October 2021. Ninety-five confirmed COVID-19 patients (75 survivors, 20 non-survivors) and 75 healthy controls were enrolled. Serum 25(OH)D levels were quantified by ELISA. Clinical severity was assessed using CURB-65, NEWS, and SOFA scores. Genotyping for the FokI (rs2228570) polymorphism in the VDR gene was performed via allele-specific PCR. Lung tissue from five survivors (biopsy) and five non-survivors (autopsy) underwent immunohistochemical staining to evaluate VDR expression. RESULTS: Serum vitamin D concentrations were markedly reduced in non-survivors (20.34 ± 0.46 ng/mL) relative to survivors (40.11 ± 0.28 ng/mL, p < 0.001). Vitamin D exhibited a negative correlation with CURB-65 (r = -0.828), NEWS (r = -0.794), and SOFA (r = -0.762) scores. Regression analysis established that vitamin D was independently associated with disease severity in our population. The TT genotype of the FokI VDR polymorphism correlated with markedly reduced vitamin D levels and elevated severity scores. Mortality exhibited a strong association with the TT genotype (OR = 10.29, 95 % CI: 2.204-49.19, p = 0.003) and the T allele (OR = 3.923, p = 0.0006). ROC analysis determined a vitamin D threshold of ≤ 20.56 ng/mL as indicative of mortality (AUC = 0.784, p < 0.0001). Immunohistochemistry demonstrated elevated VDR expression in lung tissues of deceased COVID-19 patients relative to VDR-negative controls. CONCLUSION: This study indicates that serum vitamin D levels, VDR gene polymorphism (rs2228570), and lung tissue VDR expression are strongly correlated with the severity and mortality of COVID-19. These findings validate the clinical use of vitamin D and VDR profiling may have associative markers and prospective treatment targets in the management of COVID-19.
Indole-3-propionic acid function through PXR and AhR, molecular signaling pathways, and antitoxic role in underlying diseases.
Jalili C, Hosseinkhani F, Dayer D … +3 more , Tabandeh MR, Abbasi A, Zamir Nasta T
J Steroid Biochem Mol Biol · 2026 Jan · PMID 41093016 · Publisher ↗
The host organism's balance within the body relies on its crucial symbiotic relationship with gut microbiota. This balance, known as homeostasis, can be influenced by various factors. One significant factor is the role o...
The host organism's balance within the body relies on its crucial symbiotic relationship with gut microbiota. This balance, known as homeostasis, can be influenced by various factors. One significant factor is the role of bacterial metabolites from different substrates, such as tryptophan. Recent research has revealed that these metabolites impact many biological processes. Microbial metabolites, such as Indole-3-Propionic Acid (IPA), are produced by the intestinal microbiota by converting dietary tryptophan. IPA is absorbed by intestinal epithelial cells, transported via the portal circulation, undergoes minimal hepatic metabolism, and is subsequently released into the systemic circulation to reach peripheral tissues and exert its biological effects. The Pregnane X receptor (PXR) and aryl hydrocarbon receptor (AhR) are the two main receptors of IPA which induce different gene expression profiles and subsequently diverse biological pathways in different tissues. Once absorbed by intestinal epithelial cells, IPA is released into the circulatory system and can significantly affect the immune, cardiovascular, nervous, and gastrointestinal systems. Furthermore, IPA has been found to have positive effects on a cellular level by inhibiting oxidative stress injury and preventing the synthesis of proinflammatory cytokines. Numerous studies have highlighted IPA's antioxidant, anti-inflammatory, anti-cancer, and neuroprotective effects. Therefore, dysbiosis of IPA contributes to disorders such as metabolic syndromes, inflammatory conditions, cancer, and neuropsychiatric diseases. This review provides a detailed examination of the most recent studies on indole-3-propionic acid function through PXR and AhR, outlining its molecular signaling pathways and correlation with various diseases.
Corrigendum to "From lipids to glucose: Investigating the role of dyslipidemia in the risk of insulin resistance" [J. Steroid Biochem. Mol. Biol. 250 (2025) 106744].
Jahdkaran M, Sistanizad M
J Steroid Biochem Mol Biol · 2026 Jan · PMID 41076382 · Publisher ↗
Abstract loading — click title to view on PubMed.
Advancements in understanding the role and mechanisms of mitochondria in diabetes: A comprehensive review.
Ge X, Ye M, Fei A … +2 more , Zhang Q, Yuan A
J Steroid Biochem Mol Biol · 2026 Jan · PMID 41061771 · Publisher ↗
Diabetes mellitus is a global health crisis with a rising prevalence attributed to complex interactions of genetic, lifestyle, and environmental factors. This comprehensive review delves into the pivotal role of mitochon...
Diabetes mellitus is a global health crisis with a rising prevalence attributed to complex interactions of genetic, lifestyle, and environmental factors. This comprehensive review delves into the pivotal role of mitochondrial dysfunction in the onset and progression of diabetes. It outlines how defects in mitochondrial oxidative phosphorylation, increased free radical production, and mitochondrial DNA damage contribute to insulin resistance, β-cell apoptosis, and systemic metabolic dysfunctions. The review highlights the critical roles of mitochondria in energy metabolism, oxidative balance, and the interplay of genetic and environmental factors in diabetes. It also emphasizes the association of impaired mitochondrial function with various diabetes-related complications and organ-specific diseases, underscoring the urgent need for innovative therapeutic strategies. Potential interventions discussed include pharmacological agents promoting mitochondrial biogenesis and enhancing mitochondrial dynamics, alongside dietary and lifestyle modifications that support mitochondrial function and overall metabolic health. The review calls for intensified research into mitochondrial mechanisms and their therapeutic targets, advocating for comprehensive clinical trials and support from medical and governmental institutions to advance diabetes management strategies centered on mitochondrial health.
Canine aldo-keto reductase 1C3 (AKR1C3/PGFS) exhibits 17β/20α-hydroxysteroid dehydrogenase activity and is inhibited by trilostane.
Endo S, Hayashi R, Nakada Y … +8 more , Kudo Y, Morikawa Y, Sakai Y, Suenami K, Abe N, Matsunaga T, Hara A, Ueda H
J Steroid Biochem Mol Biol · 2026 Jan · PMID 41061770 · Publisher ↗
Most members of the aldo-keto reductase (AKR) 1 C subfamily are hydroxysteroid dehydrogenases (HSDs), and their numbers are more than four in many individual mammals. In contrast, there is only one gene for the AKR1C pro...
Most members of the aldo-keto reductase (AKR) 1 C subfamily are hydroxysteroid dehydrogenases (HSDs), and their numbers are more than four in many individual mammals. In contrast, there is only one gene for the AKR1C protein (AKR1C3) in dogs, which have been used as a preclinical model for human biomedical research. Here, we report that dog AKR1C3 (known as prostaglandin-F synthase) catalyzes the conversion of the 17-keto group of estrone, 4- and 5-androstenes, and 5α-androstanes to their 17β-hydroxy-metabolites with NADPH as a coenzyme. Dog AKR1C3 also exhibited 20α-HSD activity toward 20-keto-C-steroids (deoxycorticosterone, its 5α-dihydro- and 5α-tetrahydro-derivatives, and progesterone), but, notably, did not display 3-ketosteroid reductase activity. Additionally, dog AKR1C3 reduced various nonsteroidal carbonyl compounds including endogenous 4-oxo-2-nonenal, all-trans-retinal, and isatin, of which isatin was the most excellent substrate. In the reverse reaction, the enzyme weakly oxidized 17β- and 20α-hydroxysteroids and some alicyclic alcohols. Further site-directed mutagenesis study revealed that residue M55 is responsible for the lack of 3-ketosteroid reductase activity. The enzyme was inhibited by flavonoids, nonsteroidal anti-inflammatory drugs, bile acids, benzbromarone, abiraterone, and trilostane, of which trilostane inhibited most potently (IC 0.30 µM), and its inhibition was uncompetitive and competitive with respect to the substrates in the forward and reverse reactions, respectively. Thus, dog AKR1C3 may play a role in the metabolism of steroid hormones (as a reductive 17β/20α-HSD) and nonsteroidal carbonyl compounds, and is a novel target of trilostane that is used to treat Cushing's disease in dogs.
Androgen receptor inhibitory activity of dihydrocapsaicin: Insights from in vitro, in vivo and in silico studies.
Zhao J, Liu X, Pang Y … +3 more , Luo H, Zhang J, Shao C
J Steroid Biochem Mol Biol · 2026 Jan · PMID 41045970 · Publisher ↗
As a natural capsaicinoid from Capsicum annuum L., dihydrocapsaicin is well known for its anti-obesity property by reducing fat accumulation in adipose tissue. The androgen receptor (AR) is essential for both health and...
As a natural capsaicinoid from Capsicum annuum L., dihydrocapsaicin is well known for its anti-obesity property by reducing fat accumulation in adipose tissue. The androgen receptor (AR) is essential for both health and disease in humans and is the main focus for prostate cancer treatment. This study seeks to explore how dihydrocapsaicin inhibits the AR in human prostate cancer cell lines, aiming to offer a new natural product-derived AR inhibitor for the clinical management of prostate-related conditions. At first, it was observed that dihydrocapsaicin can induce proliferation suppression in human prostate cancer cells by hindering the cell cycle at the G0/G1 phase. In addition, dihydrocapsaicin probably inhibited AR activity by blocking its movement from the cytoplasm to the nucleus through binding to the AR-LBD, highlighting its potential as an effective inhibitor. From a mechanistic perspective, dihydrocapsaicin facilitated AR release from a stabilizing chaperone complex and enhanced its ubiquitination by E3 ligases, resulting in AR partial degradation via the ubiquitin-proteasome pathway. Our study on the molecular mechanisms behind dihydrocapsaicin's inhibitory effects on the AR revealed that it not only hindered the growth of prostate cancer cells but also reduced tumor growth in vivo. These results offer both experimental evidence and a theoretical basis for the thorough development of AR inhibitors, emphasizing dihydrocapsaicin's potential for application in functional foods or nutritional supplements targeting prostatic disorders.
Quantum biochemistry characterization of representative conformations of the sex hormone-binding globulin monomer bound to estradiol, dihydrotestosterone and testosterone.
Hadad A, França VLB, Amaral JL … +2 more , Carvalho HF, Freire VN
J Steroid Biochem Mol Biol · 2026 Jan · PMID 41043563 · Publisher ↗
The transport of sex steroid hormones in the plasma is largely mediated by sex-hormone binding globulin (SHBG). SHBG is a functional homodimer, meaning it can bind two sex hormones with similar affinities. This binding o...
The transport of sex steroid hormones in the plasma is largely mediated by sex-hormone binding globulin (SHBG). SHBG is a functional homodimer, meaning it can bind two sex hormones with similar affinities. This binding occurs through a complex allosteric mechanism. This globulin plays a pivotal role in regulating the availability of sex hormones within target tissues and cells. Given the established correlation between SHBG and various pathological disorders, there has been increasing interest in characterizing the interactions between SHBG and hormones as well as in identifying potential inhibitors or modulators of the SHBG function. In this regard, the present study aims to provide novel insights into the binding of SHBG with estradiol (EST), dihydrotestosterone (DHT), and testosterone (TES). To this end, molecular docking, molecular dynamics, and quantum mechanics were employed here. The analysis of representative conformations of the highest and lowest interaction energies revealed a high degree of similarity in the binding sites. The SHBG::TES interaction, for which structural data are lacking, exhibited a high degree of structural and energetic similarity to the SHBG::EST and SHBG::DHT complexes. Quantum mechanics calculations demonstrated the following order of theoretical binding affinity, from the highest to lowest: SHBG::DHT > SHBG::EST > SHBG::TES. Furthermore, SER42, PHE67, MET107, and MET139 exhibited the lowest interaction energies, thereby emphasizing the critical role of these residues in SHBG coupling and steroid hormone transport. The energetic description of these complexes contributes to a deeper understanding of steroid hormone transport and provides new insights for targeting SHBG in drug discovery.
17β-estradiol (E2) increases ciliary beat frequency via membrane estrogen receptor β.
Noriyama K, Todo N, Tamiya N … +4 more , Shigeta M, Toda Y, Hosogi S, Ashihara E
J Steroid Biochem Mol Biol · 2026 Jan · PMID 41033561 · Publisher ↗
Estrogen receptors (ER) are expressed in various tissues, including the lungs and other respiratory tissues, independent of sex. However, the role of estrogen in the respiratory tract is not fully understood. Airway cili...
Estrogen receptors (ER) are expressed in various tissues, including the lungs and other respiratory tissues, independent of sex. However, the role of estrogen in the respiratory tract is not fully understood. Airway ciliated cells are important for mucociliary clearance (MCC), which protects the human airways from foreign substances, and ciliary beat frequency (CBF) is an important indicator of MCC efficiency. Although the function of estrogen in airway smooth muscle cells and goblet cells has been studied, its effects on airway ciliated cells remain unclear. Here, we investigated the effect of 17β-estradiol (E2) on CBF. E2 increased CBF and intracellular cAMP concentration ([cAMP]) in murine airway ciliated cells, whereas it had no effect on intracellular Ca concentration and intracellular pH. The selective ERβ inhibitor PHTPP suppressed the E2-induced increase in CBF and [cAMP]. β-Estradiol 6-(O-carboxymethyl)oxime: bovine serum albumin conjugate, which activates membrane ER, also increased CBF and [cAMP] in murine airway ciliated cells, and PHTPP suppressed these effects. The results of this study indicate that E2 increases CBF by increasing [cAMP] via membrane ERβ in murine airway ciliated cells. These results provide new insight into the function of estrogen in airway ciliated cells.
Evaluation of endogenous steroid sulfates and glucuronides in urine after oral and transdermal administration of testosterone. Part I: Male participants.
Pfeffer S, Gmeiner G, Dikic N … +2 more , Andjelkovic M, Forsdahl G
J Steroid Biochem Mol Biol · 2026 Jan · PMID 41033560 · Publisher ↗
The detection of the performance-enhancing drug testosterone (T) remains a significant challenge in doping control analysis. Longitudinal monitoring through the steroidal Athlete Biological Passport (ABP) is a valuable t...
The detection of the performance-enhancing drug testosterone (T) remains a significant challenge in doping control analysis. Longitudinal monitoring through the steroidal Athlete Biological Passport (ABP) is a valuable tool for T detection, but further research is needed to enhance its efficacy. Phase II metabolites of endogenous anabolic androgenic steroids (EAAS), including glucuronides and sulfates, have gained increasing interest as potential new biomarkers for the steroidal ABP. Notably, sulfate metabolites have demonstrated higher sensitivity to oral, transdermal, and intramuscular T administration, with extended detection windows compared to traditional biomarkers. However, before incorporating these promising biomarkers into urinary steroid profiling, it is essential to address the metabolic variations associated with different T administration methods, as well as differences related to ethnicity and sex. In this part of the study, we investigate the effects of oral and transdermal T administration on conventional biomarkers and phase II EAAS metabolites in male participants. Sulfate ratios indicated higher sensitivity to multiple administrations of testosterone undecanoate (TU) tablets and T gel, significantly prolonging detection times compared to conventional steroid profile biomarkers. Specifically, sulfate ratios such as androsterone sulfate (AS)/testosterone sulfate (TS) and epiandrosterone sulfate (EpiAS)/TS enabled detection for an average of 20 days following the last oral TU dose and at least 16 days after the last transdermal T application. These findings provide further evidence that incorporating sulfate EAAS metabolites into steroid profiling enhances detection capabilities. For advanced T doping detection, sulfate metabolites should be considered essential biomarkers in the steroid profile.
Inhibition of 14-3-3 protein enhances steroid hormone production and oxidative stress in mouse ovary: Implications for apoptosis regulation.
Upadhyay S, Dubey N, Singh A
J Steroid Biochem Mol Biol · 2026 Jan · PMID 41027487 · Publisher ↗
The ovary is a primary reproductive organ where the fine balance between steroidogenesis, oxidative stress, and apoptosis governs female reproductive health. A highly conserved protein, 14-3-3, is known to influence ster...
The ovary is a primary reproductive organ where the fine balance between steroidogenesis, oxidative stress, and apoptosis governs female reproductive health. A highly conserved protein, 14-3-3, is known to influence steroid biosynthesis, redox balance, and cell survival; however, its integrative role in ovarian physiology remains poorly defined. This study investigated the consequences of pharmacological inhibition of 14-3-3 protein using BV02 in in vitro cultured mouse ovaries. Immunohistochemical analysis revealed strong expression of 14-3-3 in granulosa cells, with moderate expression in oocytes and theca cells. In the BV02-treated ovary (100 μM), there was significant elevation in the levels of ovarian progesterone, testosterone, and estradiol, indicating enhanced steroidogenesis. However, the treated ovaries showed decreased activity of catalase and superoxide dismutase (SOD), along with increased lipid peroxidation (TBARS), indicating increased oxidative stress. Western blot analysis showed downregulation of the anti-apoptotic protein Bcl-2 together with elevated levels of the pro-apoptotic protein Caspase-3, signifying a molecular shift toward apoptosis. Correlation analysis further established strong associations (p < 0.05) between oxidative stress markers and apoptotic regulators, highlighting a mechanistic link between impaired antioxidant defenses and apoptosis. These findings reveal that 14-3-3 protein acts as a dual regulator of ovarian physiology by restraining steroid hormone production in addition to maintaining redox balance and cell survival. Disruption of this equilibrium may lead to pathological states such as polycystic ovary syndrome (PCOS) and ovarian cancer. Thus, this study provides novel mechanistic insights into the regulatory role of 14-3-3 protein in the ovary and underscores its potential as a therapeutic target in reproductive disorders.
Potential contribution of oxysterols and cholestanol in the vascular inflammatory process occurring in patients with Behcet's disease.
Messedi M, Guidara W, Samadi M … +2 more , Makni-Ayadi F, Lizard G
J Steroid Biochem Mol Biol · 2026 Jan · PMID 41005672 · Publisher ↗
Oxysterols, which are cholesterol oxidation products, can be generated by either enzymatic reactions and/or reactive oxygen species (ROS). Oxysterols considered to play key roles in health and diseases, have several phys...
Oxysterols, which are cholesterol oxidation products, can be generated by either enzymatic reactions and/or reactive oxygen species (ROS). Oxysterols considered to play key roles in health and diseases, have several physiological and biological activities. They exhibit strong immune-modulatory, pro-inflammatory and pro-oxidant properties supporting that some of them are involved in the pathogenesis of numerous chronic diseases associated with inflammation mainly cardiovascular and neurological diseases. Some oxysterols, especially those oxidized on the lateral chain, can bind to nuclear receptors such as the liver X receptors (LXR) involved in the control of transcriptional programs that regulate cell metabolism. Since Behçet's disease (BD) is an acute systemic vasculitis leading to severe vascular damage, recent studies deem that BD could be considered a chronic immune inflammatory disease. Although BD constitutes a separate disease entity, it is still underdiagnosed, and no treatments are available. Whereas the pathophysiology of BD is not well known, the vasculitis is common to its different etiologies. Therefore, as several oxysterols are known to contribute to vascular damage, these molecules were analyzed in the plasma of BD patients. Noteworthy, altered oxysterol profiles were observed in BD patients from Tunisia. These patients were characterized by abnormal levels of 7-ketocholesterol (7KC), 25-hydroxycholesterol (25-OHC), 27-hydroxycholesterol (27-OHC), and cholestane-3β,5α,6β-triol (CT). Thus, 7KC and 25-OHC were decreased whereas 27-OHC and CT were increased. Cholesterol undergoes a rapid non enzymatic oxidation to form cholesterol-5α,6α-epoxide and cholesterol-5β,6β-epoxide, and these molecules are then converted by cholesterol 5,6 epoxide hydrolase (ChEH) and/or ROS to CT. In addition, cholestanol level was increased. Therefore, there are evidence of altered oxysterol profiles and cholestanol level in BD patients. It is proposed that oxysterols and cholestanol could be used as biomarkers to characterize BD disease i) to distinguish different forms of this disease and of its outcome, and ii) to identify efficient treatments. Based on the abnormal levels of oxysterols and cholestanol observed in the plasma of BD Tunisian patients, current data support that a rupture of oxysterol homeostasis and perturbations of cholesterol metabolism, suggested by increased cholestanol level, could both contribute to the pathophysiology of Behçet's disease.
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