Pub Date : 2026-02-01Epub Date: 2025-11-25DOI: 10.1016/j.jsbmb.2025.106906
Xin Guo, Mei Zhang, Mengjun Xie
Bile acids (BAs) are crucial endogenous components involved in metabolic processes, and can also function as signaling molecules by specific BA receptors. Common BA receptors, such as the Farnesoid X Receptor (FXR), Takeda G protein-coupled receptor 5 (TGR5), Pregnane X receptor (PXR), and Vitamin D receptor (VDR), play crucial roles in regulating BA metabolism, lipid metabolism and glucose metabolism. Dysregulation of BA metabolism often interferes with the functions of these receptors and contributes to the pathogenesis of various diseases, including liver diseases, diabetes, hyperlipidemia, hypercholesterolemia, and gallstones. Traditional Chinese Medicine (TCM) has certain advantages in preventing and treating these diseases. This review summarizes current research on the mechanisms by which TCM interventions, including single herbs, extracts, and compounds, act on BA receptors. Using these receptors as a starting point, we elucidate how TCM influences various metabolic-related diseases through BA receptor-mediated and other pathways. The findings summarized herein provide valuable insights for future research on the prevention and treatment of metabolic diseases.
{"title":"Research progress on the prevention and treatment of diseases with traditional Chinese medicine: A focus on BA receptors","authors":"Xin Guo, Mei Zhang, Mengjun Xie","doi":"10.1016/j.jsbmb.2025.106906","DOIUrl":"10.1016/j.jsbmb.2025.106906","url":null,"abstract":"<div><div>Bile acids (BAs) are crucial endogenous components involved in metabolic processes, and can also function as signaling molecules by specific BA receptors. Common BA receptors, such as the Farnesoid X Receptor (FXR), Takeda G protein-coupled receptor 5 (TGR5), Pregnane X receptor (PXR), and Vitamin D receptor (VDR), play crucial roles in regulating BA metabolism, lipid metabolism and glucose metabolism. Dysregulation of BA metabolism often interferes with the functions of these receptors and contributes to the pathogenesis of various diseases, including liver diseases, diabetes, hyperlipidemia, hypercholesterolemia, and gallstones. Traditional Chinese Medicine (TCM) has certain advantages in preventing and treating these diseases. This review summarizes current research on the mechanisms by which TCM interventions, including single herbs, extracts, and compounds, act on BA receptors. Using these receptors as a starting point, we elucidate how TCM influences various metabolic-related diseases through BA receptor-mediated and other pathways. The findings summarized herein provide valuable insights for future research on the prevention and treatment of metabolic diseases.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"256 ","pages":"Article 106906"},"PeriodicalIF":2.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145641845","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}
Pub Date : 2026-02-01Epub Date: 2025-11-13DOI: 10.1016/j.jsbmb.2025.106897
Charles W. Bishop , John Choe , Stephen A. Strugnell , Samir Tabash , Akhtar Ashfaq
Intrinsic diurnal variation of serum calcifediol (25-hydroxyvitamin D3) was evaluated in healthy United States (US) adults by race, gender and age. Eligible participants (18–55 years old, body mass index 18–30 kg/m2, body weight ≥ 50 kg) were enrolled with gender balance into two groups by race: first generation Japanese (n = 35) and non-Japanese (n = 32). “First generation Japanese” was defined as having Japanese parents and grandparents and residing outside Japan for < 5 years without major lifestyle or dietary changes. “Non-Japanese” were of non-Asian descent and included 14 African-Americans, 16 Caucasians and 2 of “Other” race. Vitamin D supplementation during the prior 28 days was an exclusion criterion. Participants were housed for two days in a phase 1 unit shielded from sunlight and fed timed standardized meals devoid of vitamin D. Serum calcifediol, measured by LC-MS/MS on Day 2 at 0, 2, 4, 6, 8, 10, 12, 14, 16, 20 and 24 h, had a minor circadian rhythm (p = 0.0081) having a midline statistic of rhythm (MESOR) of 21.5 ng/mL, an amplitude of 0.19 ng/mL and an acrophase at 5:24 a.m. Mean inter-participant variation was high (CV of 30.89 %) while intra-participant variation was low (5.54 %), only nominally exceeding the assay precision (4.10 %). No significant differences in rhythmicity were observed between subgroups based on race, gender or age. These data show that intrinsic diurnal variation of circulating calcifediol is low, suggesting that avoidance of abrupt iatrogenic changes in serum total 25-hydroxyvitamin D concentrations may be important for minimizing the risk of toxicity.
{"title":"Effect of race, gender and age on intrinsic diurnal variation of serum calcifediol: Insights into vitamin D toxicity","authors":"Charles W. Bishop , John Choe , Stephen A. Strugnell , Samir Tabash , Akhtar Ashfaq","doi":"10.1016/j.jsbmb.2025.106897","DOIUrl":"10.1016/j.jsbmb.2025.106897","url":null,"abstract":"<div><div>Intrinsic diurnal variation of serum calcifediol (25-hydroxyvitamin D<sub>3</sub>) was evaluated in healthy United States (US) adults by race, gender and age. Eligible participants (18–55 years old, body mass index 18–30 kg/m<sup>2</sup>, body weight ≥ 50 kg) were enrolled with gender balance into two groups by race: first generation Japanese (n = 35) and non-Japanese (n = 32). “First generation Japanese” was defined as having Japanese parents and grandparents and residing outside Japan for < 5 years without major lifestyle or dietary changes. “Non-Japanese” were of non-Asian descent and included 14 African-Americans, 16 Caucasians and 2 of “Other” race. Vitamin D supplementation during the prior 28 days was an exclusion criterion. Participants were housed for two days in a phase 1 unit shielded from sunlight and fed timed standardized meals devoid of vitamin D. Serum calcifediol, measured by LC-MS/MS on Day 2 at 0, 2, 4, 6, 8, 10, 12, 14, 16, 20 and 24 h, had a minor circadian rhythm (<em>p</em> = 0.0081) having a midline statistic of rhythm (MESOR) of 21.5 ng/mL, an amplitude of 0.19 ng/mL and an acrophase at 5:24 a.m. Mean inter-participant variation was high (CV of 30.89 %) while intra-participant variation was low (5.54 %), only nominally exceeding the assay precision (4.10 %). No significant differences in rhythmicity were observed between subgroups based on race, gender or age. These data show that intrinsic diurnal variation of circulating calcifediol is low, suggesting that avoidance of abrupt iatrogenic changes in serum total 25-hydroxyvitamin D concentrations may be important for minimizing the risk of toxicity.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"256 ","pages":"Article 106897"},"PeriodicalIF":2.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145524881","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}
Detecting testosterone (T) doping remains a significant challenge, driving the search for novel biomarkers and advancements in the steroidal Athlete’s Biological Passport (ABP). Phase II metabolites of endogenous anabolic androgenic steroids (EAAS) have emerged as promising biomarkers, demonstrating prolonged detection times (DTs) and greater sensitivity compared to conventional biomarkers. Studies involving male participants investigated the effect of intramuscular, oral, and transdermal administration of T on these biomarkers and proposed their integration in future urinary steroid profiling. However, before the inclusion of phase II EAAS metabolites, it is crucial to address a range of possible doping scenarios and the influence of known confounding factors, like ethnicity or sex, on the steroid profile. This study addresses this gap by investigating the impact of oral and transdermal T administration on phase II EAAS metabolites in both men and women. This second part of the study presents the results for female participants, which have not been included in prior research on this topic. Results partially confirm the trends observed in men, with sulfate ratios exhibiting prolonged detection times and higher sensitivity compared to conventional steroid profile biomarkers following multiple oral and transdermal T administration. However, the evaluation in women showed greater variability due to lower steroid concentrations and greater fluctuations influenced by the menstrual cycle. This study provides additional evidence supporting the inclusion of phase II EAAS metabolites for enhanced detection of T doping. Further, it underscores the need for further research to address the unique challenges of female steroid profiling.
{"title":"Evaluation of endogenous steroid sulfates and glucuronides in urine after oral and transdermal administration of testosterone. Part II: Female participants","authors":"Sandra Pfeffer , Günter Gmeiner , Nenad Dikic , Marija Andjelkovic , Guro Forsdahl","doi":"10.1016/j.jsbmb.2025.106905","DOIUrl":"10.1016/j.jsbmb.2025.106905","url":null,"abstract":"<div><div>Detecting testosterone (T) doping remains a significant challenge, driving the search for novel biomarkers and advancements in the steroidal Athlete’s Biological Passport (ABP). Phase II metabolites of endogenous anabolic androgenic steroids (EAAS) have emerged as promising biomarkers, demonstrating prolonged detection times (DTs) and greater sensitivity compared to conventional biomarkers. Studies involving male participants investigated the effect of intramuscular, oral, and transdermal administration of T on these biomarkers and proposed their integration in future urinary steroid profiling. However, before the inclusion of phase II EAAS metabolites, it is crucial to address a range of possible doping scenarios and the influence of known confounding factors, like ethnicity or sex, on the steroid profile. This study addresses this gap by investigating the impact of oral and transdermal T administration on phase II EAAS metabolites in both men and women. This second part of the study presents the results for female participants, which have not been included in prior research on this topic. Results partially confirm the trends observed in men, with sulfate ratios exhibiting prolonged detection times and higher sensitivity compared to conventional steroid profile biomarkers following multiple oral and transdermal T administration. However, the evaluation in women showed greater variability due to lower steroid concentrations and greater fluctuations influenced by the menstrual cycle. This study provides additional evidence supporting the inclusion of phase II EAAS metabolites for enhanced detection of T doping. Further, it underscores the need for further research to address the unique challenges of female steroid profiling.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"256 ","pages":"Article 106905"},"PeriodicalIF":2.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145574895","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}
The incidence of central precocious puberty (CPP) is rising, especially during the COVID-19 pandemic. Early detection is crucial to prevent adverse outcomes in affected children. Current diagnostic methods are invasive and inconsistent, necessitating less invasive approach. Metabolomics offers a novel method to reveal CPP mechanisms and identify biomarkers.
Objectives
This study aims to identify and validate urinary metabolomic biomarkers for the diagnosis of CPP and to elucidate the sex-dimorphic metabolic mechanisms underlying this condition, with the ultimate goal of developing non-invasive diagnostic approaches.
Methods
Urine samples from CPP patients and aged-matched controls were analyzed using NMR-based metabolomics. Statistical analyses identified potential CPP biomarkers. LASSO regression and binary logistic regression (LR) screened diagnostic groups, validated using random forest, LR and support vector machine to generate receiver operating characteristic (ROC) curves and calculate area under curves (AUCs). Direct comparison between CPP boys and girls discerned gender-specific metabolic characteristics.
Results
The study identified 13, 13, 17 and 12 potential markers for CPP girls versus prepubertal/adolescent girls, and CPP boys versus prepubertal/adolescent boys, respectively. Diagnostic groups with 7, 3, 3 and 3 biomarkers were selected, yielding mean AUCs of 0.928, 0.942, 0.984 and 0.865. Eight gender-specific markers were identified.
Conclusions
The study reveals distinct metabolic differences between CPP children and controls, with gender variations. Obesity is a risk factors for CPP in girls, while CPP boys exhibit faster amino acid turnover and bone growth. Gender comparison shows distinct metabolic profiles, confirming sexual dimorphism in CPP presentation. These findings suggest that metabolic regulation interventions may be beneficial in managing CPP and highlight the need for gender-specific diagnostic approaches.
{"title":"Urinary metabolomic biomarkers for diagnosing central precocious puberty and revealing sexual dimorphism","authors":"Lingling Wen , Sheng Wu , Jingxia Wu , Zhengchang Li , Jing Chen , Guiping Shen , Jianghua Feng","doi":"10.1016/j.jsbmb.2025.106901","DOIUrl":"10.1016/j.jsbmb.2025.106901","url":null,"abstract":"<div><h3>Background</h3><div>The incidence of central precocious puberty (CPP) is rising, especially during the COVID-19 pandemic. Early detection is crucial to prevent adverse outcomes in affected children. Current diagnostic methods are invasive and inconsistent, necessitating less invasive approach. Metabolomics offers a novel method to reveal CPP mechanisms and identify biomarkers.</div></div><div><h3>Objectives</h3><div>This study aims to identify and validate urinary metabolomic biomarkers for the diagnosis of CPP and to elucidate the sex-dimorphic metabolic mechanisms underlying this condition, with the ultimate goal of developing non-invasive diagnostic approaches.</div></div><div><h3>Methods</h3><div>Urine samples from CPP patients and aged-matched controls were analyzed using NMR-based metabolomics. Statistical analyses identified potential CPP biomarkers. LASSO regression and binary logistic regression (LR) screened diagnostic groups, validated using random forest, LR and support vector machine to generate receiver operating characteristic (ROC) curves and calculate area under curves (AUCs). Direct comparison between CPP boys and girls discerned gender-specific metabolic characteristics.</div></div><div><h3>Results</h3><div>The study identified 13, 13, 17 and 12 potential markers for CPP girls versus prepubertal/adolescent girls, and CPP boys versus prepubertal/adolescent boys, respectively. Diagnostic groups with 7, 3, 3 and 3 biomarkers were selected, yielding mean AUCs of 0.928, 0.942, 0.984 and 0.865. Eight gender-specific markers were identified.</div></div><div><h3>Conclusions</h3><div>The study reveals distinct metabolic differences between CPP children and controls, with gender variations. Obesity is a risk factors for CPP in girls, while CPP boys exhibit faster amino acid turnover and bone growth. Gender comparison shows distinct metabolic profiles, confirming sexual dimorphism in CPP presentation. These findings suggest that metabolic regulation interventions may be beneficial in managing CPP and highlight the need for gender-specific diagnostic approaches.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"256 ","pages":"Article 106901"},"PeriodicalIF":2.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145543733","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}
Pub Date : 2026-02-01Epub Date: 2025-11-15DOI: 10.1016/j.jsbmb.2025.106900
M.A. Sanhueza , L.T. Pelegrina , A.R.R. Cáceres , D.A. Cardone , M. Roig Cerdeño , J. Ibañez Cannavó , F.A. Bruna , F.D. Cuello-Carrión , M.R. Laconi
Ovarian cancer remains the deadliest gynecological malignancy, with limited therapeutic options and high recurrence rates. Although progesterone (P4) metabolism has been implicated in hormone-related cancers, the biological roles of its 4-pregnene metabolites, 3α-dihydroprogesterone (3αHP) and 20α-dihydroprogesterone (20αHP), in ovarian cancer have not been explored. In this study, we investigated the effects of 3αHP and 20αHP on proliferation, apoptosis, migration, and clonogenic potential in two human ovarian cancer cell lines (IGROV-1 and SK-OV-3). Both metabolites significantly inhibited cell proliferation and clonogenicity. In IGROV-1 cells, 20αHP increased cleaved caspase-3 expression, and in SK-OV-3 increased early apoptosis, indicating pro-apoptotic activity. Neither compound altered cell migration in either cell line. These findings provide the initial evidence that 4-pregnene metabolites of progesterone modulate key features of ovarian cancer cell behavior, offering potential insights into alternative hormone-based therapeutic strategies.
{"title":"Context-dependent effects of progesterone 4-pregnene metabolites on apoptosis and proliferation in ovarian cancer cell lines IGROV-1 and SK-OV-3","authors":"M.A. Sanhueza , L.T. Pelegrina , A.R.R. Cáceres , D.A. Cardone , M. Roig Cerdeño , J. Ibañez Cannavó , F.A. Bruna , F.D. Cuello-Carrión , M.R. Laconi","doi":"10.1016/j.jsbmb.2025.106900","DOIUrl":"10.1016/j.jsbmb.2025.106900","url":null,"abstract":"<div><div>Ovarian cancer remains the deadliest gynecological malignancy, with limited therapeutic options and high recurrence rates. Although progesterone (P4) metabolism has been implicated in hormone-related cancers, the biological roles of its 4-pregnene metabolites, 3α-dihydroprogesterone (3αHP) and 20α-dihydroprogesterone (20αHP), in ovarian cancer have not been explored. In this study, we investigated the effects of 3αHP and 20αHP on proliferation, apoptosis, migration, and clonogenic potential in two human ovarian cancer cell lines (IGROV-1 and SK-OV-3). Both metabolites significantly inhibited cell proliferation and clonogenicity. In IGROV-1 cells, 20αHP increased cleaved caspase-3 expression, and in SK-OV-3 increased early apoptosis, indicating pro-apoptotic activity. Neither compound altered cell migration in either cell line. These findings provide the initial evidence that 4-pregnene metabolites of progesterone modulate key features of ovarian cancer cell behavior, offering potential insights into alternative hormone-based therapeutic strategies.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"256 ","pages":"Article 106900"},"PeriodicalIF":2.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145543780","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}
Pub Date : 2026-02-01Epub Date: 2025-11-09DOI: 10.1016/j.jsbmb.2025.106895
Rolf Jorde
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.
{"title":"Why did we end up having so few vitamin D answers and what can we do about it? A provocative and narrative review","authors":"Rolf Jorde","doi":"10.1016/j.jsbmb.2025.106895","DOIUrl":"10.1016/j.jsbmb.2025.106895","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"256 ","pages":"Article 106895"},"PeriodicalIF":2.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145479292","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}
Pub Date : 2026-02-01Epub Date: 2025-11-15DOI: 10.1016/j.jsbmb.2025.106899
Raha Osailan , Talaat Habeeb , Mohammed A.H. Khalafalla , Ali H. Bashal
Human papillomavirus type 16 (HPV-16) E2 protein has key roles in the control of viral DNA replication. Small, biocompatible ligands with known antiviral activity and acceptable toxicity that bind to E2 and slightly change its motion may disturb these functions. In this study, we used 100 ns molecular dynamics simulations together with electronic-structure calculations to investigate how chloroquine, quercetin, and luteolin interact with E2. Analysis of protein motion (RMSD, Rg, and RMSF) showed that the protein remained stable, but ligand binding was linked to changes in the flexibility of residues near DNA-binding and other functional regions. All three ligands remained mainly near these regions during the simulations. Molecular Mechanics/Poisson–Boltzmann Surface Area (MM/PBSA) analysis supported stable binding, with quercetin showing the strongest estimated affinity. The HOMO–LUMO values and global reactivity descriptors were similar for the ligands, which may help explain their ability to settle in similar regions of E2. These findings suggest that the three ligands can influence functional areas of E2 and may indicate possible synergistic effects against protein-driven viral activity.
{"title":"Molecular dynamics and electronic structure insights into chloroquine, quercetin, and luteolin binding to HPV-16 E2 protein","authors":"Raha Osailan , Talaat Habeeb , Mohammed A.H. Khalafalla , Ali H. Bashal","doi":"10.1016/j.jsbmb.2025.106899","DOIUrl":"10.1016/j.jsbmb.2025.106899","url":null,"abstract":"<div><div>Human papillomavirus type 16 (HPV-16) E2 protein has key roles in the control of viral DNA replication. Small, biocompatible ligands with known antiviral activity and acceptable toxicity that bind to E2 and slightly change its motion may disturb these functions. In this study, we used 100 ns molecular dynamics simulations together with electronic-structure calculations to investigate how chloroquine, quercetin, and luteolin interact with E2. Analysis of protein motion (RMSD, Rg, and RMSF) showed that the protein remained stable, but ligand binding was linked to changes in the flexibility of residues near DNA-binding and other functional regions. All three ligands remained mainly near these regions during the simulations. Molecular Mechanics/Poisson–Boltzmann Surface Area (MM/PBSA) analysis supported stable binding, with quercetin showing the strongest estimated affinity. The HOMO–LUMO values and global reactivity descriptors were similar for the ligands, which may help explain their ability to settle in similar regions of E2. These findings suggest that the three ligands can influence functional areas of E2 and may indicate possible synergistic effects against protein-driven viral activity.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"256 ","pages":"Article 106899"},"PeriodicalIF":2.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145543762","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}
Pub Date : 2026-02-01Epub Date: 2025-11-10DOI: 10.1016/j.jsbmb.2025.106896
Christopher S. Kovacs
Fetal mineral and bone metabolism is regulated differently compared to the neonate, child, or adult. A fundamental design difference is that the fetal mineral supply comes from active transport across the placenta rather than the intestines. Calcium, phosphorus, and magnesium also circulate at higher concentrations in the fetal blood as compared to maternal or normal adult values, which facilitates rapid accretion of skeletal mineral content before birth. Given the dependence of postnatal mineral and bone homeostasis on calcitriol, it may be expected that calcitriol and the vitamin D receptor (VDR) would be critically required during fetal development. However, calcitriol circulates at low levels in the fetal circulation, kept suppressed by increased 24-hydroxylated catabolism and low parathyroid hormone (PTH). Calcitriol does not regulate placental mineral transport, while the intestines are a trivial route of mineral delivery in the fetus. Consequently, fetuses lacking vitamin D, calcitriol, or VDRs are born with normal serum mineral concentrations, PTH, and skeletal development/mineralization. After birth, serum calcium falls and phosphorus rises, and these events trigger an increase in PTH and a subsequent rise in calcitriol. The intestines become the main source of mineral supply and it is then that the neonatal may begin to suffer the consequences of disrupted vitamin D physiology. This review discusses key data arising from animal and human studies (clinical trials, case series, epidemiological studies, associational analyses) in order to address our current knowledge on the role of vitamin D, calcitriol, and VDR in regulating fetal mineral and bone homeostasis.
{"title":"Calcitriol’s role in fetal bone and mineral metabolism: Evidence from human and animal studies","authors":"Christopher S. Kovacs","doi":"10.1016/j.jsbmb.2025.106896","DOIUrl":"10.1016/j.jsbmb.2025.106896","url":null,"abstract":"<div><div>Fetal mineral and bone metabolism is regulated differently compared to the neonate, child, or adult. A fundamental design difference is that the fetal mineral supply comes from active transport across the placenta rather than the intestines. Calcium, phosphorus, and magnesium also circulate at higher concentrations in the fetal blood as compared to maternal or normal adult values, which facilitates rapid accretion of skeletal mineral content before birth. Given the dependence of postnatal mineral and bone homeostasis on calcitriol, it may be expected that calcitriol and the vitamin D receptor (VDR) would be critically required during fetal development. However, calcitriol circulates at low levels in the fetal circulation, kept suppressed by increased 24-hydroxylated catabolism and low parathyroid hormone (PTH). Calcitriol does not regulate placental mineral transport, while the intestines are a trivial route of mineral delivery in the fetus. Consequently, fetuses lacking vitamin D, calcitriol, or VDRs are born with normal serum mineral concentrations, PTH, and skeletal development/mineralization. After birth, serum calcium falls and phosphorus rises, and these events trigger an increase in PTH and a subsequent rise in calcitriol. The intestines become the main source of mineral supply and it is then that the neonatal may begin to suffer the consequences of disrupted vitamin D physiology. This review discusses key data arising from animal and human studies (clinical trials, case series, epidemiological studies, associational analyses) in order to address our current knowledge on the role of vitamin D, calcitriol, and VDR in regulating fetal mineral and bone homeostasis.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"256 ","pages":"Article 106896"},"PeriodicalIF":2.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145507917","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}
Pub Date : 2026-01-01Epub Date: 2025-10-01DOI: 10.1016/j.jsbmb.2025.106873
André Hadad , Victor L.B. França , Jackson L. Amaral , Hernandes F. Carvalho , Valder N. Freire
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.
{"title":"Quantum biochemistry characterization of representative conformations of the sex hormone-binding globulin monomer bound to estradiol, dihydrotestosterone and testosterone","authors":"André Hadad , Victor L.B. França , Jackson L. Amaral , Hernandes F. Carvalho , Valder N. Freire","doi":"10.1016/j.jsbmb.2025.106873","DOIUrl":"10.1016/j.jsbmb.2025.106873","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"255 ","pages":"Article 106873"},"PeriodicalIF":2.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145220878","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}
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.
{"title":"Potential contribution of oxysterols and cholestanol in the vascular inflammatory process occurring in patients with Behcet’s disease","authors":"Meriam Messedi , Wassim Guidara , Mohammad Samadi , Fatma Makni-Ayadi , Gérard Lizard","doi":"10.1016/j.jsbmb.2025.106868","DOIUrl":"10.1016/j.jsbmb.2025.106868","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"255 ","pages":"Article 106868"},"PeriodicalIF":2.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145180287","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}
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