Pub Date : 2026-03-01Epub Date: 2025-12-17DOI: 10.1016/j.jsbmb.2025.106924
Xiya Ren , Lei Shi , Xinyue Chen , Yunbing Tang , Yingfen Ying , Renshan Ge , Qiqi Zhu
Bisphenol A (BPA) has been restricted for its use due to endocrine-disrupting effects and its benzene-ring-substituted derivatives (BPADs) are increasingly used. However, their effects on 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), a pivotal enzyme in glucocorticoid regulation, remain poorly characterized. Here, we evaluated, for the first time, how BPADs modulate 11β-HSD2 inhibition, providing mechanistic insights into their endocrine-disrupting potential. This study evaluated six BPADs, identifying 4-hydroxyphenyl-naphthalene (BPH) as the most potent inhibitor (human IC50 = 1.26 µM; rat IC50 = 4.17 µM), with structure-activity relationships (SAR) revealing critical roles for hydrophobicity (LogP) and steric bulk. Enzyme kinetic inhibition analyses demonstrated competitive or mixed-type inhibition of BPADs, and surface plasmon resonance (SPR) confirmed direct binding of BPH to 11β-HSD2. Molecular docking further highlighted key interactions with residues (Asn167, Lys236) in the steroid-binding pocket. Cellular assays in BeWo cells confirmed functional inhibition of endogenous 11β-HSD2. Notably, human 11β-HSD2 exhibited greater sensitivity than rat ortholog towards BPADs, attributed to a Ser92→Thr92 substitution of 11β-HSD2 sequences. These findings positioned BPADs as novel chemical probes for 11β-HSD2 studies and warranted investigation into their endocrine-disrupting potential, particularly in prenatal contexts where placental 11β-HSD2 safeguards fetal development.
{"title":"Bisphenol A derivatives as potent inhibitors of 11β-hydroxysteroid dehydrogenase 2: A structure-activity study","authors":"Xiya Ren , Lei Shi , Xinyue Chen , Yunbing Tang , Yingfen Ying , Renshan Ge , Qiqi Zhu","doi":"10.1016/j.jsbmb.2025.106924","DOIUrl":"10.1016/j.jsbmb.2025.106924","url":null,"abstract":"<div><div>Bisphenol A (BPA) has been restricted for its use due to endocrine-disrupting effects and its benzene-ring-substituted derivatives (BPADs) are increasingly used. However, their effects on 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), a pivotal enzyme in glucocorticoid regulation, remain poorly characterized. Here, we evaluated, for the first time, how BPADs modulate 11β-HSD2 inhibition, providing mechanistic insights into their endocrine-disrupting potential. This study evaluated six BPADs, identifying 4-hydroxyphenyl-naphthalene (BPH) as the most potent inhibitor (human IC<sub>50</sub> = 1.26 µM; rat IC<sub>50</sub> = 4.17 µM), with structure-activity relationships (SAR) revealing critical roles for hydrophobicity (LogP) and steric bulk. Enzyme kinetic inhibition analyses demonstrated competitive or mixed-type inhibition of BPADs, and surface plasmon resonance (SPR) confirmed direct binding of BPH to 11β-HSD2. Molecular docking further highlighted key interactions with residues (Asn167, Lys236) in the steroid-binding pocket. Cellular assays in BeWo cells confirmed functional inhibition of endogenous 11β-HSD2. Notably, human 11β-HSD2 exhibited greater sensitivity than rat ortholog towards BPADs, attributed to a Ser92→Thr92 substitution of 11β-HSD2 sequences. These findings positioned BPADs as novel chemical probes for 11β-HSD2 studies and warranted investigation into their endocrine-disrupting potential, particularly in prenatal contexts where placental 11β-HSD2 safeguards fetal development.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"257 ","pages":"Article 106924"},"PeriodicalIF":2.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145795599","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 : 2026-03-01Epub Date: 2025-12-10DOI: 10.1016/j.jsbmb.2025.106921
Samer Ali Awad Alsamawi, Khadijeh Nasiri, Abolfazl Akbari, Rozita Fathi
<div><div>Today's primary approach to enhancing reproductive function involves lifestyle modifications, dietary adjustments, the use of herbal supplements, and regular exercise. In this study, we tried to show that the use of ginger or Maca supplements along with endurance training can affect reproductive function indicators, including spermatogenesis and steroidogenesis in testicular tissue. Adult male Wistar rats (n = 42, weight: 220 ± 20 g, age: 10–12 weeks) were randomly divided into six equal groups. The groups included control, ginger (100 mg/kg body weight), Maca (100 mg/kg body weight), endurance training (ET), ET + ginger and ET + Maca. Tissue levels of testosterone were measured along with the expression of genes involved in steroidogenesis (P450Scc, P450c17, HSD17β3, and P450 aromatase) and genes involved in its regulation (LHR, FSHR, GR, and SGP-1). Spermatogenesis was assessed by counting the number of spermatogenic cells (spermatogonia and spermatocytes), Leydig and Sertoli cells, and characteristics of the seminiferous tubules. Testicular levels of GPx, MDA, and TAC were evaluated. The gene expression of P450Scc and P450c17 were upregulated in the ginger (P = 0.03) (P = 0.03), endurance training (P = 0.02) (P = 0.003) and endurance training + ginger (P = 0.01) (P = 0.001) groups compared to the control group, respectively. The testicular expression of P450 aromatase gene increased in the endurance training (P = 0.007) and the endurance training + ginger (P = 0.049) groups compared to the control group. The results of P450Scc gene expression was upregulated in the endurance training (P = 0.001) and endurance training + Maca (P = 0.01) groups compared to the control group. Also, the expression of P450c17 was increased in the endurance training (P = 0.0005) and endurance training + Maca (P = 0.0014) groups compared to the control group. No significant difference was observed in the testicular expression of genes involved in the regulation of spermatogenesis (LHR, FSHR, and SGP-1) among all groups. The results indicated that the GR gene was up-regulated in the endurance training + ginger group compared to the ginger (P = 0.03) and endurance training group (P = 0.04). The level of TAC as oxidative parameter was increased in the endurance training + Maca group compared to the control (P = 0.0182), the Maca (P = 0.0008), and the endurance training (P = 0.02) groups. The level of MDA was decreased in endurance training + ginger group compared to the ginger (P = 0.01) and endurance training (P = 0.01) groups. The GPx activity indicated a protective effect and improved oxidative status in testicular tissue in the Maca, the ginger and the endurance training groups. Consistent with our steroidogenesis results, spermatogenesis parameters were significantly increased by Maca, ginger, endurance training, and their combination with endurance training compared to the control group (P < 0.05). It can be concluded that consuming ginger or Maca alo
{"title":"The effect of endurance training with Maca or ginger on steroidogenesis and antioxidant status of testicular tissue in male rats","authors":"Samer Ali Awad Alsamawi, Khadijeh Nasiri, Abolfazl Akbari, Rozita Fathi","doi":"10.1016/j.jsbmb.2025.106921","DOIUrl":"10.1016/j.jsbmb.2025.106921","url":null,"abstract":"<div><div>Today's primary approach to enhancing reproductive function involves lifestyle modifications, dietary adjustments, the use of herbal supplements, and regular exercise. In this study, we tried to show that the use of ginger or Maca supplements along with endurance training can affect reproductive function indicators, including spermatogenesis and steroidogenesis in testicular tissue. Adult male Wistar rats (n = 42, weight: 220 ± 20 g, age: 10–12 weeks) were randomly divided into six equal groups. The groups included control, ginger (100 mg/kg body weight), Maca (100 mg/kg body weight), endurance training (ET), ET + ginger and ET + Maca. Tissue levels of testosterone were measured along with the expression of genes involved in steroidogenesis (P450Scc, P450c17, HSD17β3, and P450 aromatase) and genes involved in its regulation (LHR, FSHR, GR, and SGP-1). Spermatogenesis was assessed by counting the number of spermatogenic cells (spermatogonia and spermatocytes), Leydig and Sertoli cells, and characteristics of the seminiferous tubules. Testicular levels of GPx, MDA, and TAC were evaluated. The gene expression of P450Scc and P450c17 were upregulated in the ginger (P = 0.03) (P = 0.03), endurance training (P = 0.02) (P = 0.003) and endurance training + ginger (P = 0.01) (P = 0.001) groups compared to the control group, respectively. The testicular expression of P450 aromatase gene increased in the endurance training (P = 0.007) and the endurance training + ginger (P = 0.049) groups compared to the control group. The results of P450Scc gene expression was upregulated in the endurance training (P = 0.001) and endurance training + Maca (P = 0.01) groups compared to the control group. Also, the expression of P450c17 was increased in the endurance training (P = 0.0005) and endurance training + Maca (P = 0.0014) groups compared to the control group. No significant difference was observed in the testicular expression of genes involved in the regulation of spermatogenesis (LHR, FSHR, and SGP-1) among all groups. The results indicated that the GR gene was up-regulated in the endurance training + ginger group compared to the ginger (P = 0.03) and endurance training group (P = 0.04). The level of TAC as oxidative parameter was increased in the endurance training + Maca group compared to the control (P = 0.0182), the Maca (P = 0.0008), and the endurance training (P = 0.02) groups. The level of MDA was decreased in endurance training + ginger group compared to the ginger (P = 0.01) and endurance training (P = 0.01) groups. The GPx activity indicated a protective effect and improved oxidative status in testicular tissue in the Maca, the ginger and the endurance training groups. Consistent with our steroidogenesis results, spermatogenesis parameters were significantly increased by Maca, ginger, endurance training, and their combination with endurance training compared to the control group (P < 0.05). It can be concluded that consuming ginger or Maca alo","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"257 ","pages":"Article 106921"},"PeriodicalIF":2.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145745741","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 : 2026-03-01Epub Date: 2025-12-02DOI: 10.1016/j.jsbmb.2025.106909
Inez Schoenmakers , Alastair Forbes , Kerry S. Jones
Many studies show inverse relationships between the prevalence and severity of clinical conditions and vitamin D status. This may be partly due to reverse causality because of altered organ function, influencing vitamin D metabolism and bioavailability. Here we provide a narrative review of the impact of clinical conditions on vitamin D metabolism reviewing intestinal absorption, vitamin D binding protein (DBP) function and renal metabolism. Dietary vitamin D absorption is dependent on its incorporation in fat droplets in chylomicrons. Gastrointestinal inflammation and impaired fat digestion and absorption lead to decreased vitamin D bioavailability, whereas the hydroxylated form, 25-hydroxyvitamin D (25(OH)D), is less dependent on these factors. Vitamin D metabolites circulate predominantly bound to DBP which facilitates transportation, cellular uptake and regulates hydroxylation into 1,25-dihydroxy vitamin D (1,25(OH)2D) and catabolic products. DBP also plays a key role in scavenging of actin upon cellular damage and inflammation and activation of the innate immune response. A decline in DBP due to actin-scavenging leads to alterations in vitamin D binding, bioavailability and metabolism. The kidney has several roles in vitamin D metabolism: internalisation and hydroxylation of 25(OH)D into 1,25(OH)2D and catabolites and reabsorption of DBP-vitamin D metabolite complex from the glomerular filtrate. Renal damage leads to impairment of these functions. Specific guidance on vitamin D requirements accounting for alterations in vitamin D physiology with many clinical conditions is lacking, except for chronic kidney disease. Understanding how clinical conditions alter organ function and vitamin D metabolism is essential for management of vitamin D status and function.
{"title":"Alterations of vitamin D metabolism and requirements in clinical conditions with impaired gastro-intestinal and renal function and in critical illness","authors":"Inez Schoenmakers , Alastair Forbes , Kerry S. Jones","doi":"10.1016/j.jsbmb.2025.106909","DOIUrl":"10.1016/j.jsbmb.2025.106909","url":null,"abstract":"<div><div>Many studies show inverse relationships between the prevalence and severity of clinical conditions and vitamin D status. This may be partly due to reverse causality because of altered organ function, influencing vitamin D metabolism and bioavailability. Here we provide a narrative review of the impact of clinical conditions on vitamin D metabolism reviewing intestinal absorption, vitamin D binding protein (DBP) function and renal metabolism. Dietary vitamin D absorption is dependent on its incorporation in fat droplets in chylomicrons. Gastrointestinal inflammation and impaired fat digestion and absorption lead to decreased vitamin D bioavailability, whereas the hydroxylated form, 25-hydroxyvitamin D (25(OH)D), is less dependent on these factors. Vitamin D metabolites circulate predominantly bound to DBP which facilitates transportation, cellular uptake and regulates hydroxylation into 1,25-dihydroxy vitamin D (1,25(OH)<sub>2</sub>D) and catabolic products. DBP also plays a key role in scavenging of actin upon cellular damage and inflammation and activation of the innate immune response. A decline in DBP due to actin-scavenging leads to alterations in vitamin D binding, bioavailability and metabolism. The kidney has several roles in vitamin D metabolism: internalisation and hydroxylation of 25(OH)D into 1,25(OH)<sub>2</sub>D and catabolites and reabsorption of DBP-vitamin D metabolite complex from the glomerular filtrate. Renal damage leads to impairment of these functions. Specific guidance on vitamin D requirements accounting for alterations in vitamin D physiology with many clinical conditions is lacking, except for chronic kidney disease. Understanding how clinical conditions alter organ function and vitamin D metabolism is essential for management of vitamin D status and function.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"257 ","pages":"Article 106909"},"PeriodicalIF":2.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145652085","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 : 2026-03-01Epub Date: 2025-12-03DOI: 10.1016/j.jsbmb.2025.106910
Nur Amanina Syariff Tan , Nelli Giribabu , Naguib Salleh
Obesity, which is mostly related to high fat diet (HFD) consumption, could impair male reproductive function. How vitamin D (VD) co-administration ameliorates male reproductive dysfunction during obesity development is not fully understood. Therefore, this study aims to investigate the effect of VD co-administered with HFD on testicular and sperm functions in mice and to unravel the underlying mechanisms involved. Methods: Adult male ICR mice were given HFD with VD (HFDVD+) or without VD (HFDVD-), orally for 12 consecutive weeks. Immediately following sacrifice, blood was withdrawn and testes and epididymal sperm were harvested. Results: HFDVD+ mice exhibited higher serum testosterone, FSH, and LH levels, higher expression of testicular VD receptor (VDR), retinoic acid receptor (RXR α/β/γ) and VD metabolizing enzymes (CYP27B1), testicular steroidogenic proteins (StAR, CYP11A1, 3β-HSD, 17β-HSD, CYP17A1, SF-1 except testicular aromatase), testicular spermatogenic proteins (PLZF, SOX9, SIRT1, AR, SMAD5, ER-α) and blood-testis barrier proteins (occludin, ZO-2, vimentin, connexin-43, N-cadherin) when compared to HFDVD- mice. Additionally, upregulation of testicular RANK and RANKL proteins and downregulation of testicular OPG protein were ameliorated in HFDVD+ mice. Epididymal sperm analysis revealed improvement in sperm parameters in HFDVD+ mice which positively correlated with serum VD levels. In HFDVD+ mice sperm, lesser downregulation of VDR, mitochondrial proteins (TOMM20, ATPB, COX IV), junctional adhesion molecule-A (JAM-A), and glucose transporter 1 (GLUT1) expression were observed. Conclusion: Co-administration of VD with HFD helps to ameliorate testicular and sperm dysfunctions during obesity development, suggesting VD role in overcoming male reproductive impairment in obesity.
{"title":"Vitamin D co-administration mitigates testicular and sperm dysfunction in high fat diet- induced obese mouse model","authors":"Nur Amanina Syariff Tan , Nelli Giribabu , Naguib Salleh","doi":"10.1016/j.jsbmb.2025.106910","DOIUrl":"10.1016/j.jsbmb.2025.106910","url":null,"abstract":"<div><div>Obesity, which is mostly related to high fat diet (HFD) consumption, could impair male reproductive function. How vitamin D (VD) co-administration ameliorates male reproductive dysfunction during obesity development is not fully understood. Therefore, this study aims to investigate the effect of VD co-administered with HFD on testicular and sperm functions in mice and to unravel the underlying mechanisms involved. Methods: Adult male ICR mice were given HFD with VD (HFDVD+) or without VD (HFDVD-), orally for 12 consecutive weeks. Immediately following sacrifice, blood was withdrawn and testes and epididymal sperm were harvested. Results: HFDVD+ mice exhibited higher serum testosterone, FSH, and LH levels, higher expression of testicular VD receptor (VDR), retinoic acid receptor (RXR α/β/γ) and VD metabolizing enzymes (CYP27B1), testicular steroidogenic proteins (StAR, CYP11A1, 3β-HSD, 17β-HSD, CYP17A1, SF-1 except testicular aromatase), testicular spermatogenic proteins (PLZF, SOX9, SIRT1, AR, SMAD5, ER-α) and blood-testis barrier proteins (occludin, ZO-2, vimentin, connexin-43, N-cadherin) when compared to HFDVD- mice. Additionally, upregulation of testicular RANK and RANKL proteins and downregulation of testicular OPG protein were ameliorated in HFDVD+ mice. Epididymal sperm analysis revealed improvement in sperm parameters in HFDVD+ mice which positively correlated with serum VD levels. In HFDVD+ mice sperm, lesser downregulation of VDR, mitochondrial proteins (TOMM20, ATPB, COX IV), junctional adhesion molecule-A (JAM-A), and glucose transporter 1 (GLUT1) expression were observed. Conclusion: Co-administration of VD with HFD helps to ameliorate testicular and sperm dysfunctions during obesity development, suggesting VD role in overcoming male reproductive impairment in obesity.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"257 ","pages":"Article 106910"},"PeriodicalIF":2.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145688628","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}
Our previous studies showed that the prostates of the wild ground squirrels were capable of locally synthesizing testosterone (T), dihydrotestosterone (DHT) and estrogen. In this study, we investigated expression levels of luteinizing hormone receptor (LHR), steroidogenic factor 1 (SF-1), steroidogenic acute regulatory protein (StAR), cytochrome P450 cholesterol side-chain cleavage enzyme (P450scc), 3β-hydroxysteroid dehydrogenase (3βHSD) and 17α-hydroxylase cytochrome P450 (P450c17) in the prostates of the wild ground squirrels during the breeding and non-breeding seasons. LHR, SF-1, StAR, P450scc, 3βHSD and P450c17 were identified in the stromal cells or epithelial cells. The mRNA expression levels of LHR, SF-1, StAR, P450scc, P450c17, 3βHSD and Sterol Regulatory Element-Binding Protein 2 (Srebp2) in the prostate were remarkedly higher during the breeding period than those in the non-breeding period. In contrast, the mRNA expression levels of Melatonin Receptor 1a (Mtnr1a) and Melatonin Receptor 1b (Mtnr1b) were elevated during the non-breeding period. Consistently, the circulating LH and T as well as the prostatic T and DHT concentrations were remarkably higher in the breeding season than those of the non-breeding season, which were positively correlated with the seasonal changes of prostatic weight. Additionally, the transcriptomic study in the prostates identified that differentially expressed genes might be related to signal transduction and signaling receptor activity using GO analysis. The KEGG pathway enriched by differentially expressed genes detected to be involved in steroid biosynthesis, estrogen signaling pathway or steroidogenesis. Taken together, these findings suggested that the prostates of the wild ground squirrels potentially owned ability to synthesize steroid hormones de novo, and the steroid hormones might affect the prostatic functions of the wild ground squirrels via an autocrine or paracrine manner.
{"title":"Seasonal variation of prostatic steroid hormone synthesis capacity in wild ground squirrels (Spermophilus dauricus)","authors":"Pengyu Chen , Qingjing Gao , Wenqian Xie , Huan Yu , Yuning Liu , Haolin Zhang , Qiang Weng","doi":"10.1016/j.jsbmb.2025.106930","DOIUrl":"10.1016/j.jsbmb.2025.106930","url":null,"abstract":"<div><div>Our previous studies showed that the prostates of the wild ground squirrels were capable of locally synthesizing testosterone (T), dihydrotestosterone (DHT) and estrogen. In this study, we investigated expression levels of luteinizing hormone receptor (LHR), steroidogenic factor 1 (SF-1), steroidogenic acute regulatory protein (StAR), cytochrome P450 cholesterol side-chain cleavage enzyme (P450scc), 3β-hydroxysteroid dehydrogenase (3βHSD) and 17α-hydroxylase cytochrome P450 (P450c17) in the prostates of the wild ground squirrels during the breeding and non-breeding seasons. LHR, SF-1, StAR, P450scc, 3βHSD and P450c17 were identified in the stromal cells or epithelial cells. The mRNA expression levels of LHR, SF-1, StAR, P450scc, P450c17, 3βHSD and Sterol Regulatory Element-Binding Protein 2 (Srebp2) in the prostate were remarkedly higher during the breeding period than those in the non-breeding period. In contrast, the mRNA expression levels of Melatonin Receptor 1a (Mtnr1a) and Melatonin Receptor 1b (Mtnr1b) were elevated during the non-breeding period. Consistently, the circulating LH and T as well as the prostatic T and DHT concentrations were remarkably higher in the breeding season than those of the non-breeding season, which were positively correlated with the seasonal changes of prostatic weight. Additionally, the transcriptomic study in the prostates identified that differentially expressed genes might be related to signal transduction and signaling receptor activity using GO analysis. The KEGG pathway enriched by differentially expressed genes detected to be involved in steroid biosynthesis, estrogen signaling pathway or steroidogenesis. Taken together, these findings suggested that the prostates of the wild ground squirrels potentially owned ability to synthesize steroid hormones <em>de novo</em>, and the steroid hormones might affect the prostatic functions of the wild ground squirrels via an autocrine or paracrine manner.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"257 ","pages":"Article 106930"},"PeriodicalIF":2.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145884498","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: 2025-11-14DOI: 10.1016/j.jsbmb.2025.106898
Olivia Z.B. Ginnard , Maria Morales , Ji Youn Youn , Yong Xu , Stephanie R. Sisley
Vitamin D supplementation is linked to many beneficial health outcomes in the geriatric population, such as decreased mortality, epigenetic aging, and fracture risk. Conversely, type 2 diabetes is strongly linked to vitamin D deficiency in older adults. However, there is a discrepancy between clinical trials in adults on the efficacy of vitamin D treatment in prediabetes and diabetes. In addition, human data indicates there may be sexual dimorphism in the effect of vitamin D deficiency on dysglycemia that is more pronounced in men. These incongruities may be due to our limited understanding of the underlying mechanisms of vitamin D in glucose homeostasis among its vast target tissues across the body. Here we describe the physiological effects of vitamin D supplementation in an aged, non-obese mouse model on glucose homeostasis and associated tissue-specific gene regulation. Specifically, we found that 1) increased dietary vitamin D intake can improve glucose regulation in lean, aged male mice, and 2) these male mice also had decreased Glut4 and Insr expression in a diet low in vitamin D in various tissues indicating that dietary vitamin D may be a sex-specific key mediator in regulating glucose tolerance and protecting against insulin resistance.
{"title":"Vitamin D is glucoprotective in aging males but not females","authors":"Olivia Z.B. Ginnard , Maria Morales , Ji Youn Youn , Yong Xu , Stephanie R. Sisley","doi":"10.1016/j.jsbmb.2025.106898","DOIUrl":"10.1016/j.jsbmb.2025.106898","url":null,"abstract":"<div><div>Vitamin D supplementation is linked to many beneficial health outcomes in the geriatric population, such as decreased mortality, epigenetic aging, and fracture risk. Conversely, type 2 diabetes is strongly linked to vitamin D deficiency in older adults. However, there is a discrepancy between clinical trials in adults on the efficacy of vitamin D treatment in prediabetes and diabetes. In addition, human data indicates there may be sexual dimorphism in the effect of vitamin D deficiency on dysglycemia that is more pronounced in men. These incongruities may be due to our limited understanding of the underlying mechanisms of vitamin D in glucose homeostasis among its vast target tissues across the body. Here we describe the physiological effects of vitamin D supplementation in an aged, non-obese mouse model on glucose homeostasis and associated tissue-specific gene regulation. Specifically, we found that 1) increased dietary vitamin D intake can improve glucose regulation in lean, aged male mice, and 2) these male mice also had decreased <em>Glut4</em> and <em>Insr</em> expression in a diet low in vitamin D in various tissues indicating that dietary vitamin D may be a sex-specific key mediator in regulating glucose tolerance and protecting against insulin resistance.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"256 ","pages":"Article 106898"},"PeriodicalIF":2.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145534851","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: 2025-11-03DOI: 10.1016/j.jsbmb.2025.106886
Sarvesh Sabarathinam , Nila Ganamurali
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.
{"title":"Hyperforin as a non-steroidal modulator of the PXR–CYP3A4 regulatory axis: Mechanistic and computational insights into xenobiotic metabolism","authors":"Sarvesh Sabarathinam , Nila Ganamurali","doi":"10.1016/j.jsbmb.2025.106886","DOIUrl":"10.1016/j.jsbmb.2025.106886","url":null,"abstract":"<div><div>Hyperforin, a phloroglucinol derivative from <em>Hypericum perforatum</em> (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 <em>in silico</em> 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.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"256 ","pages":"Article 106886"},"PeriodicalIF":2.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145453935","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: 2025-11-17DOI: 10.1016/j.jsbmb.2025.106904
Azhagu Madhavan Sivalingam
Adipocytes are now recognized as active regulators of cancer progression and therapy resistance. Through metabolic, immune, and signaling interactions, they promote tumor cell proliferation, stemness, and survival. This review examines adipocyte tumor crosstalk in triple-negative breast cancer (TNBC) and oral squamous cell carcinoma (OSCC), focusing on how adipocyte-derived mediators influence tumor aggressiveness and treatment outcomes. Important adipocyte-secreted factors including complement C3, CXCL12, leptin, and adiponectin drive oncogenic signaling pathways that support tumor growth. In OSCC, C3/C3aR activation enhances cancer stemness, while in TNBC, bisphenol A-induced CXCL12 activates the CXCL12/CXCR4–PI3K/AKT axis, promoting epithelial–mesenchymal transition and therapy resistance. Additionally, circular RNAs and metabolic enzymes such as GCLC regulate HIF-1α, NF-κB, β-catenin, and mTOR pathways, further sustaining tumor progression. By establishing a tumor-supportive niche, adipocytes contribute significantly to therapy resistance. Targeting these adipocyte-tumor interactions represents a promising approach to inhibit oncogenic signaling and restore treatment sensitivity. Disrupting this metabolic crosstalk may reprogram the tumor microenvironment, offering new combinatorial strategies for aggressive cancers like TNBC and OSCC.
{"title":"Metabolic and signaling interplay in the adipocyte–tumor microenvironment","authors":"Azhagu Madhavan Sivalingam","doi":"10.1016/j.jsbmb.2025.106904","DOIUrl":"10.1016/j.jsbmb.2025.106904","url":null,"abstract":"<div><div>Adipocytes are now recognized as active regulators of cancer progression and therapy resistance. Through metabolic, immune, and signaling interactions, they promote tumor cell proliferation, stemness, and survival. This review examines adipocyte tumor crosstalk in triple-negative breast cancer (TNBC) and oral squamous cell carcinoma (OSCC), focusing on how adipocyte-derived mediators influence tumor aggressiveness and treatment outcomes. Important adipocyte-secreted factors including complement C3, CXCL12, leptin, and adiponectin drive oncogenic signaling pathways that support tumor growth. In OSCC, C3/C3aR activation enhances cancer stemness, while in TNBC, bisphenol A-induced CXCL12 activates the CXCL12/CXCR4–PI3K/AKT axis, promoting epithelial–mesenchymal transition and therapy resistance. Additionally, circular RNAs and metabolic enzymes such as GCLC regulate HIF-1α, NF-κB, β-catenin, and mTOR pathways, further sustaining tumor progression. By establishing a tumor-supportive niche, adipocytes contribute significantly to therapy resistance. Targeting these adipocyte-tumor interactions represents a promising approach to inhibit oncogenic signaling and restore treatment sensitivity. Disrupting this metabolic crosstalk may reprogram the tumor microenvironment, offering new combinatorial strategies for aggressive cancers like TNBC and OSCC.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"256 ","pages":"Article 106904"},"PeriodicalIF":2.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145551612","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}
Anabolic-androgenic steroid (AAS) abuse is associated with damage to various organs, including the liver. However, the underlying molecular mechanisms remain unclear. This study was conducted to elucidate the effect of nandrolone decanoate on liver injury, both alone and in combination with N-acetylcysteine (NAC), and its related mechanisms. Twenty-four male Wistar rats were randomly subdivided into three groups: Control (Con), Nandrolone (10 mg/kg) (ND), and Nandrolone + NAC (ND+NAC: 150 mg/kg daily). After 6 weeks, nandrolone treatment led to increased levels of triglycerides, cholesterol, LDL, AST, ALT, and ALP, along with a decreased HDL level compared to the control group. ND administration also elevated the expression of PTP1B, HNF4A, and FAT/CD36 genes, as well as protein levels of MMP-2, MMP-9, TGF-β1, SMAD-3, and SREBP-1. miRNA-29b levels decreased in liver tissue following nandrolone exposure, as determined by RT-PCR. Moreover, histopathological examination showed increased fibrosis after ND treatment. Consumption of NAC along with ND partially ameliorated gene and protein expression alterations and fibrotic changes, and improved the undesirable lipid profile and liver enzyme levels compared to the ND group. These findings indicate that ND-induced liver abnormalities may be partly associated with lipid homeostasis changes mediated by overexpression of the aforementioned genes and proteins. They also demonstrate that these effects can be reduced by using NAC as an antioxidant and anti-inflammatory agent.
{"title":"Nandrolone decanoate induces liver damage via TGF-β/Smad3/miR-29 and regulation of FAT/CD36, PTP1B, HNF4A expression in male rats: Rescue effect of N-acetylcysteine","authors":"Shadi Mohammadpour-Asl , Alireza Shirpoor , Shahriar Alipour , Roya Naderi","doi":"10.1016/j.jsbmb.2025.106902","DOIUrl":"10.1016/j.jsbmb.2025.106902","url":null,"abstract":"<div><div>Anabolic-androgenic steroid (AAS) abuse is associated with damage to various organs, including the liver. However, the underlying molecular mechanisms remain unclear. This study was conducted to elucidate the effect of nandrolone decanoate on liver injury, both alone and in combination with N-acetylcysteine (NAC), and its related mechanisms. Twenty-four male Wistar rats were randomly subdivided into three groups: Control (Con), Nandrolone (10 mg/kg) (ND), and Nandrolone + NAC (ND+NAC: 150 mg/kg daily). After 6 weeks, nandrolone treatment led to increased levels of triglycerides, cholesterol, LDL, AST, ALT, and ALP, along with a decreased HDL level compared to the control group. ND administration also elevated the expression of PTP1B, HNF4A, and FAT/CD36 genes, as well as protein levels of MMP-2, MMP-9, TGF-β1, SMAD-3, and SREBP-1. miRNA-29b levels decreased in liver tissue following nandrolone exposure, as determined by RT-PCR. Moreover, histopathological examination showed increased fibrosis after ND treatment. Consumption of NAC along with ND partially ameliorated gene and protein expression alterations and fibrotic changes, and improved the undesirable lipid profile and liver enzyme levels compared to the ND group. These findings indicate that ND-induced liver abnormalities may be partly associated with lipid homeostasis changes mediated by overexpression of the aforementioned genes and proteins. They also demonstrate that these effects can be reduced by using NAC as an antioxidant and anti-inflammatory agent.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"256 ","pages":"Article 106902"},"PeriodicalIF":2.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145534794","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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