Pub Date : 2026-03-01Epub Date: 2025-12-31DOI: 10.1016/j.jsbmb.2025.106927
Jie-Jing Xu , Chuan-Zhi Yan , Zhi-Qiang Liu , Hao-Ran Sun , Ming-Yu Zhang , Qiu-Ping Huang , Chen-Xi Tong , Cheng-Xue Pan , Jia-Le Song , Yan-Yuan Zhou
Polycystic ovary syndrome (PCOS) is a prevalent endocrine and metabolic disorder in women of reproductive age, markedly impairing their health and reducing overall quality of life. Vitexin is a natural flavonoid compound that has demonstrated diverse pharmacological properties, including anti-inflammatory and antioxidant effects. The aim of this study was to investigate the effects of vitexin on dihydrotestosterone (DHT)-induced fibrosis in KGN cells, as well as its regulatory role in the NR4A1/NLRP3 signaling pathway. Experimental findings suggested that DHT treatment resulted in decreased cell viability, disrupted sex hormone balance, increased oxidative stress, and elevated levels of inflammation and fibrosis in KGN cells. However, vitexin intervention significantly reversed these pathological changes. Transcriptomics sequencing analysis and molecular docking further indicated that NR4A1 is a pivotal target of vitexin in modulating the inflammatory response. Vitexin significantly inhibited NLRP3 inflammasome-mediated inflammation by activating NR4A1, conversely NR4A1 knockdown partially attenuated the protective effects of vitexin (P < 0.01). Therefore, vitexin was found to effectively ameliorate DHT-induced alterations in cell viability, sex hormone levels, oxidative stress, inflammation and fibrosis in KGN cells. These protective effects appear to be closely related to the regulation of the NR4A1/NLRP3 signaling pathway.
{"title":"Vitexin reduced the dihydrotestosterone (DHT)-induced fibrosis in KGN cells by regulating the NR4A1/NLRP3 pathway","authors":"Jie-Jing Xu , Chuan-Zhi Yan , Zhi-Qiang Liu , Hao-Ran Sun , Ming-Yu Zhang , Qiu-Ping Huang , Chen-Xi Tong , Cheng-Xue Pan , Jia-Le Song , Yan-Yuan Zhou","doi":"10.1016/j.jsbmb.2025.106927","DOIUrl":"10.1016/j.jsbmb.2025.106927","url":null,"abstract":"<div><div>Polycystic ovary syndrome (PCOS) is a prevalent endocrine and metabolic disorder in women of reproductive age, markedly impairing their health and reducing overall quality of life. Vitexin is a natural flavonoid compound that has demonstrated diverse pharmacological properties, including anti-inflammatory and antioxidant effects. The aim of this study was to investigate the effects of vitexin on dihydrotestosterone (DHT)-induced fibrosis in KGN cells, as well as its regulatory role in the NR4A1/NLRP3 signaling pathway. Experimental findings suggested that DHT treatment resulted in decreased cell viability, disrupted sex hormone balance, increased oxidative stress, and elevated levels of inflammation and fibrosis in KGN cells. However, vitexin intervention significantly reversed these pathological changes. Transcriptomics sequencing analysis and molecular docking further indicated that NR4A1 is a pivotal target of vitexin in modulating the inflammatory response. Vitexin significantly inhibited NLRP3 inflammasome-mediated inflammation by activating NR4A1, conversely NR4A1 knockdown partially attenuated the protective effects of vitexin (<em>P</em> < 0.01). Therefore, vitexin was found to effectively ameliorate DHT-induced alterations in cell viability, sex hormone levels, oxidative stress, inflammation and fibrosis in KGN cells. These protective effects appear to be closely related to the regulation of the NR4A1/NLRP3 signaling pathway.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"257 ","pages":"Article 106927"},"PeriodicalIF":2.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145893515","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.2025.106918
Nasser M. Al-Daghri , Amal M. Alenad , Shaun Sabico , Kaiser Wani , Yousef Al-Saleh , Malak N.K. Khattak , Abdullah M. Alnaami , Leena T. Fakhurji , Majed S. Alokail , Jean-Yves Reginster , Etienne Cavalier
Vitamin D deficiency is a widespread public health issue among Saudi adolescents, posing significant risks to bone health and long-term well-being. Traditional markers such as serum 25-hydroxyvitamin D [25(OH)D] may not fully capture functional vitamin D status, particularly during critical growth periods such as adolescence. This study aimed to evaluate vitamin D metabolite levels and their association with calcium intake and bone health markers in Saudi adolescents, with a focus on the vitamin D metabolite ratio (VMR) as a potential indicator of functional vitamin D sufficiency. A cross-sectional analysis was conducted involving 949 (54 % females) Saudi adolescents. Serum levels of vitamin D metabolites, including 25(OH)D; 24,25-dihydroxyvitamin D [24,25(OH)₂D], and 25(OH)D₂, were measured using liquid chromatography–tandem mass spectrometry (LC-MS/MS). VMR was calculated as the ratio of 24,25(OH)₂D to 25(OH)D. Dietary calcium intake was assessed via validated questionnaires. Parathyroid hormone (PTH) and serum calcium levels were analyzed in a subset of participants. Vitamin D deficiency was highly prevalent, with 86.5 % of participants showing insufficient 25(OH)D levels. Over 93 % had low 24,25(OH)₂D, 99.7 % had undetectable 25(OH)D₂, and 74.9 % exhibited low VMR. VMR was significantly associated with serum and dietary calcium intake among girls, but not boys, suggesting potential sex-specific metabolic differences. Additionally, only VMR showed a significant association with serum calcium. An inverse association between PTH and both total vitamin D (r = -0.28, p < 0.05) and serum calcium (r = -0.34, p < 0.01) was observed in the subset analysis. In conclusion, VMR may serve as a useful sex-specific biomarker of functional vitamin D status in adolescents. The findings highlight the importance of addressing both intake and metabolic processing of vitamin D to optimize bone health during adolescence.
维生素D缺乏是沙特青少年中普遍存在的公共卫生问题，对骨骼健康和长期福祉构成重大风险。血清25-羟基维生素D [25(OH)D]等传统标志物可能无法完全捕捉到维生素D的功能状态，特别是在关键的生长时期，如青春期。本研究旨在评估沙特青少年维生素D代谢物水平及其与钙摄入量和骨骼健康指标的关系，重点关注维生素D代谢物比率（VMR）作为功能性维生素D充足性的潜在指标。对949名沙特青少年（54%为女性）进行了横断面分析。血清维生素D代谢物水平，包括25(OH)D；采用液相色谱-串联质谱法（LC-MS/MS）测定24,25-二羟基维生素D [24,25（OH）₂D]和25(OH)D₂。VMR计算为24,25（OH）₂D与25(OH)D的比值。膳食钙摄入量通过有效问卷进行评估。分析了一部分参与者的甲状旁腺激素（PTH）和血清钙水平。维生素D缺乏症非常普遍，86.5%的参与者显示25(OH)D水平不足。超过93%的患者24,25(OH) 2 D含量低，99.7%的患者25(OH) 2无法检测到，74.9%的患者表现为低VMR。在女孩中，VMR与血清和膳食钙摄入量显著相关，但与男孩无关，提示潜在的性别特异性代谢差异。此外，只有VMR与血清钙有显著相关性。甲状旁腺激素与总维生素D呈负相关(r = -0.28, p
{"title":"Vitamin D metabolite ratio as a marker of nutritional bone health in adolescents","authors":"Nasser M. Al-Daghri , Amal M. Alenad , Shaun Sabico , Kaiser Wani , Yousef Al-Saleh , Malak N.K. Khattak , Abdullah M. Alnaami , Leena T. Fakhurji , Majed S. Alokail , Jean-Yves Reginster , Etienne Cavalier","doi":"10.1016/j.jsbmb.2025.106918","DOIUrl":"10.1016/j.jsbmb.2025.106918","url":null,"abstract":"<div><div>Vitamin D deficiency is a widespread public health issue among Saudi adolescents, posing significant risks to bone health and long-term well-being. Traditional markers such as serum 25-hydroxyvitamin D [25(OH)D] may not fully capture functional vitamin D status, particularly during critical growth periods such as adolescence. This study aimed to evaluate vitamin D metabolite levels and their association with calcium intake and bone health markers in Saudi adolescents, with a focus on the vitamin D metabolite ratio (VMR) as a potential indicator of functional vitamin D sufficiency. A cross-sectional analysis was conducted involving 949 (54 % females) Saudi adolescents. Serum levels of vitamin D metabolites, including 25(OH)D; 24,25-dihydroxyvitamin D [24,25(OH)₂D], and 25(OH)D₂, were measured using liquid chromatography–tandem mass spectrometry (LC-MS/MS). VMR was calculated as the ratio of 24,25(OH)₂D to 25(OH)D. Dietary calcium intake was assessed via validated questionnaires. Parathyroid hormone (PTH) and serum calcium levels were analyzed in a subset of participants. Vitamin D deficiency was highly prevalent, with 86.5 % of participants showing insufficient 25(OH)D levels. Over 93 % had low 24,25(OH)₂D, 99.7 % had undetectable 25(OH)D₂, and 74.9 % exhibited low VMR. VMR was significantly associated with serum and dietary calcium intake among girls, but not boys, suggesting potential sex-specific metabolic differences. Additionally, only VMR showed a significant association with serum calcium. An inverse association between PTH and both total vitamin D (r = -0.28, p < 0.05) and serum calcium (r = -0.34, p < 0.01) was observed in the subset analysis. In conclusion, VMR may serve as a useful sex-specific biomarker of functional vitamin D status in adolescents. The findings highlight the importance of addressing both intake and metabolic processing of vitamin D to optimize bone health during adolescence.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"257 ","pages":"Article 106918"},"PeriodicalIF":2.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145688634","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}
Tryptophan metabolism plays a central role in connecting the brain, gut, and microbiome. Microbial and host-derived metabolites influence intestinal integrity, immune activity, and neural signaling, while steroid and neurosteroid hormones shape these pathways through receptor-mediated effects. Disturbance of this metabolic network contributes to neuropsychiatric, metabolic, and inflammatory disorders. This review integrates evidence from preclinical and clinical studies to explain how tryptophan catabolism interacts with microbial activity and steroid regulation. Key neuroactive metabolites involved in these interactions are discussed, along with their potential value as biomarkers and therapeutic targets. Current limitations of animal models and the need for human-focused, multi-omics approaches are also highlighted. Together, these insights outline how coordinated tryptophan–steroid–microbiome signalling influences health and disease and identify opportunities for more precise diagnostic and therapeutic strategies.
{"title":"Tryptophan-steroid interactions in the brain–gut–microbiome axis: Neuroactive metabolites as biomarkers and therapeutic targets","authors":"Sandhya Ravishankar , Bhavya Ekambaram , Nisha Boopathi , Sharanitha Rajagopal Sakthivel , Christan M","doi":"10.1016/j.jsbmb.2025.106908","DOIUrl":"10.1016/j.jsbmb.2025.106908","url":null,"abstract":"<div><div>Tryptophan metabolism plays a central role in connecting the brain, gut, and microbiome. Microbial and host-derived metabolites influence intestinal integrity, immune activity, and neural signaling, while steroid and neurosteroid hormones shape these pathways through receptor-mediated effects. Disturbance of this metabolic network contributes to neuropsychiatric, metabolic, and inflammatory disorders. This review integrates evidence from preclinical and clinical studies to explain how tryptophan catabolism interacts with microbial activity and steroid regulation. Key neuroactive metabolites involved in these interactions are discussed, along with their potential value as biomarkers and therapeutic targets. Current limitations of animal models and the need for human-focused, multi-omics approaches are also highlighted. Together, these insights outline how coordinated tryptophan–steroid–microbiome signalling influences health and disease and identify opportunities for more precise diagnostic and therapeutic strategies.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"257 ","pages":"Article 106908"},"PeriodicalIF":2.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145702845","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: 2025-12-31DOI: 10.1016/j.jsbmb.2025.106931
Chunfang Gan , Beijun Gan , Ying Li , Yanmin Huang , Zhiping Liu , Yunqiong Gu , Haifeng Chen , Qifu Lin
The development of novel chemotherapeutic agents with high efficacy and low toxicity remains a critical challenge in oncology. In this study, a novel series of steroidal selenosemicarbazone derivatives were designed and synthesized through the selenium functionalization of diverse steroid scaffolds. Key ketone intermediates derived from cholesterol, dehydroepiandrosterone (DHEA), estrone, and pregnenolone were condensed with various selenosemicarbazides to achieve structural diversification across the steroid nucleus. The antiproliferative activities of the synthesized compounds were evaluated against a panel of human cancer cell lines. Most compounds exhibited broad-spectrum cytotoxicity, among which compound 17c, based on the DHEA scaffold, showed superior potency against MCF-7 breast cancer cells(IC50 = 4.80 ± 0.43 μM)and high selectivity over normal cells. Mechanism-of-action studies revealed that 17c induces mitochondrial-mediated apoptosis, characterized by the loss of mitochondrial membrane potential, activation of caspase-9, and G2/M phase cell cycle arrest. Molecular docking simulations implicated glutathione reductase (GR) as a potential molecular target, suggesting that the binding of 17c to GR may initiate the observed mitochondrial dysfunction. Furthermore, the concentration-dependent suppression of cell proliferation, migration, and clonogenic survival by 17c was confirmed through a suite of functional assays. Collectively, this work identifies 17c as a promising lead compound with a clarified mechanistic profile for the development of efficient and low-toxicity anticancer agents.
{"title":"Design, synthesis, and biological evaluation of novel steroidal selenosemicarbazone derivatives as potent antitumor agents","authors":"Chunfang Gan , Beijun Gan , Ying Li , Yanmin Huang , Zhiping Liu , Yunqiong Gu , Haifeng Chen , Qifu Lin","doi":"10.1016/j.jsbmb.2025.106931","DOIUrl":"10.1016/j.jsbmb.2025.106931","url":null,"abstract":"<div><div>The development of novel chemotherapeutic agents with high efficacy and low toxicity remains a critical challenge in oncology. In this study, a novel series of steroidal selenosemicarbazone derivatives were designed and synthesized through the selenium functionalization of diverse steroid scaffolds. Key ketone intermediates derived from cholesterol, dehydroepiandrosterone (DHEA), estrone, and pregnenolone were condensed with various selenosemicarbazides to achieve structural diversification across the steroid nucleus. The antiproliferative activities of the synthesized compounds were evaluated against a panel of human cancer cell lines. Most compounds exhibited broad-spectrum cytotoxicity, among which compound <strong>17c</strong>, based on the DHEA scaffold, showed superior potency against MCF-7 breast cancer cells(IC<sub>50</sub> = 4.80 ± 0.43 μM)and high selectivity over normal cells. Mechanism-of-action studies revealed that <strong>17c</strong> induces mitochondrial-mediated apoptosis, characterized by the loss of mitochondrial membrane potential, activation of caspase-9, and G2/M phase cell cycle arrest. Molecular docking simulations implicated glutathione reductase (GR) as a potential molecular target, suggesting that the binding of <strong>17c</strong> to GR may initiate the observed mitochondrial dysfunction. Furthermore, the concentration-dependent suppression of cell proliferation, migration, and clonogenic survival by <strong>17c</strong> was confirmed through a suite of functional assays. Collectively, this work identifies <strong>17c</strong> as a promising lead compound with a clarified mechanistic profile for the development of efficient and low-toxicity anticancer agents.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"257 ","pages":"Article 106931"},"PeriodicalIF":2.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145893523","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: 2025-11-29DOI: 10.1016/j.jsbmb.2025.106907
Di Cheng , Yuhua Chen , Yi Tan , Qiaoqing Zhong , Hang Liu , Lanyu Li , Yuanjie Xie , Zhongcheng Mo
Polycystic ovary syndrome (PCOS) is a common endocrine disorder, often characterized by polycystic ovarian, hyperandrogenism, and menstrual irregularities, which can lead to infertility and other metabolic issues. The mechanisms underlying these symptoms remain complex, with granulosa cells proliferation and apoptosis playing a key role in the pathogenesis of PCOS. In this study, we investigate the potential of metformin to regulate the miR-103a-3p/PTEN signaling pathway in granulosa cells, which may help address these dysfunctions. We first created an in vitro PCOS model using KGN cells treated with testosterone propionate (TP) and tested the effects of metformin alongside miR-103a-3p mimics, inhibitors, and PTEN overexpression. Additionally, a PCOS rat model was developed through TP injections, and rats were treated with metformin at varying doses. Cell viability, proliferation, and apoptosis were assessed using MTT, EdU, and TUNEL staining techniques. The results showed that TP treatment reduced KGN cell viability and promoted apoptosis, while metformin treatment restored cell viability and improved these markers. Altering miR-103a-3p levels or PTEN expression further modulated cell proliferation and apoptosis, supporting the involvement of the miR-103a-3p/PTEN axis in PCOS pathophysiology. In the rat model, metformin alleviated metabolic and reproductive dysfunctions by regulating key biomarkers. These findings suggest that metformin can promote granulosa cells proliferation and inhibit apoptosis, providing a promising therapeutic approach for PCOS through the miR-103a-3p/PTEN axis.
{"title":"Metformin improves polycystic ovary syndrome through the regulation of granulosa cell proliferation and apoptosis via the miR-103a-3p/PTEN signaling pathway","authors":"Di Cheng , Yuhua Chen , Yi Tan , Qiaoqing Zhong , Hang Liu , Lanyu Li , Yuanjie Xie , Zhongcheng Mo","doi":"10.1016/j.jsbmb.2025.106907","DOIUrl":"10.1016/j.jsbmb.2025.106907","url":null,"abstract":"<div><div>Polycystic ovary syndrome (PCOS) is a common endocrine disorder, often characterized by polycystic ovarian, hyperandrogenism, and menstrual irregularities, which can lead to infertility and other metabolic issues. The mechanisms underlying these symptoms remain complex, with granulosa cells proliferation and apoptosis playing a key role in the pathogenesis of PCOS. In this study, we investigate the potential of metformin to regulate the miR-103a-3p/PTEN signaling pathway in granulosa cells, which may help address these dysfunctions. We first created an in vitro PCOS model using KGN cells treated with testosterone propionate (TP) and tested the effects of metformin alongside miR-103a-3p mimics, inhibitors, and PTEN overexpression. Additionally, a PCOS rat model was developed through TP injections, and rats were treated with metformin at varying doses. Cell viability, proliferation, and apoptosis were assessed using MTT, EdU, and TUNEL staining techniques. The results showed that TP treatment reduced KGN cell viability and promoted apoptosis, while metformin treatment restored cell viability and improved these markers. Altering miR-103a-3p levels or PTEN expression further modulated cell proliferation and apoptosis, supporting the involvement of the miR-103a-3p/PTEN axis in PCOS pathophysiology. In the rat model, metformin alleviated metabolic and reproductive dysfunctions by regulating key biomarkers. These findings suggest that metformin can promote granulosa cells proliferation and inhibit apoptosis, providing a promising therapeutic approach for PCOS through the miR-103a-3p/PTEN axis.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"257 ","pages":"Article 106907"},"PeriodicalIF":2.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145652081","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: 2026-01-01DOI: 10.1016/j.jsbmb.2025.106932
Maryam Musavi , Farnaz Oghbaei , Mohammad Abavisani , Ahmad Ghasemi , Amir Abbas Momtazi-Borojeni
The hexosamine biosynthesis pathway (HBP) is a nutrient-sensitive branch of glucose metabolism that produces UDP-GlcNAc, a central substrate for protein glycosylation. Growing evidence links altered HBP activity to breast cancer (BC) progression and treatment response. However, the strength of evidence differs across tumor subtypes and across experimental versus patient data. This review summarizes current clinical and preclinical evidence on how HBP enzymes and HBP-derived glycosylation contribute to BC biology. Across BC cohorts and experimental models, increased expression of key HBP components has been associated with aggressive features, while mechanistic studies show that HBP activity can support oncogenic signaling through elevated O-GlcNAcylation of regulatory proteins. Work in BC models further indicates that HBP-related changes influence proliferation, survival, epithelial–mesenchymal transition, migration, and invasion, and may interact with pathways such as PI3K/AKT/mTOR, Wnt/β-catenin, and YAP. Evidence discussed in this review also links HBP output to stress-adaptation programs, including DNA damage responses and ER protein-folding capacity via N-linked glycosylation, which can promote survival under nutrient or therapy stress. Therapeutic studies described here include direct and indirect strategies to reduce HBP output, such as targeting pathway enzymes, modulating O-GlcNAc cycling, and using hexosamine analogs designed to disrupt flux or glycan function; these approaches reduce growth and metastatic behavior in several preclinical settings, but specificity and normal-tissue tolerance remain key constraints. Overall, the literature supports HBP as a plausible metabolic contributor to BC progression, but stronger patient-linked validation is needed. Future work should prioritize subtype-resolved clinical studies and direct measures of pathway activity to guide biomarker development and therapeutic targeting.
{"title":"The hexosamine biosynthesis pathway as a potent culprit in breast cancer progression","authors":"Maryam Musavi , Farnaz Oghbaei , Mohammad Abavisani , Ahmad Ghasemi , Amir Abbas Momtazi-Borojeni","doi":"10.1016/j.jsbmb.2025.106932","DOIUrl":"10.1016/j.jsbmb.2025.106932","url":null,"abstract":"<div><div>The hexosamine biosynthesis pathway (HBP) is a nutrient-sensitive branch of glucose metabolism that produces UDP-GlcNAc, a central substrate for protein glycosylation. Growing evidence links altered HBP activity to breast cancer (BC) progression and treatment response. However, the strength of evidence differs across tumor subtypes and across experimental versus patient data. This review summarizes current clinical and preclinical evidence on how HBP enzymes and HBP-derived glycosylation contribute to BC biology. Across BC cohorts and experimental models, increased expression of key HBP components has been associated with aggressive features, while mechanistic studies show that HBP activity can support oncogenic signaling through elevated O-GlcNAcylation of regulatory proteins. Work in BC models further indicates that HBP-related changes influence proliferation, survival, epithelial–mesenchymal transition, migration, and invasion, and may interact with pathways such as PI3K/AKT/mTOR, Wnt/β-catenin, and YAP. Evidence discussed in this review also links HBP output to stress-adaptation programs, including DNA damage responses and ER protein-folding capacity via N-linked glycosylation, which can promote survival under nutrient or therapy stress. Therapeutic studies described here include direct and indirect strategies to reduce HBP output, such as targeting pathway enzymes, modulating O-GlcNAc cycling, and using hexosamine analogs designed to disrupt flux or glycan function; these approaches reduce growth and metastatic behavior in several preclinical settings, but specificity and normal-tissue tolerance remain key constraints. Overall, the literature supports HBP as a plausible metabolic contributor to BC progression, but stronger patient-linked validation is needed. Future work should prioritize subtype-resolved clinical studies and direct measures of pathway activity to guide biomarker development and therapeutic targeting.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"257 ","pages":"Article 106932"},"PeriodicalIF":2.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145896926","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}
This study aimed to identify differentially expressed genes (DEGs) in the testes of Bactrian camels during estrus and anestrus and investigate the regulatory role of cholecystokinin (CCK) and its receptor (CCKBR) in androgen synthesis. RNA sequencing was performed on six testicular samples (estrus, n = 3; anestrus, n = 3). A total of 291 DEGs were identified, including 27 upregulated and 264 downregulated in estrus. Gene Ontology (GO) enrichment analysis revealed that CCKBR was significantly enriched in reproduction-related pathways, and STRING analysis showed a close association between CCK and CCKBR. Further qRT-PCR, Western blot, and immunofluorescence (IF) analyses demonstrated significantly higher mRNA and protein levels of CCK/CCKBR in estrus testes (P < 0.01), with both localized in Sertoli cells, Leydig cells, primary spermatocytes, and spermatogonia. Primary Sertoli cells, confirmed by WT1 co-localization, were transfected with p-IRES2-EGFP-CCK and siRNA-CCK. Results showed that CCK overexpression significantly reduced testosterone (T) and dihydrotestosterone (DHT) levels (P < 0.05), while upregulating androgen receptor (AR) and key androgen synthesis enzymes (StAR, P450scc, 3β-HSD) (P < 0.05 or P < 0.01). In contrast, siRNA-CCK exerted the opposite effects. In conclusion, our study highlights the CCK/CCKBR axis as a crucial regulator of seasonal testicular function in Bactrian camels, with CCK negatively regulating testicular androgen synthesis by modulating AR and androgen synthesis enzymes. These findings provide valuable insights into the reproductive biology of Bactrian camels and offer a novel pathway for understanding seasonal fertility regulation in male mammals. This has important implications for enhancing camel breeding efficiency and supporting conservation efforts.
{"title":"Cholecystokinin (CCK) mediates CCKBR to regulate androgen secretion via the steroid pathway in Bactrian camel Sertoli cells","authors":"Qi Wang, Wenjing Wang, Jinghong Nan, Yong Zhang, Xingxu Zhao","doi":"10.1016/j.jsbmb.2025.106922","DOIUrl":"10.1016/j.jsbmb.2025.106922","url":null,"abstract":"<div><div>This study aimed to identify differentially expressed genes (DEGs) in the testes of Bactrian camels during estrus and anestrus and investigate the regulatory role of cholecystokinin (CCK) and its receptor (CCKBR) in androgen synthesis. RNA sequencing was performed on six testicular samples (estrus, n = 3; anestrus, n = 3). A total of 291 DEGs were identified, including 27 upregulated and 264 downregulated in estrus. Gene Ontology (GO) enrichment analysis revealed that CCKBR was significantly enriched in reproduction-related pathways, and STRING analysis showed a close association between CCK and CCKBR. Further qRT-PCR, Western blot, and immunofluorescence (IF) analyses demonstrated significantly higher mRNA and protein levels of CCK/CCKBR in estrus testes (<em>P < 0.01</em>), with both localized in Sertoli cells, Leydig cells, primary spermatocytes, and spermatogonia. Primary Sertoli cells, confirmed by WT1 co-localization, were transfected with p-IRES2-EGFP-CCK and siRNA-CCK. Results showed that CCK overexpression significantly reduced testosterone (T) and dihydrotestosterone (DHT) levels (P < 0.05), while upregulating androgen receptor (AR) and key androgen synthesis enzymes (StAR, P450scc, 3β-HSD) (P < 0.05 or P < 0.01). In contrast, siRNA-CCK exerted the opposite effects. In conclusion, our study highlights the CCK/CCKBR axis as a crucial regulator of seasonal testicular function in Bactrian camels, with CCK negatively regulating testicular androgen synthesis by modulating AR and androgen synthesis enzymes. These findings provide valuable insights into the reproductive biology of Bactrian camels and offer a novel pathway for understanding seasonal fertility regulation in male mammals. This has important implications for enhancing camel breeding efficiency and supporting conservation efforts.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"257 ","pages":"Article 106922"},"PeriodicalIF":2.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145783580","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: 2025-12-23DOI: 10.1016/j.jsbmb.2025.106926
Meiling Zhang , Ying Huang , Wenji Du , Ting Lu , Linshuang Ye , Xiao Cheng , Xiang Zeng , Jingbo Sun
β-Sitosterol, a widely distributed phytosterol, has shown therapeutic potential against Alzheimer’s disease (AD); however, its system-level mechanisms remain unclear. This study aimed to generate testable hypotheses regarding β-sitosterol activity in AD using an integrative computational framework. Potential targets were predicted using SwissTargetPrediction and were intersected with AD-related genes. Core targets were identified via protein-protein interaction network analysis, followed by pathway enrichment and validation using Gene Expression Omnibus transcriptomic datasets. Binding interactions were evaluated using molecular docking and 100-ns molecular dynamics (MD) simulations. Mendelian randomization (MR) was used to assess the causal association between circulating estradiol levels (proxy for aromatase activity) and AD risk. Nineteen potential targets were identified, with core genes (e.g., CYP19A1, ESR1, and NR3C1) significantly enriched in steroid hormone biosynthesis pathways. Β-Sitosterol exhibited strong binding affinities to CYP19A1 (−9.7 kcal/mol) and ESR1 (−8.2 kcal/mol), and MD simulations confirmed β-sitosterol–CYP19A1 complex stability. Differential expression analysis validated the dysregulation of key targets in AD. MR analysis further indicated that genetically predicted higher estradiol levels were significantly associated with reduced AD risk (IVW: β = −11.02, SE = 2.77, p = 6.78 × 10⁻⁵). This study provides predictive evidence that β-sitosterol may influence AD pathology by modulating steroidogenic enzymes and hormone signaling. However, as all findings were computationally derived and estradiol serves only as an indirect proxy for aromatase activity, experimental validation is required to confirm these proposed mechanisms. Our results offer a hypothesis-generating framework for further investigation of β-sitosterol as a multitarget candidate for AD.
β-谷甾醇是一种广泛分布的植物甾醇，已显示出治疗阿尔茨海默病（AD）的潜力；然而，其系统级机制尚不清楚。本研究旨在通过综合计算框架生成关于β-谷甾醇在AD中的活性的可测试假设。使用SwissTargetPrediction预测潜在靶标，并与ad相关基因交叉。通过蛋白相互作用网络分析确定核心靶点，然后使用Gene Expression Omnibus转录组数据集进行途径富集和验证。结合相互作用通过分子对接和100-ns分子动力学（MD）模拟进行评估。孟德尔随机化（MR）用于评估循环雌二醇水平（芳香化酶活性的代表）与AD风险之间的因果关系。鉴定出19个潜在靶点，其中核心基因（如CYP19A1、ESR1和NR3C1）在类固醇激素生物合成途径中显著富集。Β-Sitosterol与CYP19A1 （-9.7kcal/mol）和ESR1 （-8.2kcal/mol）具有较强的结合亲和力，MD模拟证实了β-谷甾醇-CYP19A1复合物的稳定性。差异表达分析证实了AD中关键靶点的失调。磁共振分析进一步表明，基因预测的高雌二醇水平与降低AD风险显著相关（IVW: β = -11.02, SE = 2.77, p = 6.78 × 10毒血症）。本研究为β-谷甾醇可能通过调节甾体生成酶和激素信号传导影响AD病理提供了预测性证据。然而，由于所有的研究结果都是通过计算得出的，雌二醇仅作为芳香酶活性的间接代表，因此需要实验验证来证实这些提出的机制。我们的结果为进一步研究β-谷甾醇作为AD的多靶点候选物提供了一个假设生成框架。
{"title":"The multi-target mechanisms of β-sitosterol in Alzheimer’s disease: Integrative evidence from network pharmacology, molecular docking, and mendelian randomization","authors":"Meiling Zhang , Ying Huang , Wenji Du , Ting Lu , Linshuang Ye , Xiao Cheng , Xiang Zeng , Jingbo Sun","doi":"10.1016/j.jsbmb.2025.106926","DOIUrl":"10.1016/j.jsbmb.2025.106926","url":null,"abstract":"<div><div>β-Sitosterol, a widely distributed phytosterol, has shown therapeutic potential against Alzheimer’s disease (AD); however, its system-level mechanisms remain unclear. This study aimed to generate testable hypotheses regarding β-sitosterol activity in AD using an integrative computational framework. Potential targets were predicted using SwissTargetPrediction and were intersected with AD-related genes. Core targets were identified via protein-protein interaction network analysis, followed by pathway enrichment and validation using Gene Expression Omnibus transcriptomic datasets. Binding interactions were evaluated using molecular docking and 100-ns molecular dynamics (MD) simulations. Mendelian randomization (MR) was used to assess the causal association between circulating estradiol levels (proxy for aromatase activity) and AD risk. Nineteen potential targets were identified, with core genes (e.g., CYP19A1, ESR1, and NR3C1) significantly enriched in steroid hormone biosynthesis pathways. Β-Sitosterol exhibited strong binding affinities to CYP19A1 (−9.7 kcal/mol) and ESR1 (−8.2 kcal/mol), and MD simulations confirmed β-sitosterol–CYP19A1 complex stability. Differential expression analysis validated the dysregulation of key targets in AD. MR analysis further indicated that genetically predicted higher estradiol levels were significantly associated with reduced AD risk (IVW: β = −11.02, SE = 2.77, p = 6.78 × 10⁻⁵). This study provides predictive evidence that β-sitosterol may influence AD pathology by modulating steroidogenic enzymes and hormone signaling. However, as all findings were computationally derived and estradiol serves only as an indirect proxy for aromatase activity, experimental validation is required to confirm these proposed mechanisms. Our results offer a hypothesis-generating framework for further investigation of β-sitosterol as a multitarget candidate for AD.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"257 ","pages":"Article 106926"},"PeriodicalIF":2.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145835209","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: 2025-12-17DOI: 10.1016/j.jsbmb.2025.106923
Noor A. Hakim
Coffee is widely consumed in Saudi Arabia, but its relationship with vitamin D status and related health indicators remains unclear. This cross-sectional study examined associations between coffee consumption, serum 25-hydroxyvitamin D [25(OH)D], lifestyle factors, and mental health symptoms in 387 adults aged 20–60 years recruited in Saudi Arabia (February–March 2024). Participants were classified as normal (≤3 cups/day) or high (>3 cups/day) coffee consumers. Anthropometric measures and serum 25(OH)D and parathyroid hormone were obtained from medical records, and diet, physical activity, sun exposure, and mental health symptoms were assessed by questionnaire. Associations were examined using group comparisons and multivariable regression models. Compared with normal coffee consumers, high coffee consumers had higher BMI (p = 0.043) and lower serum 25(OH)D (p = 0.05). In multivariable linear regression, higher caffeine intake was associated with lower serum 25(OH)D (β = −0.04 nmol/L per mg/day; 95 % CI −0.055 to −0.027; p < 0.001). In logistic regression, higher caffeine intake was associated with lower odds of vitamin D deficiency (<30 nmol/L) (OR = 0.98 per mg/day; 95 % CI 0.97–0.99; p < 0.001). High coffee consumers more frequently reported sleep disturbance/insomnia (49.1 % vs 34.2 %), sweating (20.8 % vs 9.6 %), and raised heart rate (27.7 % vs 17.2 %) (all p < 0.01), whereas headache, irritability, anxiety, and depression did not differ between groups. In this sample of Saudi adults, higher coffee intake was associated with lower 25(OH)D, higher BMI, and more arousal-related symptoms. These observational findings warrant confirmation in longitudinal or interventional studies to clarify temporality and inform public health strategies.
{"title":"Coffee consumption and its association with vitamin D level, lifestyle factors, and mental health symptoms among adults in Saudi Arabia","authors":"Noor A. Hakim","doi":"10.1016/j.jsbmb.2025.106923","DOIUrl":"10.1016/j.jsbmb.2025.106923","url":null,"abstract":"<div><div>Coffee is widely consumed in Saudi Arabia, but its relationship with vitamin D status and related health indicators remains unclear. This cross-sectional study examined associations between coffee consumption, serum 25-hydroxyvitamin D [25(OH)D], lifestyle factors, and mental health symptoms in 387 adults aged 20–60 years recruited in Saudi Arabia (February–March 2024). Participants were classified as normal (≤3 cups/day) or high (>3 cups/day) coffee consumers. Anthropometric measures and serum 25(OH)D and parathyroid hormone were obtained from medical records, and diet, physical activity, sun exposure, and mental health symptoms were assessed by questionnaire. Associations were examined using group comparisons and multivariable regression models. Compared with normal coffee consumers, high coffee consumers had higher BMI (p = 0.043) and lower serum 25(OH)D (p = 0.05). In multivariable linear regression, higher caffeine intake was associated with lower serum 25(OH)D (β = −0.04 nmol/L per mg/day; 95 % CI −0.055 to −0.027; p < 0.001). In logistic regression, higher caffeine intake was associated with lower odds of vitamin D deficiency (<30 nmol/L) (OR = 0.98 per mg/day; 95 % CI 0.97–0.99; p < 0.001). High coffee consumers more frequently reported sleep disturbance/insomnia (49.1 % vs 34.2 %), sweating (20.8 % vs 9.6 %), and raised heart rate (27.7 % vs 17.2 %) (all p < 0.01), whereas headache, irritability, anxiety, and depression did not differ between groups. In this sample of Saudi adults, higher coffee intake was associated with lower 25(OH)D, higher BMI, and more arousal-related symptoms. These observational findings warrant confirmation in longitudinal or interventional studies to clarify temporality and inform public health strategies.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"257 ","pages":"Article 106923"},"PeriodicalIF":2.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145795623","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.2025.106920
Yu Pan , Rui Li , Huanhuan Ma , Xiaolei Hu , Jun Zhao , Juanjuan Qiao , Xiyao Dou , Yanan Wang , Yanzhi Zhang , Xiuli Wang , Lin Wang
Expression of the critical pyroptosis protein gasdermin E (GSDME) has been reported to be regulated by DNA methylation and negatively correlated with the expression of estrogen receptor (ER) in breast cancer tissues, suggesting that estrogen-induced target gene methylation may be involved in the regulation of GSDME expression in breast cancer cells. To test this hypothesis, we treated MCF-7 and T47D ER-positive breast cancer cells with 17-β-Estradiol (E2), either alone or in combination with selective ERα antagonist AZD9496, selective ERβ antagonist PHTPP, DNA methyltransferase (DNMT) inhibitor RG108, and selective ER degrader Fulvestrant (Ful). Then, GSDME protein and mRNA expression were examined with western blot and RT-qPCR. Pyroptosis was induced by short-wave ultraviolet (UV-C) and detected with morphological observation, lactate dehydrogenase (LDH) release assay, and propidium iodide-Annexin V-FITC fluorescence staining. The methylation status of the GSDME promoter was tested with methylation-specific PCR. The results demonstrated that 100 nM E2 significantly decreased GSDME protein and mRNA expression in MCF-7 and T47D cells, and significantly inhibited UV-C-induced pyroptosis. AZD9496 but not PHTPP significantly attenuated the down-regulatory effect of E2 on GSDME expression. E2 induced DNA methylation in the GSDME promoter region and up-regulated DNMT1 expression. RG108 strengthened UV-C-induced pyroptosis, and Ful reversed the inhibitory effects of E2 on UV-C-induced pyroptosis of MCF-7 and T47D cells. Taken together, our study suggests that E2 down-regulated GSDME expression in ERα-positive breast cancer by promoting GSDME promoter methylation, and inhibited UV-C-induced pyroptosis.
{"title":"17 β-Estradiol inhibits GSDME-mediated pyroptosis in ERα-positive breast cancer cells by promoting GSDME promoter methylation","authors":"Yu Pan , Rui Li , Huanhuan Ma , Xiaolei Hu , Jun Zhao , Juanjuan Qiao , Xiyao Dou , Yanan Wang , Yanzhi Zhang , Xiuli Wang , Lin Wang","doi":"10.1016/j.jsbmb.2025.106920","DOIUrl":"10.1016/j.jsbmb.2025.106920","url":null,"abstract":"<div><div>Expression of the critical pyroptosis protein gasdermin E (GSDME) has been reported to be regulated by DNA methylation and negatively correlated with the expression of estrogen receptor (ER) in breast cancer tissues, suggesting that estrogen-induced target gene methylation may be involved in the regulation of GSDME expression in breast cancer cells. To test this hypothesis, we treated MCF-7 and T47D ER-positive breast cancer cells with 17-β-Estradiol (E<sub>2</sub>), either alone or in combination with selective ERα antagonist AZD9496, selective ERβ antagonist PHTPP, DNA methyltransferase (DNMT) inhibitor RG108, and selective ER degrader Fulvestrant (Ful). Then, GSDME protein and mRNA expression were examined with western blot and RT-qPCR. Pyroptosis was induced by short-wave ultraviolet (UV-C) and detected with morphological observation, lactate dehydrogenase (LDH) release assay, and propidium iodide-Annexin V-FITC fluorescence staining. The methylation status of the <em>GSDME</em> promoter was tested with methylation-specific PCR. The results demonstrated that 100 nM E<sub>2</sub> significantly decreased GSDME protein and mRNA expression in MCF-7 and T47D cells, and significantly inhibited UV-C-induced pyroptosis. AZD9496 but not PHTPP significantly attenuated the down-regulatory effect of E<sub>2</sub> on GSDME expression. E<sub>2</sub> induced DNA methylation in the <em>GSDME</em> promoter region and up-regulated DNMT1 expression. RG108 strengthened UV-C-induced pyroptosis, and Ful reversed the inhibitory effects of E<sub>2</sub> on UV-C-induced pyroptosis of MCF-7 and T47D cells<sub>.</sub> Taken together, our study suggests that E<sub>2</sub> down-regulated GSDME expression in ERα-positive breast cancer by promoting <em>GSDME</em> promoter methylation, and inhibited UV-C-induced pyroptosis.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"257 ","pages":"Article 106920"},"PeriodicalIF":2.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145745738","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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