Pub Date : 2025-10-25DOI: 10.1016/j.jsbmb.2025.106882
Aleksandar Cirovic
Mineralocorticoid receptor antagonists (MRAs) such as finerenone have shown clinical benefits in heart failure, yet their full mechanisms remain unclear. Recent evidence suggests a novel role of aldosterone in disrupting myocardial iron homeostasis. Aldosterone, via mineralocorticoid receptor (MR) activation, downregulates key iron transporters like transferrin receptor 1 (TfR1) through SGK1 signaling, contributing to myocardial iron deficiency (MID). Cortisol, which circulates at much higher levels than aldosterone and shares similar MR affinity, may similarly promote MID—especially in tissues like the heart where 11β-HSD2 activity is low. Iron deficiency in cardiomyocytes impairs mitochondrial function, reduces ATP synthesis, and promotes fibrosis and inflammation. MRAs may counteract these effects by restoring iron uptake and improving myocardial energetics. This emerging aldosterone–iron axis offers novel insight into the cardiac effects of MR activation and identifies iron homeostasis as a potential therapeutic target. Further research is warranted to explore MRA-mediated modulation of myocardial iron metabolism.
{"title":"Excess aldosterone and cortisol promote myocardial iron deficiency: A potential pathway to cardiac injury","authors":"Aleksandar Cirovic","doi":"10.1016/j.jsbmb.2025.106882","DOIUrl":"10.1016/j.jsbmb.2025.106882","url":null,"abstract":"<div><div>Mineralocorticoid receptor antagonists (MRAs) such as finerenone have shown clinical benefits in heart failure, yet their full mechanisms remain unclear. Recent evidence suggests a novel role of aldosterone in disrupting myocardial iron homeostasis. Aldosterone, via mineralocorticoid receptor (MR) activation, downregulates key iron transporters like transferrin receptor 1 (TfR1) through SGK1 signaling, contributing to myocardial iron deficiency (MID). Cortisol, which circulates at much higher levels than aldosterone and shares similar MR affinity, may similarly promote MID—especially in tissues like the heart where 11β-HSD2 activity is low. Iron deficiency in cardiomyocytes impairs mitochondrial function, reduces ATP synthesis, and promotes fibrosis and inflammation. MRAs may counteract these effects by restoring iron uptake and improving myocardial energetics. This emerging aldosterone–iron axis offers novel insight into the cardiac effects of MR activation and identifies iron homeostasis as a potential therapeutic target. Further research is warranted to explore MRA-mediated modulation of myocardial iron metabolism.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"255 ","pages":"Article 106882"},"PeriodicalIF":2.5,"publicationDate":"2025-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145416539","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 used targeted metabolomics approach to explore the effects of strength training on sterol metabolism in Paralympic snowboarders. Sixteen national para-snowboard athletes (12 male, 4 female) were assessed during summer strength training phase. Blood and urine samples were collected during adaptation, maximal strength, and rapid strength training phases. We found that serum 25(OH)D levels improved from deficiency to insufficiency after training. Triglyceride and low-density lipoprotein cholesterol (LDL-C) levels decreased significantly after maximal and rapid strength training. Compared to the adaptation stage, 13 and 12 urinary metabolites were identified in male and female athletes, respectively, during the maximal strength phase, while 9 and 8 metabolites showed differences during the rapid strength phase. A total of 13 and 6 differential metabolites were identified in male and female athletes, respectively, when comparing the rapid strength training phase to the maximal strength training phase. Following cycle strength training, the biosynthesis of steroid hormones as well as the metabolic pathways of androgens and estrogens was activated. After the summer strength training period, urinary differential metabolites in male athletes showed a significant association with LDL-C and serum vitamin D levels. In contrast, among female athletes, urinary dihydroprogesterone levels were significantly correlated with 25(OH)D concentrations. In general, strength training improves blood lipids and serum vitamin D levels, with the most pronounced improvement in vitamin D occurring during the maximal strength phase. Steroid hormone biosynthesis, androgen and estrogen metabolic pathways, and metabolism are affected by exercise training, including bile acid metabolism in males.
{"title":"Urine sterols metabolomics study during summer training of winter paralympic snowboarders","authors":"Shengkang Jin , Junyu Wu, Yuan Zhang, Yunxin Gao, Wanting Shen, Zhenqin Cheng, Yuqing Qi , Xueping Wu , Xinkai Yu , Qun Zuo","doi":"10.1016/j.jsbmb.2025.106878","DOIUrl":"10.1016/j.jsbmb.2025.106878","url":null,"abstract":"<div><div>This study used targeted metabolomics approach to explore the effects of strength training on sterol metabolism in Paralympic snowboarders. Sixteen national para-snowboard athletes (12 male, 4 female) were assessed during summer strength training phase. Blood and urine samples were collected during adaptation, maximal strength, and rapid strength training phases. We found that serum 25(OH)D levels improved from deficiency to insufficiency after training. Triglyceride and low-density lipoprotein cholesterol (LDL-C) levels decreased significantly after maximal and rapid strength training. Compared to the adaptation stage, 13 and 12 urinary metabolites were identified in male and female athletes, respectively, during the maximal strength phase, while 9 and 8 metabolites showed differences during the rapid strength phase. A total of 13 and 6 differential metabolites were identified in male and female athletes, respectively, when comparing the rapid strength training phase to the maximal strength training phase. Following cycle strength training, the biosynthesis of steroid hormones as well as the metabolic pathways of androgens and estrogens was activated. After the summer strength training period, urinary differential metabolites in male athletes showed a significant association with LDL-C and serum vitamin D levels. In contrast, among female athletes, urinary dihydroprogesterone levels were significantly correlated with 25(OH)D concentrations. In general, strength training improves blood lipids and serum vitamin D levels, with the most pronounced improvement in vitamin D occurring during the maximal strength phase. Steroid hormone biosynthesis, androgen and estrogen metabolic pathways, and metabolism are affected by exercise training, including bile acid metabolism in males.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"255 ","pages":"Article 106878"},"PeriodicalIF":2.5,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145362995","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 : 2025-10-22DOI: 10.1016/j.jsbmb.2025.106879
Harem Khdir Awla , Baghawan Ahmed Othman , Dawan dlshad rafeeq , Shukur Wasman Smail , Raya Kh. Yashooa , Asmaa Ameen Ghareeb , Rebaz Hamza Salih , Shwan Ali Omar , Christer Janson
Background
Vitamin D is a known immunomodulator, but its predictive value in COVID-19 remains incompletely understood. This study investigates the role of vitamin D across molecular, biochemical, and histopathological levels to evaluate its association with COVID-19 severity and mortality.
Methods
A prospective case-control study was conducted in the Kurdistan Region of Iraq from May to October 2021. Ninety-five confirmed COVID-19 patients (75 survivors, 20 non-survivors) and 75 healthy controls were enrolled. Serum 25(OH)D levels were quantified by ELISA. Clinical severity was assessed using CURB-65, NEWS, and SOFA scores. Genotyping for the FokI (rs2228570) polymorphism in the VDR gene was performed via allele-specific PCR. Lung tissue from five survivors (biopsy) and five non-survivors (autopsy) underwent immunohistochemical staining to evaluate VDR expression.
Results
Serum vitamin D concentrations were markedly reduced in non-survivors (20.34 ± 0.46 ng/mL) relative to survivors (40.11 ± 0.28 ng/mL, p < 0.001). Vitamin D exhibited a negative correlation with CURB-65 (r = –0.828), NEWS (r = –0.794), and SOFA (r = –0.762) scores. Regression analysis established that vitamin D was independently associated with disease severity in our population. The TT genotype of the FokI VDR polymorphism correlated with markedly reduced vitamin D levels and elevated severity scores. Mortality exhibited a strong association with the TT genotype (OR = 10.29, 95 % CI: 2.204–49.19, p = 0.003) and the T allele (OR = 3.923, p = 0.0006). ROC analysis determined a vitamin D threshold of ≤ 20.56 ng/mL as indicative of mortality (AUC = 0.784, p < 0.0001). Immunohistochemistry demonstrated elevated VDR expression in lung tissues of deceased COVID-19 patients relative to VDR-negative controls.
Conclusion
This study indicates that serum vitamin D levels, VDR gene polymorphism (rs2228570), and lung tissue VDR expression are strongly correlated with the severity and mortality of COVID-19. These findings validate the clinical use of vitamin D and VDR profiling may have associative markers and prospective treatment targets in the management of COVID-19.
{"title":"Vitamin D pathway as a multi-level predictor of COVID-19 severity and mortality: Integrating serum levels, FokI (rs2228570) VDR polymorphism, and lung tissue expression","authors":"Harem Khdir Awla , Baghawan Ahmed Othman , Dawan dlshad rafeeq , Shukur Wasman Smail , Raya Kh. Yashooa , Asmaa Ameen Ghareeb , Rebaz Hamza Salih , Shwan Ali Omar , Christer Janson","doi":"10.1016/j.jsbmb.2025.106879","DOIUrl":"10.1016/j.jsbmb.2025.106879","url":null,"abstract":"<div><h3>Background</h3><div>Vitamin D is a known immunomodulator, but its predictive value in COVID-19 remains incompletely understood. This study investigates the role of vitamin D across molecular, biochemical, and histopathological levels to evaluate its association with COVID-19 severity and mortality.</div></div><div><h3>Methods</h3><div>A prospective case-control study was conducted in the Kurdistan Region of Iraq from May to October 2021. Ninety-five confirmed COVID-19 patients (75 survivors, 20 non-survivors) and 75 healthy controls were enrolled. Serum 25(OH)D levels were quantified by ELISA. Clinical severity was assessed using CURB-65, NEWS, and SOFA scores. Genotyping for the <em>Fok</em>I (rs2228570) polymorphism in the VDR gene was performed via allele-specific PCR. Lung tissue from five survivors (biopsy) and five non-survivors (autopsy) underwent immunohistochemical staining to evaluate VDR expression.</div></div><div><h3>Results</h3><div>Serum vitamin D concentrations were markedly reduced in non-survivors (20.34 ± 0.46 ng/mL) relative to survivors (40.11 ± 0.28 ng/mL, p < 0.001). Vitamin D exhibited a negative correlation with CURB-65 (r = –0.828), NEWS (r = –0.794), and SOFA (r = –0.762) scores. Regression analysis established that vitamin D was independently associated with disease severity in our population. The TT genotype of the <em>Fok</em>I VDR polymorphism correlated with markedly reduced vitamin D levels and elevated severity scores. Mortality exhibited a strong association with the TT genotype (OR = 10.29, 95 % CI: 2.204–49.19, p = 0.003) and the T allele (OR = 3.923, p = 0.0006). ROC analysis determined a vitamin D threshold of ≤ 20.56 ng/mL as indicative of mortality (AUC = 0.784, p < 0.0001). Immunohistochemistry demonstrated elevated VDR expression in lung tissues of deceased COVID-19 patients relative to VDR-negative controls.</div></div><div><h3>Conclusion</h3><div>This study indicates that serum vitamin D levels, VDR gene polymorphism (rs2228570), and lung tissue VDR expression are strongly correlated with the severity and mortality of COVID-19. These findings validate the clinical use of vitamin D and VDR profiling may have associative markers and prospective treatment targets in the management of COVID-19.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"255 ","pages":"Article 106879"},"PeriodicalIF":2.5,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145362994","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 : 2025-10-13DOI: 10.1016/j.jsbmb.2025.106877
Cyrus Jalili , Foruzan Hosseinkhani , Dian Dayer , Mohammad Reza Tabandeh , Ardeshir Abbasi , Touraj Zamir Nasta
The host organism's balance within the body relies on its crucial symbiotic relationship with gut microbiota. This balance, known as homeostasis, can be influenced by various factors. One significant factor is the role of bacterial metabolites from different substrates, such as tryptophan. Recent research has revealed that these metabolites impact many biological processes. Microbial metabolites, such as Indole-3-Propionic Acid (IPA), are produced by the intestinal microbiota by converting dietary tryptophan. IPA is absorbed by intestinal epithelial cells, transported via the portal circulation, undergoes minimal hepatic metabolism, and is subsequently released into the systemic circulation to reach peripheral tissues and exert its biological effects. The Pregnane X receptor (PXR) and aryl hydrocarbon receptor (AhR) are the two main receptors of IPA which induce different gene expression profiles and subsequently diverse biological pathways in different tissues. Once absorbed by intestinal epithelial cells, IPA is released into the circulatory system and can significantly affect the immune, cardiovascular, nervous, and gastrointestinal systems. Furthermore, IPA has been found to have positive effects on a cellular level by inhibiting oxidative stress injury and preventing the synthesis of proinflammatory cytokines. Numerous studies have highlighted IPA's antioxidant, anti-inflammatory, anti-cancer, and neuroprotective effects. Therefore, dysbiosis of IPA contributes to disorders such as metabolic syndromes, inflammatory conditions, cancer, and neuropsychiatric diseases. This review provides a detailed examination of the most recent studies on indole-3-propionic acid function through PXR and AhR, outlining its molecular signaling pathways and correlation with various diseases.
{"title":"Indole-3-propionic acid function through PXR and AhR, molecular signaling pathways, and antitoxic role in underlying diseases","authors":"Cyrus Jalili , Foruzan Hosseinkhani , Dian Dayer , Mohammad Reza Tabandeh , Ardeshir Abbasi , Touraj Zamir Nasta","doi":"10.1016/j.jsbmb.2025.106877","DOIUrl":"10.1016/j.jsbmb.2025.106877","url":null,"abstract":"<div><div>The host organism's balance within the body relies on its crucial symbiotic relationship with gut microbiota. This balance, known as homeostasis, can be influenced by various factors. One significant factor is the role of bacterial metabolites from different substrates, such as tryptophan. Recent research has revealed that these metabolites impact many biological processes. Microbial metabolites, such as Indole-3-Propionic Acid (IPA), are produced by the intestinal microbiota by converting dietary tryptophan. IPA is absorbed by intestinal epithelial cells, transported via the portal circulation, undergoes minimal hepatic metabolism, and is subsequently released into the systemic circulation to reach peripheral tissues and exert its biological effects. The Pregnane X receptor (PXR) and aryl hydrocarbon receptor (AhR) are the two main receptors of IPA which induce different gene expression profiles and subsequently diverse biological pathways in different tissues. Once absorbed by intestinal epithelial cells, IPA is released into the circulatory system and can significantly affect the immune, cardiovascular, nervous, and gastrointestinal systems. Furthermore, IPA has been found to have positive effects on a cellular level by inhibiting oxidative stress injury and preventing the synthesis of proinflammatory cytokines. Numerous studies have highlighted IPA's antioxidant, anti-inflammatory, anti-cancer, and neuroprotective effects. Therefore, dysbiosis of IPA contributes to disorders such as metabolic syndromes, inflammatory conditions, cancer, and neuropsychiatric diseases. This review provides a detailed examination of the most recent studies on indole-3-propionic acid function through PXR and AhR, outlining its molecular signaling pathways and correlation with various diseases.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"255 ","pages":"Article 106877"},"PeriodicalIF":2.5,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145304358","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 : 2025-10-10DOI: 10.1016/j.jsbmb.2025.106876
Mahtab Jahdkaran, Mohammad Sistanizad
{"title":"Corrigendum to “From lipids to glucose: Investigating the role of dyslipidemia in the risk of insulin resistance” [J. Steroid Biochem. Mol. Biol. 250 (2025) 106744]","authors":"Mahtab Jahdkaran, Mohammad Sistanizad","doi":"10.1016/j.jsbmb.2025.106876","DOIUrl":"10.1016/j.jsbmb.2025.106876","url":null,"abstract":"","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"255 ","pages":"Article 106876"},"PeriodicalIF":2.5,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145276539","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}
Most members of the aldo-keto reductase (AKR) 1 C subfamily are hydroxysteroid dehydrogenases (HSDs), and their numbers are more than four in many individual mammals. In contrast, there is only one gene for the AKR1C protein (AKR1C3) in dogs, which have been used as a preclinical model for human biomedical research. Here, we report that dog AKR1C3 (known as prostaglandin-F synthase) catalyzes the conversion of the 17-keto group of estrone, 4- and 5-androstenes, and 5α-androstanes to their 17β-hydroxy-metabolites with NADPH as a coenzyme. Dog AKR1C3 also exhibited 20α-HSD activity toward 20-keto-C21-steroids (deoxycorticosterone, its 5α-dihydro- and 5α-tetrahydro-derivatives, and progesterone), but, notably, did not display 3-ketosteroid reductase activity. Additionally, dog AKR1C3 reduced various nonsteroidal carbonyl compounds including endogenous 4-oxo-2-nonenal, all-trans-retinal, and isatin, of which isatin was the most excellent substrate. In the reverse reaction, the enzyme weakly oxidized 17β- and 20α-hydroxysteroids and some alicyclic alcohols. Further site-directed mutagenesis study revealed that residue M55 is responsible for the lack of 3-ketosteroid reductase activity. The enzyme was inhibited by flavonoids, nonsteroidal anti-inflammatory drugs, bile acids, benzbromarone, abiraterone, and trilostane, of which trilostane inhibited most potently (IC50 0.30 µM), and its inhibition was uncompetitive and competitive with respect to the substrates in the forward and reverse reactions, respectively. Thus, dog AKR1C3 may play a role in the metabolism of steroid hormones (as a reductive 17β/20α-HSD) and nonsteroidal carbonyl compounds, and is a novel target of trilostane that is used to treat Cushing’s disease in dogs.
{"title":"Canine aldo-keto reductase 1C3 (AKR1C3/PGFS) exhibits 17β/20α-hydroxysteroid dehydrogenase activity and is inhibited by trilostane","authors":"Satoshi Endo , Riri Hayashi , Yutaro Nakada , Yudai Kudo , Yoshifumi Morikawa , Yuji Sakai , Koichi Suenami , Naohito Abe , Toshiyuki Matsunaga , Akira Hara , Hiroshi Ueda","doi":"10.1016/j.jsbmb.2025.106874","DOIUrl":"10.1016/j.jsbmb.2025.106874","url":null,"abstract":"<div><div>Most members of the aldo-keto reductase (AKR) 1 C subfamily are hydroxysteroid dehydrogenases (HSDs), and their numbers are more than four in many individual mammals. In contrast, there is only one gene for the AKR1C protein (AKR1C3) in dogs, which have been used as a preclinical model for human biomedical research. Here, we report that dog AKR1C3 (known as prostaglandin-F synthase) catalyzes the conversion of the 17-keto group of estrone, 4- and 5-androstenes, and 5α-androstanes to their 17β-hydroxy-metabolites with NADPH as a coenzyme. Dog AKR1C3 also exhibited 20α-HSD activity toward 20-keto-C<sub>21</sub>-steroids (deoxycorticosterone, its 5α-dihydro- and 5α-tetrahydro-derivatives, and progesterone), but, notably, did not display 3-ketosteroid reductase activity. Additionally, dog AKR1C3 reduced various nonsteroidal carbonyl compounds including endogenous 4-oxo-2-nonenal, all-<em>trans</em>-retinal, and isatin, of which isatin was the most excellent substrate. In the reverse reaction, the enzyme weakly oxidized 17β- and 20α-hydroxysteroids and some alicyclic alcohols. Further site-directed mutagenesis study revealed that residue M55 is responsible for the lack of 3-ketosteroid reductase activity. The enzyme was inhibited by flavonoids, nonsteroidal anti-inflammatory drugs, bile acids, benzbromarone, abiraterone, and trilostane, of which trilostane inhibited most potently (IC<sub>50</sub> 0.30 µM), and its inhibition was uncompetitive and competitive with respect to the substrates in the forward and reverse reactions, respectively. Thus, dog AKR1C3 may play a role in the metabolism of steroid hormones (as a reductive 17β/20α-HSD) and nonsteroidal carbonyl compounds, and is a novel target of trilostane that is used to treat Cushing’s disease in dogs.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"255 ","pages":"Article 106874"},"PeriodicalIF":2.5,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145253570","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 : 2025-10-06DOI: 10.1016/j.jsbmb.2025.106875
Xia Ge , Min Ye , Aihua Fei , Qingping Zhang , Aihong Yuan
Diabetes mellitus is a global health crisis with a rising prevalence attributed to complex interactions of genetic, lifestyle, and environmental factors. This comprehensive review delves into the pivotal role of mitochondrial dysfunction in the onset and progression of diabetes. It outlines how defects in mitochondrial oxidative phosphorylation, increased free radical production, and mitochondrial DNA damage contribute to insulin resistance, β-cell apoptosis, and systemic metabolic dysfunctions. The review highlights the critical roles of mitochondria in energy metabolism, oxidative balance, and the interplay of genetic and environmental factors in diabetes. It also emphasizes the association of impaired mitochondrial function with various diabetes-related complications and organ-specific diseases, underscoring the urgent need for innovative therapeutic strategies. Potential interventions discussed include pharmacological agents promoting mitochondrial biogenesis and enhancing mitochondrial dynamics, alongside dietary and lifestyle modifications that support mitochondrial function and overall metabolic health. The review calls for intensified research into mitochondrial mechanisms and their therapeutic targets, advocating for comprehensive clinical trials and support from medical and governmental institutions to advance diabetes management strategies centered on mitochondrial health.
{"title":"Advancements in understanding the role and mechanisms of mitochondria in diabetes: A comprehensive review","authors":"Xia Ge , Min Ye , Aihua Fei , Qingping Zhang , Aihong Yuan","doi":"10.1016/j.jsbmb.2025.106875","DOIUrl":"10.1016/j.jsbmb.2025.106875","url":null,"abstract":"<div><div>Diabetes mellitus is a global health crisis with a rising prevalence attributed to complex interactions of genetic, lifestyle, and environmental factors. This comprehensive review delves into the pivotal role of mitochondrial dysfunction in the onset and progression of diabetes. It outlines how defects in mitochondrial oxidative phosphorylation, increased free radical production, and mitochondrial DNA damage contribute to insulin resistance, β-cell apoptosis, and systemic metabolic dysfunctions. The review highlights the critical roles of mitochondria in energy metabolism, oxidative balance, and the interplay of genetic and environmental factors in diabetes. It also emphasizes the association of impaired mitochondrial function with various diabetes-related complications and organ-specific diseases, underscoring the urgent need for innovative therapeutic strategies. Potential interventions discussed include pharmacological agents promoting mitochondrial biogenesis and enhancing mitochondrial dynamics, alongside dietary and lifestyle modifications that support mitochondrial function and overall metabolic health. The review calls for intensified research into mitochondrial mechanisms and their therapeutic targets, advocating for comprehensive clinical trials and support from medical and governmental institutions to advance diabetes management strategies centered on mitochondrial health.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"255 ","pages":"Article 106875"},"PeriodicalIF":2.5,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145253504","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 : 2025-10-02DOI: 10.1016/j.jsbmb.2025.106872
Jingqi Zhao , Xue Liu , Yong Pang , Haoge Luo , Jie Zhang , Chen Shao
As a natural capsaicinoid from Capsicum annuum L., dihydrocapsaicin is well known for its anti-obesity property by reducing fat accumulation in adipose tissue. The androgen receptor (AR) is essential for both health and disease in humans and is the main focus for prostate cancer treatment. This study seeks to explore how dihydrocapsaicin inhibits the AR in human prostate cancer cell lines, aiming to offer a new natural product-derived AR inhibitor for the clinical management of prostate-related conditions. At first, it was observed that dihydrocapsaicin can induce proliferation suppression in human prostate cancer cells by hindering the cell cycle at the G0/G1 phase. In addition, dihydrocapsaicin probably inhibited AR activity by blocking its movement from the cytoplasm to the nucleus through binding to the AR-LBD, highlighting its potential as an effective inhibitor. From a mechanistic perspective, dihydrocapsaicin facilitated AR release from a stabilizing chaperone complex and enhanced its ubiquitination by E3 ligases, resulting in AR partial degradation via the ubiquitin-proteasome pathway. Our study on the molecular mechanisms behind dihydrocapsaicin's inhibitory effects on the AR revealed that it not only hindered the growth of prostate cancer cells but also reduced tumor growth in vivo. These results offer both experimental evidence and a theoretical basis for the thorough development of AR inhibitors, emphasizing dihydrocapsaicin's potential for application in functional foods or nutritional supplements targeting prostatic disorders.
{"title":"Androgen receptor inhibitory activity of dihydrocapsaicin: Insights from in vitro, in vivo and in silico studies","authors":"Jingqi Zhao , Xue Liu , Yong Pang , Haoge Luo , Jie Zhang , Chen Shao","doi":"10.1016/j.jsbmb.2025.106872","DOIUrl":"10.1016/j.jsbmb.2025.106872","url":null,"abstract":"<div><div>As a natural capsaicinoid from <em>Capsicum annuum</em> L., dihydrocapsaicin is well known for its anti-obesity property by reducing fat accumulation in adipose tissue. The androgen receptor (AR) is essential for both health and disease in humans and is the main focus for prostate cancer treatment. This study seeks to explore how dihydrocapsaicin inhibits the AR in human prostate cancer cell lines, aiming to offer a new natural product-derived AR inhibitor for the clinical management of prostate-related conditions. At first, it was observed that dihydrocapsaicin can induce proliferation suppression in human prostate cancer cells by hindering the cell cycle at the G0/G1 phase. In addition, dihydrocapsaicin probably inhibited AR activity by blocking its movement from the cytoplasm to the nucleus through binding to the AR-LBD, highlighting its potential as an effective inhibitor. From a mechanistic perspective, dihydrocapsaicin facilitated AR release from a stabilizing chaperone complex and enhanced its ubiquitination by E3 ligases, resulting in AR partial degradation via the ubiquitin-proteasome pathway. Our study on the molecular mechanisms behind dihydrocapsaicin's inhibitory effects on the AR revealed that it not only hindered the growth of prostate cancer cells but also reduced tumor growth <em>in vivo</em>. These results offer both experimental evidence and a theoretical basis for the thorough development of AR inhibitors, emphasizing dihydrocapsaicin's potential for application in functional foods or nutritional supplements targeting prostatic disorders.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"255 ","pages":"Article 106872"},"PeriodicalIF":2.5,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145220879","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 : 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":"2025-10-01","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}
The detection of the performance-enhancing drug testosterone (T) remains a significant challenge in doping control analysis. Longitudinal monitoring through the steroidal Athlete Biological Passport (ABP) is a valuable tool for T detection, but further research is needed to enhance its efficacy. Phase II metabolites of endogenous anabolic androgenic steroids (EAAS), including glucuronides and sulfates, have gained increasing interest as potential new biomarkers for the steroidal ABP. Notably, sulfate metabolites have demonstrated higher sensitivity to oral, transdermal, and intramuscular T administration, with extended detection windows compared to traditional biomarkers. However, before incorporating these promising biomarkers into urinary steroid profiling, it is essential to address the metabolic variations associated with different T administration methods, as well as differences related to ethnicity and sex. In this part of the study, we investigate the effects of oral and transdermal T administration on conventional biomarkers and phase II EAAS metabolites in male participants. Sulfate ratios indicated higher sensitivity to multiple administrations of testosterone undecanoate (TU) tablets and T gel, significantly prolonging detection times compared to conventional steroid profile biomarkers. Specifically, sulfate ratios such as androsterone sulfate (AS)/testosterone sulfate (TS) and epiandrosterone sulfate (EpiAS)/TS enabled detection for an average of 20 days following the last oral TU dose and at least 16 days after the last transdermal T application. These findings provide further evidence that incorporating sulfate EAAS metabolites into steroid profiling enhances detection capabilities. For advanced T doping detection, sulfate metabolites should be considered essential biomarkers in the steroid profile.
{"title":"Evaluation of endogenous steroid sulfates and glucuronides in urine after oral and transdermal administration of testosterone. Part I: Male participants","authors":"Sandra Pfeffer , Günter Gmeiner , Nenad Dikic , Marija Andjelkovic , Guro Forsdahl","doi":"10.1016/j.jsbmb.2025.106870","DOIUrl":"10.1016/j.jsbmb.2025.106870","url":null,"abstract":"<div><div>The detection of the performance-enhancing drug testosterone (T) remains a significant challenge in doping control analysis. Longitudinal monitoring through the steroidal Athlete Biological Passport (ABP) is a valuable tool for T detection, but further research is needed to enhance its efficacy. Phase II metabolites of endogenous anabolic androgenic steroids (EAAS), including glucuronides and sulfates, have gained increasing interest as potential new biomarkers for the steroidal ABP. Notably, sulfate metabolites have demonstrated higher sensitivity to oral, transdermal, and intramuscular T administration, with extended detection windows compared to traditional biomarkers. However, before incorporating these promising biomarkers into urinary steroid profiling, it is essential to address the metabolic variations associated with different T administration methods, as well as differences related to ethnicity and sex. In this part of the study, we investigate the effects of oral and transdermal T administration on conventional biomarkers and phase II EAAS metabolites in male participants. Sulfate ratios indicated higher sensitivity to multiple administrations of testosterone undecanoate (TU) tablets and T gel, significantly prolonging detection times compared to conventional steroid profile biomarkers. Specifically, sulfate ratios such as androsterone sulfate (AS)/testosterone sulfate (TS) and epiandrosterone sulfate (EpiAS)/TS enabled detection for an average of 20 days following the last oral TU dose and at least 16 days after the last transdermal T application. These findings provide further evidence that incorporating sulfate EAAS metabolites into steroid profiling enhances detection capabilities. For advanced T doping detection, sulfate metabolites should be considered essential biomarkers in the steroid profile.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"255 ","pages":"Article 106870"},"PeriodicalIF":2.5,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145208224","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号