Pub Date : 2026-01-01Epub Date: 2025-09-18DOI: 10.1016/j.jsbmb.2025.106866
Qiannan Shang , Jiahui Huang , Shi Qin , Haichao Zhu , Riling Chen , Lina Yin , Qingzhong Hu
Human cytochrome P450 enzyme CYP7A1 catalyzes the rate-limiting 7α-hydroxylation of cholesterol in bile acid biosynthesis but is difficult to express functionally in microbial hosts. Here, we report a whole-cell Escherichia coli biocatalytic platform co-expressing truncated CYP7A1 and its redox partner cytochrome P450 reductase (CPR) using bicistronic or dual-promoter vector systems. Protein expression was improved via GroES-GroEL co-expression, and Rosetta(DE3)-pET-tCYP7A1-tCPR was identified as the optimal strain. With the aid of hydroxypropyl-β-cyclodextrin and polymyxin B, 7α-hydroxy-4-cholesten-3-one (7α-HCO) was produced at 118.3 mg·L⁻¹ ·d⁻¹ with > 98 % purity. The product was verified by NMR and high-resolution mass spectrometry. This work presents the first microbial system for 7α-HCO biosynthesis via human CYP7A1, offering a scalable strategy for steroid production and potential applications in drug metabolism and inhibitor screening.
{"title":"Efficient whole-cell biocatalytic production of 7α-hydroxy-4-cholesten-3-one via human CYP7A1 expressed in Escherichia coli","authors":"Qiannan Shang , Jiahui Huang , Shi Qin , Haichao Zhu , Riling Chen , Lina Yin , Qingzhong Hu","doi":"10.1016/j.jsbmb.2025.106866","DOIUrl":"10.1016/j.jsbmb.2025.106866","url":null,"abstract":"<div><div>Human cytochrome P450 enzyme CYP7A1 catalyzes the rate-limiting 7α-hydroxylation of cholesterol in bile acid biosynthesis but is difficult to express functionally in microbial hosts. Here, we report a whole-cell <em>Escherichia coli</em> biocatalytic platform co-expressing truncated CYP7A1 and its redox partner cytochrome P450 reductase (CPR) using bicistronic or dual-promoter vector systems. Protein expression was improved via GroES-GroEL co-expression, and Rosetta(DE3)-pET-tCYP7A1-tCPR was identified as the optimal strain. With the aid of hydroxypropyl-β-cyclodextrin and polymyxin B, 7α-hydroxy-4-cholesten-3-one (7α-HCO) was produced at 118.3 mg·L⁻¹ ·d⁻¹ with > 98 % purity. The product was verified by NMR and high-resolution mass spectrometry. This work presents the first microbial system for 7α-HCO biosynthesis via human CYP7A1, offering a scalable strategy for steroid production and potential applications in drug metabolism and inhibitor screening.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"255 ","pages":"Article 106866"},"PeriodicalIF":2.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145103056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01Epub Date: 2025-09-22DOI: 10.1016/j.jsbmb.2025.106867
Haifeng Chen , Ying Li , Zhenghui Liang , Zhiwei Zhong , Yanmin Huang , Zhiping Liu , Yunqiong Gu , Lihe Jiang , Beijun Gan , Chunfang Gan
A series of estratriene-based hydroxamic acid derivatives were rationally designed as histone deacetylase (HDAC) inhibitors, utilizing estrone and estradiol scaffolds with hydroxamic acid groups attached at the 3-position via alkoxy linkers of varying chain lengths. Structure-activity relationship studies indicated that compounds with n = 4 exhibited optimal activity. The lead compounds CFT-2b and CEC-2b showed potent antiproliferative effects against HeLa and SKOV-3 cells (IC50, 6.09–8.36 μM) and favorable selectivity indices (8.5 to >13.1 versus 293 T cells). Notably, several compounds showed superior HDAC inhibitory activity compared to SAHA. Mechanistic studies showed that CFT-2b and CEC-2b induced dose-dependent apoptosis, caused G1-phase cell-cycle arrest, and significantly increased acetylated histone H3 levels in HeLa cells, consistent with intracellular HDAC inhibition. Molecular docking supported favorable binding within the HDAC2 and HDAC6 active sites via zinc chelation and proper cap-group positioning. These findings establish estratriene-based hydroxamic acids as promising HDAC inhibitor scaffolds for cancer therapy development.
{"title":"Design, synthesis, and biological evaluation of estratriene-based hydroxamic acid derivatives as histone deacetylase inhibitors","authors":"Haifeng Chen , Ying Li , Zhenghui Liang , Zhiwei Zhong , Yanmin Huang , Zhiping Liu , Yunqiong Gu , Lihe Jiang , Beijun Gan , Chunfang Gan","doi":"10.1016/j.jsbmb.2025.106867","DOIUrl":"10.1016/j.jsbmb.2025.106867","url":null,"abstract":"<div><div>A series of estratriene-based hydroxamic acid derivatives were rationally designed as histone deacetylase (HDAC) inhibitors, utilizing estrone and estradiol scaffolds with hydroxamic acid groups attached at the 3-position via alkoxy linkers of varying chain lengths. Structure-activity relationship studies indicated that compounds with n = 4 exhibited optimal activity. The lead compounds <strong>CFT-2b</strong> and <strong>CEC-2b</strong> showed potent antiproliferative effects against HeLa and SKOV-3 cells (IC<sub>50</sub>, 6.09–8.36 μM) and favorable selectivity indices (8.5 to >13.1 versus 293 T cells). Notably, several compounds showed superior HDAC inhibitory activity compared to SAHA. Mechanistic studies showed that <strong>CFT-2b</strong> and <strong>CEC-2b</strong> induced dose-dependent apoptosis, caused G1-phase cell-cycle arrest, and significantly increased acetylated histone H3 levels in HeLa cells, consistent with intracellular HDAC inhibition. Molecular docking supported favorable binding within the HDAC2 and HDAC6 active sites via zinc chelation and proper cap-group positioning. These findings establish estratriene-based hydroxamic acids as promising HDAC inhibitor scaffolds for cancer therapy development.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"255 ","pages":"Article 106867"},"PeriodicalIF":2.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145139228","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01Epub Date: 2025-10-02DOI: 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":"2026-01-01","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 : 2026-01-01Epub 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":"2026-01-01","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}
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":"2026-01-01","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}
Pub Date : 2026-01-01Epub Date: 2025-10-27DOI: 10.1016/j.jsbmb.2025.106881
Jingjing Zhao , Solongo Khadbaatar , Haiying Bao , Hailong Liang , Die Hu , Qi Tu
Polycystic Ovary Syndrome (PCOS) is a prevalent endocrine disorder characterized by metabolic dysfunction. The research is the first to investigate the therapeutic effect of I. hispidus on polycystic ovarian syndrome (PCOS) based on non-targeted metabolomics and network pharmacology in vivo and vitro. The induction of the rat PCOS model was achieved using testosterone propionate (TP) to evaluate the therapeutic effects of I. hispidus. Firstly, in vivo experiments showed that water extracts from I. hispidus (WE) significantly alleviated ovarian damage in PCOS rats and regulated serum hormone levels. Subsequently, untargeted metabolomics research found that WE may alter the serum metabolome of rats by affecting the metabolism of arginine and proline. Network pharmacology screened multiple chemical components and selected one of the key active ingredient, coniferaldehyde (CON), for validation in vitro cell experiments. Furthermore, treatment with WE, CON and the WE medicated serum (WMS) significantly promoted cell proliferation， and diminished both the levels of reactive oxygen species (ROS) and the apoptosis of KGN cells triggered by testosterone. Meanwhile, all drug interventions significantly regulate the expression of multiple target proteins. However, WMS has the most significant effect. These findings systematically reveal that I. hispidus exerts effects in ameliorating PCOS through multiple targets and multiple components, providing new insights into the mechanism of action of I. hispidus in treating PCOS. In summary, this study accentuates the potential of I. hispidus as a therapeutic agent for PCOS, elucidates a multitarget pharmacological mechanism, provides an experimental basis for subsequent preclinical exploration of Inonotus hispidus in PCOS intervention.
{"title":"Unveiling the mechanisms of Inonotus hispidus against polycystic ovary syndrome: An integrated metabolomics and network pharmacology approach in vivo and vitro","authors":"Jingjing Zhao , Solongo Khadbaatar , Haiying Bao , Hailong Liang , Die Hu , Qi Tu","doi":"10.1016/j.jsbmb.2025.106881","DOIUrl":"10.1016/j.jsbmb.2025.106881","url":null,"abstract":"<div><div>Polycystic Ovary Syndrome (PCOS) is a prevalent endocrine disorder characterized by metabolic dysfunction. The research is the first to investigate the therapeutic effect of <em>I. hispidus</em> on polycystic ovarian syndrome (PCOS) based on non-targeted metabolomics and network pharmacology in vivo and vitro. The induction of the rat PCOS model was achieved using testosterone propionate (TP) to evaluate the therapeutic effects of <em>I. hispidus.</em> Firstly, in vivo experiments showed that water extracts from <em>I. hispidus</em> (WE) significantly alleviated ovarian damage in PCOS rats and regulated serum hormone levels. Subsequently, untargeted metabolomics research found that WE may alter the serum metabolome of rats by affecting the metabolism of arginine and proline. Network pharmacology screened multiple chemical components and selected one of the key active ingredient, coniferaldehyde (CON), for validation in vitro cell experiments. Furthermore, treatment with WE, CON and the WE medicated serum (WMS) significantly promoted cell proliferation， and diminished both the levels of reactive oxygen species (ROS) and the apoptosis of KGN cells triggered by testosterone. Meanwhile, all drug interventions significantly regulate the expression of multiple target proteins. However, WMS has the most significant effect. These findings systematically reveal that <em>I. hispidus</em> exerts effects in ameliorating PCOS through multiple targets and multiple components, providing new insights into the mechanism of action of <em>I. hispidus</em> in treating PCOS. In summary, this study accentuates the potential of <em>I. hispidus</em> as a therapeutic agent for PCOS, elucidates a multitarget pharmacological mechanism, provides an experimental basis for subsequent preclinical exploration of <em>Inonotus hispidus</em> in PCOS intervention.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"255 ","pages":"Article 106881"},"PeriodicalIF":2.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145402821","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":"2026-01-01","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 : 2026-01-01Epub Date: 2025-10-31DOI: 10.1016/j.jsbmb.2025.106884
Chang Xu , Nan Zhai , Hongshuang Wang , Fang Fang , Jingwen An , Fengrui Liu , Yan Zhong , Zheng Wang , Xiangting Wang
Salt-water retention plays key roles in chronic kidney disease (CKD) and hypertension. The mineralocorticoid receptor (MR) blocker esaxerenone could attenuate hypertension and renal injury; however, the mechanism is only partially understood. In this study, we used rats that were fed 8 % high-salt diet or/and infused with aldosterone to explore the possible mechanism of salt-water retention in CKD and hypertension, and the protective effect of esaxerenone. The blood pressure and renal injury were observed. Moreover, salt- water retention, CD8+T cells infiltration and MR activation were detected. After treatment with high-salt diet plus aldosterone, the blood pressure level was significantly increased, and renal injury was more obvious than with the high-salt diet or aldosterone alone. The expression levels of the sodium transporter, as well as the mineralocorticoid receptor (NR3C2), were significantly upregulated in the ALD+HS group. Furthermore, the infiltration of CD3+ and CD8+ T cells were increased in the ALD+HS group. Besides, our results proved that esaxerenone could alleviate high-salt diet plus aldosterone-induced salt-water retention and renal injury. In conclusion, aldosterone plus high salt diet enhances renal infiltration of CD8+T cells and upregulates NCC expression and phosphorylation, resulting in hypertension and kidney injury. Esaxerenone antagonizes the activation of mineralocorticoid receptors to decrease the infiltration of CD8+T cells and the phosphorylation level of NCC, thereby alleviating salt-water retention and kidney injury.
{"title":"Esaxerenone attenuates high salt-induced hypertension and renal damage via CD8+T cell- associated NCC activation in aldosterone treated rats","authors":"Chang Xu , Nan Zhai , Hongshuang Wang , Fang Fang , Jingwen An , Fengrui Liu , Yan Zhong , Zheng Wang , Xiangting Wang","doi":"10.1016/j.jsbmb.2025.106884","DOIUrl":"10.1016/j.jsbmb.2025.106884","url":null,"abstract":"<div><div>Salt-water retention plays key roles in chronic kidney disease (CKD) and hypertension. The mineralocorticoid receptor (MR) blocker esaxerenone could attenuate hypertension and renal injury; however, the mechanism is only partially understood. In this study, we used rats that were fed 8 % high-salt diet or/and infused with aldosterone to explore the possible mechanism of salt-water retention in CKD and hypertension, and the protective effect of esaxerenone. The blood pressure and renal injury were observed. Moreover, salt- water retention, CD8<sup>+</sup>T cells infiltration and MR activation were detected. After treatment with high-salt diet plus aldosterone, the blood pressure level was significantly increased, and renal injury was more obvious than with the high-salt diet or aldosterone alone. The expression levels of the sodium transporter, as well as the mineralocorticoid receptor (NR3C2), were significantly upregulated in the ALD+HS group. Furthermore, the infiltration of CD3<sup>+</sup> and CD8<sup>+</sup> T cells were increased in the ALD+HS group. Besides, our results proved that esaxerenone could alleviate high-salt diet plus aldosterone-induced salt-water retention and renal injury. In conclusion, aldosterone plus high salt diet enhances renal infiltration of CD8<sup>+</sup>T cells and upregulates NCC expression and phosphorylation, resulting in hypertension and kidney injury. Esaxerenone antagonizes the activation of mineralocorticoid receptors to decrease the infiltration of CD8<sup>+</sup>T cells and the phosphorylation level of NCC, thereby alleviating salt-water retention and kidney injury.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"255 ","pages":"Article 106884"},"PeriodicalIF":2.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145432981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01Epub Date: 2025-10-28DOI: 10.1016/j.jsbmb.2025.106883
Zang Yufan , Xia Aihua , Han Yulong , Fan Wei , Yang Xue , Liu Changhao , Wang Shengran , Li Jisheng
This study investigated the hypoglycemic efficacy and mechanism of action (with a focus on gut microbiota) of combined sericin-mulberry leaf alkaloid (MLA) therapy in type 2 diabetic mice, comparing it with monotherapy regimens. Male diabetic (DB/DB) and non-diabetic (DB/m) mice were used, with five treatment groups designed: Diabetic Model (diabetic + saline), Ser (diabetic + 2.4 g/kg/day sericin), MLE (diabetic + 200 mg/kg/day MLA), Ser+MLE (diabetic + 1.2 g/kg/day sericin + 100 mg/kg/day MLA), and Control (DB/m + saline). Treatment lasted 35 days. Body weight and fasting blood glucose (FBG) were measured before and after treatment. Venous serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) were detected using an automated biochemical analyzer. Histological evaluation included liver and kidney morphology (HE staining), hepatic glycogen (PAS staining), and hepatic α-smooth muscle actin (α-SMA, immunohistochemical staining). Fecal samples underwent 16S rRNA gut microbiota analysis. Experimental results showed that compared with the control group, diabetic mice exhibited increased body weight (↑20.8 %, P < 0.05), elevated fasting blood glucose (↑434 %, P < 0.05), and significantly increased serum liver enzyme levels (ALT↑387 %, AST↑91.4 %, ALP↑56.9 %, all P < 0.05), accompanied by significant gut dysbiosis in the Diabetic Model group. After treatment, all groups exhibited significant reductions in weight gain, fasting blood glucose, and liver enzyme levels (all P < 0.05); sericin, MLE, and the sericin+MLE combination also modulated functional abundance of gut microbiota. In summary, the combined treatment of sericin and MLA demonstrated superior hypoglycemic and organ-protective effects compared to monotherapy, potentially achieved through restoration of gut microbiota homeostasis and enhanced metabolism.
{"title":"Synergistic effects of sericin and mulberry leaf alkaloid combination therapy on type 2 diabetes via gut microbiota modulation","authors":"Zang Yufan , Xia Aihua , Han Yulong , Fan Wei , Yang Xue , Liu Changhao , Wang Shengran , Li Jisheng","doi":"10.1016/j.jsbmb.2025.106883","DOIUrl":"10.1016/j.jsbmb.2025.106883","url":null,"abstract":"<div><div>This study investigated the hypoglycemic efficacy and mechanism of action (with a focus on gut microbiota) of combined sericin-mulberry leaf alkaloid (MLA) therapy in type 2 diabetic mice, comparing it with monotherapy regimens. Male diabetic (DB/DB) and non-diabetic (DB/m) mice were used, with five treatment groups designed: Diabetic Model (diabetic + saline), Ser (diabetic + 2.4 g/kg/day sericin), MLE (diabetic + 200 mg/kg/day MLA), Ser+MLE (diabetic + 1.2 g/kg/day sericin + 100 mg/kg/day MLA), and Control (DB/m + saline). Treatment lasted 35 days. Body weight and fasting blood glucose (FBG) were measured before and after treatment. Venous serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) were detected using an automated biochemical analyzer. Histological evaluation included liver and kidney morphology (HE staining), hepatic glycogen (PAS staining), and hepatic α-smooth muscle actin (α-SMA, immunohistochemical staining). Fecal samples underwent 16S rRNA gut microbiota analysis. Experimental results showed that compared with the control group, diabetic mice exhibited increased body weight (↑20.8 %, P < 0.05), elevated fasting blood glucose (↑434 %, P < 0.05), and significantly increased serum liver enzyme levels (ALT↑387 %, AST↑91.4 %, ALP↑56.9 %, all P < 0.05), accompanied by significant gut dysbiosis in the Diabetic Model group. After treatment, all groups exhibited significant reductions in weight gain, fasting blood glucose, and liver enzyme levels (all P < 0.05); sericin, MLE, and the sericin+MLE combination also modulated functional abundance of gut microbiota. In summary, the combined treatment of sericin and MLA demonstrated superior hypoglycemic and organ-protective effects compared to monotherapy, potentially achieved through restoration of gut microbiota homeostasis and enhanced metabolism.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"255 ","pages":"Article 106883"},"PeriodicalIF":2.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145410811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01Epub Date: 2025-11-03DOI: 10.1016/j.jsbmb.2025.106887
Harshini Senthilkumar, Mohanapriya Arumugam
Polycystic Ovary Syndrome (PCOS) is a common endocrine condition that affects women of reproductive age. The study used high-throughput sequencing to profile gene expression in PCOS and control samples. The sequenced reads were quality assessed and aligned to the human reference genome hg38 using FastQC and the Hisat2 aligner. The R software "DESeq2" identified 1193 differentially expressed genes (DEGs) in SRP224633 and 82 DEGs in SRP353681. Notably, 8 DEGs were shared by the two datasets, and a total of 1267 DEGs were found. GO analysis revealed that DEGs in SRP224633 were enriched in biological processes related to immune response and cell activation, whereas DEGs in SRP353681 were associated with response to external stimuli and immune processes. Pathway analysis highlighted the involvement of chemokine signaling receptor, and cytokine-cytokine receptor interaction pathways in both datasets. The STRING database was used to evaluate protein-protein interaction (PPI) networks. Hub genes like IL1B, PTPRC, ITGAM, TYROBP, ITGB2, FCGR3A, CCR7, SYK, TLR2, FCGR3B were identified as crucial nodes using Cytohubba plugins in Cytoscape, highlighting their potential role in PCOS pathogenesis. Regulatory networks discovered miRNAs such as has-mir-34a-5p, hsa-miR-26a-5p, has-let-7b-5p and transcription factors such as SP1, RUNX1, ER as possible regulators of target genes implicated in PCOS pathogenesis. LASSO regression and ROC analysis indicated certain hub genes, such as IL1B, PTPRC, ITGB2, FCGR3A, CCR7, FCGR3B as relevant biomarkers due to their high coefficients, emphasizing their significance in PCOS. CCR7, FCGR3A, FCGR3B, and ITGB2 have been discovered as novel genes with significant potential as PCOS biomarkers. Our research adds to a deeper knowledge of PCOS at the molecular level by offering an extensive understanding of the etiological reasons and molecular mechanisms. The discovered DEGs, pathways, and regulatory networks and novel biomarker are promising targets for future studies and treatments in PCOS management.
{"title":"Integrative bioinformatics and transcriptomic analysis identifies biomarkers in Polycystic Ovary Syndrome through machine learning approach","authors":"Harshini Senthilkumar, Mohanapriya Arumugam","doi":"10.1016/j.jsbmb.2025.106887","DOIUrl":"10.1016/j.jsbmb.2025.106887","url":null,"abstract":"<div><div>Polycystic Ovary Syndrome (PCOS) is a common endocrine condition that affects women of reproductive age. The study used high-throughput sequencing to profile gene expression in PCOS and control samples. The sequenced reads were quality assessed and aligned to the human reference genome hg38 using FastQC and the Hisat2 aligner. The R software \"DESeq2\" identified 1193 differentially expressed genes (DEGs) in SRP224633 and 82 DEGs in SRP353681. Notably, 8 DEGs were shared by the two datasets, and a total of 1267 DEGs were found. GO analysis revealed that DEGs in SRP224633 were enriched in biological processes related to immune response and cell activation, whereas DEGs in SRP353681 were associated with response to external stimuli and immune processes. Pathway analysis highlighted the involvement of chemokine signaling receptor, and cytokine-cytokine receptor interaction pathways in both datasets. The STRING database was used to evaluate protein-protein interaction (PPI) networks. Hub genes like IL1B, PTPRC, ITGAM, TYROBP, ITGB2, FCGR3A, CCR7, SYK, TLR2, FCGR3B were identified as crucial nodes using Cytohubba plugins in Cytoscape, highlighting their potential role in PCOS pathogenesis. Regulatory networks discovered miRNAs such as has-mir-34a-5p, hsa-miR-26a-5p, has-let-7b-5p and transcription factors such as SP1, RUNX1, ER as possible regulators of target genes implicated in PCOS pathogenesis. LASSO regression and ROC analysis indicated certain hub genes, such as IL1B, PTPRC, ITGB2, FCGR3A, CCR7, FCGR3B as relevant biomarkers due to their high coefficients, emphasizing their significance in PCOS. CCR7, FCGR3A, FCGR3B, and ITGB2 have been discovered as novel genes with significant potential as PCOS biomarkers. Our research adds to a deeper knowledge of PCOS at the molecular level by offering an extensive understanding of the etiological reasons and molecular mechanisms. The discovered DEGs, pathways, and regulatory networks and novel biomarker are promising targets for future studies and treatments in PCOS management.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"255 ","pages":"Article 106887"},"PeriodicalIF":2.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145454014","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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