Pub Date : 2025-12-29DOI: 10.1016/j.mce.2025.112723
Shereen Ezzat
The field of endocrine oncology is benefiting from broad advances based on key insights in the pathogenesis of neoplasia. While traditionally regarded as unique and distinct entities from non-endocrine neoplasias, deeper molecular profiling studies of endocrine tumors are now challenging this dogma. In this group of papers, experts from across the field provide their perspectives. Each group focuses on a different endocrine gland which they use as a model that highlights the spectrum of disease behavior. It is hoped that collective reflection on these vignettes will reveal new opportunities that can facilitate more effective detection and therapeutic approaches.
{"title":"Integrative advances in endocrine oncology: From unique glimpses to familiar themes","authors":"Shereen Ezzat","doi":"10.1016/j.mce.2025.112723","DOIUrl":"10.1016/j.mce.2025.112723","url":null,"abstract":"<div><div>The field of endocrine oncology is benefiting from broad advances based on key insights in the pathogenesis of neoplasia. While traditionally regarded as unique and distinct entities from non-endocrine neoplasias, deeper molecular profiling studies of endocrine tumors are now challenging this dogma. In this group of papers, experts from across the field provide their perspectives. Each group focuses on a different endocrine gland which they use as a model that highlights the spectrum of disease behavior. It is hoped that collective reflection on these vignettes will reveal new opportunities that can facilitate more effective detection and therapeutic approaches.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"613 ","pages":"Article 112723"},"PeriodicalIF":3.6,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145878657","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-24DOI: 10.1016/j.mce.2025.112722
Sara Gemini-Piperni , Temitope Aribigbola , Marjorie Dardis Murucci , Zakariyya Muhammad Bello , Alana da Cunha Goldstein , Oluwatosin Stella Olayinka , Tran Nhat Phong Dao , Rômulo Sperduto Dezonne , Sunday Amos Onikanni , Leandro Miranda-Alves
Endocrine disorders necessitate diagnostic platforms capable of detecting rapid, low-abundance, fluctuating hormonal signals with high precision. Quantum dot (QD) technology has revolutionized this field by enabling multiplexed, ultrasensitive, and real-time biochemical profiling. Unlike traditional immunoassays limited to single-analyte detection and signal decay, QDs offer exceptional photostability, quantum-level sensitivity, and tunable emission, allowing simultaneous monitoring of various hormonal biomarkers related to thyroid, pancreatic, adrenal, and reproductive dysfunctions. Recent advancements have combined QDs with AI-assisted signal decoding, microfluidics, and wearable biosensor interfaces, creating intelligent systems capable of predicting trends rather than providing static measurements. Functionalized QDs engineered with aptameric, peptidic, or antibody-based recognition domains have shown promising diagnostic capabilities for insulin, estradiol, and thyroid hormones in complex biological samples. As biocompatible QD formulations continue to evolve, their integration with digital health platforms positions them as the next frontier in continuous endocrine monitoring, early disease detection, and personalized hormonal medicine. This review highlights key technological advancements, translational hurdles, and future directions necessary to propel QD-enabled endocrine diagnostics from the laboratory to clinical practice.
{"title":"Toward intelligent hormonal diagnostics: Quantum dots reshaping endocrine disease detection","authors":"Sara Gemini-Piperni , Temitope Aribigbola , Marjorie Dardis Murucci , Zakariyya Muhammad Bello , Alana da Cunha Goldstein , Oluwatosin Stella Olayinka , Tran Nhat Phong Dao , Rômulo Sperduto Dezonne , Sunday Amos Onikanni , Leandro Miranda-Alves","doi":"10.1016/j.mce.2025.112722","DOIUrl":"10.1016/j.mce.2025.112722","url":null,"abstract":"<div><div>Endocrine disorders necessitate diagnostic platforms capable of detecting rapid, low-abundance, fluctuating hormonal signals with high precision. Quantum dot (QD) technology has revolutionized this field by enabling multiplexed, ultrasensitive, and real-time biochemical profiling. Unlike traditional immunoassays limited to single-analyte detection and signal decay, QDs offer exceptional photostability, quantum-level sensitivity, and tunable emission, allowing simultaneous monitoring of various hormonal biomarkers related to thyroid, pancreatic, adrenal, and reproductive dysfunctions. Recent advancements have combined QDs with AI-assisted signal decoding, microfluidics, and wearable biosensor interfaces, creating intelligent systems capable of predicting trends rather than providing static measurements. Functionalized QDs engineered with aptameric, peptidic, or antibody-based recognition domains have shown promising diagnostic capabilities for insulin, estradiol, and thyroid hormones in complex biological samples. As biocompatible QD formulations continue to evolve, their integration with digital health platforms positions them as the next frontier in continuous endocrine monitoring, early disease detection, and personalized hormonal medicine. This review highlights key technological advancements, translational hurdles, and future directions necessary to propel QD-enabled endocrine diagnostics from the laboratory to clinical practice.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"613 ","pages":"Article 112722"},"PeriodicalIF":3.6,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145841087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-19DOI: 10.1016/j.mce.2025.112721
Fan Yang , Duo Liu , Liuting Hu , Hao Tan , Yajing Wei , Ruyu Yang , Biqi Huang , Qiuyu Zou , Qiong Wu , Yushi He , Huaxi Mai , Xi Lan , Ying Yan , Zixuan Huang , Xinyan Huang , Zhuangzhi Fu , Zhiyun Deng , Qinghua Huang , Shuzhong Yao , Yanchun Liang
Endometriosis (EM) affects approximately 10% of women of reproductive age and remains a prevalent estrogen-dependent gynecological disorder with limited therapeutic efficacy and high recurrence rates. Ferroptosis—an iron-dependent, non-apoptotic form of regulated cell death driven by lipid peroxidation—has recently been recognized to play a paradoxical role in EM pathogenesis. To explore ferroptosis-related mechanisms in EM, this study integrated transcriptomic profiling from five Gene Expression Omnibus datasets (GSE6364, GSE7305, GSE11691, GSE23339, GSE51981) with machine learning algorithms and functional validation. Bioinformatic analysis identified 19 ferroptosis-related differentially expressed genes, with hub genes prioritized through protein-protein interaction network analysis. LASSO regression, support vector machine, and random forest models collectively identified EGR1, HMOX1, TIMP1, and FABP4 as robust diagnostic biomarkers, with strong performance in receiver operating characteristic analysis. Clinical validation confirmed significant upregulation of EGR1 and HMOX1 in ectopic endometrial tissues. Functional assays in 12Z endometriotic cells showed that EGR1 silencing partially attenuated erastin-induced ferroptosis by restoring mitochondrial membrane potential, reducing lipid peroxidation, and modulating key ferroptosis markers. Mechanistically, JASPAR analysis predicted EGR1 binding to conserved motifs in the HMOX1 promoter, which was validated using chromatin immunoprecipitation quantitative PCR and dual-luciferase reporter assays. Together, these results identify the EGR1/HMOX1 axis as a novel regulatory hub in EM-associated ferroptosis, offering new insights into diagnostic biomarkers. Therefore, targeting this axis may disrupt iron-redox crosstalk, offering a promising therapeutic avenue to mitigate endometriosis progression.
{"title":"EGR1 promotes ferroptosis in endometriosis through transcriptional activation of HMOX1","authors":"Fan Yang , Duo Liu , Liuting Hu , Hao Tan , Yajing Wei , Ruyu Yang , Biqi Huang , Qiuyu Zou , Qiong Wu , Yushi He , Huaxi Mai , Xi Lan , Ying Yan , Zixuan Huang , Xinyan Huang , Zhuangzhi Fu , Zhiyun Deng , Qinghua Huang , Shuzhong Yao , Yanchun Liang","doi":"10.1016/j.mce.2025.112721","DOIUrl":"10.1016/j.mce.2025.112721","url":null,"abstract":"<div><div>Endometriosis (EM) affects approximately 10% of women of reproductive age and remains a prevalent estrogen-dependent gynecological disorder with limited therapeutic efficacy and high recurrence rates. Ferroptosis—an iron-dependent, non-apoptotic form of regulated cell death driven by lipid peroxidation—has recently been recognized to play a paradoxical role in EM pathogenesis. To explore ferroptosis-related mechanisms in EM, this study integrated transcriptomic profiling from five Gene Expression Omnibus datasets (GSE6364, GSE7305, GSE11691, GSE23339, GSE51981) with machine learning algorithms and functional validation. Bioinformatic analysis identified 19 ferroptosis-related differentially expressed genes, with hub genes prioritized through protein-protein interaction network analysis. LASSO regression, support vector machine, and random forest models collectively identified EGR1, HMOX1, TIMP1, and FABP4 as robust diagnostic biomarkers, with strong performance in receiver operating characteristic analysis. Clinical validation confirmed significant upregulation of EGR1 and HMOX1 in ectopic endometrial tissues. Functional assays in 12Z endometriotic cells showed that EGR1 silencing partially attenuated erastin-induced ferroptosis by restoring mitochondrial membrane potential, reducing lipid peroxidation, and modulating key ferroptosis markers. Mechanistically, JASPAR analysis predicted EGR1 binding to conserved motifs in the HMOX1 promoter, which was validated using chromatin immunoprecipitation quantitative PCR and dual-luciferase reporter assays. Together, these results identify the EGR1/HMOX1 axis as a novel regulatory hub in EM-associated ferroptosis, offering new insights into diagnostic biomarkers. Therefore, targeting this axis may disrupt iron-redox crosstalk, offering a promising therapeutic avenue to mitigate endometriosis progression.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"613 ","pages":"Article 112721"},"PeriodicalIF":3.6,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145805008","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-17DOI: 10.1016/j.mce.2025.112720
Thalles Fernando Rocha Ruiz , Stella Bicalho Silva , Vitor Grigio , Paula Rahal , Marília de Freitas Calmon , Patrícia Simone Leite Vilamaior , Ellen Cristina Rivas Leonel , Sebastião Roberto Taboga
Breast cancer is closely associated with the hormonal sensitization that the mammary gland (MG) undergoes. We evaluated the effects of endogenous (E2) and synthetic (EE2) estrogens, commonly used as hormonal therapies during menopause, in a context of a pro-carcinogenic environment of endocrine disruption. This scenario was modeled to mimic the menopausal involution of the MG during aging in the Mongolian gerbil experimental model under previous bisphenol A exposure, during pregnancy and lactation. Our findings revealed significant remodeling of the epithelial compartment, characterized by increased branching density and loss of normal features, including decreased CD117+ luminal cells and loss of E-cadherin expression. Hormonal therapy with E2 or EE2 led to the development of epithelial lesions, characterized by an increase in invasive microcarcinomas and a decrease in basal (p63+α-SMA-) and myoepithelial (p63+α-SMA+) progenitor cells, contributing to increased neoplastic invasiveness. These changes were orchestrated by overexpression of EZH2 and a decrease in BRCA1, indicating a poor prognosis, especially for EE2. Furthermore, an imbalance between proliferation (PH-H3+ cells) and apoptosis (cleaved caspase 3) was observed in the MG of females treated with E2 and EE2. Additionally, distinct hormone receptor profiles were identified, with consistent upregulation of ERα and concomitant downregulation of ERβ and PR, particularly in EE2-treated MG. These alterations may contribute to the observed dysregulation of proliferation and apoptosis. Our results demonstrate that estrogenic hormonal therapies promote neoplastic progression of the aging MG previously subjected to endocrine disruption.
{"title":"Estrogen therapies enhance mammary carcinogenesis in aging gerbil females under endocrine disruption","authors":"Thalles Fernando Rocha Ruiz , Stella Bicalho Silva , Vitor Grigio , Paula Rahal , Marília de Freitas Calmon , Patrícia Simone Leite Vilamaior , Ellen Cristina Rivas Leonel , Sebastião Roberto Taboga","doi":"10.1016/j.mce.2025.112720","DOIUrl":"10.1016/j.mce.2025.112720","url":null,"abstract":"<div><div>Breast cancer is closely associated with the hormonal sensitization that the mammary gland (MG) undergoes. We evaluated the effects of endogenous (E2) and synthetic (EE2) estrogens, commonly used as hormonal therapies during menopause, in a context of a pro-carcinogenic environment of endocrine disruption. This scenario was modeled to mimic the menopausal involution of the MG during aging in the Mongolian gerbil experimental model under previous bisphenol A exposure, during pregnancy and lactation. Our findings revealed significant remodeling of the epithelial compartment, characterized by increased branching density and loss of normal features, including decreased CD117+ luminal cells and loss of E-cadherin expression. Hormonal therapy with E2 or EE2 led to the development of epithelial lesions, characterized by an increase in invasive microcarcinomas and a decrease in basal (p63+α-SMA-) and myoepithelial (p63+α-SMA+) progenitor cells, contributing to increased neoplastic invasiveness. These changes were orchestrated by overexpression of EZH2 and a decrease in BRCA1, indicating a poor prognosis, especially for EE2. Furthermore, an imbalance between proliferation (PH-H3<sup>+</sup> cells) and apoptosis (cleaved caspase 3) was observed in the MG of females treated with E2 and EE2. Additionally, distinct hormone receptor profiles were identified, with consistent upregulation of ERα and concomitant downregulation of ERβ and PR, particularly in EE2-treated MG. These alterations may contribute to the observed dysregulation of proliferation and apoptosis. Our results demonstrate that estrogenic hormonal therapies promote neoplastic progression of the aging MG previously subjected to endocrine disruption.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"613 ","pages":"Article 112720"},"PeriodicalIF":3.6,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145788626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-15DOI: 10.1016/j.mce.2025.112715
Ana Lívia Silvério Vieira, Gustavo Monezzi Cordeiro, Vinicius Alexandre de Andrade Felipe, Matheus Naia Fioretto, Luísa Annibal Barata, Marina Pereira Pires, Pedro Menchini Vitali, Renato Mattos, Isabelle Tenori Ribeiro, Flávia Alessandra Maciel, Hecttor Sebastian Baptista, Luis Antonio Justulin
The Developmental Origins of Health and Disease (DOHaD) concept highlights that early-life development can be influenced by environmental factors, leading to long-term metabolic programming in the offspring. Maternal Protein Restriction (MPR) is a well-established model within this framework, inducing cellular stress and hormonal imbalances that disrupt basal metabolic regulation in descendants. We aim to investigate the consequences of MPR (6 %) on the metabolism and the pituitary-thyroid-adrenal axis of male and female postweaning rats. Systemically, there was a decrease in hormones T3 and T4 in the males and a decrease in T4 in the females. In the pituitary, we observed an increase in the Ppar a, Ppar g, and Neurod1 gene expression and a decrease in the Prl gene in the males of the GLLP group, while females exhibited a decrease in the Pomc and Ir gene expression. In the thyroid, male rats showed an increase in the Tshr and Ar gene expression. In gene expression of adrenal glands, we observed an increase in the expression of the Sts gene in males and a decrease in Cyp21a2 and Mao in females. In silico analyses demonstrated the potential sex-specific disturbance of MPR, mainly on developmental biology, endocrine response, endoplasmic reticulum, and endocytic pathways, indicating a risk scenario for endocrine diseases. Therefore, we conclude that MPR directly affects the early functioning of the pituitary–thyroid–adrenal axis in a sex-specific manner, highlighting its role in metabolic programming and the developmental origins of endocrine disorders.
{"title":"Endocrine programming of the pituitary–thyroid–adrenal axis: Sex-Specific effects of maternal malnutrition in rats","authors":"Ana Lívia Silvério Vieira, Gustavo Monezzi Cordeiro, Vinicius Alexandre de Andrade Felipe, Matheus Naia Fioretto, Luísa Annibal Barata, Marina Pereira Pires, Pedro Menchini Vitali, Renato Mattos, Isabelle Tenori Ribeiro, Flávia Alessandra Maciel, Hecttor Sebastian Baptista, Luis Antonio Justulin","doi":"10.1016/j.mce.2025.112715","DOIUrl":"10.1016/j.mce.2025.112715","url":null,"abstract":"<div><div>The Developmental Origins of Health and Disease (DOHaD) concept highlights that early-life development can be influenced by environmental factors, leading to long-term metabolic programming in the offspring. Maternal Protein Restriction (MPR) is a well-established model within this framework, inducing cellular stress and hormonal imbalances that disrupt basal metabolic regulation in descendants. We aim to investigate the consequences of MPR (6 %) on the metabolism and the pituitary-thyroid-adrenal axis of male and female postweaning rats. Systemically, there was a decrease in hormones T3 and T4 in the males and a decrease in T4 in the females. In the pituitary, we observed an increase in the <em>Ppar a</em>, <em>Ppar g</em>, and <em>Neurod1</em> gene expression and a decrease in the <em>Prl</em> gene in the males of the GLLP group, while females exhibited a decrease in the <em>Pomc</em> and <em>Ir</em> gene expression. In the thyroid, male rats showed an increase in the <em>Tshr</em> and <em>Ar</em> gene expression. In gene expression of adrenal glands, we observed an increase in the expression of the <em>Sts</em> gene in males and a decrease in <em>Cyp21a2</em> and <em>Mao</em> in females. In silico analyses demonstrated the potential sex-specific disturbance of MPR, mainly on developmental biology, endocrine response, endoplasmic reticulum, and endocytic pathways, indicating a risk scenario for endocrine diseases. Therefore, we conclude that MPR directly affects the early functioning of the pituitary–thyroid–adrenal axis in a sex-specific manner, highlighting its role in metabolic programming and the developmental origins of endocrine disorders.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"613 ","pages":"Article 112715"},"PeriodicalIF":3.6,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145774969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-13DOI: 10.1016/j.mce.2025.112718
Rutger Laterveer , Susanne Hetty , Argyri Mathioudaki , Martin H. Lundqvist , Maria K. Svensson , Magnus Sundbom , Petros Katsogiannos , Jan W. Eriksson , Maria J. Pereira
FK506-binding protein 51 (FKBP51, encoded by the FKBP5 gene) is a key regulator of glucocorticoid signaling and has been implicated in metabolism and insulin sensitivity, but its specific role in human adipose tissue remains unclear. This study investigated the role of FKBP51 in human adipose tissue and its impact on glucose metabolism and insulin signaling. FKBP5 was measured in paired subcutaneous (SAT) and omental (OAT) adipose tissue samples from 56 subjects with and without obesity, and in SAT from individuals with obesity during weight loss up to 104 weeks post-bariatric surgery. Furthermore, FKBP51 knockdown adipocytes were used to study its effects on insulin signaling and glucose uptake. FKBP5 gene expression, but not protein expression, was significantly lower in obese individuals in both SAT and OAT compared to lean and overweight subjects, and it inversely correlated with insulin resistance measured by homeostatic model assessment of insulin resistance (HOMA-IR). After bariatric surgery, FKBP5 expression in SAT increased to levels similar to those in non-obese controls. Knockdown of FKBP5 in human adipocytes reduced GLUT1 gene expression and insulin-stimulated AKT Ser473 phosphorylation, however, maximal insulin-stimulated glucose uptake rate remained unchanged. Our findings suggest that FKBP5 levels in adipose tissue are reduced in obesity, and this decrease impairs insulin signaling in adipocytes without altering maximal glucose capacity, indicating a limited effect on glucose uptake under the tested conditions.
{"title":"Role of FKBP5 in adipose tissue function: Implications for obesity and insulin sensitivity","authors":"Rutger Laterveer , Susanne Hetty , Argyri Mathioudaki , Martin H. Lundqvist , Maria K. Svensson , Magnus Sundbom , Petros Katsogiannos , Jan W. Eriksson , Maria J. Pereira","doi":"10.1016/j.mce.2025.112718","DOIUrl":"10.1016/j.mce.2025.112718","url":null,"abstract":"<div><div>FK506-binding protein 51 (FKBP51, encoded by the <em>FKBP5</em> gene) is a key regulator of glucocorticoid signaling and has been implicated in metabolism and insulin sensitivity, but its specific role in human adipose tissue remains unclear. This study investigated the role of FKBP51 in human adipose tissue and its impact on glucose metabolism and insulin signaling. <em>FKBP5</em> was measured in paired subcutaneous (SAT) and omental (OAT) adipose tissue samples from 56 subjects with and without obesity, and in SAT from individuals with obesity during weight loss up to 104 weeks post-bariatric surgery. Furthermore, FKBP51 knockdown adipocytes were used to study its effects on insulin signaling and glucose uptake. <em>FKBP5</em> gene expression, but not protein expression, was significantly lower in obese individuals in both SAT and OAT compared to lean and overweight subjects, and it inversely correlated with insulin resistance measured by homeostatic model assessment of insulin resistance (HOMA-IR). After bariatric surgery, <em>FKBP5</em> expression in SAT increased to levels similar to those in non-obese controls. Knockdown of <em>FKBP5</em> in human adipocytes reduced <em>GLUT1</em> gene expression and insulin-stimulated AKT Ser473 phosphorylation, however, maximal insulin-stimulated glucose uptake rate remained unchanged. Our findings suggest that <em>FKBP5</em> levels in adipose tissue are reduced in obesity, and this decrease impairs insulin signaling in adipocytes without altering maximal glucose capacity, indicating a limited effect on glucose uptake under the tested conditions.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"613 ","pages":"Article 112718"},"PeriodicalIF":3.6,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145763113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-12DOI: 10.1016/j.mce.2025.112719
Amanda Cecilia Swart , Bianca Heyns , Martin Kidd , Rialet Pieters , Stephen Lawrence Atkin
The steroid metabolome remains incomplete as the metabolic pathways of the 11-oxyprogestogens and 11-oxyandrogens, biosynthesized in the adrenal and converted in the periphery, have never been characterized in vivo.
This study aims to identify these 11-oxy steroids in the human hair follicle. Hair segments provide a matrix representing one month of steroid production, unaffected by the circadian rhythm. Steroids were extracted from 37 segments using a novel automated method, and 52 steroids were analyzed using ultra-performance convergence chromatography-tandem mass spectrometry.
Quantification of intermediates and end-products of 11-hydroxyprogesterone, 21-deoxycortisol, 11-hydroxyandrostenedione and 11-hydroxytestosterone identified nine novel 11-oxy steroids and showed: 11-hydroxyprogesterone metabolites >21-deoxycortisol metabolites: 170–1400 v. 190–540 pg/mg; 11-oxyandrogens > classical androgens: 600–1500 v. 110–350 pg/mg; active 11-oxyandrogens > active classical androgens: in females, 36.5 v. 1.3 pg/mg, and in males, 60.75 v. 11.7 pg/mg. The most abundant active androgen in both genders was 11-hydroxydihydrotestosterone; 11-ketodihydrotestosterone was detected in males only; 11-hydroxytestosterone levels were comparable, and 11-ketotestosterone levels were higher in males. The most abundant 11-oxyprogestogens in both genders were 11-ketoprogesterone (55.7–2173.8 pg/mg) and two metabolites, 11-oxo-17-hydroxyallopregnanolone (11KPdione) and 11,17-dihydroxyallopregnanolone (11OHPdiol). Metabolites included the neurosteroid, alfaxalone (11-ketoallopregnanolone), and another potential neurosteroid 11-hydroxyallopregnanolone.
This is the first targeted study profiling the 11-oxyandrogens and the 11-oxyprogestogens and their respective metabolites in humans. Novel in vivo steroidogenic pathways have been confirmed, not necessarily linked to clinical conditions, having utility in clinical diagnostics reliant on the steroid metabolome.
类固醇代谢组仍然不完整，因为11-羟孕激素和11-羟雄激素的代谢途径，在肾上腺中生物合成并在外周转化，从未在体内被表征。本研究旨在鉴定人类毛囊中这些11-氧基类固醇。毛发片段提供了一个矩阵，代表一个月的类固醇生产，不受昼夜节律的影响。使用新型自动化方法从37个片段中提取类固醇，并使用超高性能收敛色谱-串联质谱法分析52种类固醇。11-羟孕酮、21-去氧皮质醇、11-羟基雄烯二酮和11-羟睾酮的中间体和终产物定量鉴定了9种新的11-羟类固醇，并显示：11-羟孕酮代谢物> 21-去氧皮质醇代谢物：170-1400 vs . 190-540 pg/mg；11-氧雄激素>经典雄激素：600-1500 v 110-350 pg/mg；活性11-氧雄激素>活性经典雄激素：女性为36.5 v. 1.3 pg/mg，男性为60.75 v. 11.7 pg/mg。两性中活性雄激素含量最高的是11-羟基二氢睾酮；11-酮二氢睾酮仅在男性中检测到；11-羟睾酮水平比较，男性11-酮睾酮水平较高。11-羟孕酮在两性中含量最高的是11-酮孕酮（557 -2173.8 pg/mg）和两种代谢物11-氧-17-羟基异孕酮（11KPdione）和11,17-二羟基异孕酮（11OHPdiol）。代谢物包括神经类固醇，alfaxone（11-酮异孕酮）和另一种潜在的神经类固醇11-羟基异孕酮。这是第一次有针对性地研究11-氧雄激素和11-氧孕激素及其在人体内的代谢产物。新的体内类固醇生成途径已被证实，不一定与临床条件相关，在依赖类固醇代谢组的临床诊断中具有实用性。
{"title":"The in vivo metabolism of 11-oxyandrogens and 11-oxyprogesterones: novel pathways in the steroid metabolome","authors":"Amanda Cecilia Swart , Bianca Heyns , Martin Kidd , Rialet Pieters , Stephen Lawrence Atkin","doi":"10.1016/j.mce.2025.112719","DOIUrl":"10.1016/j.mce.2025.112719","url":null,"abstract":"<div><div>The steroid metabolome remains incomplete as the metabolic pathways of the 11-oxyprogestogens and 11-oxyandrogens, biosynthesized in the adrenal and converted in the periphery, have never been characterized <em>in vivo</em>.</div><div>This study aims to identify these 11-oxy steroids in the human hair follicle. Hair segments provide a matrix representing one month of steroid production, unaffected by the circadian rhythm. Steroids were extracted from 37 segments using a novel automated method, and 52 steroids were analyzed using ultra-performance convergence chromatography-tandem mass spectrometry.</div><div>Quantification of intermediates and end-products of 11-hydroxyprogesterone, 21-deoxycortisol, 11-hydroxyandrostenedione and 11-hydroxytestosterone identified nine novel 11-oxy steroids and showed: 11-hydroxyprogesterone metabolites >21-deoxycortisol metabolites: 170–1400 v. 190–540 pg/mg; 11-oxyandrogens > classical androgens: 600–1500 v. 110–350 pg/mg; active 11-oxyandrogens > active classical androgens: in females, 36.5 v. 1.3 pg/mg, and in males, 60.75 v. 11.7 pg/mg. The most abundant active androgen in both genders was 11-hydroxydihydrotestosterone; 11-ketodihydrotestosterone was detected in males only; 11-hydroxytestosterone levels were comparable, and 11-ketotestosterone levels were higher in males. The most abundant 11-oxyprogestogens in both genders were 11-ketoprogesterone (55.7–2173.8 pg/mg) and two metabolites, 11-oxo-17-hydroxyallopregnanolone (11KPdione) and 11,17-dihydroxyallopregnanolone (11OHPdiol). Metabolites included the neurosteroid, alfaxalone (11-ketoallopregnanolone), and another potential neurosteroid 11-hydroxyallopregnanolone.</div><div>This is the first targeted study profiling the 11-oxyandrogens and the 11-oxyprogestogens and their respective metabolites in humans. Novel <em>in vivo</em> steroidogenic pathways have been confirmed, not necessarily linked to clinical conditions, having utility in clinical diagnostics reliant on the steroid metabolome.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"613 ","pages":"Article 112719"},"PeriodicalIF":3.6,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145756948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Postpartum metabolic stress increases non-esterified fatty acid (NEFA) concentration in follicular fluid, thereby impairing oocyte and granulosa cell (GC) function. CD36, a multifunctional scavenger receptor, is involved in the uptake of NEFAs in various cell types. This study examines lipid droplet (LD) accumulation and CD36 expression in GCs treated with oleate (OA), palmitate (PA), stearate (SA), and their combination. We also explored the role of CD36 in lipid uptake, glucose metabolism, and steroidogenesis in GCs. Flow cytometry analysis revealed that SA, OA, and the combined NEFA treatments resulted in significant LD accumulation, while PA had a minimal effect. Interestingly, CD36 expression mirrored the levels of LD accumulation in all treatments. However, SLC27A1, another highly expressed NEFA transporter, was upregulated by SA but was unchanged by PA and OA treatments. Combination of OA, PA, and SA has increased both CD36 and SLC27A1 expression. OA treatment induced a dose-dependent increase in LD accumulation and CD36 expression. However, CD36 knockdown did not affect either LD accumulation or triglyceride levels, indicating that CD36 is not essential for NEFA uptake, despite its increased expression. Previously, we showed that OA enhances glycolysis in GCs; here, we found that CD36 is involved in glucose metabolism as its silencing significantly reduced the extracellular acidification rate and mitochondrial membrane potential in GCs. Furthermore, CD36 knockdown significantly reduced progesterone production. These findings suggest that while CD36 is dispensable for NEFA uptake, it may play a regulatory role in maintaining glycolytic activity, mitochondrial function, and steroidogenesis in GCs under elevated NEFA levels.
{"title":"CD36 may regulate glycolytic and steroidogenic processes but not the fatty acid uptake in bovine granulosa cells","authors":"Xuelian Tao, Marten Michaelis, Julia Brenmoehl, Jens Vanselow, Vijay Simha Baddela","doi":"10.1016/j.mce.2025.112717","DOIUrl":"10.1016/j.mce.2025.112717","url":null,"abstract":"<div><div>Postpartum metabolic stress increases non-esterified fatty acid (NEFA) concentration in follicular fluid, thereby impairing oocyte and granulosa cell (GC) function. CD36, a multifunctional scavenger receptor, is involved in the uptake of NEFAs in various cell types. This study examines lipid droplet (LD) accumulation and <em>CD36</em> expression in GCs treated with oleate (OA), palmitate (PA), stearate (SA), and their combination. We also explored the role of <em>CD36</em> in lipid uptake, glucose metabolism, and steroidogenesis in GCs. Flow cytometry analysis revealed that SA, OA, and the combined NEFA treatments resulted in significant LD accumulation, while PA had a minimal effect. Interestingly, <em>CD36</em> expression mirrored the levels of LD accumulation in all treatments. However, <em>SLC27A1</em>, another highly expressed NEFA transporter, was upregulated by SA but was unchanged by PA and OA treatments. Combination of OA, PA, and SA has increased both <em>CD36</em> and <em>SLC27A1</em> expression. OA treatment induced a dose-dependent increase in LD accumulation and <em>CD36</em> expression. However, <em>CD36</em> knockdown did not affect either LD accumulation or triglyceride levels, indicating that <em>CD36</em> is not essential for NEFA uptake, despite its increased expression. Previously, we showed that OA enhances glycolysis in GCs; here, we found that <em>CD36</em> is involved in glucose metabolism as its silencing significantly reduced the extracellular acidification rate and mitochondrial membrane potential in GCs. Furthermore, <em>CD36</em> knockdown significantly reduced progesterone production. These findings suggest that while <em>CD36</em> is dispensable for NEFA uptake, it may play a regulatory role in maintaining glycolytic activity, mitochondrial function, and steroidogenesis in GCs under elevated NEFA levels.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"613 ","pages":"Article 112717"},"PeriodicalIF":3.6,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145752012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-11DOI: 10.1016/j.mce.2025.112716
João Carlos de Oliveira Borges , Ilana Souza Correa , Gabriela Mandú Gimenes , Liliane de Araújo Ferreira , Maria Andréa Rodrigues de Moura Silva , Janaina Ribeiro Barbosa Pauferro , Tiago Bertola Lobato , Amara Cassandra dos Anjos Alves , Ana Carolina Gomes Pereira , Karolayne Oliveira Souza , Camila Soares dos Santos , Adriana Cristina Levada- Pires , Tania Cristina Pithon-Curi , Gabriel Nasri Marzuca-Nassr , Sandro Massao Hirabara , Rui Curi , Renata Gorjão , Laureane Nunes Masi
Chronic hyperglycemia induces changes in the bone marrow (BM) microenvironment, favoring the expansion and differentiation of stem cells toward a pro-inflammatory profile. Since leukocyte recruitment plays a key role in chronic inflammation during the onset of type 2 diabetes mellitus (T2DM), the aim of this study was to evaluate the influence of bone marrow transplantation (BMT) on glycemic control and inflammatory markers in Goto-Kakizaki (GK) rats transplanted after weaning. GK rats are spontaneously non-obese, T2DM animals. We performed BMT from normoglycemic Wistar (WT) rats to GK animals (aged 28 days), previously immunosuppressed with busulfan (20 mg/kg) and cyclophosphamide (150 mg/kg). The mRNA expression of pro-inflammatory cytokines IL-1β and IL-7 was increased in the BM of weaned GK rats, and it was reduced in the BM mononuclear cells (BMMCs) 100 days after BMT. Hepatic cytokine levels were also evaluated by flow cytometry to calculate the Inflammatory Marker Index (based on IFN-γ, TNF-α, IL-6, and IL-10), which was decreased in transplanted GK rats. Moreover, transplanted GK rats also showed reduced fasting glucose evaluated at 30, 60, and 90 days after transplantation. BMT also induced a significant decrease in plasma insulin and attenuated insulin resistance (HOMA-IR). Overall, BMT in just-weaned GK rats, characterized by an elevated inflammatory profile in the BM and liver, culminated in improvement of glycemic control compared with non-transplanted GK animals. In conclusion, modulation of the BM microenvironment emerges as a novel therapeutic avenue for managing non-obese T2DM and preventing its complications.
{"title":"Bone marrow transplantation attenuates inflammation and improves glycemic control in type 2 non-obese diabetic Goto-Kakizaki rats","authors":"João Carlos de Oliveira Borges , Ilana Souza Correa , Gabriela Mandú Gimenes , Liliane de Araújo Ferreira , Maria Andréa Rodrigues de Moura Silva , Janaina Ribeiro Barbosa Pauferro , Tiago Bertola Lobato , Amara Cassandra dos Anjos Alves , Ana Carolina Gomes Pereira , Karolayne Oliveira Souza , Camila Soares dos Santos , Adriana Cristina Levada- Pires , Tania Cristina Pithon-Curi , Gabriel Nasri Marzuca-Nassr , Sandro Massao Hirabara , Rui Curi , Renata Gorjão , Laureane Nunes Masi","doi":"10.1016/j.mce.2025.112716","DOIUrl":"10.1016/j.mce.2025.112716","url":null,"abstract":"<div><div>Chronic hyperglycemia induces changes in the bone marrow (BM) microenvironment, favoring the expansion and differentiation of stem cells toward a pro-inflammatory profile. Since leukocyte recruitment plays a key role in chronic inflammation during the onset of type 2 diabetes mellitus (T2DM), the aim of this study was to evaluate the influence of bone marrow transplantation (BMT) on glycemic control and inflammatory markers in Goto-Kakizaki (GK) rats transplanted after weaning. GK rats are spontaneously non-obese, T2DM animals. We performed BMT from normoglycemic Wistar (WT) rats to GK animals (aged 28 days), previously immunosuppressed with busulfan (20 mg/kg) and cyclophosphamide (150 mg/kg). The mRNA expression of pro-inflammatory cytokines IL-1β and IL-7 was increased in the BM of weaned GK rats, and it was reduced in the BM mononuclear cells (BMMCs) 100 days after BMT. Hepatic cytokine levels were also evaluated by flow cytometry to calculate the Inflammatory Marker Index (based on IFN-γ, TNF-α, IL-6, and IL-10), which was decreased in transplanted GK rats. Moreover, transplanted GK rats also showed reduced fasting glucose evaluated at 30, 60, and 90 days after transplantation. BMT also induced a significant decrease in plasma insulin and attenuated insulin resistance (HOMA-IR). Overall, BMT in just-weaned GK rats, characterized by an elevated inflammatory profile in the BM and liver, culminated in improvement of glycemic control compared with non-transplanted GK animals. In conclusion, modulation of the BM microenvironment emerges as a novel therapeutic avenue for managing non-obese T2DM and preventing its complications.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"613 ","pages":"Article 112716"},"PeriodicalIF":3.6,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145718887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-10DOI: 10.1016/j.mce.2025.112707
C. Urrutia-Lopez , L. González-Carranza , A. Barajas-Salinas , E. Bonilla , J.J. Rodriguez-Mercado , A. Aviles , E. Langley , J.P. Reyes-Grajeda , F. Casillas , A. Lopez , E. Casas , M. Betancourt , M.C. González-Torres , I. Bahena-Ocampo
Polycystic Ovary Syndrome (PCOS), is the most common female endocrine disorder affecting women of reproductive age. Its prevalence is estimated to be up to 13 % worldwide. This heterogeneous clinical condition is characterized by marked clinical and/or biochemical hyperandrogenism, ovulatory dysfunction, and frequent development of polycystic ovaries. Several studies have focused on the relationship between endocrine-disrupting pollutants and PCOS development. Perfluorooctanesulfonate (PFOS) is ubiquitously detected in the environment. Exposure to endocrine-disrupting chemicals, including PFOS, during early fetal development may lead to alterations similar to the PCOS phenotype. Using mice as a model, we compared the effects of prenatal exposure to PFOS or dihydrotestosterone (a model of PCOS induction). After analyzing steroid status, we detected delayed pubertal onset accompanied by increased testosterone concentrations in adulthood, as well as altered estrous cycles with a longer metestrus phase. At this point, two of three Rotterdam criteria have been confirmed as PCOS features. Finally, we identified endocrine disruption in the ovaries from adult females prenatally exposed to PFOS, as evidenced by altered expression of genes involved in steroidogenesis pathways, as well as altered expression of gonadotropin hormone receptors, and Amh signaling. These data support a role of PFOS in endocrine disruption and in promoting development of PCOS symptom development.
{"title":"Prenatal perfluorooctanoic sulfonate exposure is associated with polycystic ovary syndrome-like and related traits in female offspring mice","authors":"C. Urrutia-Lopez , L. González-Carranza , A. Barajas-Salinas , E. Bonilla , J.J. Rodriguez-Mercado , A. Aviles , E. Langley , J.P. Reyes-Grajeda , F. Casillas , A. Lopez , E. Casas , M. Betancourt , M.C. González-Torres , I. Bahena-Ocampo","doi":"10.1016/j.mce.2025.112707","DOIUrl":"10.1016/j.mce.2025.112707","url":null,"abstract":"<div><div>Polycystic Ovary Syndrome (PCOS), is the most common female endocrine disorder affecting women of reproductive age. Its prevalence is estimated to be up to 13 % worldwide. This heterogeneous clinical condition is characterized by marked clinical and/or biochemical hyperandrogenism, ovulatory dysfunction, and frequent development of polycystic ovaries. Several studies have focused on the relationship between endocrine-disrupting pollutants and PCOS development. Perfluorooctanesulfonate (PFOS) is ubiquitously detected in the environment. Exposure to endocrine-disrupting chemicals, including PFOS, during early fetal development may lead to alterations similar to the PCOS phenotype. Using mice as a model, we compared the effects of prenatal exposure to PFOS or dihydrotestosterone (a model of PCOS induction). After analyzing steroid status, we detected delayed pubertal onset accompanied by increased testosterone concentrations in adulthood, as well as altered estrous cycles with a longer metestrus phase. At this point, two of three Rotterdam criteria have been confirmed as PCOS features. Finally, we identified endocrine disruption in the ovaries from adult females prenatally exposed to PFOS, as evidenced by altered expression of genes involved in steroidogenesis pathways, as well as altered expression of gonadotropin hormone receptors, and Amh signaling. These data support a role of PFOS in endocrine disruption and in promoting development of PCOS symptom development.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"613 ","pages":"Article 112707"},"PeriodicalIF":3.6,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145743426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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