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}
Pub Date : 2025-11-24DOI: 10.1016/j.mce.2025.112706
Nadia Saadat , Rehma Saeed , Brooke Pallas , Arpita K. Vyas , Richard J. Auchus , Vasantha Padmanabhan
Gestational hyperandrogenism may disrupt the steroid and lipid metabolism homeostatic balance that is important for pregnancy progression. We hypothesized that excess gestational testosterone would disrupt the maternal steroid profile and the steroid-lipid relationship. Using sheep, we investigated maternal delta-4 (Δ4) and delta-5 (Δ5) steroids and the steroid-lipidome relationship in gestational testosterone excess (n = 12, 100 mg T-propionate days 30–90 of gestation twice-weekly intramuscularly) and control (n = 5, vehicle) Suffolk sheep. Steroids were measured using liquid chromatography-tandem mass spectrometry and lipids by shotgun lipidomics. Principal component analysis showed clear separation of control and the gestational testosterone excess groups. The main impact of testosterone excess was on the Δ5 pathway, with reductions in 17-OH pregnenolone, androstenediol, allopregnanolone, and androsterone. In the Δ4 pathway only a trend for reduced androstenedione and a large magnitude increase in corticosterone and decrease in 11-deoxycorticosterone was observed. Dimensionality reduction partial least squares regression models revealed disruptive impact of testosterone-excess on the steroid-lipid relationship prevailing in controls namely with lipid biosynthesis and metabolism and enrichment in cholesterol biosynthetic, circadian clock and transcriptional regulatory, and liver steatosis pathways. Disrupted steroid-lipid associations in the gestational testosterone excess group showed linkage to complex disease-profiles centering on lipid metabolism and transport, cholesterol, and of relevance to hyperlipidemia, gestational diabetes, and hypertension in the enrichment analysis. Fewer lipid species were associated with individual steroids in gestational testosterone excess group, indicative of loss of the majority of the homeostatic steroid-lipid associations. This study provides a novel screening insight into the steroid-lipid relationship that prevails during normal pregnancy and the disruptive impact of hyperandrogenism in perturbing this homeostasis.
妊娠期高雄激素症可能会破坏类固醇和脂质代谢的稳态平衡，这对妊娠进展很重要。我们假设，过量的妊娠期睾酮会破坏母体类固醇谱和类固醇脂质关系。以羊为研究对象，研究了母羊δ -4（Δ4）和δ -5（Δ5）类固醇以及妊娠睾酮过量（n=12，妊娠30-90天每周两次肌注100mg t -丙酸）和对照（n=5，载体）萨福克羊的类固醇-脂质组关系。类固醇采用液相色谱-串联质谱法测定，脂质采用散弹枪脂质组学测定。主成分分析显示对照组与妊娠期睾酮过量组明显分离。睾酮过量主要影响Δ5通路，17-OH孕烯醇酮、雄烯二醇、异孕烯醇酮和雄酮减少。在Δ4通路中，只观察到雄烯二酮的减少和皮质酮的大量增加和11-脱氧皮质酮的减少。降维偏最小二乘回归模型揭示了睾酮过量对对照组中普遍存在的类固醇-脂质关系的破坏性影响，即脂质生物合成、代谢和胆固醇生物合成、生物钟和转录调节以及肝脏脂肪变性途径中的富集。在浓缩分析中，妊娠期睾酮过量组的类固醇-脂质关联中断显示出与以脂质代谢和转运、胆固醇为中心的复杂疾病谱相关，并与高脂血症、妊娠期糖尿病和高血压相关。在妊娠期睾酮过量组中，与单个类固醇相关的脂质种类较少，表明大多数体内平衡类固醇-脂质关联丢失。这项研究为正常妊娠期间普遍存在的类固醇-脂质关系以及高雄激素症扰乱这种体内平衡的破坏性影响提供了一种新的筛选见解。
{"title":"Developmental programming: gestational exposure to excess testosterone disrupts maternal steroid homeostasis and perturbs the steroid-lipid relationship in sheep","authors":"Nadia Saadat , Rehma Saeed , Brooke Pallas , Arpita K. Vyas , Richard J. Auchus , Vasantha Padmanabhan","doi":"10.1016/j.mce.2025.112706","DOIUrl":"10.1016/j.mce.2025.112706","url":null,"abstract":"<div><div>Gestational hyperandrogenism may disrupt the steroid and lipid metabolism homeostatic balance that is important for pregnancy progression. We hypothesized that excess gestational testosterone would disrupt the maternal steroid profile and the steroid-lipid relationship. Using sheep, we investigated maternal delta-4 (Δ4) and delta-5 (Δ5) steroids and the steroid-lipidome relationship in gestational testosterone excess (n = 12, 100 mg T-propionate days 30–90 of gestation twice-weekly intramuscularly) and control (n = 5, vehicle) Suffolk sheep. Steroids were measured using liquid chromatography-tandem mass spectrometry and lipids by shotgun lipidomics. Principal component analysis showed clear separation of control and the gestational testosterone excess groups. The main impact of testosterone excess was on the Δ5 pathway, with reductions in 17-OH pregnenolone, androstenediol, allopregnanolone, and androsterone. In the Δ4 pathway only a trend for reduced androstenedione and a large magnitude increase in corticosterone and decrease in 11-deoxycorticosterone was observed. Dimensionality reduction partial least squares regression models revealed disruptive impact of testosterone-excess on the steroid-lipid relationship prevailing in controls namely with lipid biosynthesis and metabolism and enrichment in cholesterol biosynthetic, circadian clock and transcriptional regulatory, and liver steatosis pathways. Disrupted steroid-lipid associations in the gestational testosterone excess group showed linkage to complex disease-profiles centering on lipid metabolism and transport, cholesterol, and of relevance to hyperlipidemia, gestational diabetes, and hypertension in the enrichment analysis. Fewer lipid species were associated with individual steroids in gestational testosterone excess group, indicative of loss of the majority of the homeostatic steroid-lipid associations. This study provides a novel screening insight into the steroid-lipid relationship that prevails during normal pregnancy and the disruptive impact of hyperandrogenism in perturbing this homeostasis.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"613 ","pages":"Article 112706"},"PeriodicalIF":3.6,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145636099","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 : 2025-11-22DOI: 10.1016/j.mce.2025.112705
I-Chen Li , Yu-En Chan , Yu-Li Lin , Tzong-Yuan Wu , Liang-Yi Wu , Ching-Yi Tsai , Hsin-Tang Lin , Chin-Chu Chen
In the face of the global obesity epidemic (globesity), we present the first comprehensive investigation of fermented Sanghuangporus sanghuang mycelia extract (SS-IM1) and its novel bioactive compound hypholomine B in brown adipose tissue activation. Using HEK293 cells with FNDC5 promoter-EGFP constructs and differentiated 3T3-L1 adipocytes, we demonstrate that both compounds significantly enhance FNDC5 expression and irisin secretion. We reveal distinct mechanistic profiles: SS-IM1 showed superior efficacy in irisin induction and thermogenesis activation, while isolated hypholomine B demonstrated unprecedented potency in reducing lipid accumulation. Seahorse analysis revealed enhanced mitochondrial respiration and UCP1-mediated proton leak, confirming their thermogenic effects. Furthermore, we discovered that SS-IM1 uniquely enhanced glucose uptake through GLUT4 upregulation. These findings not only elucidate novel molecular mechanisms underlying the anti-obesity effects of S. sanghuang but also establish hypholomine B as a promising first-in-class therapeutic candidate for addressing the worldwide challenges of obesity and metabolic disorders.
{"title":"In vitro activation of brown adipocyte thermogenesis by fermented hypholomine B-enriched Sanghuangporus sanghuang mycelia through FNDC5/Irisin pathway","authors":"I-Chen Li , Yu-En Chan , Yu-Li Lin , Tzong-Yuan Wu , Liang-Yi Wu , Ching-Yi Tsai , Hsin-Tang Lin , Chin-Chu Chen","doi":"10.1016/j.mce.2025.112705","DOIUrl":"10.1016/j.mce.2025.112705","url":null,"abstract":"<div><div>In the face of the global obesity epidemic (globesity), we present the first comprehensive investigation of fermented <em>Sanghuangporus sanghuang</em> mycelia extract (SS-IM1) and its novel bioactive compound hypholomine B in brown adipose tissue activation. Using HEK293 cells with FNDC5 promoter-EGFP constructs and differentiated 3T3-L1 adipocytes, we demonstrate that both compounds significantly enhance FNDC5 expression and irisin secretion. We reveal distinct mechanistic profiles: SS-IM1 showed superior efficacy in irisin induction and thermogenesis activation, while isolated hypholomine B demonstrated unprecedented potency in reducing lipid accumulation. Seahorse analysis revealed enhanced mitochondrial respiration and UCP1-mediated proton leak, confirming their thermogenic effects. Furthermore, we discovered that SS-IM1 uniquely enhanced glucose uptake through GLUT4 upregulation. These findings not only elucidate novel molecular mechanisms underlying the anti-obesity effects of <em>S. sanghuang</em> but also establish hypholomine B as a promising first-in-class therapeutic candidate for addressing the worldwide challenges of obesity and metabolic disorders.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"612 ","pages":"Article 112705"},"PeriodicalIF":3.6,"publicationDate":"2025-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145596771","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 : 2025-11-20DOI: 10.1016/j.mce.2025.112704
Wayne A. Ayers-Creech , Jennifer L. Steiner , Grant R. Laskin , Bradley S. Gordon
Background
Androgens such as testosterone regulate whole-body metabolic homeostasis. Low androgen levels lead to undesirable shifts in metabolism including lower glucose oxidation, greater lipid reliance, and altered amino acid metabolism. Skeletal muscle is a primary site regulating fuel substrate metabolism, but whether all muscles contribute to the undesirable metabolic shifts in response to low androgen levels is unclear.
Methods and results
Male mice underwent sham or castration surgery and muscles were harvested 7, 14-, 21-, 28-, or 49-days post-surgery. The content of genes related to glucose, lipid, and amino acid metabolism were assessed in the tibialis anterior (TA) and gastrocnemius muscles. The content of genes related to glucose metabolism were altered in a manner consistent with lower rates of oxidation in both the TA and gastrocnemius following castration although the magnitudes of change were generally more pronounced in the TA. Genes related to lipid oxidation were altered in a manner consistent with higher oxidation rates only in the TA following castration. Genes related to amino acid catabolism were paradoxically unaltered or even lower in both muscles in response to castration.
Conclusion
These findings indicate that the TA undergoes more pronounced transcriptional changes related to glucose and lipid metabolism compared to the gastrocnemius, likely contributing more to whole-body metabolic shifts during androgen deprivation.
{"title":"Androgen deprivation induces distinct muscle-specific transcriptional changes to genes regulating glucose, lipid, and amino acid metabolism","authors":"Wayne A. Ayers-Creech , Jennifer L. Steiner , Grant R. Laskin , Bradley S. Gordon","doi":"10.1016/j.mce.2025.112704","DOIUrl":"10.1016/j.mce.2025.112704","url":null,"abstract":"<div><h3>Background</h3><div>Androgens such as testosterone regulate whole-body metabolic homeostasis. Low androgen levels lead to undesirable shifts in metabolism including lower glucose oxidation, greater lipid reliance, and altered amino acid metabolism. Skeletal muscle is a primary site regulating fuel substrate metabolism, but whether all muscles contribute to the undesirable metabolic shifts in response to low androgen levels is unclear.</div></div><div><h3>Methods and results</h3><div>Male mice underwent sham or castration surgery and muscles were harvested 7, 14-, 21-, 28-, or 49-days post-surgery. The content of genes related to glucose, lipid, and amino acid metabolism were assessed in the tibialis anterior (TA) and gastrocnemius muscles. The content of genes related to glucose metabolism were altered in a manner consistent with lower rates of oxidation in both the TA and gastrocnemius following castration although the magnitudes of change were generally more pronounced in the TA. Genes related to lipid oxidation were altered in a manner consistent with higher oxidation rates only in the TA following castration. Genes related to amino acid catabolism were paradoxically unaltered or even lower in both muscles in response to castration.</div></div><div><h3>Conclusion</h3><div>These findings indicate that the TA undergoes more pronounced transcriptional changes related to glucose and lipid metabolism compared to the gastrocnemius, likely contributing more to whole-body metabolic shifts during androgen deprivation.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"612 ","pages":"Article 112704"},"PeriodicalIF":3.6,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145577833","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 : 2025-11-15DOI: 10.1016/j.mce.2025.112703
Chinelo Uju, Suraj Unniappan
Brain-derived neurotrophic factor (BDNF) was previously reported as a positive modulator of zebrafish reproduction, yet the mechanism of action of BDNF that elicits this function is unknown. We hypothesized that the pro-reproductive effects of BDNF in female zebrafish are mediated by TrkB signaling. In zebrafish liver (ZFL) cells, a TrkB antagonist (ANA-12) blocked the stimulatory effect of BDNF on transcript abundance of vitellogenin (vtg1, 2, 4, and 7) and steroidogenic factor 1 (sf-1). No changes were observed in hepatocyte nuclear factor 4 alpha, specificity protein 1, cAMP response element-binding protein 1a, or forkhead box L2. Blocking the mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K), and phospholipase C gamma (PLC-γ) pathways significantly attenuated BDNF-induced upregulation of vtg and sf-1 transcripts. Total vtg protein was increased by BDNF, an effect that was blunted when TrkB, MAPK, PI3K, or PLC-γ were blocked. The estrogen receptor alpha (Esrα) fluorescence immunoreactivity in the ZFL cells treated with BDNF was significantly reduced in the presence of ANA-12. In the zebrafish follicles, BDNF-induced oocyte maturation was attenuated by TrkB, MAPK-, and PI3K inhibitors, but not a PLC-γ blocker. Similarly, the positive effects of BDNF on maturation-related genes 3β-hydroxysteroid dehydrogenase 2 enzyme (3bhsd2), cytochrome P450 family 17, hyaluronan synthase 2, luteinizing hormone receptor, and prostaglandin synthase 2 were significantly attenuated when TrkB, MAPK, or PI3K was blocked. PLC-γ inhibition prevented the BDNF-induced upregulation of 3bhsd1 in the oocytes. This study demonstrates that BDNF promotes vitellogenesis via the TrkB-MAPK/PI3K/PLC-γ signaling pathways. Meanwhile, BNDF enhances oocyte maturation through the TrkB-MAPK/PI3K pathways in zebrafish.
{"title":"Brain derived neurotrophic factor promotes oocyte maturation through the TrkB-MAPK-PI3K pathway in zebrafish","authors":"Chinelo Uju, Suraj Unniappan","doi":"10.1016/j.mce.2025.112703","DOIUrl":"10.1016/j.mce.2025.112703","url":null,"abstract":"<div><div>Brain-derived neurotrophic factor (BDNF) was previously reported as a positive modulator of zebrafish reproduction, yet the mechanism of action of BDNF that elicits this function is unknown. We hypothesized that the pro-reproductive effects of BDNF in female zebrafish are mediated by TrkB signaling. In zebrafish liver (ZFL) cells, a TrkB antagonist (ANA-12) blocked the stimulatory effect of BDNF on transcript abundance of vitellogenin <em>(vtg1</em>, <em>2</em>, <em>4</em>, and <em>7)</em> and <em>steroidogenic factor 1</em> (<em>sf-1</em>). No changes were observed in hepatocyte nuclear factor 4 alpha, specificity protein 1, cAMP response element-binding protein 1a, or forkhead box L2. Blocking the mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K), and phospholipase C gamma (PLC-γ) pathways significantly attenuated BDNF-induced upregulation of <em>vtg</em> and <em>sf-1</em> transcripts. Total vtg protein was increased by BDNF, an effect that was blunted when TrkB, MAPK, PI3K, or PLC-γ were blocked. The estrogen receptor alpha (Esrα) fluorescence immunoreactivity in the ZFL cells treated with BDNF was significantly reduced in the presence of ANA-12. In the zebrafish follicles, BDNF-induced oocyte maturation was attenuated by TrkB, MAPK-, and PI3K inhibitors, but not a PLC-γ blocker. Similarly, the positive effects of BDNF on maturation-related genes 3β-hydroxysteroid dehydrogenase 2 enzyme (<em>3bhsd2</em>), cytochrome P450 family 17, hyaluronan synthase 2, luteinizing hormone receptor, and prostaglandin synthase 2 were significantly attenuated when TrkB, MAPK, or PI3K was blocked. PLC-γ inhibition prevented the BDNF-induced upregulation of <em>3bhsd1</em> in the oocytes. This study demonstrates that BDNF promotes vitellogenesis via the TrkB-MAPK/PI3K/PLC-γ signaling pathways. Meanwhile, BNDF enhances oocyte maturation through the TrkB-MAPK/PI3K pathways in zebrafish.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"612 ","pages":"Article 112703"},"PeriodicalIF":3.6,"publicationDate":"2025-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145541334","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}
Visfatin/Nampt, an adipokine upregulated in obesity, has been implicated in oocyte maturation, but its role in early embryogenesis remains poorly understood. This study investigated visfatin/Nampt function during preimplantation development in normal-weight and high-fat diet–induced obese mice.
Nampt mRNA expression was examined in embryos from the 1-cell to the blastocyst stage, and siRNA-mediated Nampt silencing was performed at the 1-cell stage. Embryo development was assessed by cleavage and blastocyst formation rates, while molecular effects were evaluated via qPCR analysis of maternal-effect and proliferation/apoptosis, differentiation genes, immunofluorescence detection of pluripotency/differentiation markers, and transcriptome profiling (RNA-seq). The functional reproductive outcomes, including implantation rates, offspring number, and ovarian gene expression (qPCR) in the progeny, were also analyzed.
Nampt expression decreases during early embryogenesis. Nampt silencing impaired blastocyst formation in obese mice and altered lineage marker expression, increasing NANOG in normal-weight embryos and reducing GATA6-positive cells in obese embryos. Transcriptomic analysis of normal-weight blastocysts revealed 73 upregulated and 24 downregulated genes enriched in pathways regulating apoptosis, energy metabolism, and development. Although the implantation rates and offspring numbers were unchanged, offspring from Nampt-silenced embryos presented altered ovarian gene expression linked to steroidogenesis and oogenesis.
This work provides the first transcriptomic analysis of blastocysts following siRNA-mediated Nampt silencing and demonstrates that visfatin/Nampt modulates early lineage allocation in a manner dependent on maternal metabolic status. These findings extend visfatin research beyond oocyte maturation and highlight its potential contribution to embryonic programming.
{"title":"Role of visfatin on early embryogenesis in normal weight and obese mice. Studies on siRNA induced knockdown model","authors":"Patrycja Kurowska , Shinnosuke Honda , Genta Tanaka , Gao Yuwei , Naojiro Minami , Agnieszka Rak , Shuntaro Ikeda","doi":"10.1016/j.mce.2025.112702","DOIUrl":"10.1016/j.mce.2025.112702","url":null,"abstract":"<div><div>Visfatin/Nampt, an adipokine upregulated in obesity, has been implicated in oocyte maturation, but its role in early embryogenesis remains poorly understood. This study investigated visfatin/Nampt function during preimplantation development in normal-weight and high-fat diet–induced obese mice.</div><div><em>Nampt</em> mRNA expression was examined in embryos from the 1-cell to the blastocyst stage, and siRNA-mediated <em>Nampt</em> silencing was performed at the 1-cell stage. Embryo development was assessed by cleavage and blastocyst formation rates, while molecular effects were evaluated via qPCR analysis of maternal-effect and proliferation/apoptosis, differentiation genes, immunofluorescence detection of pluripotency/differentiation markers, and transcriptome profiling (RNA-seq). The functional reproductive outcomes, including implantation rates, offspring number, and ovarian gene expression (qPCR) in the progeny, were also analyzed.</div><div><em>Nampt</em> expression decreases during early embryogenesis. <em>Nampt</em> silencing impaired blastocyst formation in obese mice and altered lineage marker expression, increasing NANOG in normal-weight embryos and reducing GATA6-positive cells in obese embryos. Transcriptomic analysis of normal-weight blastocysts revealed 73 upregulated and 24 downregulated genes enriched in pathways regulating apoptosis, energy metabolism, and development. Although the implantation rates and offspring numbers were unchanged, offspring from <em>Nampt</em>-silenced embryos presented altered ovarian gene expression linked to steroidogenesis and oogenesis.</div><div>This work provides the first transcriptomic analysis of blastocysts following siRNA-mediated <em>Nampt</em> silencing and demonstrates that visfatin/Nampt modulates early lineage allocation in a manner dependent on maternal metabolic status. These findings extend visfatin research beyond oocyte maturation and highlight its potential contribution to embryonic programming.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"612 ","pages":"Article 112702"},"PeriodicalIF":3.6,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145530784","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 : 2025-10-31DOI: 10.1016/j.mce.2025.112692
Larissa Pereira Paixão , José Xavier do Nascimento Junior , Maria Eduarda Sant'Ana Faria Do Espírito Santo , Ricardo Imbroisi Filho , João Gabriel Bernardo Leandro , Davi Mundim , Jessica Ristow Branco , Luis Eduardo Santos , Sérgio T. Ferreira , Luciana Pizzatti , Mauro Sola-Penna , Patricia Zancan
Serotonin (5-HT), a key regulator of epithelial homeostasis, plays a paradoxical role in breast cancer progression. This study investigates the impact of 5-HT signaling on hormone receptor expression, cell proliferation, therapeutic response, and tumor aggressiveness in breast cancer cells. We demonstrate that 5-HT activates transcriptional factors in MCF-7 cells, collectively enhancing cancer hallmarks such as sustained proliferation and invasiveness. Notably, 5-HT downregulates mRNA expression of estrogen receptor (ER), progesterone receptor (PR), and HER2, inducing a phenotype reminiscent of triple-negative breast cancer. Despite these phenotypic changes, acute 5-HT treatment does not impair the effectiveness of tamoxifen in vitro. In vivo, administration of fluoxetine, a selective serotonin reuptake inhibitor, accelerates tumor growth and increases malignancy in a murine model. These findings underscore the ability of 5-HT to reprogram hormone receptors expression profiles and to promote a more aggressive cancer phenotype.
{"title":"Serotonin promotes aggressive features in breast cancer cells by modulating proliferation and migration, hormone receptors and HER2 expression","authors":"Larissa Pereira Paixão , José Xavier do Nascimento Junior , Maria Eduarda Sant'Ana Faria Do Espírito Santo , Ricardo Imbroisi Filho , João Gabriel Bernardo Leandro , Davi Mundim , Jessica Ristow Branco , Luis Eduardo Santos , Sérgio T. Ferreira , Luciana Pizzatti , Mauro Sola-Penna , Patricia Zancan","doi":"10.1016/j.mce.2025.112692","DOIUrl":"10.1016/j.mce.2025.112692","url":null,"abstract":"<div><div>Serotonin (5-HT), a key regulator of epithelial homeostasis, plays a paradoxical role in breast cancer progression. This study investigates the impact of 5-HT signaling on hormone receptor expression, cell proliferation, therapeutic response, and tumor aggressiveness in breast cancer cells. We demonstrate that 5-HT activates transcriptional factors in MCF-7 cells, collectively enhancing cancer hallmarks such as sustained proliferation and invasiveness. Notably, 5-HT downregulates mRNA expression of estrogen receptor (ER), progesterone receptor (PR), and HER2, inducing a phenotype reminiscent of triple-negative breast cancer. Despite these phenotypic changes, acute 5-HT treatment does not impair the effectiveness of tamoxifen <em>in vitro</em>. <em>In vivo</em>, administration of fluoxetine, a selective serotonin reuptake inhibitor, accelerates tumor growth and increases malignancy in a murine model. These findings underscore the ability of 5-HT to reprogram hormone receptors expression profiles and to promote a more aggressive cancer phenotype.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"612 ","pages":"Article 112692"},"PeriodicalIF":3.6,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145431855","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 : 2025-10-29DOI: 10.1016/j.mce.2025.112691
Alexsandra Zimmer , Vitória Rosa de Oliveira , Tânia Regina G. Fernandes , Ramison Santos , Patrick Turck , Victor de Mello Palma , Fernanda Visioli , Elissa Fernandes , Silvio Tasca , Cristina Campos Carraro , Adriane Belló-Klein , Alex Sander da Rosa Araujo , Alexandre Luz de Castro
Background
Adrenergic overload is a central feature of cardiovascular diseases, contributing to right ventricular (RV) injury. Although widely studied, limited data are available on melatonin's impact on the RV and extracardiac tissues.
Objective
To investigate the effects of melatonin on RV remodeling, inflammation, and oxidative stress in the lung and gastrocnemius muscle of rats subjected to isoproterenol (ISO)-induced adrenergic stress.
Methods
Male Wistar rats were divided into Control, ISO, and ISO + melatonin groups. ISO (5 mg/kg, s.c.) was administered for 7 days, and ISO + M received ISO plus melatonin (10 mg/kg/day, gavage). Control animals received saline (s.c) and the non-treated groups received only saline by gavage. Cardiac function and hypertrophy was assessed by echocardiography and morphometric analyses, respectively. RV inflammation and fibrosis were examined histologically, while protein expression in the RV (TLR4, NF-κB, Bax) and lungs (eNOS, ETAR) was analyzed by western blotting. Oxidative stress markers (ROS, TBARS, sulfhydryl groups, nitrite) were measured in lung and gastrocnemius.
Results
ISO reduced cardiac output and heart rate, effects preserved by melatonin. RV hypertrophy induced by ISO was not prevented, but inflammatory infiltrate, fibrosis, and upregulation of TLR4, NF-κB, and Bax were attenuated by melatonin. In the lungs, no significant alterations were observed, except for increased nitrite levels in ISO + M. Gastrocnemius oxidative stress was unchanged. Conclusions: Melatonin attenuates RV inflammation and apoptosis under adrenergic overload without preventing hypertrophy or markedly affecting lungs and skeletal muscle, supporting its potential as adjunctive therapy in cardiac diseases.
{"title":"Melatonin administration protects the right ventricle from adrenergic stress via anti-inflammatory and anti-apoptotic mechanisms","authors":"Alexsandra Zimmer , Vitória Rosa de Oliveira , Tânia Regina G. Fernandes , Ramison Santos , Patrick Turck , Victor de Mello Palma , Fernanda Visioli , Elissa Fernandes , Silvio Tasca , Cristina Campos Carraro , Adriane Belló-Klein , Alex Sander da Rosa Araujo , Alexandre Luz de Castro","doi":"10.1016/j.mce.2025.112691","DOIUrl":"10.1016/j.mce.2025.112691","url":null,"abstract":"<div><h3>Background</h3><div>Adrenergic overload is a central feature of cardiovascular diseases, contributing to right ventricular (RV) injury. Although widely studied, limited data are available on melatonin's impact on the RV and extracardiac tissues.</div></div><div><h3>Objective</h3><div>To investigate the effects of melatonin on RV remodeling, inflammation, and oxidative stress in the lung and gastrocnemius muscle of rats subjected to isoproterenol (ISO)-induced adrenergic stress.</div></div><div><h3>Methods</h3><div>Male Wistar rats were divided into Control, ISO, and ISO + melatonin groups. ISO (5 mg/kg, s.c.) was administered for 7 days, and ISO + M received ISO plus melatonin (10 mg/kg/day, gavage). Control animals received saline (s.c) and the non-treated groups received only saline by gavage. Cardiac function and hypertrophy was assessed by echocardiography and morphometric analyses, respectively. RV inflammation and fibrosis were examined histologically, while protein expression in the RV (TLR4, NF-κB, Bax) and lungs (eNOS, ETAR) was analyzed by western blotting. Oxidative stress markers (ROS, TBARS, sulfhydryl groups, nitrite) were measured in lung and gastrocnemius.</div></div><div><h3>Results</h3><div>ISO reduced cardiac output and heart rate, effects preserved by melatonin. RV hypertrophy induced by ISO was not prevented, but inflammatory infiltrate, fibrosis, and upregulation of TLR4, NF-κB, and Bax were attenuated by melatonin. In the lungs, no significant alterations were observed, except for increased nitrite levels in ISO + M. Gastrocnemius oxidative stress was unchanged. <strong>Conclusions</strong>: Melatonin attenuates RV inflammation and apoptosis under adrenergic overload without preventing hypertrophy or markedly affecting lungs and skeletal muscle, supporting its potential as adjunctive therapy in cardiac diseases.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"611 ","pages":"Article 112691"},"PeriodicalIF":3.6,"publicationDate":"2025-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145418263","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 : 2025-10-28DOI: 10.1016/j.mce.2025.112690
Diego Alvarez de la Rosa , Zuleima Ramos-Hernández , Julián Weller-Pérez , Thomas A. Johnson , Gordon L. Hager
{"title":"Corrigendum to “The impact of mineralocorticoid and glucocorticoid receptor interaction on corticosteroid transcriptional outcomes” [Molecul. Cell. Endocrinol. 594 (2024) 112389]","authors":"Diego Alvarez de la Rosa , Zuleima Ramos-Hernández , Julián Weller-Pérez , Thomas A. Johnson , Gordon L. Hager","doi":"10.1016/j.mce.2025.112690","DOIUrl":"10.1016/j.mce.2025.112690","url":null,"abstract":"","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"611 ","pages":"Article 112690"},"PeriodicalIF":3.6,"publicationDate":"2025-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145391459","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 : 2025-10-17DOI: 10.1016/j.mce.2025.112688
Leonardo Guedes de Andrade , Valério Marques Portela , Karine de Vargas Aires , Natalia Jakuc , Ana Paula da Silva , Alfredo Quites Antoniazzi , Paulo Bayard Dias Gonçalves , Gustavo Zamberlam
During the ovarian follicle growth of monovulatory species, the dominant follicle is characterized by a greater capacity for estradiol (E2) production mainly due to an increased granulosa cell (GC) CYP19A1 transcription level. The connective tissue growth factor (CTGF) has emerged as a potential novel and important player in the modulation of CYP19A1 expression in this cell type. To gain insight into how CTGF is regulated in GC and to better understand its role during GC differentiation into a more estrogenic phenotype, we have performed in the present study a series of experiments employing bovine GC cultures. We demonstrate herein that CTGF mRNA levels are downregulated by insulin-like growth factor 1 (IGF1) and E2, two critical regulators of follicle dominance establishment in vivo. In turn, CTGF suppresses CYP19A1 mRNA levels in bovine GC both in the presence or absence of FSH or IGF1, through a mechanism that seems to involve altering the phosphorylation pattern of AKT and the modulation of NR5A2, a critical transcription factor of CYP19A1. Overall, our study indicates that CTGF downregulation in GC may represent a critical step for enabling the increased CYP19A1 transcriptional activity of the dominant follicle in cattle.
{"title":"The importance of CTGF regulation by FSH, IGF1, and estradiol in bovine granulosa cells","authors":"Leonardo Guedes de Andrade , Valério Marques Portela , Karine de Vargas Aires , Natalia Jakuc , Ana Paula da Silva , Alfredo Quites Antoniazzi , Paulo Bayard Dias Gonçalves , Gustavo Zamberlam","doi":"10.1016/j.mce.2025.112688","DOIUrl":"10.1016/j.mce.2025.112688","url":null,"abstract":"<div><div>During the ovarian follicle growth of monovulatory species, the dominant follicle is characterized by a greater capacity for estradiol (E2) production mainly due to an increased granulosa cell (GC) <em>CYP19A1</em> transcription level. The connective tissue growth factor (CTGF) has emerged as a potential novel and important player in the modulation of <em>CYP19A1</em> expression in this cell type. To gain insight into how CTGF is regulated in GC and to better understand its role during GC differentiation into a more estrogenic phenotype, we have performed in the present study a series of experiments employing bovine GC cultures. We demonstrate herein that <em>CTGF</em> mRNA levels are downregulated by insulin-like growth factor 1 (IGF1) and E2, two critical regulators of follicle dominance establishment <em>in vivo</em>. In turn, CTGF suppresses <em>CYP19A1</em> mRNA levels in bovine GC both in the presence or absence of FSH or IGF1, through a mechanism that seems to involve altering the phosphorylation pattern of AKT and the modulation of <em>NR5A2</em>, a critical transcription factor of <em>CYP19A1.</em> Overall, our study indicates that <em>CTGF</em> downregulation in GC may represent a critical step for enabling the increased <em>CYP19A1</em> transcriptional activity of the dominant follicle in cattle.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"611 ","pages":"Article 112688"},"PeriodicalIF":3.6,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145318517","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}
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