Pub Date : 2025-05-19DOI: 10.1016/j.mce.2025.112581
Dan-Dan Jin , Yu-Ying He , Feng Ran , Hong-Yuan Yang , Gui-Jun Yan , Zeng-Ming Yang
Decidualization of endometrial stromal cells is important for pregnancy in rodents and humans. Dysfunction of decidualization can lead to implantation failure and recurrent miscarriage. Although the amount of PGF2α in uterine fluid increases during embryo implantation, what stimulates the production of PGF2α in the uterus and whether PGF2α is involved in embryo implantation and decidualization are still unknown. In our study, human chorionic gonadotropin (hCG), an embryo-derived protein, stimulates human endometrial epithelial cells to increase the levels of PGF2α synthesis-related enzymes (cPLA2, COX-1, COX-2, and AKR1C3) and to secrete PGF2α. Epithelial PGF2α induces EREG and HB-EGF secretion by activating ADAM17. The level of IGFBP1, a marker of human in vitro decidualization, is significantly increased by EREG or HB-EGF. PGF2α is also able to increase the IGFBP1 level in humans during in vitro decidualization. Our results indicate that hCG stimulates uterine epithelial PGF2α production to induce in vitro decidualization through EREG and HB-EGF.
{"title":"Embryo-derived human chorionic gonadotropin promotes human decidualization through activating epithelial prostaglandin F2α secretion","authors":"Dan-Dan Jin , Yu-Ying He , Feng Ran , Hong-Yuan Yang , Gui-Jun Yan , Zeng-Ming Yang","doi":"10.1016/j.mce.2025.112581","DOIUrl":"10.1016/j.mce.2025.112581","url":null,"abstract":"<div><div>Decidualization of endometrial stromal cells is important for pregnancy in rodents and humans. Dysfunction of decidualization can lead to implantation failure and recurrent miscarriage. Although the amount of PGF2α in uterine fluid increases during embryo implantation, what stimulates the production of PGF2α in the uterus and whether PGF2α is involved in embryo implantation and decidualization are still unknown. In our study, human chorionic gonadotropin (hCG), an embryo-derived protein, stimulates human endometrial epithelial cells to increase the levels of PGF2α synthesis-related enzymes (cPLA2, COX-1, COX-2, and AKR1C3) and to secrete PGF2α. Epithelial PGF2α induces EREG and HB-EGF secretion by activating ADAM17. The level of IGFBP1, a marker of human in vitro decidualization, is significantly increased by EREG or HB-EGF. PGF2α is also able to increase the IGFBP1 level in humans during in vitro decidualization. Our results indicate that hCG stimulates uterine epithelial PGF2α production to induce in vitro decidualization through EREG and HB-EGF.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"606 ","pages":"Article 112581"},"PeriodicalIF":3.8,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144120270","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 : 2025-05-15DOI: 10.1016/j.mce.2025.112573
Pratyusa Das, Caitlin E. Stallings , Ridwanullah A. Abubakar, Nooshin Mojahed, Shalini Guha, Dania Abou-Jabal, Buffy S. Ellsworth
Glucocorticoids play a pivotal role in terminal differentiation of pituitary somatotropes. However, the mechanisms for this remain poorly understood. Here we demonstrate that loss of the forkhead transcription factor, FOXO1, severely impairs glucocorticoid-induced expression of the gene encoding growth hormone (Gh1) both in vitro and in vivo. The mechanism appears to involve glucocorticoid induction of Foxo1 expression, nuclear localization, and increased binding associated with the Gh1 gene. An additional mechanism includes stabilization of the glucocorticoid receptor, NR3C1, possibly through FOXO1 induction of the chaperone protein, HSP90. Together these data suggest that glucocorticoid signaling and FOXO1 cooperate to promote Gh1 expression, an essential aspect of somatotrope terminal differentiation.
{"title":"The interplay between FOXO1 and glucocorticoid signaling in promoting the terminal differentiation of somatotropes","authors":"Pratyusa Das, Caitlin E. Stallings , Ridwanullah A. Abubakar, Nooshin Mojahed, Shalini Guha, Dania Abou-Jabal, Buffy S. Ellsworth","doi":"10.1016/j.mce.2025.112573","DOIUrl":"10.1016/j.mce.2025.112573","url":null,"abstract":"<div><div>Glucocorticoids play a pivotal role in terminal differentiation of pituitary somatotropes. However, the mechanisms for this remain poorly understood. Here we demonstrate that loss of the forkhead transcription factor, FOXO1, severely impairs glucocorticoid-induced expression of the gene encoding growth hormone (<em>Gh1</em>) both <em>in vitro</em> and <em>in vivo</em>. The mechanism appears to involve glucocorticoid induction of <em>Foxo1</em> expression, nuclear localization, and increased binding associated with the <em>Gh1</em> gene. An additional mechanism includes stabilization of the glucocorticoid receptor, NR3C1, possibly through FOXO1 induction of the chaperone protein, HSP90. Together these data suggest that glucocorticoid signaling and FOXO1 cooperate to promote <em>Gh1</em> expression, an essential aspect of somatotrope terminal differentiation.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"606 ","pages":"Article 112573"},"PeriodicalIF":3.8,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144094365","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 : 2025-05-14DOI: 10.1016/j.mce.2025.112572
Yoon Seok Jung , Kamalakannan Radhakrishnan , Jung-Ran Noh , Yong-Hoon Kim , Chul-Ho Lee , Hueng-Sik Choi
Aims
Growth differentiation factor 15 (GDF15) is a stress-induced hepatokine with emerging roles in liver injury. Estrogen-related receptor γ (ERRγ), a nuclear receptor regulating mitochondrial function and metabolic stress, has also been implicated in various liver injury conditions. However, the regulatory interplay between ERRγ and GDF15 remains unclear. This study investigates the molecular mechanisms underlying GDF15 expression and secretion in the liver, focusing on the role of ERRγ during acute and chronic liver injury.
Materials and methods
Wild-type and hepatocyte-specific ERRγ knockout (ERRγ-LKO) mice were administered with a single dose of carbon tetrachloride (CCl4) or fed an alcohol-containing diet for 4 weeks to establish acute or chronic liver injury models, respectively. ERRγ was overexpressed through an adenoviral construct (Ad-ERRγ). The ERRγ-specific inverse agonist GSK5182 was employed to inhibit the transactivation of ERRγ. The luciferase reporter assays were used to assess the binding of ERRγ protein to the regulatory region of GDF15 gene.
Key findings
Hepatic ERRγ and GDF15 gene expression, and GDF15 protein secretion were significantly elevated in both acute and chronic liver injury. Adenovirus-mediated overexpression of ERRγ is sufficient to substantially increase hepatic GDF15 expression and secretion. Genetic ablation of ERRγ expression or pharmacological inhibition of ERRγ transactivation substantially inhibited the upregulation of hepatic GDF15 expression and production in both acute and chronic liver injury. Furthermore, reporter assays showed that ERRγ, but not ERRα or ERRβ, directly binds to and activates the GDF15 gene promoter.
Significance
Our findings highlight the crucial role of ERRγ in transcriptional regulation of GDF15 gene expression and production in response to liver damage. Understanding the regulatory mechanisms of GDF15 expression could lead to new therapeutic targets for protecting the liver from various types of injuries and associated diseases.
{"title":"Hepatic estrogen-related receptor gamma is a key regulator of GDF15 production in acute and chronic liver injury","authors":"Yoon Seok Jung , Kamalakannan Radhakrishnan , Jung-Ran Noh , Yong-Hoon Kim , Chul-Ho Lee , Hueng-Sik Choi","doi":"10.1016/j.mce.2025.112572","DOIUrl":"10.1016/j.mce.2025.112572","url":null,"abstract":"<div><h3>Aims</h3><div>Growth differentiation factor 15 (GDF15) is a stress-induced hepatokine with emerging roles in liver injury. Estrogen-related receptor γ (ERRγ), a nuclear receptor regulating mitochondrial function and metabolic stress, has also been implicated in various liver injury conditions. However, the regulatory interplay between ERRγ and GDF15 remains unclear. This study investigates the molecular mechanisms underlying GDF15 expression and secretion in the liver, focusing on the role of ERRγ during acute and chronic liver injury.</div></div><div><h3>Materials and methods</h3><div>Wild-type and hepatocyte-specific ERRγ knockout (ERRγ-LKO) mice were administered with a single dose of carbon tetrachloride (CCl<sub>4</sub>) or fed an alcohol-containing diet for 4 weeks to establish acute or chronic liver injury models, respectively. ERRγ was overexpressed through an adenoviral construct (Ad-ERRγ). The ERRγ-specific inverse agonist GSK5182 was employed to inhibit the transactivation of ERRγ. The luciferase reporter assays were used to assess the binding of ERRγ protein to the regulatory region of GDF15 gene.</div></div><div><h3>Key findings</h3><div>Hepatic ERRγ and GDF15 gene expression, and GDF15 protein secretion were significantly elevated in both acute and chronic liver injury. Adenovirus-mediated overexpression of ERRγ is sufficient to substantially increase hepatic GDF15 expression and secretion. Genetic ablation of ERRγ expression or pharmacological inhibition of ERRγ transactivation substantially inhibited the upregulation of hepatic GDF15 expression and production in both acute and chronic liver injury. Furthermore, reporter assays showed that ERRγ, but not ERRα or ERRβ, directly binds to and activates the GDF15 gene promoter.</div></div><div><h3>Significance</h3><div>Our findings highlight the crucial role of ERRγ in transcriptional regulation of GDF15 gene expression and production in response to liver damage. Understanding the regulatory mechanisms of GDF15 expression could lead to new therapeutic targets for protecting the liver from various types of injuries and associated diseases.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"606 ","pages":"Article 112572"},"PeriodicalIF":3.8,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086637","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}
Inhibition of the renin-angiotensin system prevents vascular dysfunction induced by estrogen deficiency in rats. However, the role of aldosterone in ovarian hormone deficiency-related vascular dysfunction is unclear. Therefore, we aimed to investigate the role of the aldosterone pathway in the endothelial dysfunction observed in isolated resistance and conduit arteries in a model of endogenous female hormone deficiency. Female Wistar rats (8 weeks old) underwent bilateral ovariectomy (Ovx) and were randomly assigned to receive daily treatment with spironolactone (Ovx Spi, 80 mg/kg), placebo (Ovx) and Sham treatment with spironolactone (Sham Spi, 80 mg/kg) or placebo (Sham group) for 60 days. In isolated aortic rings, but not mesenteric resistance arteries, Ovx increased vascular reactivity to phenylephrine that was prevented by spironolactone. Incubation with L-NAME increased the phenylephrine response in the isolated aorta in all groups, but this effect was smaller in Ovx rats. The muted response in the Ovx rats was restored by spironolactone. Apocynin, catalase, SOD, tiron and ML-171 attenuated the vascular reactivity to phenylephrine in the aorta of Ovx rats, but this effect was prevented by spironolactone. Corroborating these findings, the reduction of nitric oxide, and the increases in superoxide anion, hydrogen peroxide, NOX4 and NOX2 protein expression in aorta of Ovx rats were prevented by spironolactone. Therefore, spironolactone treatment prevented endothelial dysfunction in aorta from Ovx rats by increasing nitric oxide bioavailability and reducing NADPH oxidase-derived ROS production, suggesting a potential role of the pathway in the vascular dysfunction produced by female hormone deficiency in rats.
{"title":"The role of aldosterone on the endothelial dysfunction induced by female hormone deficiency","authors":"Wena Dantas Marcarini , Vinicius Bermond Marques , Ariane Calazans Teixeira , Nathanne Santos Ferreira , Dieli Oliveira Nunes , Anna Karolina Nascimento Costa , Katyana K.S. Ferreira , Rita C. Tostes , Eduardo Hertel Ribeiro , Alessandra Simão Padilha , Ivanita Stefanon","doi":"10.1016/j.mce.2025.112571","DOIUrl":"10.1016/j.mce.2025.112571","url":null,"abstract":"<div><div>Inhibition of the renin-angiotensin system prevents vascular dysfunction induced by estrogen deficiency in rats. However, the role of aldosterone in ovarian hormone deficiency-related vascular dysfunction is unclear. Therefore, we aimed to investigate the role of the aldosterone pathway in the endothelial dysfunction observed in isolated resistance and conduit arteries in a model of endogenous female hormone deficiency. Female Wistar rats (8 weeks old) underwent bilateral ovariectomy (Ovx) and were randomly assigned to receive daily treatment with spironolactone (Ovx Spi, 80 mg/kg), placebo (Ovx) and Sham treatment with spironolactone (Sham Spi, 80 mg/kg) or placebo (Sham group) for 60 days. In isolated aortic rings, but not mesenteric resistance arteries, Ovx increased vascular reactivity to phenylephrine that was prevented by spironolactone. Incubation with L-NAME increased the phenylephrine response in the isolated aorta in all groups, but this effect was smaller in Ovx rats. The muted response in the Ovx rats was restored by spironolactone. Apocynin, catalase, SOD, tiron and ML-171 attenuated the vascular reactivity to phenylephrine in the aorta of Ovx rats, but this effect was prevented by spironolactone. Corroborating these findings, the reduction of nitric oxide, and the increases in superoxide anion, hydrogen peroxide, NOX4 and NOX2 protein expression in aorta of Ovx rats were prevented by spironolactone. Therefore, spironolactone treatment prevented endothelial dysfunction in aorta from Ovx rats by increasing nitric oxide bioavailability and reducing NADPH oxidase-derived ROS production, suggesting a potential role of the pathway in the vascular dysfunction produced by female hormone deficiency in rats.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"605 ","pages":"Article 112571"},"PeriodicalIF":3.8,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144071958","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 : 2025-05-09DOI: 10.1016/j.mce.2025.112570
Jin-Yong Chung, Nelmari Ruiz-Otero, Ronadip R. Banerjee
Pregnancy and postpartum states drive dynamic expansion and regression of maternal β-cell mass. Little is known about what regulates postpartum regression. We recently profiled murine islets from late gestation and early postpartum to identify regulators of β-cell apoptosis or survival. One hit was c-Jun, a transcription factor which regulates proliferation, apoptosis, and survival in various tissues. Here, we examine c-Jun regulation and function during gestation and postpartum and in murine and human islets. To examine the regulation of c-Jun within β-cells we used a mouse genetic model lacking β-cell prolactin receptor (PRLR) and stimulation of human and murine cultured islets with recombinant prolactin. Knockdown of c-Jun in MIN6 cells was accomplished using siRNA and lentiviral-shRNA, or in islets using pharmacologic inhibitors. We found that c-Jun expression in β-cells is temporally restricted to late gestation and early postpartum and requires PRLR signaling. Moreover, c-Jun expression was mutually exclusive with apoptotic β-cells identified by TUNEL staining. Prolactin treatment induces c-Jun expression downstream of MAPK/ERK signaling in both murine and human islets. Inhibition of c-Jun blocks prolactin-mediated survival of β-cells following pro-apoptotic stress, via the pro-survival factors Bcl2l1 (Bcl-xL) and Birc5 (Survivin). Finally, islets from pregnant donors exhibit increased c-Jun expression in β-cells, while absent in β-cells from donors with gestational diabetes (GDM). Together, our findings indicate that c-Jun contributes to pro-survival effects of lactogens downstream of PRLR/MAPK signaling in β-cells. c-Jun regulation is conserved in human islets and pregnancy and dysregulated in GDM.
{"title":"c-Jun regulates postpartum β-cell apoptosis and survival downstream of prolactin signaling","authors":"Jin-Yong Chung, Nelmari Ruiz-Otero, Ronadip R. Banerjee","doi":"10.1016/j.mce.2025.112570","DOIUrl":"10.1016/j.mce.2025.112570","url":null,"abstract":"<div><div>Pregnancy and postpartum states drive dynamic expansion and regression of maternal β-cell mass. Little is known about what regulates postpartum regression. We recently profiled murine islets from late gestation and early postpartum to identify regulators of β-cell apoptosis or survival. One hit was c-Jun, a transcription factor which regulates proliferation, apoptosis, and survival in various tissues. Here, we examine c-Jun regulation and function during gestation and postpartum and in murine and human islets. To examine the regulation of c-Jun within β-cells we used a mouse genetic model lacking β-cell prolactin receptor (PRLR) and stimulation of human and murine cultured islets with recombinant prolactin. Knockdown of c-Jun in MIN6 cells was accomplished using siRNA and lentiviral-shRNA, or in islets using pharmacologic inhibitors. We found that c-Jun expression in β-cells is temporally restricted to late gestation and early postpartum and requires PRLR signaling. Moreover, c-Jun expression was mutually exclusive with apoptotic β-cells identified by TUNEL staining. Prolactin treatment induces c-Jun expression downstream of MAPK/ERK signaling in both murine and human islets. Inhibition of c-Jun blocks prolactin-mediated survival of β-cells following pro-apoptotic stress, via the pro-survival factors <em>Bcl2l1</em> (Bcl-xL) and <em>Birc5</em> (Survivin). Finally, islets from pregnant donors exhibit increased c-Jun expression in β-cells, while absent in β-cells from donors with gestational diabetes (GDM). Together, our findings indicate that c-Jun contributes to pro-survival effects of lactogens downstream of PRLR/MAPK signaling in β-cells. c-Jun regulation is conserved in human islets and pregnancy and dysregulated in GDM.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"606 ","pages":"Article 112570"},"PeriodicalIF":3.8,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143982345","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 : 2025-05-06DOI: 10.1016/j.mce.2025.112569
Anjali Tripathi, Ayushi Chhabra, Sheeba Rizvi, Rakesh K. Tyagi
Endocrine-related disorders are highly prevalent globally, affecting millions of people. Such diseases are multifactorial in origin and are influenced by the complex interplay of genetics, lifestyle, and environmental factors. Recurring disruptions in the endocrine homeostasis can lead to a cascade of endocrine-related cancers. It is well known that nuclear receptors (NRs), particularly estrogen receptor and androgen receptor malfunctioning promote the oncogenesis of breast cancer and prostate cancer, respectively. However, existing therapeutics against these diseases, including aromatase inhibitors, (anti-) hormonal therapy, etc., often yield limited success, prompting to explore alternative methods of disease management. Additionally, drug resistance is prominent in cancer patients undergoing multidrug therapy. Currently, novel drug design strategies targeting NRs are being implemented for the discovery of a new generation of small molecule modulators, including selective NR modulators (SNuRMs) and degraders (SNuRDs). Moreover, proteolysis-targeting chimeras (PROTACs) as NR degraders, are also being developed primarily to overcome drug resistance, enhance protein selectivity, and mitigate off-target toxicity. This review highlights recent advancements in SNuRMs and SNuRDs for managing NRs-associated endocrine/metabolic disorders. Furthermore, we discuss the therapeutic potential of PROTAC degraders as a stand-alone strategy for receptor-mediated disease intervention, offering new avenues for precision medicine.
{"title":"Selective steroid receptor modulators, degraders and PROTACs: Therapeutic strategies in management of endocrine-related cancers","authors":"Anjali Tripathi, Ayushi Chhabra, Sheeba Rizvi, Rakesh K. Tyagi","doi":"10.1016/j.mce.2025.112569","DOIUrl":"10.1016/j.mce.2025.112569","url":null,"abstract":"<div><div>Endocrine-related disorders are highly prevalent globally, affecting millions of people. Such diseases are multifactorial in origin and are influenced by the complex interplay of genetics, lifestyle, and environmental factors. Recurring disruptions in the endocrine homeostasis can lead to a cascade of endocrine-related cancers. It is well known that nuclear receptors (NRs), particularly estrogen receptor and androgen receptor malfunctioning promote the oncogenesis of breast cancer and prostate cancer, respectively. However, existing therapeutics against these diseases, including aromatase inhibitors, (anti-) hormonal therapy, etc., often yield limited success, prompting to explore alternative methods of disease management. Additionally, drug resistance is prominent in cancer patients undergoing multidrug therapy. Currently, novel drug design strategies targeting NRs are being implemented for the discovery of a new generation of small molecule modulators, including selective NR modulators (SNuRMs) and degraders (SNuRDs). Moreover, proteolysis-targeting chimeras (PROTACs) as NR degraders, are also being developed primarily to overcome drug resistance, enhance protein selectivity, and mitigate off-target toxicity. This review highlights recent advancements in SNuRMs and SNuRDs for managing NRs-associated endocrine/metabolic disorders. Furthermore, we discuss the therapeutic potential of PROTAC degraders as a stand-alone strategy for receptor-mediated disease intervention, offering new avenues for precision medicine.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"605 ","pages":"Article 112569"},"PeriodicalIF":3.8,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143937484","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 : 2025-05-03DOI: 10.1016/j.mce.2025.112568
Chunqing Han , Peiwen Wang , Junxing Ye , Ruijian Wang , Xian Shi , Guoqin Hu , Xiping Hu , Jin Shen , Mengqing Zhang , Xian Zhang , Yu Wu
Estrogen regulates osteoblast activity at the epigenetic level. Setdb1 is an epigenetic regulator that functions in skeleton homeostasis maintenance. Setdb1 shows nuclear and cytoplasm localization in cells; however, the subcellular distribution of Setdb1 and the role of cytoplasmic Setdb1 in osteoblasts are largely unknown. Here, immunofluorescence staining and immunoblotting analysis showed that the distribution of Setdb1 in the cytoplasm increased upon β-estradiol treatment by increasing nuclear Setdb1 stability in osteoblasts. In β-estradiol-treated MC3T3-E1 cells, knocking-down Atf7ip expression enhanced Setdb1 cytoplasmic localization, but the cytoplasmic distribution of Setdb1 decreased in cells treated with the Setdb1 inhibitor (R,R)-59. Moreover, ovariectomized (OVX) mice lacking Atf7ip in mature osteoblasts showed better bone microstructure than the OVX controls. The proteomic analysis of the cytoplasmic binding of Setdb1 showed that cytoplasmic Setdb1 in osteoblasts mainly functioned to regulate protein homeostasis. Setdb1 binds to Serpinh1, a regulator of pro-collagen folding and maturation, and enhances Serpinh1 stability. Interrupting Setdb1 cytoplasmic localization by treating the cells with Leptomycin B (LMB) or (R,R)-59 led to an accumulation of unfolded protein and the elicitation of endoplasmic reticulum (ER) stress. The findings revealed a previously unrecognized role of cytoplasmic Setdb1 in the regulation of β-estradiol-mediated osteoblast homeostasis, which could enhance the understanding of estrogen's mechanism of action in regulating osteoblasts.
雌激素在表观遗传水平上调控成骨细胞的活性。Setdb1是一种表观遗传调节因子，在维持骨骼稳态中起作用。Setdb1显示细胞核和细胞质在细胞中的定位；然而，Setdb1的亚细胞分布和细胞质Setdb1在成骨细胞中的作用在很大程度上是未知的。这里，免疫荧光染色和免疫印迹分析显示，β-雌二醇处理增加了成骨细胞核Setdb1的稳定性，从而增加了Setdb1在细胞质中的分布。在β-雌二醇处理的MC3T3-E1细胞中，敲低Atf7ip表达增强了Setdb1的胞质定位，但Setdb1抑制剂（R，R）-59处理的细胞中Setdb1的胞质分布减少。此外，成熟成骨细胞中缺乏Atf7ip的卵巢切除（OVX）小鼠的骨微观结构优于OVX对照组。对Setdb1细胞质结合的蛋白质组学分析表明，Setdb1在成骨细胞细胞质中主要起调节蛋白稳态的作用。Setdb1与Serpinh1结合，Serpinh1是前胶原折叠和成熟的调节因子，并增强Serpinh1的稳定性。用Leptomycin B （LMB）或（R，R）-59处理细胞，阻断Setdb1细胞质定位，导致未折叠蛋白的积累和内质网（ER）应激的引发。这些发现揭示了细胞质Setdb1在调节β-雌二醇介导的成骨细胞稳态中的作用，这有助于进一步了解雌激素调节成骨细胞的作用机制。
{"title":"Estrogen increases Setdb1 cytoplasmic localization to stabilize Serpinh1 and improve protein homeostasis in osteoblasts","authors":"Chunqing Han , Peiwen Wang , Junxing Ye , Ruijian Wang , Xian Shi , Guoqin Hu , Xiping Hu , Jin Shen , Mengqing Zhang , Xian Zhang , Yu Wu","doi":"10.1016/j.mce.2025.112568","DOIUrl":"10.1016/j.mce.2025.112568","url":null,"abstract":"<div><div>Estrogen regulates osteoblast activity at the epigenetic level. Setdb1 is an epigenetic regulator that functions in skeleton homeostasis maintenance. Setdb1 shows nuclear and cytoplasm localization in cells; however, the subcellular distribution of Setdb1 and the role of cytoplasmic Setdb1 in osteoblasts are largely unknown. Here, immunofluorescence staining and immunoblotting analysis showed that the distribution of Setdb1 in the cytoplasm increased upon β-estradiol treatment by increasing nuclear Setdb1 stability in osteoblasts. In β-estradiol-treated MC3T3-E1 cells, knocking-down Atf7ip expression enhanced Setdb1 cytoplasmic localization, but the cytoplasmic distribution of Setdb1 decreased in cells treated with the Setdb1 inhibitor (R,R)-59. Moreover, ovariectomized (OVX) mice lacking Atf7ip in mature osteoblasts showed better bone microstructure than the OVX controls. The proteomic analysis of the cytoplasmic binding of Setdb1 showed that cytoplasmic Setdb1 in osteoblasts mainly functioned to regulate protein homeostasis. Setdb1 binds to Serpinh1, a regulator of pro-collagen folding and maturation, and enhances Serpinh1 stability. Interrupting Setdb1 cytoplasmic localization by treating the cells with Leptomycin B (LMB) or (R,R)-59 led to an accumulation of unfolded protein and the elicitation of endoplasmic reticulum (ER) stress. The findings revealed a previously unrecognized role of cytoplasmic Setdb1 in the regulation of β-estradiol-mediated osteoblast homeostasis, which could enhance the understanding of estrogen's mechanism of action in regulating osteoblasts.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"605 ","pages":"Article 112568"},"PeriodicalIF":3.8,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143928512","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 : 2025-04-29DOI: 10.1016/j.mce.2025.112559
Michal Zeman , Peter Stefanik , Valentina Sophia Rumanova , Monika Okuliarova
Light pollution is an increasing global environmental risk factor that contributes to the recent burden of metabolic diseases. The underlying mechanisms are not understood, but disruption of circadian control of physiological and behavioural processes may be involved. The negative consequences of chronodisruption can be augmented by co-exposure to high energy intake. Therefore, we investigated the individual and combined effects of artificial light at night (ALAN) and 10 % fructose in drinking water on the central clock in the suprachiasmatic nuclei (SCN) of the hypothalamus and circadian hormonal outputs in male rats. After 10 weeks of ALAN exposure and high fructose intake, the clockwork in the SCN was attenuated as indicated by eliminated day/night differences in the core clock gene Per1. Additionally, ALAN suppressed the daily variability and fructose induced upregulation of a gamma-aminobutyric acid–synthesising enzyme (GAD65), potentially affecting inhibitory neurotransmission in the SCN. ALAN and fructose additively inhibited plasma melatonin levels revealing excessive fructose intake as a chronodisruptive factor that can be potentiated by ALAN. In contrast to melatonin, daytime plasma testosterone concentrations were increased by high fructose and supressed by ALAN. Furthermore, high fructose intake elevated the plasma levels of two adipokines, leptin and adiponectin, but this response was absent specifically during the daytime in rats exposed to ALAN, indicating that ALAN reduced adipose tissue responsiveness. Our results document the complex consequences of ALAN and high fructose intake on endocrine control mechanisms that can have a long-term negative impact on metabolic health.
{"title":"Interactive effects of light at night and high fructose intake on the central circadian clock and endocrine outputs in rats","authors":"Michal Zeman , Peter Stefanik , Valentina Sophia Rumanova , Monika Okuliarova","doi":"10.1016/j.mce.2025.112559","DOIUrl":"10.1016/j.mce.2025.112559","url":null,"abstract":"<div><div>Light pollution is an increasing global environmental risk factor that contributes to the recent burden of metabolic diseases. The underlying mechanisms are not understood, but disruption of circadian control of physiological and behavioural processes may be involved. The negative consequences of chronodisruption can be augmented by co-exposure to high energy intake. Therefore, we investigated the individual and combined effects of artificial light at night (ALAN) and 10 % fructose in drinking water on the central clock in the suprachiasmatic nuclei (SCN) of the hypothalamus and circadian hormonal outputs in male rats. After 10 weeks of ALAN exposure and high fructose intake, the clockwork in the SCN was attenuated as indicated by eliminated day/night differences in the core clock gene <em>Per1</em>. Additionally, ALAN suppressed the daily variability and fructose induced upregulation of a gamma-aminobutyric acid–synthesising enzyme (GAD65), potentially affecting inhibitory neurotransmission in the SCN. ALAN and fructose additively inhibited plasma melatonin levels revealing excessive fructose intake as a chronodisruptive factor that can be potentiated by ALAN. In contrast to melatonin, daytime plasma testosterone concentrations were increased by high fructose and supressed by ALAN. Furthermore, high fructose intake elevated the plasma levels of two adipokines, leptin and adiponectin, but this response was absent specifically during the daytime in rats exposed to ALAN, indicating that ALAN reduced adipose tissue responsiveness. Our results document the complex consequences of ALAN and high fructose intake on endocrine control mechanisms that can have a long-term negative impact on metabolic health.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"605 ","pages":"Article 112559"},"PeriodicalIF":3.8,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143898846","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 : 2025-04-28DOI: 10.1016/j.mce.2025.112558
Denilson de Sousa Anselmo , Damáris Barcelos Cunha Azeredo , Reinaldo Röpke Junior , Luana Lopes de Souza , Patrícia Cristina Lisboa , Jones Bernardes Graceli , Lycia de Brito Gitirana , Andrea Claudia Freitas Ferreira , Francisca Diana Paiva-Melo , Leandro Miranda-Alves
Endocrine disrupting-chemicals (EDCs) are chemical compounds found in the environment that can have adverse impacts on human health. Among these agents are tributyltin (TBT) and bisphenol S (BPS). TBT is used in anti-fouling paints, and its indiscriminate use has health repercussions. BPS is found in plastic products and marketed as a safe alternative to bisphenol A (BPA). Little is known about the effects resulting from interactions between different EDCs on the organisms. The aim of this study was to analyze changes induced by exposure to these compounds in hypothalamic-pituitary-gonadal (HPG) axis and uterus. We divided four groups: Control, TBT 100 ng kg−1.day−1, BPS 50 μg kg−1.day−1, and the group simultaneously exposed to TBT and BPS. Rats were gavaged for 15 days and euthanized in the estrus phase. All EDCs groups showed uterus with cellular hyperplasia, glandular degeneration, increased epithelial thickness, and vacuolization. In the ovaries, there was an increase in atretic follicles in all EDCs groups. In the hypothalamus, the group exposed to the mixture showed an increase in the GnRH gene. In the blood, all EDCs groups had reduced levels of FSH and LH. Additionally, the BPS and mixture groups exhibited reduced levels of prolactin. Therefore, we suggest that exposure to these agents may contribute to damage to the female reproductive system, and that doses considered safe by regulatory agencies need to be reassessed.
内分泌干扰化学物质（EDCs）是在环境中发现的对人体健康有不利影响的化合物。其中有三丁基锡（TBT）和双酚S （BPS）。TBT用于防污涂料，它的滥用对健康有影响。BPS存在于塑料制品中，并作为双酚a （BPA）的安全替代品销售。人们对不同EDCs之间相互作用对生物体的影响知之甚少。本研究的目的是分析暴露于这些化合物引起的下丘脑-垂体-性腺轴和子宫的变化。我们分为四组：对照组，TBT 100 ng kg−1。day−1,BPS 50 μg kg−1。第1天，同时暴露于TBT和BPS的组。大鼠灌胃15 d，在发情期实施安乐死。所有EDCs组均表现为子宫细胞增生、腺体变性、上皮细胞厚度增加、空泡化。在卵巢中，所有EDCs组的闭锁卵泡均有所增加。在下丘脑中，暴露于混合物的组显示出GnRH基因的增加。在血液中，所有EDCs组的FSH和LH水平都有所降低。此外，BPS组和混合组泌乳素水平降低。因此，我们建议，暴露于这些物质可能会对女性生殖系统造成损害，监管机构认为安全的剂量需要重新评估。
{"title":"The environmental contaminants, tributyltin and bisphenol S, alone or in combination, harm the hypothalamus-pituitary-gonadal axis and uterus","authors":"Denilson de Sousa Anselmo , Damáris Barcelos Cunha Azeredo , Reinaldo Röpke Junior , Luana Lopes de Souza , Patrícia Cristina Lisboa , Jones Bernardes Graceli , Lycia de Brito Gitirana , Andrea Claudia Freitas Ferreira , Francisca Diana Paiva-Melo , Leandro Miranda-Alves","doi":"10.1016/j.mce.2025.112558","DOIUrl":"10.1016/j.mce.2025.112558","url":null,"abstract":"<div><div>Endocrine disrupting-chemicals (EDCs) are chemical compounds found in the environment that can have adverse impacts on human health. Among these agents are tributyltin (TBT) and bisphenol S (BPS). TBT is used in anti-fouling paints, and its indiscriminate use has health repercussions. BPS is found in plastic products and marketed as a safe alternative to bisphenol A (BPA). Little is known about the effects resulting from interactions between different EDCs on the organisms. The aim of this study was to analyze changes induced by exposure to these compounds in hypothalamic-pituitary-gonadal (HPG) axis and uterus. We divided four groups: Control, TBT 100 ng kg<sup>−1</sup>.day<sup>−1</sup>, BPS 50 μg kg<sup>−1</sup>.day<sup>−1</sup>, and the group simultaneously exposed to TBT and BPS. Rats were gavaged for 15 days and euthanized in the estrus phase. All EDCs groups showed uterus with cellular hyperplasia, glandular degeneration, increased epithelial thickness, and vacuolization. In the ovaries, there was an increase in atretic follicles in all EDCs groups. In the hypothalamus, the group exposed to the mixture showed an increase in the <em>GnRH</em> gene. In the blood, all EDCs groups had reduced levels of FSH and LH. Additionally, the BPS and mixture groups exhibited reduced levels of prolactin. Therefore, we suggest that exposure to these agents may contribute to damage to the female reproductive system, and that doses considered safe by regulatory agencies need to be reassessed.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"605 ","pages":"Article 112558"},"PeriodicalIF":3.8,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143916551","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}
The pituitary glycoprotein hormones (GPHs) control several physiological processes in vertebrates such as reproduction and metabolism. They include the luteinizing hormone (LH), the follicle-stimulating hormone (FSH), and the thyroid-stimulating hormone (TSH), which activate their cognate leucine-rich repeat G protein-coupled receptors (LGRs), LHR, FSHR, and TSHR. Each GPH consists of a common α subunit and a specific βFSH, βLH or βTSH subunit. More recently, two supplementary GPH proteins, GPA and GPB, were identified in nearly all bilaterians and are the ancestors of the pituitary GPH α- and β-subunits, respectively. Chondrichthyans (holocephalans and elasmobranchs), the sister group of bony vertebrates, are the most ancient clade to possess diversified GPH subunits. In the present study, GPA2, GPB5, TSHβ2, but not TSHβ1, and TSHR sequences have been identified in several elasmobranch genomes, and their 3D models were analyzed. Functional hormone-receptor interactions were studied in the small-spotted catshark (Scyliorhinus canicula) and showed that conditioned media from cells expressing the recombinant single-chain ScGPB5-ScGPA2 were more effective than independent subunits in activating ScTSHR, ScFSHR, and ScLHR. Expression profiles were analyzed by real-time PCR, in situ hybridization, and immunohistochemistry along the male genital tract, other male and female tissues, and female tissues. A broader tissue distribution expression was observed for tshr and gpa2 than for gpb5, which was mainly observed in the testes. In testis, expression of tshr and gpb5 by Sertoli cells and of gpa2 by germ cells suggested paracrine/autocrine functions of GPA2/GPB5/GPHR signaling during spermatogenesis. This study complements the data on GPA2 and GPB5 by studying a chondrichthyan of phylogenetic interest for understanding the evolution of endocrine regulation in vertebrates.
{"title":"Pleiotropic signaling of single-chain thyrostimulin (GPB5-GPA2) on homologous glycoprotein hormone receptors (ScFSHR, ScLHR, ScTSHR) in the elasmobranch Scyliorhinus canicula reproduction","authors":"Fabian Jeanne , Stanislas Pilet , Yves Combarnous , Benoît Bernay , Sylvie Dufour , Pascal Favrel , Pascal Sourdaine","doi":"10.1016/j.mce.2025.112553","DOIUrl":"10.1016/j.mce.2025.112553","url":null,"abstract":"<div><div>The pituitary glycoprotein hormones (GPHs) control several physiological processes in vertebrates such as reproduction and metabolism. They include the luteinizing hormone (LH), the follicle-stimulating hormone (FSH), and the thyroid-stimulating hormone (TSH), which activate their cognate leucine-rich repeat G protein-coupled receptors (LGRs), LHR, FSHR, and TSHR. Each GPH consists of a common α subunit and a specific βFSH, βLH or βTSH subunit. More recently, two supplementary GPH proteins, GPA and GPB, were identified in nearly all bilaterians and are the ancestors of the pituitary GPH α- and β-subunits, respectively. Chondrichthyans (holocephalans and elasmobranchs), the sister group of bony vertebrates, are the most ancient clade to possess diversified GPH subunits. In the present study, GPA2, GPB5, TSHβ2, but not TSHβ1, and TSHR sequences have been identified in several elasmobranch genomes, and their 3D models were analyzed. Functional hormone-receptor interactions were studied in the small-spotted catshark (<em>Scyliorhinus canicula</em>) and showed that conditioned media from cells expressing the recombinant single-chain <em>Sc</em>GPB5-<em>Sc</em>GPA2 were more effective than independent subunits in activating <em>Sc</em>TSHR, <em>Sc</em>FSHR, and <em>Sc</em>LHR. Expression profiles were analyzed by real-time PCR, <em>in situ</em> hybridization, and immunohistochemistry along the male genital tract, other male and female tissues, and female tissues. A broader tissue distribution expression was observed for <em>tshr</em> and <em>gpa2</em> than for <em>gpb5,</em> which was mainly observed in the testes. In testis, expression of <em>tshr</em> and <em>gpb5</em> by Sertoli cells and of <em>gpa2</em> by germ cells suggested paracrine/autocrine functions of GPA2/GPB5/GPHR signaling during spermatogenesis. This study complements the data on GPA2 and GPB5 by studying a chondrichthyan of phylogenetic interest for understanding the evolution of endocrine regulation in vertebrates.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"604 ","pages":"Article 112553"},"PeriodicalIF":3.8,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143864064","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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