Molecular and Cellular Endocrinology最新文献_第5页

SP600125 decreases cAMP/PKA-dependent steroid production through ATF4/DDIT3 activation in MA-10 Leydig cells SP600125通过ATF4/DDIT3激活MA-10间质细胞，减少cAMP/ pka依赖性类固醇的产生

IF 3.8 3区医学

Molecular and Cellular Endocrinology Pub Date : 2025-07-09 DOI: 10.1016/j.mce.2025.112613

Audrey Basque , Liel-Sarah Izichkis , Luc J. Martin

{"title":"SP600125 decreases cAMP/PKA-dependent steroid production through ATF4/DDIT3 activation in MA-10 Leydig cells","authors":"Audrey Basque , Liel-Sarah Izichkis , Luc J. Martin","doi":"10.1016/j.mce.2025.112613","DOIUrl":"10.1016/j.mce.2025.112613","url":null,"abstract":"<div><div>Leydig cells, located between seminiferous tubules within the testis, are the primary source of testosterone in males. In these cells, the luteinizing hormone (LH)/cAMP/protein kinase A (PKA) signaling pathway mainly regulates androgen biosynthesis. We have previously reported that the <em>connexin43</em> (<em>Gja</em>) promoter can be activated in mouse MA-10 Leydig cells as a result of a cooperation between the AP-1 transcription factors JUN and FOS. The mitogen-activated protein kinases (MAPK) signaling pathway, through the JUN N-terminal kinase (JNK), can phosphorylate members of the AP-1 family of transcription factors, modulating their activities. Hence, MA-10 Leydig cells were treated for 4 h with the JNK inhibitor SP600125 (pyrazolanthrone) at 25 μM, in the absence or presence of the activator of adenylate cyclase forskolin (FSK) at 10 μM, followed by RNA extractions and 3′Tag RNA-Seq analysis of the transcriptome. Interestingly, SP600125 decreases cAMP/PKA dependent expression of genes related to cholesterol and steroid biosynthetic/metabolic processes, resulting in decreased cAMP/PKA dependent progesterone production in MA-10 cells. Moreover, SP600125 increases the expression of genes involved in the endoplasmic reticulum stress response related to ATF4, resulting in activation of DDIT3 and apoptosis as indicated with cleaved caspase 3. Overall, our results suggest that SP600125 increases the ATF4/DDIT3-dependent endoplasmic reticulum stress response independently of MAPK9 (JNK2) inhibition, and inhibits LH/cAMP/PKA-dependent androgen synthesis in Leydig cells.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"607 ","pages":"Article 112613"},"PeriodicalIF":3.8,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144596889","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}

引用次数: 0

Timing of glucose intake drives distinct hepatic outcomes: Divergent glucose and lipid metabolism 葡萄糖摄入的时间驱动不同的肝脏结果：不同的葡萄糖和脂质代谢

IF 3.8 3区医学

Molecular and Cellular Endocrinology Pub Date : 2025-07-08 DOI: 10.1016/j.mce.2025.112611

Xiaofu Zhang , Chenfei Ma , Shichen Chang , Xiaoying Li , Qiuyu Wang

{"title":"Timing of glucose intake drives distinct hepatic outcomes: Divergent glucose and lipid metabolism","authors":"Xiaofu Zhang , Chenfei Ma , Shichen Chang , Xiaoying Li , Qiuyu Wang","doi":"10.1016/j.mce.2025.112611","DOIUrl":"10.1016/j.mce.2025.112611","url":null,"abstract":"<div><h3>Objective</h3><div>Excessive sugar intake is strongly associated with insulin resistance and type 2 diabetes (T2D), yet the metabolic consequences of nutrient timing—specifically glucose consumption during fasting versus feeding—remain poorly understood.</div></div><div><h3>Methods</h3><div>C57BL/6 mice were subjected to an every-other-day fasting (EODF) regimen and randomly divided into three groups: control (tap water only), food-glucose (FG; glucose water during feeding), and starvation-glucose (SG; glucose water during fasting). After 22 weeks, metabolic phenotypes, hepatic lipid profiles, insulin signaling markers, and hepatic transcriptomes were analyzed.</div></div><div><h3>Results</h3><div>Glucose intake during fasting (SG) induced marked hepatic insulin resistance, as evidenced by reduced phosphorylation of Akt and FoxO1. In contrast, glucose intake during feeding (FG) promoted hepatic triglyceride accumulation, upregulated lipogenic genes (e.g., Acaca, Fasn), and increased expression of SREBP-1c and PPARγ. Transcriptomic and pathway enrichment analyses revealed distinct activation patterns of insulin signaling and lipid metabolism between FG and SG groups.</div></div><div><h3>Conclusions</h3><div>Nutrient timing critically influences hepatic metabolic responses: glucose intake during feeding promotes lipogenesis, whereas intake during fasting triggers insulin resistance. These findings underscore the importance of chrononutritional strategies in preventing T2D and suggest that personalized dietary timing may offer therapeutic benefits.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"607 ","pages":"Article 112611"},"PeriodicalIF":3.8,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144596976","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}

引用次数: 0

Maternal thyroid hormones affect zebrafish embryo development 母体甲状腺激素影响斑马鱼胚胎发育。

IF 3.8 3区医学

Molecular and Cellular Endocrinology Pub Date : 2025-07-05 DOI: 10.1016/j.mce.2025.112610

Maira da Silva Rodrigues , Beatriz Marques de Souza , Ivana Felipe Rosa , Lucas Benites Doretto , Rafael Henrique Nóbrega

{"title":"Maternal thyroid hormones affect zebrafish embryo development","authors":"Maira da Silva Rodrigues , Beatriz Marques de Souza , Ivana Felipe Rosa , Lucas Benites Doretto , Rafael Henrique Nóbrega","doi":"10.1016/j.mce.2025.112610","DOIUrl":"10.1016/j.mce.2025.112610","url":null,"abstract":"<div><div>Thyroid hormones (THs), including thyroxine (T4) and triiodothyronine (T3), regulate vertebrate development, influencing critical processes during embryogenesis and larval stages. However, their maternal transfer and developmental roles in fish remain poorly understood. This study investigates maternal THs' impact on zebrafish development, focusing on the somatotropic axis, a key regulator of growth and metabolism. Female zebrafish were fed diets with 12.5 or 25 μg T4/g body weight/day for five days, while controls received vehicle-only food. Plasma TH levels were measured, and females were bred with untreated males. Embryos and larvae were assessed from 0 to 144 h post-fertilization for survival, heartbeat, morphology, T3 content, and gene expression. Elevated maternal T4 increased embryonic T3, causing growth retardation, edema, spinal deformities, tachycardia, and mortality. Gene expression analysis revealed dysregulation of TH axis components and somatotropic genes, highlighting the maternal THs' critical role in developmental trajectories and normal growth.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"607 ","pages":"Article 112610"},"PeriodicalIF":3.8,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144575900","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}

引用次数: 0

Estrogen upregulates nucleophosmin 1 expression in mouse uterus through MYC induction 雌激素通过MYC诱导上调小鼠子宫内核磷蛋白1的表达。

IF 3.8 3区医学

Molecular and Cellular Endocrinology Pub Date : 2025-07-04 DOI: 10.1016/j.mce.2025.112612

Giwan Lee , Yeonju Suh , Byeongseok Kim , Joohee Kim , Jimin Lee , Sangok Park , Ok-Hee Lee , Kwonho Hong , Man Ryul Lee , Youngsok Choi

{"title":"Estrogen upregulates nucleophosmin 1 expression in mouse uterus through MYC induction","authors":"Giwan Lee , Yeonju Suh , Byeongseok Kim , Joohee Kim , Jimin Lee , Sangok Park , Ok-Hee Lee , Kwonho Hong , Man Ryul Lee , Youngsok Choi","doi":"10.1016/j.mce.2025.112612","DOIUrl":"10.1016/j.mce.2025.112612","url":null,"abstract":"<div><div>The uterus undergoes transcriptional changes regulated by estrogen and progesterone throughout the menstrual cycle. Although the estrogen-regulated transcriptome has been extensively studied, the implications of gene expression alterations are not fully elucidated. Our analysis of publicly available RNA-seq and ChIP-seq data revealed that estrogen upregulates genes involved in ribosome biogenesis and MYC pathway. Specifically, we observed increased expression of nucleophosmin 1 (NPM1), a key regulator of ribosome biogenesis with MYC-binding sites in its promoter, in estrogen-stimulated endometrial epithelium. Utilizing an estrogen receptor (ER) antagonist, we demonstrated that estrogen's upregulation of <em>Npm1</em> and <em>Myc</em> in the uterus is dependent on ER activation. Further, estrogen treatment of isolated endometrial epithelium from the uterus confirmed an increase in <em>Myc</em> and <em>Npm1</em> expression. The application of <em>Myc</em> siRNA attenuated the estrogen-induced <em>Npm1</em> expression in the isolated epithelium. These findings suggest that estrogen-enhanced MYC expression, mediated by ER, may play a crucial role in <em>Npm1</em> expression in the uterus. This, in turn, contributes to ribosome biogenesis, underscoring its significance in endometrial proliferation and thickening. Therefore, our findings offer significant insights into NPM1 role in normal endometrial physiology, highlighting the connection between estrogen-mediated transcriptional regulation and ribosome biogenesis in the uterus.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"607 ","pages":"Article 112612"},"PeriodicalIF":3.8,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144575899","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}

引用次数: 0

Exploring thyroid development and function: A systems biology search for new chemical disruptor targets 探索甲状腺发育和功能：新的化学干扰物目标的系统生物学搜索

IF 3.8 3区医学

Molecular and Cellular Endocrinology Pub Date : 2025-07-02 DOI: 10.1016/j.mce.2025.112609

Jamilli Zenzeluk , Jeane Maria Oliveira , Ana Carolina Sater , Paula Bargi-Souza , Marco Aurelio Romano , Caroline Serrano-Nascimento , Renata Marino Romano

{"title":"Exploring thyroid development and function: A systems biology search for new chemical disruptor targets","authors":"Jamilli Zenzeluk , Jeane Maria Oliveira , Ana Carolina Sater , Paula Bargi-Souza , Marco Aurelio Romano , Caroline Serrano-Nascimento , Renata Marino Romano","doi":"10.1016/j.mce.2025.112609","DOIUrl":"10.1016/j.mce.2025.112609","url":null,"abstract":"<div><div>Indiscriminate exposure to chemical substances has emerged as a critical global health concern. Human exposure to emerging contaminants, including pharmaceutical residues, pesticides, food additives, and chemicals employed in packaging and bottle production, is associated with an increased incidence of diseases, including thyroid disorders. Several chemicals potentially dysregulate thyroid embryonic development and the adult hypothalamic‒pituitary‒thyroid (HPT) axis. In this study, we applied systems biology approaches to identify biological processes associated with the most highly upregulated and downregulated genes in human thyroid transcriptome data from both the embryonic and adult stages. As a result, new gene/protein‒chemical interactions linked to recognized toxicities in the thyroid gland and the HPT axis were identified. This analysis identified 195 distinct chemical substances that may interact with these highly expressed proteins and exhibit thyroid toxicity. Our findings underscore the developmental period as a critical window of vulnerability to chemical exposure, with potential adverse effects on thyroid development and programming. Finally, our data suggest new targets for emerging chemicals in the thyroids of adult individuals, potentially compromising thyroid function.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"607 ","pages":"Article 112609"},"PeriodicalIF":3.8,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144549615","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}

引用次数: 0

Ghrelin treatment and exercise improve sperm quality in rats fed an obesogenic diet:A potential link to LEAP2 促生长素治疗和运动改善了喂食致肥饮食的大鼠的精子质量：与LEAP2的潜在联系

IF 3.8 3区医学

Molecular and Cellular Endocrinology Pub Date : 2025-06-26 DOI: 10.1016/j.mce.2025.112608

E.M. Luque , V.P. Carlini , P. Guantay , D. Machuca , P. Torres , N. Ramírez , V. Cantarelli , M. Ponzio , D. Castrogiovanni , M. Perelló , A.C. Martini

{"title":"Ghrelin treatment and exercise improve sperm quality in rats fed an obesogenic diet:A potential link to LEAP2","authors":"E.M. Luque , V.P. Carlini , P. Guantay , D. Machuca , P. Torres , N. Ramírez , V. Cantarelli , M. Ponzio , D. Castrogiovanni , M. Perelló , A.C. Martini","doi":"10.1016/j.mce.2025.112608","DOIUrl":"10.1016/j.mce.2025.112608","url":null,"abstract":"<div><div>This study aimed to evaluate whether ghrelin, with or without exercise, can reverse the alterations caused by an obesogenic diet on sperm quality, metabolism, and endocrine profile with emphasis on LEAP2 levels.</div><div>Fifty five male Wistar rats were randomly assigned, from weaning to postnatal day (pnd) 103, to five groups (n = 11/group): CD (standard chow + water); ObD (chow enriched with 30 % pork fat + water with 5 % fructose); ObD + ghrelin (obesogenic diet + 6 nmol/animal/day of ghrelin from pnd 85); ObD + Exc (obesogenic diet + standardized exercise in a running wheel, 15 min/day, 3 days/week); and ObD + ghrelin + Exc.</div><div>Body weight gain was accelerated in ObD, but ghrelin and/or Exc slowed it down. At pnd 103, all treatment groups were significantly lighter than the ObD group. Metabolic parameters were impaired in ObD animals, with exercise markedly improving them, reducing cholesterol and triglyceride levels close to control values, while ghrelin exerted a modest effect, partially reducing triglycerides and the triglyceride/HDL index but leaving values still dysregulated. Sperm concentration and motility were significantly reduced in the ObD vs. CD; ghrelin and/or Exc completely reversed these detrimental effects. Plasma LEAP2 was significantly higher in the animals receiving the obesogenic diet, and, LEAP2 correlated inversely with sperm concentration, explaining 22 % of its variation. No synergistic effects were found between ghrelin and Exc.</div><div>We demonstrated for the first time the potential of ghrelin to reverse sperm quality alterations secondary to obesity. Furthermore, ghrelin exhibited weight gain-slowing effects comparable to those of Exc. We also found an association between LEAP2 and sperm concentration, which warrants further investigation.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"607 ","pages":"Article 112608"},"PeriodicalIF":3.8,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144513848","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}

引用次数: 0

Enteroendocrine cell differentiation: Implications for human disease 肠内分泌细胞分化：对人类疾病的影响

IF 3.8 3区医学

Molecular and Cellular Endocrinology Pub Date : 2025-06-26 DOI: 10.1016/j.mce.2025.112607

Elisa Saint-Denis , Bianca Frintu , Madelyn Goldsmith , Guilherme P. Ramos , Daniel Zeve

{"title":"Enteroendocrine cell differentiation: Implications for human disease","authors":"Elisa Saint-Denis , Bianca Frintu , Madelyn Goldsmith , Guilherme P. Ramos , Daniel Zeve","doi":"10.1016/j.mce.2025.112607","DOIUrl":"10.1016/j.mce.2025.112607","url":null,"abstract":"<div><div>Enteroendocrine cells are the most abundant hormone producing cells in humans. Though they make up less than 1 % of the gastrointestinal epithelium, these cells have a large physiological impact through the secretion of hormones that act both locally and systemically to regulate intestinal function and whole-body metabolism, among other functions. The differentiation of enteroendocrine cells from intestinal stem cells is complex, involving not only lineage, but hormonal specification. This review highlights the specific signaling pathways and transcription factors that regulate enteroendocrine cell differentiation and hormone production, integrating newer findings into our growing understanding of this process. Further, it also describes how enteroendocrine cells and their differentiation are involved and altered in human health and disease: specifically aging, inflammatory bowel disease, obesity, and diabetes mellitus. Finally, we focus on how enteroendocrine cells can be targeted to produce insulin, a growing field with significant implications. Understanding what drives enteroendocrine differentiation, both molecularly and physiologically, will provide important insights into how these cells can serve as future therapeutic targets.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"607 ","pages":"Article 112607"},"PeriodicalIF":3.8,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144522989","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}

引用次数: 0

Gremlin 1 regulates granulosa cell apoptosis through the TGF-β/SMAD signaling pathway during bovine follicular atresia Gremlin 1通过TGF-β/SMAD信号通路调控牛卵泡闭锁期间颗粒细胞凋亡。

IF 3.8 3区医学

Molecular and Cellular Endocrinology Pub Date : 2025-06-25 DOI: 10.1016/j.mce.2025.112605

Yupeng Xu , Mingming Liu , Ting Yang , Baoli Zhao , Yao Li , Jie Wang , Yiqun Wang , Pengfei Lin , Huatao Chen , Aihua Wang , Yaping Jin , Keqiong Tang

{"title":"Gremlin 1 regulates granulosa cell apoptosis through the TGF-β/SMAD signaling pathway during bovine follicular atresia","authors":"Yupeng Xu , Mingming Liu , Ting Yang , Baoli Zhao , Yao Li , Jie Wang , Yiqun Wang , Pengfei Lin , Huatao Chen , Aihua Wang , Yaping Jin , Keqiong Tang","doi":"10.1016/j.mce.2025.112605","DOIUrl":"10.1016/j.mce.2025.112605","url":null,"abstract":"<div><div>Gremlin 1 is a highly conserved secretory glycoprotein of the DAN family that plays significant roles in human and mouse follicular development and ovulation through both BMP-dependent and BMP-independent pathways. However, its function and mechanisms in bovine follicular development and atresia remain unclear. This study investigated its specific molecular mechanism during follicular development in bovines. Gremlin 1 protein is expressed in ovarian follicles at various developmental stages, with both its mRNA and protein levels increasing in correlation with the progression of follicular atresia. Following Si-RNA mediated knockdown of Gremlin 1 expression, a reduction in apoptosis and an enhancement in proliferative activity were observed in granulosa cells (GCs). In contrast, recombinant human Gremlin 1 (Rh-Gremlin 1) protein significantly induced apoptosis of GCs and inhibited cell proliferation. Previous studies have shown that Gremlin 1 can mediate apoptosis in a variety of cells through the TGF-β/SMAD signaling pathway. In our study, we observed that Gremlin 1 was associated with the phosphorylation levels of SMAD-2/3, and treatment with the TGF-β signaling pathway inhibitor SB431542 partially reversed Gremlin 1-induced apoptosis of GCs. Moreover, SB431542 significantly restored the proliferative viability and cell cycle progression of GCs. The results showed that Gremlin 1 was involved in follicular atresia-related processes by regulating the apoptosis and proliferation of GCs, and partially mediated this process through the TGF-β/SMAD signaling pathway. This provides a new avenue for further exploration of its role in follicular development.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"607 ","pages":"Article 112605"},"PeriodicalIF":3.8,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144512195","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}

引用次数: 0

Mdivi-1 promotes steroidogenesis in granulosa cells by inhibiting mitochondrial fission Mdivi-1通过抑制线粒体裂变促进颗粒细胞中的类固醇生成。

IF 3.8 3区医学

Molecular and Cellular Endocrinology Pub Date : 2025-06-24 DOI: 10.1016/j.mce.2025.112606

Ying He , Xiaoyan Li , Dan Kuai , Huiying Zhang , Yingmei Wang , Kan Wang , Wenyan Tian

{"title":"Mdivi-1 promotes steroidogenesis in granulosa cells by inhibiting mitochondrial fission","authors":"Ying He , Xiaoyan Li , Dan Kuai , Huiying Zhang , Yingmei Wang , Kan Wang , Wenyan Tian","doi":"10.1016/j.mce.2025.112606","DOIUrl":"10.1016/j.mce.2025.112606","url":null,"abstract":"<div><div>Targeted metabolomics and ELISAs shown that Mdivi-1 treatment increased the levels of steroid hormones (progesterone and estradiol) in the supernatants of KGN cell culture medium. The purpose of this study was to explore the mechanism of Mdivi-1 promoting steroid hormone synthesis in granulosa cells (GCs). In vitro experiments revealed that Mdivi-1 did not affect the total protein expression of Drp1 in KGN cells or human luteinized GCs but increased Drp1 Ser637 phosphorylation, reduced Drp1 Ser616 phosphorylation, inhibited Drp1 mitochondrial translocation, and upregulated mitochondrial fusion proteins, promoting mitochondrial fusion. In terms of energy production, Mdivi-1 increased the expression of mitochondrial complexes I and V and the ATP concentration in GCs, increasing the energy supply for steroidogenesis. Mdivi-1 exposure significantly increased the expression and mitochondrial localization of StAR and CYP11A1 in the steroid production pathway of GCs. Further in vivo experiments demonstrated that, compared with the controls, Mdivi-1 treatment significantly increased the levels of Drp1 Ser637, StAR and CYP11A1 in ovarian tissue and the serum levels of progesterone and estradiol. Taken together, these findings suggest that Mdivi-1 induces mitochondrial fusion by increasing Drp1 phosphorylation at Ser637 and weakening the interaction between Drp1 and mitochondria. Moreover, mitochondrial fusion increases the cellular bioenergetics and the expression of StAR and CYP11A1 as well as their mitochondrial localization, thereby enhancing the activity of steroidogenesis in GCs.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"607 ","pages":"Article 112606"},"PeriodicalIF":3.8,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144506829","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}

引用次数: 0

CYR61 and CTGF mediate the stimulatory effect of amphiregulin on COX-2 expression in human granulosa-lutein cells CYR61和CTGF介导双调节蛋白对人颗粒叶黄素细胞COX-2表达的刺激作用

IF 3.8 3区医学

Molecular and Cellular Endocrinology Pub Date : 2025-06-10 DOI: 10.1016/j.mce.2025.112604

Bingxin Fu , Manman Guo , Yuanyuan Jia, Xiaoyu Han, Beibei Bi, Lanlan Fang, Jung-Chien Cheng

{"title":"CYR61 and CTGF mediate the stimulatory effect of amphiregulin on COX-2 expression in human granulosa-lutein cells","authors":"Bingxin Fu , Manman Guo , Yuanyuan Jia, Xiaoyu Han, Beibei Bi, Lanlan Fang, Jung-Chien Cheng","doi":"10.1016/j.mce.2025.112604","DOIUrl":"10.1016/j.mce.2025.112604","url":null,"abstract":"<div><div>Amphiregulin (AREG), an epidermal growth factor (EGF)-like ligand, is the predominant epidermal growth factor receptor (EGFR) ligand in human follicular fluid and mediates the effects of luteinizing hormone (LH) on ovarian function. In this study, we investigated whether AREG regulates the expression of cysteine-rich angiogenic inducer 61 (CYR61) and connective tissue growth factor (CTGF), two key matricellular proteins involved in ovarian function, and whether they mediate AREG-induced cyclooxygenase-2 (COX-2) expression. Using the human granulosa cell tumor-derived KGN cell line and primary human granulosa-lutein (hGL) cells, we demonstrated that AREG treatment upregulated CYR61 and CTGF protein levels in an EGFR-dependent manner. Mechanistic analysis revealed that AREG-induced expression of CYR61 and CTGF was mediated through the ERK1/2, AKT, CREB, and YAP signaling pathways. Inhibition of these pathways using specific inhibitors or small interfering RNA blocked AREG-induced CYR61 and CTGF expression, indicating their essential roles in this process. Moreover, knockdown of CYR61 and CTGF attenuated AREG-induced COX-2 expression, establishing their role as key mediators of AREG signaling in human granulosa cells. Finally, our results showed that LH treatment induced the expression of CYR61 and CTGF, and this induction was attenuated by EGFR inhibition. Moreover, knockdown of CYR61 and CTGF reduced LH-induced COX-2 expression. These findings provide novel insights into the molecular mechanisms by which AREG regulates ovarian function and highlight potential targets for reproductive health research.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"607 ","pages":"Article 112604"},"PeriodicalIF":3.8,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144264011","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}

引用次数: 0