Molecular and Cellular Endocrinology最新文献_第10页

Structural comparison of androstenediol recognition by the human estrogen receptor ligand binding domains 人雌激素受体配体结合域识别雄烯二醇的结构比较

IF 3.8 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2025-09-15 Epub Date: 2025-06-05 DOI: 10.1016/j.mce.2025.112588

Jordan L. Pederick, John B. Bruning

Estrogen receptors α (ERα) and β (ERβ) are ligand-regulated transcription factors that control important biological processes in humans. The endogenous steroid androstenediol possesses estrogenic activity, despite being a precursor of the primary androgen, testosterone. While androstenediol is an agonist of both ERs, it is ∼ 3-fold selective for ERβ. Additionally, it has been reported that androstenediol can repress proinflammatory responses of the central nervous system (CNS) in an ERβ-dependent manner, but the primary estrogen, estradiol (E2), cannot. As no structural characterization of the interaction between ERα or ERβ with androstenediol has been reported, the basis of ERβ selectivity, and whether this is responsible for the anti-inflammatory effects of androstenediol, remains unclear. To address these gaps in knowledge we determined crystal structures of the human ER LBDs (hERα and hERβ) complexed with androstenediol and coactivator-derived peptide. This revealed that androstenediol stabilizes the active conformation of both receptors in the same manner as E2. The binding mode of androstenediol between the hERα and hERβ LBDs is extremely similar, suggesting that subtle differences in the van der Waals interactions mediated by non-conserved residues of the ligand binding pocket confer selectivity toward hERβ. Finally, in both receptors the coactivator-derived peptide occupied the activation function 2 (AF2) surface, as observed for previous agonist-bound hER structures. Therefore, as androstenediol does not induce any distinct structural changes within the hERβ LBD compared to E2, this suggests that the hERβ-dependent anti-inflammatory effects of androstenediol on the CNS are mediated by other factors.

雌激素受体α (ERα)和β (ERβ)是配体调节的转录因子，控制着人体重要的生物过程。内源性类固醇雄烯二醇具有雌激素活性，尽管它是主要雄激素睾酮的前体。虽然雄烯二醇是这两种er的激动剂，但它对ERβ具有约3倍的选择性。此外，据报道，雄烯二醇可以以er β依赖的方式抑制中枢神经系统（CNS）的促炎反应，但主要雌激素雌二醇（E2）不能。由于没有关于ERα或ERβ与雄烯二醇相互作用的结构表征报道，ERβ选择性的基础以及这是否与雄烯二醇的抗炎作用有关尚不清楚。为了解决这些知识上的空白，我们确定了人内质网lbd （hERα和hERβ）与雄烯二醇和辅激活剂衍生肽络合的晶体结构。这表明雄烯二醇以与E2相同的方式稳定两种受体的活性构象。雄烯二醇在hERα和hERβ lbd之间的结合模式非常相似，这表明配体结合囊的非保守残基介导的范德瓦尔斯相互作用的细微差异赋予了对hERβ的选择性。最后，在这两种受体中，辅激活剂衍生的肽占据了激活功能2 （AF2）表面，正如之前的激动剂结合hER结构所观察到的那样。因此，与E2相比，雄烯二醇不会引起hERβ LBD内任何明显的结构变化，这表明雄烯二醇对中枢神经系统的hERβ依赖性抗炎作用是由其他因素介导的。

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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 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2025-09-15 Epub 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

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.

靶向代谢组学和elisa结果显示，Mdivi-1处理增加了KGN细胞培养基上清液中类固醇激素（孕酮和雌二醇）的水平。本研究旨在探讨Mdivi-1促进颗粒细胞（GCs）中类固醇激素合成的机制。体外实验发现，Mdivi-1不影响KGN细胞或人黄体素化GCs中Drp1总蛋白表达，但增加Drp1 Ser637磷酸化，降低Drp1 Ser616磷酸化，抑制Drp1线粒体易位，上调线粒体融合蛋白，促进线粒体融合。在能量产生方面，Mdivi-1增加了GCs中线粒体复合物I和V的表达以及ATP浓度，增加了类固醇生成的能量供应。Mdivi-1暴露显著增加了GCs类固醇生成通路中StAR和CYP11A1的表达和线粒体定位。进一步的体内实验表明，与对照组相比，Mdivi-1处理显著提高了卵巢组织中Drp1 Ser637、StAR和CYP11A1的水平以及血清中孕酮和雌二醇的水平。综上所述，这些发现表明Mdivi-1通过增加Drp1 Ser637位点的磷酸化并减弱Drp1与线粒体之间的相互作用来诱导线粒体融合。此外，线粒体融合增加了细胞生物能量学，增加了StAR和CYP11A1的表达及其线粒体定位，从而增强了GCs中类固醇生成的活性。

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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 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2025-09-15 Epub 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

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.

不加区分地接触化学物质已成为一个严重的全球健康问题。人类接触新出现的污染物，包括药品残留、农药、食品添加剂以及包装和瓶子生产中使用的化学品，与包括甲状腺疾病在内的疾病发病率增加有关。几种化学物质可能会对甲状腺胚胎发育和成人下丘脑-垂体-甲状腺（HPT）轴造成失调。在这项研究中，我们应用系统生物学方法来确定与胚胎和成年阶段人类甲状腺转录组数据中最高度上调和下调的基因相关的生物学过程。结果，新的基因/蛋白质-化学相互作用与甲状腺和HPT轴中已识别的毒性相关。该分析确定了195种不同的化学物质可能与这些高表达蛋白相互作用并表现出甲状腺毒性。我们的研究结果强调了发育时期是易受化学物质暴露的关键窗口，对甲状腺发育和编程有潜在的不利影响。最后，我们的数据提示了成人甲状腺中新出现的化学物质的新靶点，这些化学物质可能会损害甲状腺功能。

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引用次数: 0

Aggressive pituitary tumours and pituitary carcinomas: molecular insights guiding management and the role of precision oncology 侵袭性垂体肿瘤和垂体癌：分子见解指导管理和精确肿瘤学的作用。

IF 3.8 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2025-09-15 Epub Date: 2025-06-05 DOI: 10.1016/j.mce.2025.112598

LS Lamb , HW Sim , SJ Ramus , AI McCormack

Aggressive pituitary neuroendocrine tumours and pituitary carcinomas are associated with high morbidity and mortality and have limited treatment options. Increased understanding of the molecular pathogenesis of pituitary tumours has led to identification of molecular drivers of aggressive behaviour and prognostic markers, as well as identification of therapeutic targets. Mechanisms for pituitary tumourigenesis include chromosomal genomic instability, defective DNA repair, loss of cell cycle control, epigenetic changes, dysregulation of intracellular signalling pathways and alterations within the pituitary tumour immune microenvironment. Novel therapeutic treatment options including VEGF targeted therapies and immune checkpoint inhibitors have been used with varied responses. The application of precision oncology platforms to identify therapeutic targets is well described in other cancers and should be considered in the management of aggressive pituitary tumours and pituitary carcinomas. Histopathological analysis of established prognostic markers should be included in routine clinical practice.

侵袭性垂体神经内分泌肿瘤和垂体癌具有高发病率和死亡率，治疗选择有限。对垂体肿瘤分子发病机制的了解增加，导致了对攻击行为和预后标志物的分子驱动因素的识别，以及对治疗靶点的识别。垂体肿瘤发生的机制包括染色体基因组不稳定、DNA修复缺陷、细胞周期控制丧失、表观遗传改变、细胞内信号通路失调以及垂体肿瘤免疫微环境的改变。新的治疗选择包括VEGF靶向治疗和免疫检查点抑制剂已被用于不同的反应。精确肿瘤学平台用于确定治疗靶点的应用在其他癌症中得到了很好的描述，在侵袭性垂体肿瘤和垂体癌的治疗中应予以考虑。对已确定的预后标志物进行组织病理学分析应纳入常规临床实践。

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引用次数: 0

NOC2L inhibits trophoblast ferroptosis in preeclampsia through the p53/SLC7A11 pathway no2l通过p53/SLC7A11途径抑制子痫前期滋养细胞铁下垂。

IF 3.8 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2025-09-15 Epub Date: 2025-06-04 DOI: 10.1016/j.mce.2025.112589

Fengyun Su , Fanhua Shi , Chun Yang , Fei Zhao , Xiaolin Geng , Xiaojing Yang , Xudong Zhao

Background

NOC2L is downregulated in preeclampsia (PE). However, the underlying functional mechanisms of NOC2L in the pathogenesis of PE remain unclear.

Methods

Cell viability, migration, and invasion were determined in hypoxia-stimulated HTR-8/SVneo cells in CCK-8, wound healing, and Transwell assays. The levels of GSH, MDA and Fe²⁺ were measured using specific commercial kits. Lipid ROS levels were determined through C11-BODIPY staining. The protein levels were analyzed via western blotting. Additionally, a rat model of PE was used to examine the influence of NOC2L on the progression of PE and the associated ferroptosis.

Results

NOC2L overexpression increased the viability of hypoxia-treated trophoblast cells and increased the levels of GSH, SLC7A11, and GPX4 while simultaneously reducing Fe²⁺, MDA, and lipid ROS levels. Furthermore, both NOC2L overexpression and ferrostatin-1 application facilitated trophoblast migration and invasion. In contrast, NOC2L knockdown exacerbated the hypoxia-induced increase in ferroptosis and inhibited cell migratory and invasive capabilities. Notably, treatment with PFT-α, a p53 inhibitor, abolished the influence of NOC2L silencing on trophoblast cell functions. NOC2L overexpression was associated with improved blood pressure and urinary protein concentration, reduced pathological damage in the placenta, alterations in ferroptosis-related markers, and an increased survival rate in rat fetuses.

Conclusion

NOC2L inhibits trophoblast ferroptosis through the p53/SLC7A11 signaling pathway, potentially preventing the progression of PE.

背景：no2l在先兆子痫（PE）中下调。然而，NOC2L在PE发病中的潜在功能机制尚不清楚。方法：对缺氧刺激的HTR-8/SVneo细胞进行CCK-8、伤口愈合和Transwell试验，测定细胞活力、迁移和侵袭。GSH、MDA和Fe2+的水平用特定的商业试剂盒测定。通过C11-BODIPY染色测定脂质ROS水平。western blotting分析蛋白水平。此外，采用大鼠PE模型研究no2l对PE进展及相关铁下垂的影响。结果：no2l过表达可提高缺氧处理的滋养细胞活力，提高GSH、SLC7A11和GPX4水平，同时降低Fe2+、MDA和脂质ROS水平。此外，no2l过表达和铁抑素-1的应用都促进了滋养细胞的迁移和侵袭。相反，no2l敲低加重了缺氧诱导的铁下垂，抑制了细胞的迁移和侵袭能力。值得注意的是，PFT-α（一种p53抑制剂）可以消除no2l沉默对滋养细胞功能的影响。no2l过表达与大鼠胎儿血压和尿蛋白浓度的改善、胎盘病理损伤的减轻、死铁相关标志物的改变以及存活率的提高有关。结论：no2l通过p53/SLC7A11信号通路抑制滋养细胞铁下垂，可能阻止PE的进展。

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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 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2025-09-15 Epub 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

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.

甲状腺激素（THs），包括甲状腺素（T4）和三碘甲状腺原氨酸（T3），调节脊椎动物的发育，影响胚胎发生和幼虫阶段的关键过程。然而，它们在鱼类中的母体转移和发育作用仍然知之甚少。本研究探讨了母体THs对斑马鱼发育的影响，重点关注了生长和代谢的关键调节因子——体致轴。雌性斑马鱼饲喂12.5或25 μg T4/g体重/天的饲料，连续5天，对照组饲喂纯饲料。测量血浆TH水平，并将雌性与未经治疗的雄性交配。在受精后0 ~ 144小时评估胚胎和幼虫的存活、心跳、形态、T3含量和基因表达。母体T4升高会增加胚胎T3，导致生长迟缓、水肿、脊柱畸形、心动过速和死亡。基因表达分析揭示了TH轴组分和促生长基因的失调，突出了母体TH在发育轨迹和正常生长中的关键作用。

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引用次数: 0

From Gut to Brain: The roles of intestinal microbiota, immune system, and hormones in intestinal physiology and gut–brain–axis 从肠道到大脑：肠道微生物群、免疫系统和激素在肠道生理和肠-脑轴中的作用。

IF 3.8 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2025-09-15 Epub Date: 2025-06-06 DOI: 10.1016/j.mce.2025.112599

Muhammad Talha Khan , Muhammad Zohair , Areeba Khan , Ahmed Kashif , Sadia Mumtaz , Fiza Muskan

The intestine plays numerous roles in the normal physiology of our body. Gut-brain axis (GBA) is a complex communication network linking the gastrointestinal (GI) tract and central nervous system (CNS). This bidirectional system integrates endocrine, neural, and immune signals, impacting host metabolism and cognition. The gut microbiota, a critical component of the GBA, significantly impacts gut hormones, neurotransmission, neural development, and other components of gut-brain-axis. The microbiota-gut-brain axis facilitates communication via metabolites such as short chain fatty acids (SCFAs), and neurotransmitters such as dopamine, γ-amino butyric acid (GABA) and serotonin. The microbiota influences gut peptide production, including ghrelin, glucagon like pepetide-1 (GLP-1), serotonin, and cholecystokinin (CCK), thereby modulating nutrient absorption and immune responses. Gut hormones such as ghrelin, CCK, GLP-1, gastric inhibitory peptide (GIP), serotonin (5-HT), neurotensin, peptide YY (PYY) and melatonin play key roles in the GBA. These hormones play several roles including modulation of appetite and satiety, metabolism of nutrients such as lipid and glucose, insulin and glucagon secretion, and influence on gut inflammation, mood, learning and cognition. The interaction between gut microbiota and these hormones underscores their role in maintaining gut-brain homeostasis. Dysbiosis, or microbial imbalance, is linked to altered stress responses, anxiety, and depressive behaviors, highlighting the therapeutic potential of microbiota modulation. Despite the significant roles of gut hormones and microbiota in the GBA, literature on their cellular and molecular mechanisms is limited, and often based on animal models. This review synthesizes current understanding of hormones secreted by the intestine, their physiological effects and the cellular and molecular mechanisms of action underlying these effects, with a focus on their roles in the GBA. By elucidating these complex relationships, the review aims to advance research and clinical applications, offering insights into gastrointestinal and systemic health.

肠道在我们身体的正常生理中起着许多作用。肠脑轴（GBA）是连接胃肠道和中枢神经系统的复杂通讯网络。这个双向系统整合了内分泌、神经和免疫信号，影响宿主的代谢和认知。肠道微生物群是大湾区的重要组成部分，对肠道激素、神经传递、神经发育和肠-脑轴的其他组成部分有显著影响。微生物-肠-脑轴通过代谢物如短链脂肪酸（SCFAs）和神经递质如多巴胺、γ-氨基丁酸（GABA）和血清素促进交流。微生物群影响肠道肽的产生，包括胃饥饿素、胰高血糖素样肽-1 （GLP-1）、血清素和胆囊收缩素（CCK），从而调节营养吸收和免疫反应。胃饥饿素、CCK、GLP-1、胃抑制肽（GIP）、血清素（5-HT）、神经紧张素、多肽YY （PYY）和褪黑激素等肠道激素在GBA中发挥关键作用。这些激素起着多种作用，包括调节食欲和饱腹感、脂质和葡萄糖等营养物质的代谢、胰岛素和胰高血糖素的分泌以及对肠道炎症、情绪、学习和认知的影响。肠道微生物群和这些激素之间的相互作用强调了它们在维持肠-脑稳态中的作用。生态失调或微生物失衡与应激反应、焦虑和抑郁行为的改变有关，这突出了微生物群调节的治疗潜力。尽管肠道激素和微生物群在GBA中发挥着重要作用，但关于其细胞和分子机制的文献有限，而且通常基于动物模型。本文综述了目前对肠道分泌的激素、其生理作用以及这些作用背后的细胞和分子机制的了解，重点介绍了它们在GBA中的作用。通过阐明这些复杂的关系，本综述旨在推进研究和临床应用，为胃肠道和全身健康提供见解。

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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 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2025-09-15 Epub 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

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.

双调节蛋白（AREG）是一种表皮生长因子（EGF）样配体，是人卵泡液中主要的表皮生长因子受体（EGFR）配体，介导促黄体生成素（LH）对卵巢功能的影响。在本研究中，我们研究了AREG是否调节富半胱氨酸血管生成诱导因子61 （CYR61）和结缔组织生长因子（CTGF）这两个参与卵巢功能的关键基质细胞蛋白的表达，以及它们是否介导AREG诱导的环氧化酶-2 （COX-2）表达。利用人颗粒细胞肿瘤源性KGN细胞系和原代人颗粒叶黄素（hGL）细胞，我们证明了AREG处理以egfr依赖的方式上调CYR61和CTGF蛋白水平。机制分析显示，areg诱导CYR61和CTGF的表达是通过ERK1/2、AKT、CREB和YAP信号通路介导的。使用特异性抑制剂或小干扰RNA抑制这些途径可阻断areg诱导的CYR61和CTGF的表达，表明它们在这一过程中发挥重要作用。此外，CYR61和CTGF的下调减弱了AREG诱导的COX-2表达，确立了它们作为人颗粒细胞AREG信号传导的关键介质的作用。最后，我们的研究结果表明，LH处理诱导CYR61和CTGF的表达，并且这种诱导被EGFR抑制减弱。此外，CYR61和CTGF的下调降低了lh诱导的COX-2表达。这些发现为研究AREG调控卵巢功能的分子机制提供了新的见解，并突出了生殖健康研究的潜在目标。

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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 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2025-09-15 Epub 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

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.

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.

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.

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.

本研究旨在评估在运动或不运动的情况下，生长素是否可以逆转肥胖饮食对精子质量、代谢和内分泌（重点是LEAP2水平）造成的改变。取55只雄性Wistar大鼠，从断奶至产后第103天（pnd），随机分为5组（n = 11/组）：CD（标准饲料+水）；ObD（添加30%猪油+ 5%果糖的水的饲料）；ObD +胃饥饿素（致肥性饮食+ 6 nmol/只/天的pnd 85胃饥饿素）；ObD + Exc（致肥性饮食+标准化跑步轮运动，每天15分钟，每周3天）；ObD组体重增加加快，但ghrelin和/或Exc减慢体重增加。在pnd 103时，所有治疗组均明显轻于ObD组。ObD动物的代谢参数受损，运动显著改善代谢参数，使胆固醇和甘油三酯水平降至接近控制值，而胃饥饿素发挥适度作用，部分降低甘油三酯和甘油三酯/HDL指数，但仍使数值失调。与CD相比，ObD组精子浓度和活力显著降低；ghrelin和/或Exc完全逆转了这些有害影响。在接受致肥性饮食的动物中，血浆LEAP2明显更高，并且，LEAP2与精子浓度呈负相关，解释了22%的变异。我们首次证明了ghrelin逆转肥胖引起的精子质量改变的潜力。此外，ghrelin表现出与Exc相当的体重增加减缓作用。我们还发现LEAP2与精子浓度之间存在关联，这值得进一步研究。

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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 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2025-09-15 Epub Date: 2025-06-26 DOI: 10.1016/j.mce.2025.112607

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

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.

肠内分泌细胞是人类体内最丰富的激素产生细胞。虽然它们占胃肠道上皮的比例不到1%，但这些细胞通过分泌局部和全身作用的激素来调节肠道功能和全身代谢等功能，具有很大的生理影响。肠内分泌细胞与肠干细胞的分化是一个复杂的过程，不仅涉及谱系，而且涉及激素的调节。这篇综述强调了调节肠内分泌细胞分化和激素产生的特定信号通路和转录因子，并将最新发现整合到我们对这一过程日益增长的理解中。此外，它还描述了肠内分泌细胞及其分化如何参与和改变人类健康和疾病：特别是衰老，炎症性肠病，肥胖和糖尿病。最后，我们关注肠内分泌细胞如何靶向产生胰岛素，这是一个具有重要意义的新兴领域。了解驱动肠内分泌分化的分子和生理因素，将为这些细胞如何作为未来的治疗靶点提供重要的见解。

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