Molecular and Cellular Endocrinology最新文献_第9页

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 : 2025-06-24 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

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 : 2025-06-10 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

Corrigendum to “Angiotensin II type 2 receptor mediates high fat diet-induced cardiomyocyte hypertrophy and hypercholesterolemia” [Mol. Cell. Endocrinol. (2019), 498, 110576 (doi: 10.1016/j.mce.2019.110576)] “血管紧张素II型2受体介导高脂肪饮食诱导的心肌细胞肥大和高胆固醇血症”的勘误表[Mol. Cell]。性。[j].地球科学进展（2019），498,110576 （doi: 10.1016/j.m ece .2019.110576）。

IF 3.8 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2025-06-10 DOI: 10.1016/j.mce.2025.112590

Vanessa M. Lima , Caroline A. Lino , Nathalia Senger , Tábatha de Oliveira Silva , Renata I.B. Fonseca , Michael Bader , Robson A.S. Santos , Jose Donato Júnior , Maria Luiza M. Barreto-Chaves , Gabriela P. Diniz

引用次数: 0

Inhibition of the RIPK4 enhances suppression of human melanoma growth through vitamin D signaling RIPK4的抑制通过维生素D信号传导增强了对人类黑色素瘤生长的抑制。

IF 3.8 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2025-06-07 DOI: 10.1016/j.mce.2025.112603

Bartlomiej Olajossy , Andrzej T. Slominski , Agnieszka Wolnicka–Glubisz

Downregulation of Receptor-Interacting Protein Kinase 4 (RIPK4) inhibits NF-κB and Wnt/β-catenin signaling in melanoma and xenograft growth in mice. The active form of vitamin D3 (1,25-D3), in addition to regulating calcium and phosphate metabolism in humans through the vitamin D receptor (VDR), can inhibit the NF-κB signaling pathway and can affect the proliferation and differentiation of normal and malignant cells, including melanoma. An hyperactive NF-κB pathway maintains the malignant behavior of melanoma, which can be influenced by both RIPK4 and activated VDR. As their interactions affecting the response to 1,25-D3 in melanoma have not been studied, we tested whether downregulation of RIPK4 affects the sensitivity of melanoma cells to 1,25-D3. Our results have shown that both siRIPK4 and CRISPR/Cas9-mediated RIPK4 knockout increase VDR expression in melanoma cells. Furthermore, a decrease in CYP24A1 expression and an increase in 1,25 D3-induced VDR levels were observed in cells with RIPK4 downregulation. Treatment with 1,25- D3 of RIPK4.KO cells, compared to their wild-type counterparts, significantly reduced proliferation in 2D and 3D culture (MTT or ATP assay) and decreased p-p65 and cyclin D1 levels in melanoma cells. These results indicate that RIPK4 knockout may enhance the therapeutic efficacy of 1,25-D3 against melanoma, which encourages further studies on targeting RIPK4 signaling for anti-melanoma effects in preclinical models.

受体相互作用蛋白激酶4 （RIPK4）下调抑制小鼠黑色素瘤和异种移植物生长中NF-κB和Wnt/β-catenin信号传导活性形式的维生素D3 （1,25-D3）除了通过维生素D受体（VDR）调节人体钙和磷酸盐代谢外，还可以抑制NF-κB信号通路，影响包括黑色素瘤在内的正常和恶性细胞的增殖和分化。过度活跃的NF-κB通路维持了黑色素瘤的恶性行为，这可能受到RIPK4和激活的VDR的影响。由于它们之间的相互作用影响黑色素瘤对1,25- d3的反应尚未被研究，我们测试了RIPK4的下调是否会影响黑色素瘤细胞对1,25- d3的敏感性。我们的研究结果表明，siRIPK4和CRISPR/ cas9介导的RIPK4敲除均可增加黑色素瘤细胞中VDR的表达。此外，在RIPK4下调的细胞中，CYP24A1表达降低，1,25 d3诱导的VDR水平升高。RIPK4的1,25- D3处理。与野生型相比，KO细胞在2D和3D培养（MTT或ATP测定）中显著降低增殖，并降低黑色素瘤细胞中的p-p65和cyclin D1水平。这些结果表明，敲除RIPK4可能会增强1,25- d3对黑色素瘤的治疗效果，这鼓励在临床前模型中进一步研究靶向RIPK4信号通路的抗黑色素瘤作用。

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引用次数: 0

Sarcospan, a candidate gene of fat distribution, may affect lipid storage in adipocytes Sarcospan是脂肪分布的一个候选基因，可能影响脂肪细胞中的脂质储存。

IF 3.8 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2025-06-07 DOI: 10.1016/j.mce.2025.112602

Katharina Anastasia Dinter , Samantha Aurich , Luise Müller , Adhideb Ghosh , Falko Noé , Christian Wolfrum , Matthias Blüher , Anne Hoffmann , Peter Kovacs , Maria Keller

Background and aims

Genetic and epigenetic variations in the Sarcospan (SSPN) gene are associated with parameters of fat distribution (body mass index, waist-to-hip ratio), glucose homeostasis and adipocyte size in human potentially by affecting adipogenesis. This study aims at clarifying the impact of SSPN on adipogenesis, particularly focusing on its promoter methylation.

Materials and methods

Immortalized murine epididymal preadipocytes were transfected with fluorescence-marked plasmids coding for DNMT3a, CRISPR/dCas9-Suntag and vectors carrying guide RNAs complementary to the transcription start site region and differentiated to mature adipocytes. We performed siRNA-mediated Sspn knockdown in epididymal preadipocytes, measured target DNA methylation using pyrosequencing and quantified transcriptional changes of Sspn and adipogenic genes by qPCR. Additionally, we correlated SSPN mRNA values and clinical characteristics from a large human adipose tissue biobank (Leipzig Obesity Biobank).

Results

Epigenetic editing of the Sspn regulatory region in preadipocytes resulted in a significant increase (up to 35 %) in DNA promoter methylation throughout adipocyte differentiation but showed only minor effects on Sspn expression and fat storage. Though siRNA knockdown could also not contribute to understand the role of Sspn in a 2D adipogenesis model, large-scale correlation analyses still indicate the gene to be a key player in fat distribution and glucose homeostasis.

Conclusions

Although the epigenetic downregulation of Sspn showed only marginal effects on adipogenesis, associations of SSPN expression in human adipose tissue with parameters of fat distribution and glucose homeostasis make it a promising candidate for further studies addressing metabolic processes in adipose tissue.

背景和目的：Sarcospan （SSPN）基因的遗传和表观遗传变异与人体脂肪分布参数（体重指数、腰臀比）、葡萄糖稳态和脂肪细胞大小有关，可能通过影响脂肪形成。本研究旨在阐明SSPN对脂肪形成的影响，特别关注其启动子甲基化。材料和方法：用编码DNMT3a、CRISPR/dCas9-Suntag的荧光标记质粒和携带转录起始位点区域互补的引导rna的载体转染永生化小鼠附睾前脂肪细胞，分化为成熟脂肪细胞。我们在附睾前脂肪细胞中进行了sirna介导的Sspn敲低，使用焦磷酸测序测量了目标DNA甲基化，并通过qPCR量化了Sspn和脂肪生成基因的转录变化。此外，我们将来自大型人类脂肪组织生物库（Leipzig Obesity biobank）的SSPN mRNA值与临床特征相关联。结果：前脂肪细胞中Sspn调控区域的表观遗传编辑导致脂肪细胞分化过程中DNA启动子甲基化显著增加（高达35%），但对Sspn表达和脂肪储存的影响很小。虽然siRNA敲低也不能帮助理解Sspn在二维脂肪形成模型中的作用，但大规模相关分析仍然表明该基因在脂肪分布和葡萄糖稳态中起关键作用。结论：尽管Sspn的表观遗传下调对脂肪形成的影响微乎其微，但人类脂肪组织中Sspn表达与脂肪分布和葡萄糖稳态参数的关联使其成为进一步研究脂肪组织代谢过程的有希望的候选物。

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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 : 2025-06-06 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

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 : 2025-06-05 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

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 : 2025-06-05 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 : 2025-06-04 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

White beans (Phaseolus vulgaris L.) in diet reduces hypothalamic pro-inflammatory cytokines improving insulin resistance in small litter grown rats 饮食中的白豆（Phaseolus vulgaris L.）减少下丘脑促炎细胞因子，改善小窝大鼠的胰岛素抵抗

IF 3.8 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2025-05-26 DOI: 10.1016/j.mce.2025.112587

Ester Vieira Alves , Tatiane Vieira Alves , Lauro Sergio Barrozo Junior , Marcos Vinícius de Freitas Ribeiro , Adriel Felipe Freitas Nunes , Camila Luiza Rodrigues dos Santos Ricken , Ingridys Regina Borkenhagen , Bruno Vargas Teixeira Cavalheiro , Ginislene Dias , Ricardo de Oliveira , Gisele Facholi Bomfim , Júlio Cezar de Oliveira

In the present study we were interested in studying the effect of white beans (Phaseolus vulgaris L.) as diet supplementation on glucose-insulin and metabolic homeostasis in early overfeeding rats. Small litter (SL) was adjusted to 3 pups on post-natal day 3, while normal litter (NL) was kept with 8 pups. The milk collection and milk intake were performed, and the rat-offspring when weaned (at 22 days old), were fed a standard (NL-SD and SL-SD groups) or a white bean (2.5 % w/w) supplemented diet (NL-WB and SL-WB groups). Body weight, food and water intake were measured from weaning until adulthood (100 days old). Glucose and insulin tolerance, and intracerebroventricular insulin (10⁻³ mmol/L) tests were performed to assess peripheral and central insulin-glucose homeostasis in adult rats. Blood, hypothalamus, visceral fat pad and lean mass were collected. Milk from SL mothers displays high content of glucose, cholesterol, triglycerides and energy (P < 0.05). Milk consumption by SL rat-offspring, in early stage of suckling, was higher than NL rats (P<0.05). At adulthood, SL-SD rats were obese, hyperphagic, dyslipidemic, hyperglycemic, glucose intolerant and IR (P < 0.05). At adulthood, SL-SD rats displayed central IR and higher hypothalamic pro-inflammatory (TNF-α, 43.5 %; IL-6, 78.5 % and IL-1β, 50.1 %, P < 0.05) cytokine. The habitual ingestion of white beans-dietary supplementation prevented all those metabolic disruptions. In summary, white beans-dietary supplementation prevented obesity and glucose-insulin homeostasis deregulation in early overfeeding rats, avoiding hypothalamic inflammatory cytokines high levels and improving insulin sensitivity.

本研究旨在研究白豆（Phaseolus vulgaris L.）对早期过度喂养大鼠葡萄糖-胰岛素和代谢稳态的影响。产后第3天调整小窝（SL）为3只，正常窝（NL）为8只。取奶和采奶，断奶（22日龄）后分别饲喂标准饲粮（NL-SD组和SL-SD组）或添加白豆（2.5% w/w）的饲粮（NL-WB组和SL-WB组）。从断奶至成年（100日龄）测量体重、食物和水的摄入量。通过葡萄糖和胰岛素耐量以及脑室内胰岛素（10−3 mmol/L）测试来评估成年大鼠外周和中枢胰岛素-葡萄糖稳态。采集血液、下丘脑、内脏脂肪垫和瘦肉块。来自SL母鼠的乳汁显示出高含量的葡萄糖、胆固醇、甘油三酯和能量(P <；0.05)。在哺乳早期，SL大鼠子代的产奶量高于NL大鼠（P<0.05）。成年后，SL-SD大鼠出现肥胖、贪食、血脂异常、高血糖、葡萄糖不耐受和IR (P <；0.05)。成年后，SL-SD大鼠表现出中枢性IR和更高的下丘脑促炎因子(TNF-α, 43.5%；IL-6, 78.5%, IL-1β, 50.1%, P <；0.05)细胞因子。经常摄入白豆作为膳食补充剂可以防止所有这些代谢紊乱。综上所述，白豆膳食补充剂可预防早期过度喂养大鼠的肥胖和葡萄糖-胰岛素稳态失调，避免下丘脑炎症细胞因子高水平，改善胰岛素敏感性。

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