Molecular and Cellular Endocrinology最新文献_第2页

Special issue: An endocrinological perspective on metabolic diseases. 特刊：代谢疾病的内分泌学视角。

IF 3.6 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2026-02-04 DOI: 10.1016/j.mce.2026.112755

Alice C Rodrigues, Laureane Nunes Masi, Maria Teresa Nunes

引用次数: 0

HIF-2α expression is controlled by the progesterone receptor and regulates hCG-induced gene expression in granulosa cells during ovulation in mice HIF-2α的表达受孕激素受体的控制，并调节小鼠排卵期间颗粒细胞中hcg诱导的基因表达。

IF 3.6 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2026-02-03 DOI: 10.1016/j.mce.2026.112754

Alison E. Roennfeldt , Doan T. Dinh , Timothy R. McPhee , Ryan D. Rose , Kirsten M. Smith , Minnu Jayapal , Timothy P. Allen , Rebecca L. Robker , David C. Bersten , Daniel J. Peet , Darryl L. Russell

Ovulation is induced via a surge in gonadotrophin hormones, which increases the expression of the essential ovulatory transcription factor progesterone receptor (PGR) and its target genes. The importance of PGR in ovulation is well defined; however, the role of its many downstream genes largely remains unknown. Using mouse models of ovulation, we show that the Epas1 gene, which encodes the hypoxia inducible transcription factor 2α (HIF-2α), is expressed in a PGR-dependent manner during ovulation. Numerous HIF target genes increase in expression upon gonadotrophin stimulation in mouse granulosa cells, with expression of Epas1, but not its related isoform, Hif1a, increasing in a PGR-dependent manner. PGR directly binds introns of the Epas1 locus to enhance chromatin accessibility in ovarian granulosa cells in vivo, yet no evidence of PGR-dependent Epas1 expression was observed in PGR-expressing breast cancer cell lines, suggesting ovary-specific mechanisms of PGR-dependent Epas1 regulation. PGR activation in response to hormonal stimulation induced expression of a HIF reporter system in primary human granulosa cells, with HIF-2 inhibition with the small molecule PT-2385 confirming a HIF-2 contribution to this response. Upon HIF-2 inhibition with PT-2385 in mice, no change in ovulation counts were observed. However, gonadotrophin-induced ovary gene expression was significantly disrupted, supporting a model where HIF-2α contributes to the control of periovulatory gene expression downstream of PGR. In particular, inflammatory gene expression was dysregulated and a cohort of gonadotrophin-dependent genes, including Pgr, were elevated, suggesting impaired downregulation post-ovulation. These findings provide an important insight into regulation of the hypoxia inducible transcription factors during ovulation and how targeting HIF-2α may be of benefit in future fertility treatments.

排卵是通过促性腺激素的激增而诱导的，促性腺激素增加了必要的排卵转录因子黄体酮受体（PGR）及其靶基因的表达。PGR在排卵中的重要性是明确的；然而，它的许多下游基因的作用在很大程度上仍然未知。通过小鼠排卵模型，我们发现编码缺氧诱导转录因子2α (HIF-2α)的Epas1基因在排卵过程中以pgr依赖的方式表达。在小鼠颗粒细胞中，许多HIF靶基因在促性腺激素刺激下表达增加，其中Epas1的表达以pgr依赖的方式增加，而其相关亚型Hif1a的表达则不增加。在体内，PGR直接结合Epas1基因座的内含子增强卵巢颗粒细胞的染色质可及性，但在表达PGR的乳腺癌细胞系中未观察到PGR依赖性Epas1表达的证据，提示PGR依赖性Epas1调控的卵巢特异性机制。激素刺激下的PGR激活诱导原代人颗粒细胞中HIF报告系统的表达，而小分子PT-2385对HIF-2的抑制证实了HIF-2对这一反应的贡献。在用PT-2385抑制小鼠HIF-2后，未观察到排卵计数的变化。然而，促性腺激素诱导的卵巢基因表达明显中断，支持HIF-2α参与调控PGR下游围排卵期基因表达的模型。特别是，炎症基因表达失调，促性腺激素依赖基因（包括Pgr）升高，提示排卵后下调受损。这些发现为了解排卵过程中缺氧诱导转录因子的调控以及靶向HIF-2α如何在未来的生育治疗中获益提供了重要的见解。

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引用次数: 0

The impact of maternal vitamin D deficiency during pregnancy and lactation on autism-like behavior in offspring 孕期和哺乳期母亲维生素D缺乏对后代自闭症样行为的影响。

IF 3.6 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2026-01-29 DOI: 10.1016/j.mce.2026.112737

Xiao-Yue Song , Hong-Ning He , Lin-Jing Tuo , Bo Wang , Heng Zhang , De-Xiang Xu

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social impairments and stereotyped behaviors. Many epidemiological studies have found a potential relationship between vitamin D deficiency (VDD) and ASD. However, the mechanism remains unclear. In this study, a VDD model was established by feeding a vitamin D-depleted diet to 5-week-old female mice, from their adulthood through pregnancy to end of lactation. Social deficits, repetitive stereotyped behaviors and anxiety-like behaviors were evaluated in the offspring. The results showed the number of buried marbles was increased in the female offspring of the VDD group. Social defects were observed in both male and female offspring in the VDD group. Mechanistically, several markers of cell proliferation, such as Pcna and Ki67, were upregulated. And the number of TBR2⁺ cell, an intermediate progenitor cell, was increased in cerebral cortex of VDD-fed fetuses. Moreover, DKK1, a WNT/β-catenin pathway repressor, was elevated in cerebral cortex of VDD-fed fetuses. By contrast, β-catenin, a critical effector of the WNT/β-catenin pathway, was reduced in cerebral cortex of GD14 VDD fetuses. These results provide partial evidence that maternal vitamin D deficiency during pregnancy and lactation induces autism-like behaviors partly by suppressing WNT/β-catenin pathway in the cerebral cortex.

自闭症谱系障碍（ASD）是一种以社交障碍和刻板行为为特征的神经发育障碍。许多流行病学研究已经发现维生素D缺乏（VDD）和自闭症之间的潜在关系。然而，其机制尚不清楚。在本研究中，通过给5周龄的雌性小鼠喂食缺乏维生素d的饮食，从成年期到妊娠期到哺乳期结束，建立了VDD模型。对后代的社交缺陷、重复刻板行为和焦虑样行为进行了评估。结果显示，在VDD组的雌性后代中，埋弹珠的数量增加了。VDD组雌雄子代均存在社会性缺陷。机制上，一些细胞增殖标志物，如Pcna和Ki67，上调。在vdd喂养的胎儿大脑皮层中，中间祖细胞TBR2+细胞数量增加。此外，WNT/β-catenin通路抑制因子DKK1在vdd喂养的胎儿大脑皮层中升高。相比之下，WNT/β-catenin通路的关键效应因子β-catenin在GD14 VDD胎儿的大脑皮层中减少。这些结果提供了部分证据，证明孕期和哺乳期母体维生素D缺乏部分通过抑制大脑皮层WNT/β-catenin通路诱导自闭症样行为。

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引用次数: 0

Plasma proteome mendelian randomization and network pharmacology reveal therapeutic targets for thyroid disorders 血浆蛋白质组孟德尔随机化和网络药理学揭示甲状腺疾病的治疗靶点

IF 3.6 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2026-01-29 DOI: 10.1016/j.mce.2026.112752

Chao Wang , Yi Cai , Xing Yang, Jie Jie

Introduction

Thyroid disorders, including hypothyroidism, hyperthyroidism, and thyroid cancer, impose a substantial global health burden. Existing treatments face limitations due to adverse effects and incomplete efficacy, highlighting the need for innovative therapeutic strategies informed by genetic and molecular insights.

Methods

We integrated Mendelian randomization (MR) with network pharmacology to systematically prioritize druggable targets. Genetic correlations between different thyroid disorders were evaluated using linkage disequilibrium score regression analysis. Plasma protein quantitative trait loci from 4907 plasma proteins were leveraged as instrumental variables in MR analyses across two independent cohorts. Bayesian colocalization validated shared causal variants. Network pharmacology methods encompassed constructing protein-protein interaction networks, conducting functional enrichment analyses, and identifying potential therapeutic compounds via the DSigDB database. Docking and dynamics simulations assessed binding and stability, while PheWAS assessed off-target effects.

Results

The LDSC analysis identified notable genetic correlations of hypothyroidism with hyperthyroidism (Rg = 0.167, P = 0.017), as well as hyperthyroidism with thyroid cancer (Rg = 0.286, P = 0.033). MR and colocalization identified seven causal proteins: IL2RB, CDH1, FGF19 (hypothyroidism); PSAPL1 (hyperthyroidism); DCP1B, SPRN, RPS6KA6 (thyroid cancer). Drug prediction prioritized compounds such as BI-2536 (binding energy: −9.5 kcal/mol with RPS6KA6) and deoxycholic acid. PheWAS confirmed minimal pleiotropic risks.

Conclusions

By synergizing genetic epidemiology with network pharmacology, this study delineates shared genetic architecture among thyroid disorders and nominates seven high-confidence targets with therapeutic potential. The integrative framework advances precision medicine by bridging causal plasma protein identification, mechanistic pathway mapping, and drug repurposing, offering a blueprint for multi-omics-driven drug discovery in endocrine pathologies.

甲状腺疾病，包括甲状腺功能减退、甲状腺功能亢进和甲状腺癌，造成了巨大的全球健康负担。由于不良反应和不完整的疗效，现有的治疗方法面临局限性，这突出了对基于遗传和分子见解的创新治疗策略的需求。方法将孟德尔随机化与网络药理学相结合，系统优选可用药靶点。使用连锁不平衡评分回归分析评估不同甲状腺疾病之间的遗传相关性。来自4907个血浆蛋白的血浆蛋白数量性状位点被用作两个独立队列中MR分析的工具变量。贝叶斯共定位验证了共享的因果变量。网络药理学方法包括构建蛋白质-蛋白质相互作用网络，进行功能富集分析，并通过DSigDB数据库识别潜在的治疗化合物。对接和动力学模拟评估了结合和稳定性，而PheWAS评估了脱靶效应。结果LDSC分析发现甲状腺功能减退与甲状腺功能亢进（Rg = 0.167, P = 0.017）、甲状腺功能亢进与甲状腺癌（Rg = 0.286, P = 0.033）具有显著的遗传相关性。MR和共定位鉴定出7种致病蛋白：IL2RB、CDH1、FGF19（甲状腺功能减退）；PSAPL1(甲状腺机能亢进);DCP1B， SPRN, RPS6KA6（甲状腺癌）。药物预测优先考虑BI-2536（与RPS6KA6的结合能：−9.5 kcal/mol）和脱氧胆酸等化合物。PheWAS证实多效性风险最小。结论本研究将遗传流行病学与网络药理学相结合，描绘了甲状腺疾病的共同遗传结构，并确定了7个具有治疗潜力的高可信度靶点。该整合框架通过连接因果血浆蛋白鉴定、机制通路绘制和药物再利用来推进精准医学，为内分泌病理中多组学驱动的药物发现提供了蓝图。

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引用次数: 0

FNDC4 regulates M2 polarization of tumor-associated macrophages to affect colorectal cancer metastasis FNDC4调节肿瘤相关巨噬细胞M2极化影响结直肠癌转移。

IF 3.6 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2026-01-28 DOI: 10.1016/j.mce.2026.112738

Shengyuan Liu , Feng Huang , Jianmin Wang , Jingfeng Liu

A very dangerous tumor, colon cancer has the potential to spread and come back. Investigating FNDC4's function in colon cancer and its molecular mechanism is the goal of this study. The expression of FNDC4 and M2 macrophage-related genes (CD163 and CD206) in tumor tissues was found using immunohistochemistry. After transfecting colorectal cancer cells with the FNDC4 knockdown plasmid, CCK8, clone formation, scratch assay, and Transwell test were used to determine cell proliferation, migration, and invasion. Using flow cytometry, the amount of CD163, CD206, and the rate of cell death were found. Western blot was utilized to identify the expression of proteins associated with the Akt/STAT3 pathway, M2 macrophages, and epithelial-mesenchymal cells. To see how sh-FNDC4 affected tumor growth, a xenograft tumor model was created, and H&E staining was used to look at liver tissue metastases. The findings demonstrated that FNDC4 was favorably connected with the expression of CD206 and CD163 and that it was substantially expressed in colorectal cancer. Tumor cell proliferation, migration, invasion, EMT, and M2 macrophage polarization were all reduced by FNDC4 knockdown. Furthermore, FNDC4 knockdown suppressed tumor growth and liver metastasis in vivo by blocking the Akt/STAT3 pathway. In conclusion, FNDC4's modulation of the Akt/STAT3 pathway may be the reason why its knockdown prevented colorectal cancer cell proliferation, metastasis, and M2 macrophage polarization.

结肠癌是一种非常危险的肿瘤，有扩散和复发的可能。探讨FNDC4在结肠癌中的功能及其分子机制是本研究的目的。免疫组化检测肿瘤组织中FNDC4和M2巨噬细胞相关基因（CD163和CD206）的表达。用FNDC4敲低质粒转染结直肠癌细胞后，采用CCK8、克隆形成、划痕试验和Transwell试验检测细胞增殖、迁移和侵袭。流式细胞术检测CD163、CD206的表达量及细胞死亡率。Western blot检测Akt/STAT3通路相关蛋白、M2巨噬细胞和上皮间充质细胞的表达。为了观察sh-FNDC4如何影响肿瘤生长，我们制作了一个异种移植肿瘤模型，并用H&E染色观察肝组织转移。研究结果表明，FNDC4与CD206和CD163的表达密切相关，并在结直肠癌中大量表达。FNDC4敲低后，肿瘤细胞的增殖、迁移、侵袭、EMT、M2巨噬细胞极化均降低。此外，FNDC4敲低通过阻断Akt/STAT3通路，在体内抑制肿瘤生长和肝转移。综上所述，FNDC4对Akt/STAT3通路的调控可能是其敲低抑制结直肠癌细胞增殖、转移和M2巨噬细胞极化的原因。

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引用次数: 0

2-Hydroxyestradiol regulates extracellular matrix deposition through estrogen receptor beta activation in airway smooth muscle cells 2-羟基雌二醇通过激活气道平滑肌细胞雌激素受体调节细胞外基质沉积

IF 3.6 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2026-01-28 DOI: 10.1016/j.mce.2026.112753

Ashish Kumar , Mohammad Irshad Reza , Anurag Banerjee , Nilesh Sudhakar Ambhore , Premanand Balraj , Buddhadev Layek , Michael A. Thompson , John R. Hawse , Christina M. Pabelick , Y.S. Prakash , Venkatachalem Sathish

Airway remodeling in asthma is characterized by increased extracellular matrix (ECM) production and deposition by airway smooth muscle (ASM) cells. Existing studies have shown contrasting effects of 17β-estradiol (E₂) in regulating ASM cellular remodeling via differential activation of estrogen receptors (ERs: α and β). Even though downstream metabolites of E₂ (2-hydroxyestradiol: 2-HE and 16-hydroxyestradiol: 16αHE₂) are gaining recognition for their biological roles in various cellular systems, their role in ASM remodeling remains largely unexplored. Here, we explore the effects of 2-HE and 16αHE₂, a highly potent metabolites, on ECM remodeling in ASM. ECM mRNA's/proteins expression and deposition were determined by Western blotting, qRT-PCR, and In-Cell Western analysis. Interaction of metabolites with ERs was performed using a docking study and their impact on regulation of an estrogen response element (ERE) was monitored via a luciferase reporter assay. Further, the ER-specific effect of metabolites was validated using shRNA-mediated ERα and ERβ knockdown ASM cells. 16αHE₂ exposure showed no notable changes in transforming growth factor-β (TGF-β)-induced ECM proteins expression and deposition, whereas 2-HE exposure blunted the TGF-β effects. Molecular docking unveiled the binding of 16αHE₂ with ERα, while 2-HE more strongly bound to ERβ, which was also confirmed by ERE-luciferase assay. In ERβ knockdown ASM cells, 2-HE inhibited the TGF-β-induced phosphorylation of SMAD2/3, AKT, and ERK1/2. However, 16αHE₂ failed to elicit any of these effects. Furthermore, 2-HE significantly decreased the TGF-β-induced transcriptional activities of AP-1 and NF-κB. Overall, our findings suggest 2-HE blunts TGF-β-induced ECM through ERβ; therefore, it may serve as a novel therapeutic target for airway remodeling and asthma.

哮喘气道重塑的特征是气道平滑肌（ASM）细胞细胞外基质（ECM）的产生和沉积增加。已有研究表明，17β-雌二醇（E2）通过雌激素受体（er: α和β）的差异激活调节ASM细胞重塑的不同作用。尽管E2的下游代谢物（2-羟基雌二醇：2-HE和16-羟基雌二醇：16αHE2）在各种细胞系统中的生物学作用已得到认可，但它们在ASM重塑中的作用仍未得到充分研究。在这里，我们探讨了2-HE和16αHE2（一种高效的代谢物）对ASM中ECM重塑的影响。通过Western blotting、qRT-PCR和In-Cell Western分析检测ECM mRNA /蛋白的表达和沉积。代谢物与内质网的相互作用是通过对接研究进行的，它们对雌激素反应元件（ERE）调节的影响是通过荧光素酶报告试验监测的。此外，通过shrna介导的ERα和ERβ敲除ASM细胞，验证了代谢物的er特异性作用。16αHE2暴露对转化生长因子-β (TGF-β)诱导的ECM蛋白表达和沉积无显著影响，而2-HE暴露对TGF-β的作用减弱。分子对接发现16αHE2与ERα结合，而2-HE与ERβ结合更强，这也被ere荧光素酶实验证实。在ERβ敲除的ASM细胞中，2-HE抑制TGF-β诱导的SMAD2/3、AKT和ERK1/2的磷酸化。然而，16αHE2没有引起任何这些影响。2-HE显著降低TGF-β-诱导的AP-1和NF-κB的转录活性。总的来说，我们的研究结果表明，2-HE通过ERβ减弱TGF-β诱导的ECM；因此，它可能成为气道重塑和哮喘治疗的新靶点。

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引用次数: 0

Metabolite profiling of the effect of prenatal stimuli across postnatal treatments in the liver 产前刺激对肝脏产后治疗影响的代谢物分析

IF 3.6 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2026-01-28 DOI: 10.1016/j.mce.2026.112744

Bruce R. Southey , Andrea N. Gomez , Gloria R. Sunderland , Chance W. Riggins , Maria B. Villamil , Sandra L. Rodriguez-Zas

Hepatic molecular mechanisms can be modulated by pro- and anti-inflammatory signals associated with infections and nutritional changes that can, in turn, affect the endocrine system. The sex-specific interplay between stimuli on hepatic pathways was studied using a biomedical model. The liver metabolome of pigs exposed to a prenatal immune activation from maternal infection was compared to that of matching female and male controls. Within prenatal treatment and sex group, the postnatal treatments were synthetic inflammatory factor, feeding deprivation (fasting), or saline. Liquid chromatography mass spectrometry enabled the detection of 2554 metabolites with significant (False Discovery Rate-adjusted p-value <0.05) sex, prenatal, and postnatal treatment effects. The glycine, serine, and threonine metabolism, RNA metabolism, and neurotransmitter transporters pathways included metabolites with prenatal-by-postnatal treatment interaction effects, such as alanine, arginine, and ketobutyric acid. These disruptions can impact hepatic detoxification, protein synthesis, and methylation. The synergistic interaction for adenosylhomocysteine was characterized by higher levels in the postnatal fasted relative to the saline-treated group, whereas this trend was 4.5-fold higher in the prenatal immune-activated group compared to controls. The antagonistic interaction for chenodeoxycholyltaurine was characterized by higher levels in prenatal-activated relative to controls under saline conditions, whereas this trend declined 2.2-fold in the postnatal-stimulated groups. Sex-specific effects were observed for glutamic acid, with differences between prenatal groups 4.7 times higher in males than in females. These findings offer insights into the interplay between sex, prenatal, and postnatal stimuli across pathways that must be considered in the development of therapies to optimize liver function.

肝脏分子机制可通过与感染和营养变化相关的促炎和抗炎信号调节，进而影响内分泌系统。使用生物医学模型研究了刺激对肝脏通路的性别特异性相互作用。将暴露于母体感染的产前免疫激活的猪的肝脏代谢组与匹配的雌性和雄性对照进行比较。在产前治疗组和性别组中，产后治疗分别为合成炎症因子治疗、禁食治疗和生理盐水治疗。液相色谱-质谱法检测出2554种代谢物，其性别、产前和产后治疗效果显著（经错误发现率调整p值<；0.05）。甘氨酸、丝氨酸和苏氨酸代谢、RNA代谢和神经递质转运途径包括具有产前-产后治疗相互作用的代谢物，如丙氨酸、精氨酸和酮丁酸。这些破坏会影响肝脏解毒、蛋白质合成和甲基化。与盐水处理组相比，产后禁食组的腺苷型同型半胱氨酸的协同作用水平较高，而产前免疫激活组的这一趋势是对照组的4.5倍。在生理盐水条件下，与对照组相比，产前激活组的鹅脱氧胆磺酸的拮抗相互作用水平较高，而产后刺激组的这一趋势下降了2.2倍。对谷氨酸的性别特异性影响被观察到，在产前组之间，男性的差异是女性的4.7倍。这些发现为性别、产前和产后刺激之间的相互作用提供了见解，在优化肝功能的治疗开发中必须考虑这些途径。

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引用次数: 0

Triploidy alters hormonal and paracrine signaling to promote male development in zebrafish 三倍体改变荷尔蒙和旁分泌信号，促进斑马鱼的雄性发育。

IF 3.6 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2026-01-27 DOI: 10.1016/j.mce.2026.112740

Aarón Torres-Martínez , Tomáš Tichopád , Martin Pšenička , Roman Franěk

Sex differentiation in zebrafish is governed by a complex interplay of genetic and endocrine signals. Triploid zebrafish, which are largely sterile, consistently develop as males, but the underlying mechanisms remain elusive. Here, we combined histological and transcriptomic analyses to examine how triploidy and exposure to 17α-ethinylestradiol (EE2) modulate sex differentiation in zebrafish. Triploidy disrupted hormonal and paracrine signaling, with downregulation of fshr and amh, upregulation of igf3, potential activation of β-catenin pathway, and suppression of ptger2a and dio1, resulting in complete masculinization. In diploids, EE2 exposure resulted in a wide range of gonadal phenotypes, from testes and ovotestes to fully developed ovaries, reflecting the complexity and variable sensitivity of zebrafish sex differentiation to hormonal stimuli. Potential mechanistic insights underlying these outcomes are provided. By contrast, long exposure of triploid zebrafish to EE2 promoted the expansion of early germ cells, but failed to induce ovarian differentiation, suggesting a fixed male trajectory induced by triploidy. Triploids also showed a distinct endocrine state, lacking the EE2-induced suppression of cyp11c1 observed in diploids, suggesting altered corticosteroid homeostasis that may reinforce masculinization. Both triploidy and EE2 administration altered meiosis and spermiogenesis, consistent with the downregulation of klhl10 and constrained retinoic acid signaling through dhrs3a and/or cyp26b1. At the molecular level, both triploidy and EE2 converged on suppression of early steroidogenic genes, including star and cyp11a1, indicating limited androgen and estrogen biosynthesis. Together, these findings reveal how triploidy reshapes endocrine regulation and responsiveness and reveal shared and unique molecular pathways by which EE2 influences zebrafish gonadal fate.

斑马鱼的性别分化是由遗传和内分泌信号复杂的相互作用所控制的。三倍体斑马鱼在很大程度上是不育的，它们一直发育为雄性，但潜在的机制仍然是难以捉摸的。在这里，我们结合组织学和转录组学分析来研究三倍体和暴露于17α-炔雌醇（EE2）如何调节斑马鱼的性别分化。三倍体破坏激素和旁分泌信号，下调fshr和amh，上调igf3，潜在激活β-catenin通路，抑制ptger2a和dio1，导致完全雄性化。在二倍体中，EE2暴露导致了广泛的性腺表型，从睾丸和卵睾丸到完全发育的卵巢，反映了斑马鱼性别分化对激素刺激的复杂性和可变敏感性。提供了这些结果的潜在机制见解。相比之下，长时间暴露于EE2的三倍体斑马鱼促进了早期生殖细胞的扩增，但未能诱导卵巢分化，这表明三倍体诱导的雄性轨迹是固定的。三倍体也表现出独特的内分泌状态，缺乏二倍体中观察到的ee2诱导的cyp11c1抑制，这表明皮质类固醇体内平衡的改变可能会加强雄性化。三倍体和EE2都改变了减数分裂和精子发生，这与klhl10的下调和通过dhrs3a和/或cyp26b1抑制维甲酸信号传导一致。在分子水平上，三倍体和EE2趋同于抑制早期类固醇基因，包括star和cyp11a1，表明雄激素和雌激素的生物合成受到限制。总之，这些发现揭示了三倍体如何重塑内分泌调节和反应性，并揭示了EE2影响斑马鱼性腺命运的共同和独特的分子途径。

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引用次数: 0

Glial activation and increased blood brain barrier permeability in the medial preoptic area of male mice lacking neural androgen receptor 缺乏雄激素受体的雄性小鼠内侧视前区神经胶质活化和血脑屏障通透性增加

IF 3.6 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2026-01-27 DOI: 10.1016/j.mce.2026.112742

Nida Karameh , Afnan Atallah , Danaé Nuzzaci , Valérie Grange-Messent , Sakina Mhaouty-Kodja

We have previously shown that testosterone depletion in adult male mice induced neural androgen receptor (Ar) down-regulation and led to neuroinflammation and increased blood brain barrier (BBB) permeability in the medial preoptic area. In the present study, we investigated the effects of neural Ar deletion on glial function and BBB integrity in male mice. For this purpose, we used control and mutant littermates obtained from a mouse line deleted for the Ar in neural progenitors by Cre-loxP technology. Neural Ar deletion induced glial activation evidenced by increased immunoreactivity against markers of astrocytes (glial fibrillary acidic protein -GFAP- and N-myc downstream-regulated gene 2) and microglia (ionized calcium binding adaptor molecule 1). Fluoro-Jade® C fluorescent labeling was increased and inflammatory molecules such as inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX2) were detected in the vicinity of capillaries in the male medial preoptic area of neural Ar knockout mice. Analysis of BBB integrity showed enhanced permeability for Evans Blue tracer and endogenous immunoglobulins in mutant animals compared to their control littermates. In addition, modifications in the ultrastructural organization of capillary endothelial tight junctions were observed by electron tomography. These effects were specific to neural Ar deletion since no changes were observed for GFAP-immunoreactivity, BBB permeability or Fluoro-Jade® C labeling in male mice expressing the wild type Ar allele and carrying the Cre transgene.

Altogether, these data indicate the key role of the neural AR in testosterone-induced regulation of astrocyte, microglial and BBB functions in the medial preoptic area of male mice.

我们之前的研究表明，成年雄性小鼠的睾酮消耗诱导神经雄激素受体（Ar）下调，导致神经炎症和内侧视前区血脑屏障（BBB）通透性增加。在本研究中，我们研究了神经Ar缺失对雄性小鼠神经胶质功能和血脑屏障完整性的影响。为此，我们使用了通过Cre-loxP技术从神经祖细胞中删除Ar的小鼠系中获得的对照和突变幼崽。神经Ar缺失诱导胶质细胞活化，这可以通过增强对星形胶质细胞（胶质纤维酸性蛋白- gfap -和N-myc下游调控基因2）和小胶质细胞（离子钙结合接头分子1）标记物的免疫反应性来证明。Fluoro-Jade®C荧光标记增强，在雄性神经Ar敲除小鼠内侧视前区毛细血管附近检测到诱导型一氧化氮合酶（iNOS）和环氧化酶2 （COX2）等炎症分子。血脑屏障完整性分析显示，与对照组相比，突变动物的Evans Blue示踪剂和内源性免疫球蛋白的渗透性增强。此外，通过电子断层扫描观察到毛细血管内皮紧密连接的超微结构组织的变化。这些影响是神经Ar缺失所特有的，因为在表达野生型Ar等位基因并携带Cre转基因的雄性小鼠中，没有观察到gfap免疫反应性、血脑屏障通透性或Fluoro-Jade®C标记的变化。总之，这些数据表明，神经AR在睾丸激素诱导的雄性小鼠内侧视前区星形胶质细胞、小胶质细胞和血脑屏障功能的调节中起关键作用。

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引用次数: 0

Hyperglycemia differentially regulates osteoblast and osteoclast autophagy via AMPK/mTOR/p70 S6K signaling in diabetic osteoporosis 糖尿病骨质疏松症中，高血糖通过AMPK/mTOR/p70 S6K信号调控成骨细胞和破骨细胞自噬的差异

IF 3.6 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2026-01-27 DOI: 10.1016/j.mce.2026.112739

Bin Zhou , Fen Feng , Cila Zhou , Kuang Yao , Ping Huang

Type 2 diabetes mellitus (T2DM) often induces diabetic osteoporosis (DOP) with impaired bone remodeling, yet its underlying mechanism remains elusive. This study identified the differential regulatory role of the AMPK/mTOR/p70 S6K signaling axis in bone cell function. In vivo, diabetes reduced AMPK phosphorylation, enhanced mTOR/p70 S6K activation, and diminished autophagy in rat femoral tissue. In vitro, HG exerted cell-type-specific effects via the AMPK signaling pathway: in osteoblasts, HG inhibited AMPK phosphorylation, activated mTOR/p70 S6K, suppressed autophagy, and impaired mineralization as well as alkaline phosphatase (ALP) activity; conversely, in osteoclasts, HG enhanced autophagy through the inverse regulatory pathway and accelerated osteoclast differentiation and bone resorption. Collectively, these findings illustrate that hyperglycemia disrupts bone homeostasis via cell-type-specific regulation of AMPK, suggesting that AMPK-mediated autophagy serves as a potential critical therapeutic target for diabetes-related bone diseases.

2型糖尿病（T2DM）常诱发糖尿病性骨质疏松症（DOP）并伴骨重塑受损，但其潜在机制尚不清楚。本研究确定了AMPK/mTOR/p70 S6K信号轴在骨细胞功能中的差异调节作用。在体内，糖尿病降低了AMPK的磷酸化，增强了mTOR/p70 S6K的激活，减少了大鼠股组织的自噬。在体外，HG通过AMPK信号通路发挥细胞类型特异性作用：在成骨细胞中，HG抑制AMPK磷酸化，激活mTOR/p70 S6K，抑制自噬，损害矿化和碱性磷酸酶（ALP）活性；相反，在破骨细胞中，HG通过逆调控途径增强自噬，加速破骨细胞分化和骨吸收。总之，这些发现表明，高血糖通过细胞类型特异性调节AMPK破坏骨稳态，表明AMPK介导的自噬是糖尿病相关骨病的潜在关键治疗靶点。

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