Molecular and Cellular Endocrinology最新文献_第9页

Corrigendum to “The BRAFV600E mutation maintains the aggressiveness of papillary thyroid cancers requiring downregulation of primary cilia” [Mol. Cell. Endocrinol. 581 (2024) 112113] “BRAFV600E突变维持甲状腺乳头状癌的侵袭性需要下调初级纤毛”的更正[Mol. Cell.]。中西医结合杂志[j].中华医学杂志。2016,36(2):444 - 444。

IF 3.6 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2025-07-31 DOI: 10.1016/j.mce.2025.112626

Cheng-Xu Ma , Xiao-Ni Ma , Jin-Jin Liu , Cong-Hui Guan , Ying-Dong Li , Nan Zhao , Dídac Mauricio , Song-Bo Fu

引用次数: 0

The effect of Semaglutide on mitochondrial function and insulin sensitivity in a myotube model of insulin resistance 西马鲁肽对胰岛素抵抗肌管模型线粒体功能和胰岛素敏感性的影响

IF 3.6 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2025-07-31 DOI: 10.1016/j.mce.2025.112629

Emmalie R. Spry, Kipton B. Travis, Kayla J. Ragland, Alexa J. Klein, John M. Zimmerman, Roger A. Vaughan

Aims

Semaglutide (SEMA) is a glucagon-like peptide-1 receptor agonist (GLP-1RA) that has recently emerged as a popular pharmacological treatment for type 2 diabetes and insulin resistance due to its weight loss properties. Previous studies have examined the metabolic effects of SEMA using supra-pharmacokinetically (but not pharmacokinetically attainable) concentrations. The aim of the present study was to determine the metabolic effects of pharmacokinetically attainable levels of SEMA on mitochondrial function and metabolism, which are often reduced during insulin resistance.

Methods

C2C12 myotubes were treated for 24 h with SEMA at 10 nM which approximates pharmacokinetically attainable blood concentrations in vivo. Metabolic gene expression was measured using qRT-PCR. pAkt expression was assessed using Western blot. Seahorse metabolic assays were also used to measure mitochondrial and glycolytic metabolism. Fluorescent staining was used to assess mitochondrial and lipid content.

Results

Treatment with SEMA did not alter mitochondrial function, content, or related gene expression. Similarly, SEMA had no significant effect on glycolytic metabolism or related gene expression, nor did it alter cellular lipid content or lipogenic signaling.

Conclusions

High concentrations of SEMA may promote mitochondrial function during in vitro experiments, however the findings from the present report suggest pharmacokinetically attainable levels of SEMA do not alter myotube metabolism or expression of related molecular targets. Disparities in the present report and past observations may be a result of the lower concentrations of SEMA used in the present experiments. Further in vivo studies will be necessary to elucidate the full metabolic effects of SEMA on skeletal muscle.

SEMA （SEMA）是一种胰高血糖素样肽-1受体激动剂（GLP-1RA），由于其减肥特性，最近成为2型糖尿病和胰岛素抵抗的流行药物治疗。以前的研究已经使用超药代动力学（但不是药代动力学可达到的）浓度检测了SEMA的代谢作用。本研究的目的是确定药代动力学可达到的SEMA水平对线粒体功能和代谢的代谢影响，这在胰岛素抵抗期间通常会降低。方法sc2c12肌管用10 nM的SEMA处理24 h，该浓度接近体内药代动力学可达到的血药浓度。采用qRT-PCR检测代谢基因表达。Western blot检测pAkt表达。海马代谢测定也用于测定线粒体和糖酵解代谢。荧光染色测定线粒体和脂质含量。结果SEMA治疗未改变线粒体功能、含量或相关基因表达。同样，SEMA对糖酵解代谢或相关基因表达没有显著影响，也没有改变细胞脂质含量或脂肪生成信号。结论：在体外实验中，高浓度SEMA可能促进线粒体功能，但本报告的研究结果表明，可达到的SEMA药代动力学水平不会改变肌管代谢或相关分子靶点的表达。本报告与过去观察结果的差异可能是由于本实验中使用的SEMA浓度较低所致。进一步的体内研究将有必要阐明SEMA对骨骼肌的全面代谢作用。

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引用次数: 0

The sex-chromosomes related cellular dimorphism in physiology and pathology 生理和病理上与性染色体有关的细胞二态性

IF 3.6 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2025-07-30 DOI: 10.1016/j.mce.2025.112630

Cristina Antinozzi, Paolo Sgrò, Luigi Di Luigi

Sex-based biological differences have a profound impact on health and disease. Historically, these disparities were primarily attributed to differences in gonadal hormones. Recent advances in biochemistry and molecular biology, however, have revealed additional contributing mechanisms—most notably, the critical role of genes located on the X and Y chromosomes. The expression of Y-linked genes, increased dosage of X-linked genes in XX compared to XY cells due to incomplete X-chromosome inactivation, genomic imprinting, and the presence of non-coding and micro-RNAs on the X chromosome are all factors that require consideration in the development of in vitro models addressing sex dimorphism.

In the present narrative review, we propose studies showing sex differences in vascular and cardiac cells, skeletal muscle cells, adipose tissue, liver, immune cells, cancer tissues and brain tissues. Given the absence of appropriate experimental methodologies for reproducing in vitro the sex differences observed in vivo and the limited research conducted at the cellular and molecular level to elucidate the mechanisms responsible for the observed dimorphism, the present review has two objectives. Firstly, it aims to emphasize the necessity of incorporating sex as a variable in preclinical research. Secondly, it highlights the importance of sex chromosome differences as a biological variable that can influence cell physiology and biological responses, which is crucial when conducting in vitro studies.

基于性别的生物差异对健康和疾病有着深远的影响。从历史上看，这些差异主要归因于性腺激素的差异。然而，生物化学和分子生物学的最新进展揭示了其他的作用机制——最值得注意的是，位于X和Y染色体上的基因的关键作用。与XY细胞相比，由于X染色体不完全失活，XX细胞中y连锁基因的表达，X连锁基因的剂量增加，基因组印记，以及X染色体上非编码rna和微rna的存在，都是在建立解决性别二态性的体外模型时需要考虑的因素。在目前的叙述性回顾中，我们提出了在血管和心脏细胞、骨骼肌细胞、脂肪组织、肝脏、免疫细胞、癌症组织和脑组织中显示性别差异的研究。鉴于缺乏适当的实验方法来在体外再现体内观察到的性别差异，以及在细胞和分子水平上进行的有限研究来阐明所观察到的二态现象的机制，本综述有两个目的。首先，它旨在强调将性别作为临床前研究变量的必要性。其次，它强调了性染色体差异作为一种可以影响细胞生理和生物反应的生物学变量的重要性，这在进行体外研究时至关重要。

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引用次数: 0

Liraglutide induces enhanced suppression of food intake in mice lacking the growth hormone secretagogue receptor 利拉鲁肽诱导缺乏生长激素促分泌素受体小鼠食物摄入的增强抑制。

IF 3.6 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2025-07-28 DOI: 10.1016/j.mce.2025.112627

Daniela A. Cassano , Julieta Aguggia , Lucía Giovanini , Florencia Heredia , Pablo N. De Francesco , María F. Andreoli , Helgi B. Schöth , Abdella M. Habib , Gimena Fernandez , Mario Perello

The glucagon-like peptide-1 receptor (GLP-1R) and the growth hormone secretagogue receptor (GHSR) exert opposing effects on food intake. GLP-1R activation produces potent appetite-suppressing effects, whereas GHSR activation strongly stimulates food intake. Here, we tested the hypothesis that blocking GHSR could affect the anorectic and weight-reducing effects of liraglutide, a GLP-1R agonist widely used to treat diabetes and obesity. We first found that liraglutide induced a stronger reduction in food intake in ad libitum-fed GHSR-deficient mice compared to wild-type (WT) controls, regardless of sex. Liraglutide treatment also resulted in greater gastric content mass in ad libitum-fed GHSR-deficient mice than in WT mice. Interestingly, GLP-1R immunolabeling was elevated in the paraventricular nucleus of the hypothalamus (PVH) in GHSR-deficient mice, whereas the number of proopiomelanocortin (POMC) neurons and liraglutide-induced c-Fos activation—either in the entire arcuate nucleus or specifically within POMC neurons—remained unchanged compared to WT controls. Liraglutide-induced c-Fos expression in the lateral septum and PVH was reduced in GHSR-deficient mice. Conversely, pharmacological GHSR blockade using either JMV2959 or the endogenous antagonist/inverse agonist liver-expressed antimicrobial peptide 2 did not enhance liraglutide-induced food intake reduction. In conclusion, our findings reveal that genetic GHSR deficiency amplifies liraglutide's anorectic effects and provide new insight into the neurobiological mechanisms underlying this interaction. These results suggest that dual modulation of the GHSR and GLP-1R systems may represent a promising strategy for obesity treatment, though careful selection of GHSR-targeting agents and therapeutic protocols will be essential to optimize clinical outcomes.

胰高血糖素样肽-1受体（GLP-1R）和生长激素促分泌素受体（GHSR）在食物摄入方面发挥相反的作用。GLP-1R激活产生强烈的食欲抑制作用，而GHSR激活则强烈刺激食物摄入。在这里，我们验证了阻断GHSR可能影响利拉鲁肽（一种广泛用于治疗糖尿病和肥胖的GLP-1R激动剂）的厌食和减肥作用的假设。我们首先发现，与野生型（WT）对照相比，利拉鲁肽诱导随意喂养的ghsr缺陷小鼠的食物摄入量减少更大，无论性别如何。利拉鲁肽治疗还导致随意喂养的ghsr缺陷小鼠的胃内容物质量大于WT小鼠。有趣的是，ghsr缺陷小鼠下丘脑室旁核（PVH）的GLP-1R免疫标记升高，而propropiomanocortin （POMC）神经元和利拉鲁肽诱导的c-Fos激活的数量（无论是在整个弓形核中还是在POMC神经元中）与WT对照组相比保持不变。利拉鲁肽诱导的ghsr缺陷小鼠侧隔和PVH中c-Fos表达降低。相反，使用JMV2959或内源性拮抗剂/逆激动剂肝脏表达的抗菌肽2对GHSR进行药理学阻断并没有增强利拉鲁肽诱导的食物摄入减少。总之，我们的研究结果表明，基因GHSR缺乏放大了利拉鲁肽的厌食作用，并为这种相互作用背后的神经生物学机制提供了新的见解。这些结果表明，GHSR和GLP-1R系统的双重调节可能代表了一种很有前途的肥胖治疗策略，尽管仔细选择GHSR靶向药物和治疗方案对于优化临床结果至关重要。

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引用次数: 0

Breaking immune evasion in breast cancer by targeting COX-2/PGE2 pathway 靶向COX-2/PGE2通路打破乳腺癌免疫逃避

IF 3.6 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2025-07-23 DOI: 10.1016/j.mce.2025.112617

Xuewei Zheng , Junxiang Wang , Yanan OuYang , Kaiyuan Yao , Jiayu Zheng , Li Zeng , Jingjing Wang , Hetao Chen , Haoming Du , Dongliao Fu , Linlin Shi , Anshun Zhao , Qinan Yin

The cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) pathway plays a pivotal role in breast cancer (BC) progression by promoting immune suppression, tumor growth, and metastasis. PGE2 mediates these effects through EP receptors (EP1–EP4), suppressing anti-tumor immunity while fostering an immunosuppressive tumor microenvironment (TME). This includes the recruitment and activation of tumor-associated macrophages (TAMs), dendritic cells (DCs), cancer-associated fibroblasts (CAFs), myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs), ultimately impairing cytotoxic T lymphocyte and natural killer (NK) cell function. Targeting the COX-2/PGE2 axis presents a promising strategy for BC treatment. Dual inhibition of EP2 and EP4 has demonstrated superior efficacy in reversing immune suppression compared to single-receptor blockade. Additionally, combining EP4 antagonists with immune checkpoint inhibitors (ICIs) such as anti-PD-1 and anti-CTLA-4 enhances T cell infiltration and tumoricidal activity, leading to improved therapeutic outcomes. Another emerging approach involves enhancing the activity of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the key enzyme responsible for PGE2 degradation, to counteract PGE2-driven immune evasion. PTGES1 inhibitors have shown great potential in overcoming the immunosuppressive TME in BC patients. Elevated TIL levels in TNBC and HER2-positive BC are associated with improved prognosis; however, COX-2 inhibitors such as celecoxib failed to enhance survival and carry potential cardiovascular risks, highlighting the need for TIL-stratified trials to refine immunotherapeutic strategies. This review highlights the immunosuppressive mechanisms of the COX-2/PGE2 pathway in BC and explores novel therapeutic strategies targeting this axis. Understanding the intricate crosstalk between PGE2 signaling and immune modulation may lead to the development of more effective BC treatments, particularly in combination with immunotherapies.

环氧化酶-2 (COX-2)/前列腺素E2 （PGE2）通路通过促进免疫抑制、肿瘤生长和转移在乳腺癌（BC）进展中起关键作用。PGE2通过EP受体（EP1-EP4）介导这些作用，抑制抗肿瘤免疫，同时培养免疫抑制肿瘤微环境（TME）。这包括肿瘤相关巨噬细胞（tam）、树突状细胞（DCs）、癌症相关成纤维细胞（CAFs）、髓源性抑制细胞（MDSCs）和调节性T细胞（Tregs）的募集和激活，最终损害细胞毒性T淋巴细胞和自然杀伤细胞（NK）功能。针对COX-2/PGE2轴是一种很有前景的BC治疗策略。与单受体阻断相比，双重抑制EP2和EP4在逆转免疫抑制方面显示出更好的效果。此外，EP4拮抗剂与免疫检查点抑制剂（ICIs）如抗pd -1和抗ctla -4联合使用可增强T细胞浸润和肿瘤杀伤活性，从而改善治疗效果。另一种新出现的方法涉及提高15-羟基前列腺素脱氢酶（15-PGDH）的活性，这是负责PGE2降解的关键酶，以抵消PGE2驱动的免疫逃避。PTGES1抑制剂在克服BC患者的免疫抑制性TME方面显示出巨大的潜力。TNBC和her2阳性BC中TIL水平升高与预后改善相关；然而，COX-2抑制剂如塞来昔布未能提高生存率，并携带潜在的心血管风险，这突出了对til分层试验的需求，以完善免疫治疗策略。本文综述了BC中COX-2/PGE2通路的免疫抑制机制，并探索了针对该轴的新治疗策略。了解PGE2信号和免疫调节之间复杂的串扰可能会导致更有效的BC治疗的发展，特别是与免疫疗法的结合。

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引用次数: 0

RUNX3 drives HTR-8/SVneo cell ferroptosis and spontaneous abortion: involvement of the suppression of GDF15 transcriptional activity RUNX3驱动HTR-8/SVneo细胞铁下垂和自然流产：参与抑制GDF15转录活性。

IF 3.6 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2025-07-23 DOI: 10.1016/j.mce.2025.112618

Lanlan Cheng, Jie Zhang, Yungai Xiang, Li Tan

Spontaneous abortion (SA) refers to the loss of a pregnancy without external intervention. The runt-related transcription factor 3 (RUNX3) is associated with gestational disorders in view of previous studies. However, RUNX3 has not been reported in SA. RUNX3 is significantly upregulated in the placental villi of abortion patients based on the GSE123719 microarray data. Herein, we further validated and found that the expression of RUNX3 in placental villi of SA women was higher than those of induced abortion (IA) women. In vitro, we constructed human RUNX3 overexpression or interference adenovirus vectors to modulate RUNX3 expression in trophoblast cells. Our findings revealed that RUNX3 overexpression accelerated trophoblast cell ferroptosis, while RUNX3 knockdown alleviated erastin-induced ferroptosis. Subsequently, the dual luciferase reporter assay was performed to confirm that RUNX3 bound to the GDF15 promoter to transcriptionally repress GDF15 transcriptional activity. Importantly, GDF15 attenuated the pro-ferroptosis effects of RUNX3 on HTR-8/SVneo cells. In vivo, mouse RUNX3 interference adenovirus vectors were used to silence RUNX3 in mice. The results presented that the reduction of RUNX3 inhibited embryo adsorption rate in SA mice, involving ferroptosis and the interaction between RUNX3 and GDF15. Taken together, this study established that RUNX3 advanced SA progression by enhancing trophoblast ferroptosis via transcriptionally repressing GDF15. These findings may provide novel therapeutic strategies for SA management.

自然流产（SA）是指在没有外界干预的情况下流产。根据以往的研究，矮小相关转录因子3 （RUNX3）与妊娠疾病有关。然而，RUNX3在SA中尚未报道。基于GSE123719芯片数据，RUNX3在流产患者胎盘绒毛中显著上调。我们进一步验证并发现RUNX3在SA女性胎盘绒毛中的表达高于人工流产（IA）女性。体外构建人RUNX3过表达或干扰腺病毒载体，调控RUNX3在滋养细胞中的表达。我们的研究结果显示，RUNX3过表达加速了滋养细胞铁下垂，而RUNX3敲低则减轻了erastin诱导的铁下垂。随后，进行双荧光素酶报告基因测定，证实RUNX3与GDF15启动子结合，转录抑制GDF15的转录活性。重要的是，GDF15减弱了RUNX3对HTR-8/SVneo细胞的促铁下垂作用。在体内，利用小鼠RUNX3干扰腺病毒载体沉默小鼠RUNX3。结果表明，RUNX3的降低抑制了SA小鼠胚胎吸附率，涉及铁下垂和RUNX3与GDF15的相互作用。综上所述，本研究证实RUNX3通过转录抑制GDF15促进滋养细胞铁下垂，从而促进SA进展。这些发现可能为SA的治疗提供新的治疗策略。

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引用次数: 0

Palmitate-induced downregulation of lipocalin prostaglandin D2 synthase accompanies hepatic lipid accumulation in HepG2 cells 棕榈酸盐诱导的脂钙素-前列腺素D2合酶下调伴HepG2细胞肝脂质积累。

IF 3.8 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2025-07-19 DOI: 10.1016/j.mce.2025.112615

Rhema Khairnar, Md Asrarul Islam, Divya K. Shetty, Vikas V. Dukhande, Sunil Kumar

Metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with multiple metabolic dysfunctions and poses a significant global health challenge. Our prior in vivo studies demonstrated that the absence of lipocalin prostaglandin D2 synthase (L-PGDS) leads to the development of fatty liver disease, and L-PGDS expression significantly decreased when C57BL/6 mice were kept on a high-fat diet. Briefly, L-PGDS belongs to the arachidonic acid pathway and enzymatically isomerizes prostaglandin H2 to prostaglandin D2, which imparts pharmacological effects via two receptors called DP1 and DP2. L-PGDS is an essential key player in fatty liver disease, but its mechanistic regulation still remains unknown. Therefore, we aimed to study the mechanistic regulation of L-PGDS using a palmitate-induced cellular MASLD model. We successfully recapitulated the MASLD phenotype in HepG2 cells with palmitate treatment. Our results showed significant lipid accumulation and increased lipidassociated protein and gene expression, along with palmitate concentration-dependent L-PGDS downregulation. To study the L-PGDS downregulation, we employed MG132, chloroquine, and cycloheximide to assess proteasomal degradation, autophagy, and translational activity, respectively. Our gene and protein expression data suggested the possible reason for L-PGDS downregulation via inhibiting transcription and subsequently translation. Additionally, our autophagy results also showed a role in LPGDS downregulation. In summary, it can be concluded that palmitate treatment downregulated L-PGDS, possibly involving transcription-translation and/or autophagy pathways. However, further studies are needed to delineate the precise molecular mechanism and apply this knowledge to MASLD pathogenesis and treatment.

代谢功能障碍相关脂肪变性肝病（MASLD）与多种代谢功能障碍相关，是全球健康面临的重大挑战。我们之前的体内研究表明，脂钙素前列腺素D2合成酶（L-PGDS）的缺乏会导致脂肪性肝病的发生，当C57BL/6小鼠保持高脂肪饮食时，L-PGDS的表达显著降低。简而言之，L-PGDS属于花生四烯酸途径，可将前列腺素H2酶异构化为前列腺素D2，并通过DP1和DP2两种受体发挥药理作用。L-PGDS在脂肪肝疾病中起着至关重要的作用，但其机制调控尚不清楚。因此，我们旨在利用棕榈酸盐诱导的细胞MASLD模型研究L-PGDS的调控机制。我们在棕榈酸盐处理的HepG2细胞中成功重现了MASLD表型。我们的研究结果显示了显著的脂质积累和脂质相关蛋白和基因表达的增加，以及棕榈酸盐浓度依赖性的L-PGDS下调。为了研究L-PGDS的下调，我们分别使用MG132、氯喹和环己亚胺来评估蛋白酶体降解、自噬和翻译活性。我们的基因和蛋白表达数据表明，L-PGDS下调的可能原因是抑制转录和随后的翻译。此外，我们的自噬结果也显示了LPGDS下调的作用。综上所述，可以得出结论，棕榈酸盐处理下调了L-PGDS，可能涉及转录-翻译和/或自噬途径。然而，需要进一步的研究来描述精确的分子机制，并将这些知识应用于MASLD的发病机制和治疗。

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引用次数: 0

Transcriptomic profiling of hypothalamic development in female rats 雌性大鼠下丘脑发育的转录组学分析。

IF 3.8 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2025-07-19 DOI: 10.1016/j.mce.2025.112616

Emily N. Hilz , Madeline Streifer , Tyler M. Milewski , Andrea C. Gore

The hypothalamic arcuate nucleus (ARC) and anteroventral periventricular nucleus (AVPV) are critical regulators of reproductive function, energy balance, stress, and neuromodulation. These regions undergo substantial changes in neural and glial populations over development that enable the acquisition of adult functions. Although previous studies have examined developmental changes in specific hypothalamic cell populations or gene families, to our knowledge, none has comprehensively compared unbiased/bulk transcriptional profiles across key developmental stages in both the ARC and AVPV. In this study, we used 3′ targeted RNA sequencing to profile gene expression in the ARC and AVPV of female rats at infantile (P8), peripubertal (P30), and adult (P60) life stages. We conducted unbiased and a priori selected differential gene expression analyses, the latter genes selected for their roles in reproduction, metabolism, stress, and neuromodulation. We also measured serum hormones as an index of physiology. Developmental analyses revealed robust differential gene expression between the infantile and prepubertal periods in both the ARC and AVPV, with substantial transcriptional overlap between regions. Fewer and more region-specific transcriptional changes were observed during the transition to adulthood. Gene ontology (GO) analyses revealed coordinated developmental programming prior to puberty, including downregulation of developmental processes and upregulation of metabolic and regulatory pathways. In adulthood, the AVPV showed continued transcriptional remodeling, while the ARC remained comparatively stable. FSH emerged as the strongest hormonal correlate of a priori hypothalamic gene expression. These data provide a reference for understanding hypothalamic development and hormone–gene interactions across life stages in the female rat.

下丘脑弓状核（ARC）和腹侧脑室周围核（AVPV）是生殖功能、能量平衡、应激和神经调节的关键调节器。这些区域在神经和胶质细胞群的发育过程中经历了实质性的变化，从而能够获得成人的功能。虽然以前的研究已经检查了特定下丘脑细胞群或基因家族的发育变化，但据我们所知，没有一个研究全面比较了ARC和AVPV在关键发育阶段的无偏倚/大量转录谱。在这项研究中，我们使用3'靶向RNA测序来分析雌性大鼠在婴儿期（P8）、青春期前期（P30）和成年期（P60）的ARC和AVPV中的基因表达。我们进行了无偏和先验选择的差异基因表达分析，后者基因因其在生殖、代谢、应激和神经调节中的作用而被选择。我们还测量了血清激素作为生理指标。发育分析显示，ARC和AVPV在婴儿期和青春期前的基因表达存在显著差异，区域之间存在大量转录重叠。在向成年期过渡期间，观察到的区域特异性转录变化越来越少。基因本体论（GO）分析揭示了青春期前的协调发育程序，包括发育过程的下调和代谢和调节途径的上调。在成年期，AVPV表现出持续的转录重塑，而ARC保持相对稳定。卵泡刺激素是与先天下丘脑基因表达最相关的激素。这些数据为了解雌性大鼠下丘脑发育和激素-基因相互作用提供了参考。

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引用次数: 0

Association between BRAFV600E mutation and gene expression of CLDN1, TIMP1, and KRT19 in papillary thyroid cancer BRAFV600E突变与甲状腺乳头状癌CLDN1、TIMP1和KRT19基因表达的关系

IF 3.8 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2025-07-14 DOI: 10.1016/j.mce.2025.112614

Andrea Ross-Orozco , Anette Roxana Gastelum-Quiroz , Marco Alvarez-Arrazola , Fred Luque-Ortega , Alejandra Martínez-Camberos , Karla Morales-Hernandez , F. Lopez-Herrera y Cairo , Noemí García-Magallanes

The molecular mechanisms driving Papillary Thyroid Cancer (PTC) progression remain incompletely understood, although mutations in BRAF, are believed to affect the expression of key markers involved in PTC development. This study aimed to investigate the BRAFV600E mutation and its association with the expression of CLDN1, TIMP1, and KRT19 in PTC. A total of 93 thyroid samples were retrospectively analyzed: 42 cytologically diagnosed as PTC (Bethesda VI/V), 4 suspicious for malignancy (Bethesda V), and 47 as nodular hyperplasia (Bethesda II). The presence of the BRAFV600E mutation and the expression levels of CLDN1, TIMP1, and KRT19 were determined using qPCR. BRAFV600E genotypes included 70.2 % TT (wild-type), 17 % TA (heterozygous), and 12.8 % AA (mutant homozygous), with a mutated allele frequency of 0.210. The TA genotype was exclusive to the cancer group and significantly increased malignancy risk (OR 3.667; 95 % CI 2.473–5.437; p < 0.001). Patients harboring the mutated A allele were significantly younger (p = 0.029) and exhibited higher expression of all three genes. Using Youden-derived cutoffs from ROC analysis, TIMP1 overexpression (cutoff 1.148) was most strongly associated with BRAFV600E (OR 4.34; 95 % CI 1.82–10.33; p < 0.001). The BRAFV600E mutation and TIMP1 overexpression are strongly associated with malignant thyroid nodules, suggesting a role in the molecular pathogenesis of PTC.

驱动甲状腺乳头状癌（PTC）进展的分子机制仍不完全清楚，尽管BRAF突变被认为会影响PTC发展中关键标志物的表达。本研究旨在探讨BRAFV600E突变及其与PTC中CLDN1、TIMP1和KRT19表达的关系。回顾性分析93例甲状腺标本：42例细胞学诊断为PTC (Bethesda VI/V)， 4例可疑恶性肿瘤（Bethesda V）， 47例结节性增生（Bethesda II）。采用qPCR检测BRAFV600E突变的存在以及CLDN1、TIMP1和KRT19的表达水平。BRAFV600E基因型包括70.2% TT（野生型）、17% TA（杂合型）和12.8% AA（突变纯合型），突变等位基因频率为0.210。TA基因型为癌症组独有，显著增加恶性肿瘤风险(OR 3.667；95% ci 2.473-5.437；P < 0.001)。携带突变A等位基因的患者明显更年轻（p = 0.029），并且三种基因的表达都更高。使用来自ROC分析的youden衍生截断值，TIMP1过表达（截断值1.148）与BRAFV600E相关性最强(OR 4.34；95% ci 1.82-10.33；P < 0.001)。BRAFV600E突变和TIMP1过表达与恶性甲状腺结节密切相关，提示在PTC的分子发病机制中起作用。

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引用次数: 0

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 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2025-07-09 DOI: 10.1016/j.mce.2025.112613

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

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 connexin43 (Gja) 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.

睾丸间质细胞位于睾丸内的精小管之间，是男性睾酮的主要来源。在这些细胞中，黄体生成素(LH)/cAMP/蛋白激酶A （PKA）信号通路主要调控雄激素的生物合成。我们之前报道过连接蛋白43 （connexin43, Gja）启动子可以在小鼠MA-10间质细胞中被激活，这是AP-1转录因子JUN和FOS之间合作的结果。丝裂原活化蛋白激酶（MAPK）信号通路通过JUN n端激酶（JNK）磷酸化AP-1转录因子家族成员，调节其活性。因此，MA-10间质细胞被JNK抑制剂SP600125 （pyrazolanthrone）在25 μM下处理4小时，在10 μM下不存在腺苷酸环化酶forskolin （FSK）激活剂，然后提取RNA并对转录组进行3'Tag RNA- seq分析。有趣的是，SP600125降低了cAMP/PKA依赖性胆固醇和类固醇生物合成/代谢过程相关基因的表达，导致MA-10细胞中cAMP/PKA依赖性孕酮产生减少。此外，SP600125增加了与ATF4相关的内质网应激反应相关基因的表达，导致DDIT3的激活和凋亡，如cleaved caspase 3所示。总之，我们的研究结果表明，SP600125增加ATF4/ ddit3依赖性内质网应激反应，独立于MAPK9 （JNK2）抑制，并抑制间质细胞LH/cAMP/ pka依赖性雄激素合成。

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