Molecular and Cellular Endocrinology最新文献_第4页

CD36 may regulate glycolytic and steroidogenic processes but not the fatty acid uptake in bovine granulosa cells CD36调节牛颗粒细胞的糖酵解和类固醇生成过程，但不调节脂肪酸摄取。

IF 3.6 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2025-12-11 DOI: 10.1016/j.mce.2025.112717

Xuelian Tao, Marten Michaelis, Julia Brenmoehl, Jens Vanselow, Vijay Simha Baddela

Postpartum metabolic stress increases non-esterified fatty acid (NEFA) concentration in follicular fluid, thereby impairing oocyte and granulosa cell (GC) function. CD36, a multifunctional scavenger receptor, is involved in the uptake of NEFAs in various cell types. This study examines lipid droplet (LD) accumulation and CD36 expression in GCs treated with oleate (OA), palmitate (PA), stearate (SA), and their combination. We also explored the role of CD36 in lipid uptake, glucose metabolism, and steroidogenesis in GCs. Flow cytometry analysis revealed that SA, OA, and the combined NEFA treatments resulted in significant LD accumulation, while PA had a minimal effect. Interestingly, CD36 expression mirrored the levels of LD accumulation in all treatments. However, SLC27A1, another highly expressed NEFA transporter, was upregulated by SA but was unchanged by PA and OA treatments. Combination of OA, PA, and SA has increased both CD36 and SLC27A1 expression. OA treatment induced a dose-dependent increase in LD accumulation and CD36 expression. However, CD36 knockdown did not affect either LD accumulation or triglyceride levels, indicating that CD36 is not essential for NEFA uptake, despite its increased expression. Previously, we showed that OA enhances glycolysis in GCs; here, we found that CD36 is involved in glucose metabolism as its silencing significantly reduced the extracellular acidification rate and mitochondrial membrane potential in GCs. Furthermore, CD36 knockdown significantly reduced progesterone production. These findings suggest that while CD36 is dispensable for NEFA uptake, it may play a regulatory role in maintaining glycolytic activity, mitochondrial function, and steroidogenesis in GCs under elevated NEFA levels.

产后代谢应激增加卵泡液中非酯化脂肪酸（NEFA）浓度，从而损害卵母细胞和颗粒细胞（GC）功能。CD36是一种多功能清道夫受体，参与多种细胞对nefa的摄取。本研究检测了油酸酯（OA）、棕榈酸酯（PA）、硬脂酸酯（SA）及其组合处理的gc中脂滴（LD）的积累和CD36的表达。我们还探讨了CD36在GCs中脂质摄取、葡萄糖代谢和类固醇生成中的作用。流式细胞术分析显示，SA、OA和NEFA联合治疗导致LD显著积累，而PA的影响很小。有趣的是，CD36的表达反映了所有处理中LD积累的水平。然而，另一种高表达的NEFA转运蛋白SLC27A1被SA上调，但在PA和OA处理下没有变化。OA、PA和SA联合使用可增加CD36和SLC27A1的表达。OA处理诱导LD积累和CD36表达的剂量依赖性增加。然而，CD36敲低并不影响LD积累或甘油三酯水平，这表明尽管CD36的表达增加，但它并不是NEFA摄取所必需的。之前，我们发现OA增强了GCs的糖酵解；在这里，我们发现CD36参与葡萄糖代谢，因为它的沉默显著降低了GCs的细胞外酸化速率和线粒体膜电位。此外，CD36敲除显著减少黄体酮的产生。这些发现表明，虽然CD36对于NEFA的摄取是不可缺少的，但在NEFA水平升高的情况下，它在维持糖酵解活性、线粒体功能和GCs的类固醇生成方面发挥着调节作用。

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引用次数: 0

Bone marrow transplantation attenuates inflammation and improves glycemic control in type 2 non-obese diabetic Goto-Kakizaki rats 骨髓移植减轻2型非肥胖糖尿病Goto-Kakizaki大鼠的炎症并改善血糖控制

IF 3.6 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2025-12-11 DOI: 10.1016/j.mce.2025.112716

João Carlos de Oliveira Borges , Ilana Souza Correa , Gabriela Mandú Gimenes , Liliane de Araújo Ferreira , Maria Andréa Rodrigues de Moura Silva , Janaina Ribeiro Barbosa Pauferro , Tiago Bertola Lobato , Amara Cassandra dos Anjos Alves , Ana Carolina Gomes Pereira , Karolayne Oliveira Souza , Camila Soares dos Santos , Adriana Cristina Levada- Pires , Tania Cristina Pithon-Curi , Gabriel Nasri Marzuca-Nassr , Sandro Massao Hirabara , Rui Curi , Renata Gorjão , Laureane Nunes Masi

Chronic hyperglycemia induces changes in the bone marrow (BM) microenvironment, favoring the expansion and differentiation of stem cells toward a pro-inflammatory profile. Since leukocyte recruitment plays a key role in chronic inflammation during the onset of type 2 diabetes mellitus (T2DM), the aim of this study was to evaluate the influence of bone marrow transplantation (BMT) on glycemic control and inflammatory markers in Goto-Kakizaki (GK) rats transplanted after weaning. GK rats are spontaneously non-obese, T2DM animals. We performed BMT from normoglycemic Wistar (WT) rats to GK animals (aged 28 days), previously immunosuppressed with busulfan (20 mg/kg) and cyclophosphamide (150 mg/kg). The mRNA expression of pro-inflammatory cytokines IL-1β and IL-7 was increased in the BM of weaned GK rats, and it was reduced in the BM mononuclear cells (BMMCs) 100 days after BMT. Hepatic cytokine levels were also evaluated by flow cytometry to calculate the Inflammatory Marker Index (based on IFN-γ, TNF-α, IL-6, and IL-10), which was decreased in transplanted GK rats. Moreover, transplanted GK rats also showed reduced fasting glucose evaluated at 30, 60, and 90 days after transplantation. BMT also induced a significant decrease in plasma insulin and attenuated insulin resistance (HOMA-IR). Overall, BMT in just-weaned GK rats, characterized by an elevated inflammatory profile in the BM and liver, culminated in improvement of glycemic control compared with non-transplanted GK animals. In conclusion, modulation of the BM microenvironment emerges as a novel therapeutic avenue for managing non-obese T2DM and preventing its complications.

慢性高血糖诱导骨髓（BM）微环境的变化，有利于干细胞向促炎方向的扩张和分化。由于白细胞募集在2型糖尿病（T2DM）发病期间的慢性炎症中起着关键作用，本研究的目的是评估断奶后移植的Goto-Kakizaki （GK）大鼠骨髓移植（BMT）对血糖控制和炎症标志物的影响。GK大鼠是自发非肥胖的2型糖尿病动物。我们将血糖正常的Wistar （WT）大鼠移植到GK动物（28日龄），之前用丁硫丹（20 mg/kg）和环磷酰胺（150 mg/kg）进行免疫抑制。促炎因子IL-1β和IL-7 mRNA在断奶GK大鼠骨髓中表达升高，在骨髓单核细胞（BMMCs）中表达降低。通过流式细胞术评估肝脏细胞因子水平，计算炎症标志物指数（基于IFN-γ， TNF-α， IL-6和IL-10），移植GK大鼠的炎症标志物指数降低。此外，移植的GK大鼠在移植后30,60和90天也显示空腹血糖降低。BMT还导致血浆胰岛素显著下降和胰岛素抵抗（HOMA-IR）减弱。总体而言，与未移植的GK动物相比，刚断奶的GK大鼠的BMT以BM和肝脏炎症升高为特征，最终改善了血糖控制。总之，调节脑基微环境是治疗非肥胖型2型糖尿病和预防其并发症的一种新的治疗途径。

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引用次数: 0

Prenatal perfluorooctanoic sulfonate exposure is associated with polycystic ovary syndrome-like and related traits in female offspring mice 产前全氟辛烷磺酸暴露与雌性后代小鼠多囊卵巢综合征样及相关性状相关

IF 3.6 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2025-12-10 DOI: 10.1016/j.mce.2025.112707

C. Urrutia-Lopez , L. González-Carranza , A. Barajas-Salinas , E. Bonilla , J.J. Rodriguez-Mercado , A. Aviles , E. Langley , J.P. Reyes-Grajeda , F. Casillas , A. Lopez , E. Casas , M. Betancourt , M.C. González-Torres , I. Bahena-Ocampo

Polycystic Ovary Syndrome (PCOS), is the most common female endocrine disorder affecting women of reproductive age. Its prevalence is estimated to be up to 13 % worldwide. This heterogeneous clinical condition is characterized by marked clinical and/or biochemical hyperandrogenism, ovulatory dysfunction, and frequent development of polycystic ovaries. Several studies have focused on the relationship between endocrine-disrupting pollutants and PCOS development. Perfluorooctanesulfonate (PFOS) is ubiquitously detected in the environment. Exposure to endocrine-disrupting chemicals, including PFOS, during early fetal development may lead to alterations similar to the PCOS phenotype. Using mice as a model, we compared the effects of prenatal exposure to PFOS or dihydrotestosterone (a model of PCOS induction). After analyzing steroid status, we detected delayed pubertal onset accompanied by increased testosterone concentrations in adulthood, as well as altered estrous cycles with a longer metestrus phase. At this point, two of three Rotterdam criteria have been confirmed as PCOS features. Finally, we identified endocrine disruption in the ovaries from adult females prenatally exposed to PFOS, as evidenced by altered expression of genes involved in steroidogenesis pathways, as well as altered expression of gonadotropin hormone receptors, and Amh signaling. These data support a role of PFOS in endocrine disruption and in promoting development of PCOS symptom development.

多囊卵巢综合征（PCOS）是影响育龄妇女最常见的女性内分泌疾病。据估计，其全球患病率高达13%。这种异质性临床状况的特点是临床和/或生化上明显的高雄激素、排卵功能障碍和多囊卵巢的频繁发展。一些研究集中在内分泌干扰污染物与多囊卵巢综合征发展之间的关系。全氟辛烷磺酸（PFOS）在环境中无处不在。胎儿早期发育期间暴露于干扰内分泌的化学物质，包括全氟辛烷磺酸，可能导致与多囊卵巢综合征表型相似的改变。以小鼠为模型，我们比较了产前暴露于全氟辛烷磺酸或二氢睾酮（PCOS诱导模型）的影响。在分析类固醇状态后，我们检测到青春期开始延迟伴随着成年期睾酮浓度的增加，以及月经周期的改变和更长的月经期。在这一点上，三个鹿特丹标准中的两个已被确认为PCOS特征。最后，我们发现成年女性在产前暴露于全氟辛烷磺酸后，卵巢内分泌受到干扰，这可以通过类固醇生成途径相关基因的表达改变，以及促性腺激素受体和Amh信号的表达改变来证明。这些数据支持全氟辛烷磺酸在内分泌干扰和促进多囊卵巢综合征症状发展中的作用。

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引用次数: 0

Developmental programming: gestational exposure to excess testosterone disrupts maternal steroid homeostasis and perturbs the steroid-lipid relationship in sheep 发育规划：妊娠期暴露于过量的睾酮会破坏母体类固醇体内平衡，并扰乱绵羊体内类固醇-脂质关系。

IF 3.6 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2025-11-24 DOI: 10.1016/j.mce.2025.112706

Nadia Saadat , Rehma Saeed , Brooke Pallas , Arpita K. Vyas , Richard J. Auchus , Vasantha Padmanabhan

Gestational hyperandrogenism may disrupt the steroid and lipid metabolism homeostatic balance that is important for pregnancy progression. We hypothesized that excess gestational testosterone would disrupt the maternal steroid profile and the steroid-lipid relationship. Using sheep, we investigated maternal delta-4 (Δ4) and delta-5 (Δ5) steroids and the steroid-lipidome relationship in gestational testosterone excess (n = 12, 100 mg T-propionate days 30–90 of gestation twice-weekly intramuscularly) and control (n = 5, vehicle) Suffolk sheep. Steroids were measured using liquid chromatography-tandem mass spectrometry and lipids by shotgun lipidomics. Principal component analysis showed clear separation of control and the gestational testosterone excess groups. The main impact of testosterone excess was on the Δ5 pathway, with reductions in 17-OH pregnenolone, androstenediol, allopregnanolone, and androsterone. In the Δ4 pathway only a trend for reduced androstenedione and a large magnitude increase in corticosterone and decrease in 11-deoxycorticosterone was observed. Dimensionality reduction partial least squares regression models revealed disruptive impact of testosterone-excess on the steroid-lipid relationship prevailing in controls namely with lipid biosynthesis and metabolism and enrichment in cholesterol biosynthetic, circadian clock and transcriptional regulatory, and liver steatosis pathways. Disrupted steroid-lipid associations in the gestational testosterone excess group showed linkage to complex disease-profiles centering on lipid metabolism and transport, cholesterol, and of relevance to hyperlipidemia, gestational diabetes, and hypertension in the enrichment analysis. Fewer lipid species were associated with individual steroids in gestational testosterone excess group, indicative of loss of the majority of the homeostatic steroid-lipid associations. This study provides a novel screening insight into the steroid-lipid relationship that prevails during normal pregnancy and the disruptive impact of hyperandrogenism in perturbing this homeostasis.

妊娠期高雄激素症可能会破坏类固醇和脂质代谢的稳态平衡，这对妊娠进展很重要。我们假设，过量的妊娠期睾酮会破坏母体类固醇谱和类固醇脂质关系。以羊为研究对象，研究了母羊δ -4（Δ4）和δ -5（Δ5）类固醇以及妊娠睾酮过量（n=12，妊娠30-90天每周两次肌注100mg t -丙酸）和对照（n=5，载体）萨福克羊的类固醇-脂质组关系。类固醇采用液相色谱-串联质谱法测定，脂质采用散弹枪脂质组学测定。主成分分析显示对照组与妊娠期睾酮过量组明显分离。睾酮过量主要影响Δ5通路，17-OH孕烯醇酮、雄烯二醇、异孕烯醇酮和雄酮减少。在Δ4通路中，只观察到雄烯二酮的减少和皮质酮的大量增加和11-脱氧皮质酮的减少。降维偏最小二乘回归模型揭示了睾酮过量对对照组中普遍存在的类固醇-脂质关系的破坏性影响，即脂质生物合成、代谢和胆固醇生物合成、生物钟和转录调节以及肝脏脂肪变性途径中的富集。在浓缩分析中，妊娠期睾酮过量组的类固醇-脂质关联中断显示出与以脂质代谢和转运、胆固醇为中心的复杂疾病谱相关，并与高脂血症、妊娠期糖尿病和高血压相关。在妊娠期睾酮过量组中，与单个类固醇相关的脂质种类较少，表明大多数体内平衡类固醇-脂质关联丢失。这项研究为正常妊娠期间普遍存在的类固醇-脂质关系以及高雄激素症扰乱这种体内平衡的破坏性影响提供了一种新的筛选见解。

{"title":"Developmental programming: gestational exposure to excess testosterone disrupts maternal steroid homeostasis and perturbs the steroid-lipid relationship in sheep","authors":"Nadia Saadat , Rehma Saeed , Brooke Pallas , Arpita K. Vyas , Richard J. Auchus , Vasantha Padmanabhan","doi":"10.1016/j.mce.2025.112706","DOIUrl":"10.1016/j.mce.2025.112706","url":null,"abstract":"<div><div>Gestational hyperandrogenism may disrupt the steroid and lipid metabolism homeostatic balance that is important for pregnancy progression. We hypothesized that excess gestational testosterone would disrupt the maternal steroid profile and the steroid-lipid relationship. Using sheep, we investigated maternal delta-4 (Δ4) and delta-5 (Δ5) steroids and the steroid-lipidome relationship in gestational testosterone excess (n = 12, 100 mg T-propionate days 30–90 of gestation twice-weekly intramuscularly) and control (n = 5, vehicle) Suffolk sheep. Steroids were measured using liquid chromatography-tandem mass spectrometry and lipids by shotgun lipidomics. Principal component analysis showed clear separation of control and the gestational testosterone excess groups. The main impact of testosterone excess was on the Δ5 pathway, with reductions in 17-OH pregnenolone, androstenediol, allopregnanolone, and androsterone. In the Δ4 pathway only a trend for reduced androstenedione and a large magnitude increase in corticosterone and decrease in 11-deoxycorticosterone was observed. Dimensionality reduction partial least squares regression models revealed disruptive impact of testosterone-excess on the steroid-lipid relationship prevailing in controls namely with lipid biosynthesis and metabolism and enrichment in cholesterol biosynthetic, circadian clock and transcriptional regulatory, and liver steatosis pathways. Disrupted steroid-lipid associations in the gestational testosterone excess group showed linkage to complex disease-profiles centering on lipid metabolism and transport, cholesterol, and of relevance to hyperlipidemia, gestational diabetes, and hypertension in the enrichment analysis. Fewer lipid species were associated with individual steroids in gestational testosterone excess group, indicative of loss of the majority of the homeostatic steroid-lipid associations. This study provides a novel screening insight into the steroid-lipid relationship that prevails during normal pregnancy and the disruptive impact of hyperandrogenism in perturbing this homeostasis.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"613 ","pages":"Article 112706"},"PeriodicalIF":3.6,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145636099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

In vitro activation of brown adipocyte thermogenesis by fermented hypholomine B-enriched Sanghuangporus sanghuang mycelia through FNDC5/Irisin pathway 通过FNDC5/鸢尾素途径发酵富含菌丝碱b的桑黄孢子菌丝体外激活棕色脂肪细胞产热

IF 3.6 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2025-11-22 DOI: 10.1016/j.mce.2025.112705

I-Chen Li , Yu-En Chan , Yu-Li Lin , Tzong-Yuan Wu , Liang-Yi Wu , Ching-Yi Tsai , Hsin-Tang Lin , Chin-Chu Chen

In the face of the global obesity epidemic (globesity), we present the first comprehensive investigation of fermented Sanghuangporus sanghuang mycelia extract (SS-IM1) and its novel bioactive compound hypholomine B in brown adipose tissue activation. Using HEK293 cells with FNDC5 promoter-EGFP constructs and differentiated 3T3-L1 adipocytes, we demonstrate that both compounds significantly enhance FNDC5 expression and irisin secretion. We reveal distinct mechanistic profiles: SS-IM1 showed superior efficacy in irisin induction and thermogenesis activation, while isolated hypholomine B demonstrated unprecedented potency in reducing lipid accumulation. Seahorse analysis revealed enhanced mitochondrial respiration and UCP1-mediated proton leak, confirming their thermogenic effects. Furthermore, we discovered that SS-IM1 uniquely enhanced glucose uptake through GLUT4 upregulation. These findings not only elucidate novel molecular mechanisms underlying the anti-obesity effects of S. sanghuang but also establish hypholomine B as a promising first-in-class therapeutic candidate for addressing the worldwide challenges of obesity and metabolic disorders.

面对全球肥胖流行（globesity），我们首次全面研究了发酵桑黄孢子桑黄菌丝体提取物（SS-IM1）及其新型生物活性化合物-丝孢胺B在棕色脂肪组织激活中的作用。通过构建FNDC5启动子egfp的HEK293细胞和分化的3T3-L1脂肪细胞，我们发现这两种化合物都能显著提高FNDC5的表达和鸢尾素的分泌。我们揭示了不同的机制：SS-IM1在鸢尾素诱导和生热活化方面表现出卓越的功效，而分离的丝光胺B在减少脂质积累方面表现出前所未有的效力。海马分析显示，线粒体呼吸和ucp1介导的质子泄漏增强，证实了它们的产热作用。此外，我们发现SS-IM1通过上调GLUT4独特地增强葡萄糖摄取。这些发现不仅阐明了桑黄抗肥胖作用的新分子机制，而且确立了连色胺B作为解决全球肥胖和代谢紊乱挑战的有前景的一流治疗候选者。

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引用次数: 0

Androgen deprivation induces distinct muscle-specific transcriptional changes to genes regulating glucose, lipid, and amino acid metabolism 雄激素剥夺可诱导调节葡萄糖、脂质和氨基酸代谢的基因发生明显的肌肉特异性转录变化

IF 3.6 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2025-11-20 DOI: 10.1016/j.mce.2025.112704

Wayne A. Ayers-Creech , Jennifer L. Steiner , Grant R. Laskin , Bradley S. Gordon

Background

Androgens such as testosterone regulate whole-body metabolic homeostasis. Low androgen levels lead to undesirable shifts in metabolism including lower glucose oxidation, greater lipid reliance, and altered amino acid metabolism. Skeletal muscle is a primary site regulating fuel substrate metabolism, but whether all muscles contribute to the undesirable metabolic shifts in response to low androgen levels is unclear.

Methods and results

Male mice underwent sham or castration surgery and muscles were harvested 7, 14-, 21-, 28-, or 49-days post-surgery. The content of genes related to glucose, lipid, and amino acid metabolism were assessed in the tibialis anterior (TA) and gastrocnemius muscles. The content of genes related to glucose metabolism were altered in a manner consistent with lower rates of oxidation in both the TA and gastrocnemius following castration although the magnitudes of change were generally more pronounced in the TA. Genes related to lipid oxidation were altered in a manner consistent with higher oxidation rates only in the TA following castration. Genes related to amino acid catabolism were paradoxically unaltered or even lower in both muscles in response to castration.

Conclusion

These findings indicate that the TA undergoes more pronounced transcriptional changes related to glucose and lipid metabolism compared to the gastrocnemius, likely contributing more to whole-body metabolic shifts during androgen deprivation.

背景：雄激素如睾酮调节全身代谢稳态。低雄激素水平导致代谢的不良变化，包括葡萄糖氧化降低，脂质依赖增加，氨基酸代谢改变。骨骼肌是调节燃料底物代谢的主要部位，但是否所有肌肉都参与了低雄激素水平下的不良代谢变化尚不清楚。方法和结果小鼠分别在术后7、14、21、28、49天进行假手术或去势手术。测定胫骨前肌（TA）和腓肠肌中葡萄糖、脂质和氨基酸代谢相关基因的含量。与葡萄糖代谢相关的基因含量发生了改变，这与阉割后TA和腓肠肌的氧化率降低一致，尽管TA的变化幅度通常更明显。与脂质氧化相关的基因以一种与阉割后TA较高的氧化率一致的方式改变。与氨基酸分解代谢相关的基因在阉割后没有改变，甚至更低。结论与腓肠肌相比，TA在糖脂代谢方面发生了更明显的转录变化，可能在雄激素剥夺过程中对全身代谢变化的贡献更大。

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引用次数: 0

Brain derived neurotrophic factor promotes oocyte maturation through the TrkB-MAPK-PI3K pathway in zebrafish 脑源性神经营养因子通过TrkB-MAPk-PI3K通路促进斑马鱼卵母细胞成熟。

IF 3.6 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2025-11-15 DOI: 10.1016/j.mce.2025.112703

Chinelo Uju, Suraj Unniappan

Brain-derived neurotrophic factor (BDNF) was previously reported as a positive modulator of zebrafish reproduction, yet the mechanism of action of BDNF that elicits this function is unknown. We hypothesized that the pro-reproductive effects of BDNF in female zebrafish are mediated by TrkB signaling. In zebrafish liver (ZFL) cells, a TrkB antagonist (ANA-12) blocked the stimulatory effect of BDNF on transcript abundance of vitellogenin (vtg1, 2, 4, and 7) and steroidogenic factor 1 (sf-1). No changes were observed in hepatocyte nuclear factor 4 alpha, specificity protein 1, cAMP response element-binding protein 1a, or forkhead box L2. Blocking the mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K), and phospholipase C gamma (PLC-γ) pathways significantly attenuated BDNF-induced upregulation of vtg and sf-1 transcripts. Total vtg protein was increased by BDNF, an effect that was blunted when TrkB, MAPK, PI3K, or PLC-γ were blocked. The estrogen receptor alpha (Esrα) fluorescence immunoreactivity in the ZFL cells treated with BDNF was significantly reduced in the presence of ANA-12. In the zebrafish follicles, BDNF-induced oocyte maturation was attenuated by TrkB, MAPK-, and PI3K inhibitors, but not a PLC-γ blocker. Similarly, the positive effects of BDNF on maturation-related genes 3β-hydroxysteroid dehydrogenase 2 enzyme (3bhsd2), cytochrome P450 family 17, hyaluronan synthase 2, luteinizing hormone receptor, and prostaglandin synthase 2 were significantly attenuated when TrkB, MAPK, or PI3K was blocked. PLC-γ inhibition prevented the BDNF-induced upregulation of 3bhsd1 in the oocytes. This study demonstrates that BDNF promotes vitellogenesis via the TrkB-MAPK/PI3K/PLC-γ signaling pathways. Meanwhile, BNDF enhances oocyte maturation through the TrkB-MAPK/PI3K pathways in zebrafish.

脑源性神经营养因子（BDNF）先前被报道为斑马鱼生殖的正调节因子，但BDNF引发这一功能的作用机制尚不清楚。我们假设雌性斑马鱼BDNF的促生殖作用是通过TrkB信号介导的。在斑马鱼肝脏（ZFL）细胞中，TrkB拮抗剂（ANA-12）阻断了BDNF对卵黄蛋白原（vtg1、2、4和7）和甾体生成因子1 （sf-1）转录丰度的刺激作用。肝细胞核因子4 α、特异性蛋白1、cAMP反应元件结合蛋白1a、叉头盒L2均未见变化。阻断丝裂原活化蛋白激酶（MAPK）、磷脂酰肌醇3-激酶（PI3K）和磷脂酶C γ (PLC-γ)通路可显著减弱bdnf诱导的vtg和sf-1转录物上调。BDNF增加了vtg总蛋白，当TrkB、MAPK、PI3K或PLC-γ被阻断时，这种作用减弱。与BDNF相比，ANA-12的存在显著降低了ZFL细胞的雌激素受体α (Esrα)荧光免疫反应性。在斑马鱼卵泡中，TrkB、MAPK-和PI3K抑制剂能减弱bdnf诱导的卵母细胞成熟，但PLC-γ阻断剂不能。同样，当TrkB、MAPK或PI3K被阻断时，BDNF对成熟相关基因3β-羟基类固醇脱氢酶2 （3bhsd2）、细胞色素P450家族17、透明质酸合成酶2、黄体生成素受体和前列腺素合成酶2的积极作用显著减弱。PLC-γ抑制抑制bdnf诱导的卵母细胞中3bhsd1的上调。本研究表明BDNF通过TrkB-MAPK/PI3K/PLC-γ信号通路促进卵黄形成。同时，BNDF通过TrkB-MAPK/PI3K通路促进雌斑马鱼卵母细胞成熟。

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引用次数: 0

Role of visfatin on early embryogenesis in normal weight and obese mice. Studies on siRNA induced knockdown model visfatin在正常体重和肥胖小鼠早期胚胎发生中的作用。siRNA诱导敲低模型的研究。

IF 3.6 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2025-11-13 DOI: 10.1016/j.mce.2025.112702

Patrycja Kurowska , Shinnosuke Honda , Genta Tanaka , Gao Yuwei , Naojiro Minami , Agnieszka Rak , Shuntaro Ikeda

Visfatin/Nampt, an adipokine upregulated in obesity, has been implicated in oocyte maturation, but its role in early embryogenesis remains poorly understood. This study investigated visfatin/Nampt function during preimplantation development in normal-weight and high-fat diet–induced obese mice.

Nampt mRNA expression was examined in embryos from the 1-cell to the blastocyst stage, and siRNA-mediated Nampt silencing was performed at the 1-cell stage. Embryo development was assessed by cleavage and blastocyst formation rates, while molecular effects were evaluated via qPCR analysis of maternal-effect and proliferation/apoptosis, differentiation genes, immunofluorescence detection of pluripotency/differentiation markers, and transcriptome profiling (RNA-seq). The functional reproductive outcomes, including implantation rates, offspring number, and ovarian gene expression (qPCR) in the progeny, were also analyzed.

Nampt expression decreases during early embryogenesis. Nampt silencing impaired blastocyst formation in obese mice and altered lineage marker expression, increasing NANOG in normal-weight embryos and reducing GATA6-positive cells in obese embryos. Transcriptomic analysis of normal-weight blastocysts revealed 73 upregulated and 24 downregulated genes enriched in pathways regulating apoptosis, energy metabolism, and development. Although the implantation rates and offspring numbers were unchanged, offspring from Nampt-silenced embryos presented altered ovarian gene expression linked to steroidogenesis and oogenesis.

This work provides the first transcriptomic analysis of blastocysts following siRNA-mediated Nampt silencing and demonstrates that visfatin/Nampt modulates early lineage allocation in a manner dependent on maternal metabolic status. These findings extend visfatin research beyond oocyte maturation and highlight its potential contribution to embryonic programming.

Visfatin/Nampt是一种在肥胖中上调的脂肪因子，与卵母细胞成熟有关，但其在早期胚胎发生中的作用尚不清楚。本研究研究了正常体重和高脂肪饮食诱导的肥胖小鼠着床前发育过程中visfatin/Nampt的功能。在1细胞至囊胚期的胚胎中检测Nampt mRNA的表达，并在1细胞期进行sirna介导的Nampt沉默。通过卵裂率和囊胚形成率来评估胚胎发育，通过qPCR分析母体效应和增殖/凋亡、分化基因、多能/分化标记的免疫荧光检测和转录组分析（RNA-seq）来评估分子效应。并分析了功能生殖结果，包括着床率、子代数量和子代卵巢基因表达（qPCR）。在胚胎发生早期，Nampt表达减少。Nampt沉默会损害肥胖小鼠的囊胚形成，改变谱系标记的表达，增加正常体重胚胎的NANOG，减少肥胖胚胎的gata6阳性细胞。正常体重囊胚的转录组学分析显示，在细胞凋亡、能量代谢和发育的调控途径中，有73个基因上调，24个基因下调。虽然着床率和后代数量不变，但来自nampt沉默胚胎的后代表现出与类固醇发生和卵子发生相关的卵巢基因表达改变。这项工作首次提供了sirna介导的Nampt沉默后囊胚的转录组学分析，并证明visfatin/Nampt以依赖于母体代谢状态的方式调节早期谱系分配。这些发现将visfatin的研究扩展到卵母细胞成熟之外，并突出了其对胚胎编程的潜在贡献。

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引用次数: 0

Serotonin promotes aggressive features in breast cancer cells by modulating proliferation and migration, hormone receptors and HER2 expression 血清素通过调节增殖和迁移、激素受体和HER2表达促进乳腺癌细胞的侵袭性特征。

IF 3.6 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2025-10-31 DOI: 10.1016/j.mce.2025.112692

Larissa Pereira Paixão , José Xavier do Nascimento Junior , Maria Eduarda Sant'Ana Faria Do Espírito Santo , Ricardo Imbroisi Filho , João Gabriel Bernardo Leandro , Davi Mundim , Jessica Ristow Branco , Luis Eduardo Santos , Sérgio T. Ferreira , Luciana Pizzatti , Mauro Sola-Penna , Patricia Zancan

Serotonin (5-HT), a key regulator of epithelial homeostasis, plays a paradoxical role in breast cancer progression. This study investigates the impact of 5-HT signaling on hormone receptor expression, cell proliferation, therapeutic response, and tumor aggressiveness in breast cancer cells. We demonstrate that 5-HT activates transcriptional factors in MCF-7 cells, collectively enhancing cancer hallmarks such as sustained proliferation and invasiveness. Notably, 5-HT downregulates mRNA expression of estrogen receptor (ER), progesterone receptor (PR), and HER2, inducing a phenotype reminiscent of triple-negative breast cancer. Despite these phenotypic changes, acute 5-HT treatment does not impair the effectiveness of tamoxifen in vitro. In vivo, administration of fluoxetine, a selective serotonin reuptake inhibitor, accelerates tumor growth and increases malignancy in a murine model. These findings underscore the ability of 5-HT to reprogram hormone receptors expression profiles and to promote a more aggressive cancer phenotype.

5-羟色胺（5-HT）是上皮稳态的关键调节因子，在乳腺癌的进展中起着矛盾的作用。本研究探讨了5-HT信号对乳腺癌细胞中激素受体表达、细胞增殖、治疗反应和肿瘤侵袭性的影响。我们证明5-HT激活MCF-7细胞中的转录因子，共同增强癌症特征，如持续增殖和侵袭性。值得注意的是，5-HT下调雌激素受体（ER）、孕激素受体（PR）和HER2的mRNA表达，诱导三阴性乳腺癌的表型。尽管有这些表型变化，急性5-HT治疗并不影响他莫昔芬的体外疗效。在体内，氟西汀（一种选择性5 -羟色胺再摄取抑制剂）在小鼠模型中加速肿瘤生长并增加恶性肿瘤。这些发现强调了5-HT重编程激素受体表达谱和促进更具侵袭性的癌症表型的能力。

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引用次数: 0

Melatonin administration protects the right ventricle from adrenergic stress via anti-inflammatory and anti-apoptotic mechanisms 褪黑素通过抗炎和抗凋亡机制保护右心室免受肾上腺素能应激

IF 3.6 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2025-10-29 DOI: 10.1016/j.mce.2025.112691

Alexsandra Zimmer , Vitória Rosa de Oliveira , Tânia Regina G. Fernandes , Ramison Santos , Patrick Turck , Victor de Mello Palma , Fernanda Visioli , Elissa Fernandes , Silvio Tasca , Cristina Campos Carraro , Adriane Belló-Klein , Alex Sander da Rosa Araujo , Alexandre Luz de Castro

Background

Adrenergic overload is a central feature of cardiovascular diseases, contributing to right ventricular (RV) injury. Although widely studied, limited data are available on melatonin's impact on the RV and extracardiac tissues.

Objective

To investigate the effects of melatonin on RV remodeling, inflammation, and oxidative stress in the lung and gastrocnemius muscle of rats subjected to isoproterenol (ISO)-induced adrenergic stress.

Methods

Male Wistar rats were divided into Control, ISO, and ISO + melatonin groups. ISO (5 mg/kg, s.c.) was administered for 7 days, and ISO + M received ISO plus melatonin (10 mg/kg/day, gavage). Control animals received saline (s.c) and the non-treated groups received only saline by gavage. Cardiac function and hypertrophy was assessed by echocardiography and morphometric analyses, respectively. RV inflammation and fibrosis were examined histologically, while protein expression in the RV (TLR4, NF-κB, Bax) and lungs (eNOS, ETAR) was analyzed by western blotting. Oxidative stress markers (ROS, TBARS, sulfhydryl groups, nitrite) were measured in lung and gastrocnemius.

Results

ISO reduced cardiac output and heart rate, effects preserved by melatonin. RV hypertrophy induced by ISO was not prevented, but inflammatory infiltrate, fibrosis, and upregulation of TLR4, NF-κB, and Bax were attenuated by melatonin. In the lungs, no significant alterations were observed, except for increased nitrite levels in ISO + M. Gastrocnemius oxidative stress was unchanged. Conclusions: Melatonin attenuates RV inflammation and apoptosis under adrenergic overload without preventing hypertrophy or markedly affecting lungs and skeletal muscle, supporting its potential as adjunctive therapy in cardiac diseases.

背景：能量过载是心血管疾病的核心特征，可导致右心室（RV）损伤。虽然研究广泛，但关于褪黑素对右心室和心外组织的影响的数据有限。目的探讨褪黑素对异丙肾上腺素（ISO）诱导的肾上腺素能应激大鼠肺和腓肠肌RV重构、炎症和氧化应激的影响。方法将Wistar大鼠分为对照组、ISO组和ISO +褪黑素组。ISO （5 mg/kg, s.c）给药7天，ISO + M给予ISO加褪黑激素（10 mg/kg/天，灌胃）。对照组大鼠灌胃生理盐水（s.c），未给药组只灌胃生理盐水。分别通过超声心动图和形态计量学分析评估心功能和肥厚。组织病理学检查右心室炎症和纤维化，western blotting分析右心室（TLR4、NF-κB、Bax）和肺（eNOS、ETAR）蛋白表达。测定肺和腓肠肌的氧化应激标志物（ROS、TBARS、巯基、亚硝酸盐）。结果iso降低了心输出量和心率，褪黑素的作用得以保留。虽然不能阻止ISO诱导的RV肥大，但褪黑素可以减轻炎症浸润、纤维化以及TLR4、NF-κB和Bax的上调。在肺中，除了ISO +腓肠肌分枝杆菌中亚硝酸盐水平升高外，未观察到明显的变化。结论：褪黑素可减轻肾上腺素能超负荷下的RV炎症和凋亡，但不会防止肥大或显著影响肺和骨骼肌，支持其作为心脏病辅助治疗的潜力。

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引用次数: 0