Journal of Steroid Biochemistry and Molecular Biology最新文献_第6页

Specific and potent inhibition of steroid hormone pre-receptor regulator AKR1C2 by perfluorooctanoic acid: Implications for androgen metabolism 全氟辛酸对类固醇激素前受体调节器 AKR1C2 的特异性强效抑制：对雄激素代谢的影响。

IF 2.7 2区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Steroid Biochemistry and Molecular Biology

Pub Date : 2024-11-20 DOI: 10.1016/j.jsbmb.2024.106641

Andrea Andress Huacachino , Anna Chung , Kim Sharp , Trevor M. Penning

Per- and polyfluoroalkyl substances (PFAS) are ubiquitous environmental pollutants that are highly stable synthetic organofluorine compounds. One congener perfluorooctanoic acid (PFOA) can be detected in nearly all humans and is recognized as an endocrine disrupting chemical (EDC). EDCs disrupt hormone synthesis and metabolism and receptor function. One mechanism of steroid hormone action is the pre-receptor regulation of ligand access to steroid hormone receptors by aldo-keto reductases. Here we report PFOA inhibition of AKR family 1 member C2 (AKR1C2), leading to dysregulation of androgen action. Spectrofluorimetric inhibitor screens identified PFOA as a competitive and tight binding inhibitor of AKR1C2, whose role is to inactivate 5α-dihydrotestosterone (5α-DHT). Further site directed mutagenesis studies along with molecular docking simulations revealed the importance of residue Valine 54 in mediating AKR1C2 inhibitor specificity. Binding site restrictions were explored by testing inhibition of other related PFAS chemicals, confirming that steric hinderance is a key factor. Furthermore, radiochromatography using HPLC and in line radiometric detection confirmed the accumulation of 5α-DHT as a result of PFOA inhibition of AKR1C2. We showed that PFOA could enhance the transactivation of AR in reporter genes assays in which 5α-DHT metabolism was blocked by AKR1C2 inhibition in HeLa cells. Taken together, these data suggest PFOA has a role in disrupting androgen action through inhibiting AKR1C2. Our work identifies an EDC function for PFOA not previously revealed.

全氟和多氟烷基物质（PFAS）是无处不在的环境污染物，是高度稳定的合成有机氟化合物。其中一种同系物全氟辛酸（PFOA）几乎可以在所有人体中检测到，并被公认为是一种干扰内分泌的化学物质（EDCs）。EDCs 会破坏荷尔蒙的合成、代谢和受体功能。类固醇激素的作用机制之一是通过醛酮还原酶对配体进入类固醇激素受体进行前受体调节。在此，我们报告了 PFOA 对 AKR 家族 1 成员 C2（AKR1C2）的抑制作用，导致雄激素作用失调。光谱荧光法抑制剂筛选发现，PFOA 是 AKR1C2 的竞争性紧密结合抑制剂，其作用是灭活 5α-二氢睾酮（5α-DHT）。进一步的定点突变研究和分子对接模拟揭示了残基缬氨酸 54 在 AKR1C2 抑制剂特异性中的重要性。通过测试其他相关全氟辛烷磺酸化学物质的抑制作用，探索了结合位点的限制，证实立体阻碍是一个关键因素。此外，利用高效液相色谱法和在线辐射检测法进行的放射性色谱分析证实，PFOA 对 AKR1C2 的抑制会导致 5α-DHT 的积累。我们在报告基因试验中发现，在 HeLa 细胞中抑制 AKR1C2 后，5α-DHT 的新陈代谢受阻，PFOA 可增强 AR 的转录活化作用。总之，这些数据表明，PFOA 可通过抑制 AKR1C2 干扰雄激素的作用。我们的研究发现了 PFOA 以前未被发现的 EDC 功能。

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引用次数: 0

Influence of cholecalciferol supplementation on changes in total 25OHD, free 25OHD, and free 25OHD % in relation to calcium, bone, and glucose homeostasis in young, infertile men 补充胆钙化醇对年轻不育男性总25OHD、游离25OHD和游离25OHD%变化的影响与钙、骨骼和葡萄糖稳态的关系

IF 2.7 2区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Steroid Biochemistry and Molecular Biology

Pub Date : 2024-11-20 DOI: 10.1016/j.jsbmb.2024.106640

Sam Kafai Yahyavi , Rune Holt , Mads Joon Jorsal , Lív Bech Árting , Ebbe Eldrup , Anders Juul , Niels Jørgensen , Martin Blomberg Jensen

Background and objective

While all types of vitamin D metabolites are bound to vitamin D binding protein and albumin leaving only a small fraction in its free active form, only serum concentrations of total 25-hydroxy vitamin D (25OHD) are used to determine vitamin D status in clinical practice. This study aimed to describe the association of total 25-hydroxy vitamin D (25OHD), calculated free 25OHD, and free 25OHD% (free 25OHD × 100 %/total 25OHD) with mineral, bone, and metabolic variables and assess the impact of cholecalciferol supplementation.

Research design and methods

Secondary data from a single-center, double-blinded, randomized, placebo-controlled clinical trial (NCT01304927) in 307 infertile men. The treatment group (n = 151) initially received 300,000 IU cholecalciferol as a bolus followed by 1400 IU daily for 150 days and was compared to a placebo group (n = 156).

Results

At baseline men with free 25OHD% > 0.03 % had lower serum triglycerides (mmol/L) (0.8 vs. 1.0; p = 0.002), lower LDL (mmol/L) (2.7 vs. 3.1; p = 0.003), lower fasting blood glucose (mmol/L) (4.9 vs. 5.2; p = 0.012), and lower PTH (pmol/L) (3.8 vs. 4.6; p = 0.015) compared to men with free 25OHD% < 0.02 %. When the study population was stratified according to total 25OHD or free 25OHD, the metabolic markers and bone variables did not show any differences. Cholecalciferol supplementation increased total 25OHD after 150 days compared to placebo and the difference was highest in men with lowest vitamin D status. Cholecalciferol supplementation did not change free 25OHD%.

Conclusion

The free 25OHD% is better associated with metabolic health markers such as serum triglycerides, LDL, and fasting blood glucose, but not bone or calciotrophic markers except parathyroid hormone. The free 25OHD% is not affected by cholecalciferol supplementation.

背景和目的：虽然所有类型的维生素 D 代谢物都与维生素 D 结合蛋白和白蛋白结合，只留下一小部分以游离活性形式存在，但在临床实践中，只有血清中总 25- 羟基维生素 D (25OHD) 的浓度被用来确定维生素 D 状态。本研究旨在描述总25-羟基维生素D（25OHD）、计算出的游离25OHD和游离25OHD%（游离25OHD x100%/总25OHD）与矿物质、骨骼和代谢变量的关系，并评估补充胆钙化醇的影响：307名不育男性的单中心、双盲、随机、安慰剂对照临床试验（NCT01304927）的二次数据。治疗组（人数=151）最初接受30万IU胆钙化醇的栓剂治疗，然后在150天内每天服用1400IU，并与安慰剂组（人数=156）进行比较：基线时游离25OHD%>0.03%的男性血清甘油三酯（mmol/L）较低（0.8 vs. 1.0；p=0.002），低密度脂蛋白（mmol/L）较低（2.7 vs. 3.1；p=0.003）、较低的空腹血糖（mmol/L）（4.9 vs. 5.2；p=0.012）和较低的 PTH（pmol/L）（3.8 vs. 4.6；p=0.015）：游离 25OHD% 与血清甘油三酯、低密度脂蛋白和空腹血糖等代谢健康指标有较好的相关性，但与除甲状旁腺激素外的骨或钙营养指标无关。游离 25OHD% 不受胆钙化醇补充剂的影响。

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引用次数: 0

GPER1 activation by estrogenic compounds in the inflammatory profile of breast cancer cells 雌激素化合物在乳腺癌细胞炎症特征中的 GPER1 激活。

IF 2.7 2区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Steroid Biochemistry and Molecular Biology

Pub Date : 2024-11-19 DOI: 10.1016/j.jsbmb.2024.106639

Segovia-Mendoza Mariana , Reyes-Plata Brenda , Prado-Garcia Heriberto , Lemini Cristina , Barrera David , Ángeles-López Guadalupe

Breast cancer (BC) is the most frequent female neoplasm worldwide. Its establishment and development have been related to inflammatory cytokine expression. Steroid hormones such as estradiol (E₂) can regulate proinflammatory cytokine secretion through interaction with its nuclear receptors. However, little is known regarding the activation of its membrane estrogen receptor (GPER1) and the inflammatory cytokine environment in BC. We have studied the synthesis and biological effects of molecules analogs to E₂ for hormone replacement therapy (HRT), such as pentolame. Nevertheless, its interaction with GPER1 and the modulation of inflammatory cytokines in different BC types has been barely studied and deserves deeper investigation. In this research, the role of GPER1 in the proliferation and modulation of inflammatory cytokines involved in carcinogenesis and metastatic processes in different BC cell lines was assessed by binding to various compounds. To achieve this goal, the presence of GPER1 was identified in different BC cell lines. Subsequently, cell proliferation after exposure to E₂, pentolame and GPER1 agonist, G1, was subsequently determined alone or in combination with the GPER1 antagonist, G15. Finally, the pro-inflammatory cytokine secretion derived from the supernatants of BC cells exposed to the previous treatments was also assessed. Interestingly, GPER1 activation or inhibition has significant effects on the cytokine regulation associated with invasion in BC. Notably, pentolame did not induce cell proliferation or increase the proinflammatory cytokine expression compared to E₂ in BC cell lines. In addition, pentolame did not induce the presence of the cell adhesion molecule PECAM-1. In contrast, E2 treatment weakly induced the expression of PECAM-1 in MCF-7 and HCC1937 cells, and G1 treatment showed this effect only in MCF-7 cells. The results suggest that GPER1 might be a significant inflammatory modulator with angiogenic-related effects in BC cells. In addition, pentolame might represent an HRT alternative in patients with BC predisposition.

乳腺癌（BC）是全球最常见的女性肿瘤。它的形成和发展与炎性细胞因子的表达有关。雌二醇（E2）等类固醇激素可通过与其核受体相互作用来调节促炎细胞因子的分泌。然而，人们对其膜雌激素受体（GPER1）的激活和 BC 炎症细胞因子环境知之甚少。我们研究了用于激素替代疗法（HRT）的 E2 分子类似物（如喷托胺）的合成和生物效应。然而，我们几乎没有研究过它与 GPER1 的相互作用以及对不同类型 BC 中炎症细胞因子的调节作用，这一点值得深入研究。在这项研究中，通过与各种化合物结合，评估了 GPER1 在不同 BC 细胞系的增殖和炎症细胞因子的调控中的作用。为实现这一目标，研究人员在不同的 BC 细胞系中发现了 GPER1 的存在。随后，单独或与 GPER1 拮抗剂 G15 结合测定了暴露于 E2、戊巴醇和 GPER1 激动剂 G1 后的细胞增殖情况。最后，还评估了暴露于先前处理的 BC 细胞上清液中的促炎细胞因子分泌情况。有趣的是，GPER1 的激活或抑制对与 BC 侵袭相关的细胞因子调控有显著影响。值得注意的是，与 E2 相比，在 BC 细胞系中，五氯苯胺不会诱导细胞增殖或增加促炎细胞因子的表达。此外，戊唑醇也不会诱导细胞粘附分子 PECAM-1 的存在。相比之下，E2 处理能微弱地诱导 MCF-7 和 HCC1937 细胞中 PECAM-1 的表达，而 G1 处理仅在 MCF-7 细胞中显示出这种效应。这些结果表明，GPER1 可能是一种重要的炎症调节剂，对 BC 细胞具有血管生成相关作用。此外，对于有 BC 易感性的患者来说，五氯苯胺可能是一种激素替代疗法。

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引用次数: 0

Effects of parabens on human and rat placental 3β-hydroxysteroid dehydrogenase isoforms: Structure activity relationship and docking analysis 对羟基苯甲酸酯对人和大鼠胎盘 3β- 羟类固醇脱氢酶异构体的影响：结构活性关系和对接分析。

IF 2.7 2区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Steroid Biochemistry and Molecular Biology

Pub Date : 2024-11-19 DOI: 10.1016/j.jsbmb.2024.106638

Jie Xiang , Mingzhu Zhong , Qian Zhang , Yang Zhu , Peipei Pan , Huitao Li , Qianjin Fei , Rongying Ou , Ren-shan Ge , Weibing Zhang

Parabens are widely used as preservatives in personal care products and are linked to potential disruptions in placental steroidogenesis. However, their exact impact remains unclear. This study aimed to explore the inhibition, mechanisms, structure-activity relationships (SAR) of parabens on human placental 3β-hydroxysteroid dehydrogenase type 1 (h3β-HSD1) and its rat counterpart, r3β-HSD4.3β-HSD activity was assayed in placental microsomes using pregnenolone as substrate and HPLC-MS/MS to measure progesterone and the effects of parabens on 3β-HSD was evaluated and SAR was performed. The research identified their inhibition against h3β-HSD1, with nonylparaben showing the highest potency (IC₅₀, 4.17 µM), followed by phenylparaben, heptylparaben, hexylparaben, benzylparaben, butylparaben, propylparaben, and ethylparaben. The inhibition was characterized as mixed/noncompetitive. Additionally, these parabens inhibited progesterone secretion in human JAr cells at ≤100 µM. Similar trends were observed for r3β-HSD4. Docking simulations indicated that parabens interact with NAD⁺ and steroid-binding sites of both enzymes. A negative correlation between LogP, molecular weight, volume, and alcohol chain carbon with IC₅₀ values highlighted the role of carbon chain length in determining inhibitory efficacy. The inhibitory potency of parabens on 3β-HSD is significantly influenced by their structural attributes, particularly the length of their carbon chains and LogP values.

对羟基苯甲酸酯类被广泛用作个人护理产品的防腐剂，并与胎盘类固醇生成的潜在干扰有关。然而，它们的确切影响仍不清楚。本研究旨在探讨对羟基苯甲酸酯类对人胎盘 3β-hydroxysteroid dehydrogenase type 1（h3β-HSD1）及其大鼠对应物 r3β-HSD4 的抑制作用、机制和结构-活性关系（SAR）。以孕烯醇酮为底物检测胎盘微粒体中 3β-HSD 的活性，以 HPLC-MS/MS 测定孕酮，评估对羟基苯甲酸酯类对 3β-HSD 的影响并进行 SAR 分析。研究确定了它们对 h3β-HSD1 的抑制作用，其中壬基苯甲酸酯的效力最高（IC50，4.17µM），其次是苯甲酸酯、庚基苯甲酸酯、己基苯甲酸酯、苄基苯甲酸酯、丁基苯甲酸酯、丙基苯甲酸酯和乙基苯甲酸酯。抑制作用的特点是混合/非竞争性。此外，这些对羟基苯甲酸酯在≤100µM时可抑制人JAr细胞的孕酮分泌。在 r3β-HSD4 中也观察到了类似的趋势。对接模拟表明，对羟基苯甲酸酯与这两种酶的 NAD+ 和类固醇结合位点相互作用。对羟基苯甲酸酯的 LogP、分子量、体积和醇链碳与 IC50 值呈负相关，这突出表明碳链长度在决定抑制效力方面的作用。对羟基苯甲酸酯对 3β-HSD 的抑制效力受其结构属性的显著影响，尤其是碳链长度和 LogP 值。

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引用次数: 0

The role of estrogen receptors in intracellular estrogen signaling pathways, an overview 雌激素受体在细胞内雌激素信号通路中的作用概述。

IF 2.7 2区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Steroid Biochemistry and Molecular Biology

Pub Date : 2024-11-16 DOI: 10.1016/j.jsbmb.2024.106632

Zichang Gui , Wei Shi , Fangting Zhou , Yongqing Yan , Yuntian Li , Yang Xu

To date five members of estrogen receptors (ESRs) have been reported. They are grouped into two classes, the nuclear estrogen receptors are members of the nuclear receptor family which found at nuclear, cytoplasm and plasma membrane, and the membrane estrogen receptors, such as G protein-coupled estrogen receptor 1, ESR-X and Gq-coupled membrane estrogen receptor. The structure and function of estrogen receptors, and interaction between ESR and coregulators were reviewed. In canonical pathway ESRs can translocate to the nucleus, bind to the target gene promotor with or without estrogen responsive element and regulate transcription, mediating the genomic effects of estrogen. Coactivators and corepressors are recruited to activate or inhibit transcription by activated ESRs. Many coactivators and corepressors are recruited to activate or inhibit ESR mediated gene transcription via different mechanisms. ESRs also indirectly bind to the promoter via interaction with other transcription factors, tethering the transcription factors. ESRs can be phosphorylated by several kinases such as p38, extracellular-signal-regulated kinase, and activated protein kinase B, and which activates transcription without ligand binding. Non-genomic estrogen action can be manifested by the increases of cytoplasmic NO and Ca²⁺ through the activation of membrane ESRs. In female, ESRs signaling is crucial for folliculogenesis, oocyte growth, ovulation, oviduct and uterus. In male, ESRs signaling modulates libido, erectile function, leydig cell steroidogenesis, sertoli cell’s function, and epididymal fluid homeostatsis, supporting spermatogenesis and sperm maturation. The abnormal ESRs signaling is believed to be closely related to reproductive diseases and cancer.

迄今为止，已报道了五种雌激素受体（ESRs）。它们被分为两类，一类是核雌激素受体，即存在于细胞核、细胞质和质膜的核受体家族成员；另一类是膜雌激素受体，如 G 蛋白偶联雌激素受体 1、ESR-X 和 Gq 偶联膜雌激素受体。综述了雌激素受体的结构和功能，以及 ESR 与核心调控因子之间的相互作用。在典型途径中，ESR可转位至细胞核，与含有或不含雌激素反应元件的靶基因启动子结合并调控转录，介导雌激素的基因组效应。激活的 ESR 可招募辅助激活因子和核心加压因子来激活或抑制转录。许多辅激活因子和核心加压因子通过不同的机制被招募来激活或抑制 ESR 介导的基因转录。ESR 还会通过与其他转录因子的相互作用间接结合到启动子上，拴住转录因子。ESR 可被多种激酶磷酸化，如 p38、细胞外信号调节激酶和活化蛋白激酶 B，从而在不与配体结合的情况下激活转录。非基因组雌激素的作用可通过激活膜 ESRs 来增加细胞质 NO 和 Ca2+。在女性中，ESRs 信号对卵泡生成、卵母细胞生长、排卵、输卵管和子宫至关重要。在男性中，ESRs 信号调节性欲、勃起功能、卵巢细胞类固醇生成、睾丸细胞功能和附睾液稳态，支持精子发生和精子成熟。异常 ESRs 信号被认为与生殖疾病和癌症密切相关。

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引用次数: 0

Oxysterols in tumor immune microenvironment (TIME) 肿瘤免疫微环境中的氧基甾醇（TIME）。

IF 2.7 2区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Steroid Biochemistry and Molecular Biology

Pub Date : 2024-11-16 DOI: 10.1016/j.jsbmb.2024.106634

Yuanxin Liu , Jie Qin , Xiaorui Li , Guangzhen Wu

Oxysterols are compounds generated through oxidative reactions involving cholesterol and other steroid molecules. They play a crucial role in the tumor immune microenvironment by interacting with molecules such as the cell membrane receptor EBI2 and nuclear receptors like LXR and PXR. This interaction regulates immune cell signaling pathways, affecting proliferation, apoptosis, migration, and invasion in tumor-related processes. Activating these receptors alters the function and behavior of immune cells—such as macrophages, T cells, and dendritic cells—within the tumor microenvironment, thus promoting or inhibiting tumor development. Certain oxidized steroids can increase both the number and activation of infiltrating T cells, synergizing with anti-PD-1 to enhance anti-tumor efficacy. An in-depth study of the biological mechanisms of oxidized sterols will not only enhance our understanding of the complexity of the tumor immune microenvironment but may also reveal new therapeutic targets, providing innovative strategies for tumor immunotherapy.

氧基固醇是胆固醇和其他类固醇分子发生氧化反应生成的化合物。它们与细胞膜受体 EBI2 和核受体 LXR 和 PXR 等分子相互作用，在肿瘤免疫微环境中发挥着重要作用。这种相互作用可调节免疫细胞信号通路，影响肿瘤相关过程中的增殖、凋亡、迁移和侵袭。激活这些受体会改变肿瘤微环境中免疫细胞（如巨噬细胞、T 细胞和树突状细胞）的功能和行为，从而促进或抑制肿瘤的发展。某些氧化类固醇可以增加浸润T细胞的数量和活化，与抗PD-1协同增强抗肿瘤疗效。深入研究氧化固醇的生物学机制不仅能加深我们对肿瘤免疫微环境复杂性的理解，还能发现新的治疗靶点，为肿瘤免疫疗法提供创新策略。

引用次数: 0

The validation of an LC-MS/MS method for the quantification of vitamin D metabolites in human milk and their biological variability in Gambian women 验证用于定量检测冈比亚妇女母乳中维生素 D 代谢物及其生物变异性的 LC-MS/MS 方法。

IF 2.7 2区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Steroid Biochemistry and Molecular Biology

Pub Date : 2024-11-14 DOI: 10.1016/j.jsbmb.2024.106633

Kerry S. Jones , Sarah R. Meadows , Georgia Billing , Albert Koulman , Ann Prentice

Vitamin D is required for healthy growth and development, but data on human milk vitamin D content is limited. We describe a liquid chromatography tandem mass spectrometry (LC-MS/MS) method for the analysis of vitamin D metabolites in human milk, and its application in samples collected on two consecutive days from women in rural Gambia. Vitamin D compounds were extracted from 1 mL of milk by liquid-liquid extraction and derivatised with 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD) prior to analysis by LC-MS/MS. The limit of quantification was 0.05 nmol/L for vitamin D₂, 0.025 nmol/L for vitamin D₃ and 0.1 nmol/L for 25(OH)D₂ and 25(OH)D₃. Within- and between-day imprecision was <12 % for all analytes except vitamin D₂ (14 %).

From all data combined, geometric mean (-/+ 1 SD) vitamin D₃ concentration was 0.94 (0.43, 1.80) nmol/L and for 25(OH)D₃ 0.32 (0.23, 0.42) nmol/L. The within-person (intra-individual) coefficient of variation (%CV) was 32 % and 12 % for vitamin D₃ and 25(OH)D₃, respectively. Between-person (inter-individual) %CVs were 89 % and 34 % for vitamin D₃ and 25(OH)D₃, respectively. There was no significant association between vitamin D metabolite concentrations and milk fat (creamatocrit). Mean vitamin D content of human milk as ARA averaged 42 IU/L with 25(OH)D₃ responsible for around two-thirds of the biological activity. In conclusion, this work describes a reliable LC-MS/MS method for quantification of vitamin D and 25(OH)D in low volumes of human milk providing a platform for future work. This study contributes to current understanding of variability of milk vitamin D content.

健康的生长发育需要维生素 D，但有关母乳中维生素 D 含量的数据却很有限。我们介绍了一种用于分析母乳中维生素 D 代谢物的液相色谱串联质谱（LC-MS/MS）方法，以及该方法在冈比亚农村妇女连续两天采集的样本中的应用。用液液萃取法从 1 毫升牛奶中提取维生素 D 复合物，并用 4-苯基-1,2,4-三唑啉-3,5-二酮（PTAD）衍生，然后用 LC-MS/MS 进行分析。维生素 D2 的定量限为 0.05 nmol/L，维生素 D3 为 0.025 nmol/L，25(OH)D2 和 25(OH)D3 为 0.1 nmol/L。日内和日间不精确度为 2（14%）。综合所有数据，维生素 D3 浓度的几何平均数（-/+ 1SD）为 0.94 (0.43, 1.80) nmol/L，25(OH)D3 为 0.32 (0.23, 0.42) nmol/L。维生素 D3 和 25(OH)D3 的个体内变异系数 (%CV) 分别为 32% 和 12%。维生素 D3 和 25(OH)D3 的个体间变异系数分别为 89% 和 34%。维生素 D 代谢物浓度与乳脂（乳脂率）之间无明显关联。人乳中作为 ARA 的维生素 D 平均含量为 42 IU/L，其中 25(OH)D3 约占生物活性的三分之二。总之，这项工作描述了一种可靠的 LC-MS/MS 方法，用于定量检测低浓度母乳中的维生素 D 和 25(OH)D，为今后的工作提供了一个平台。这项研究有助于人们了解牛奶中维生素 D 含量的变化。

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引用次数: 0

Interactions of sphingomyelin with biologically crucial side chain-hydroxylated cholesterol derivatives 鞘磷脂与生物学上至关重要的侧链-羟基化胆固醇衍生物的相互作用。

IF 2.7 2区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Steroid Biochemistry and Molecular Biology

Pub Date : 2024-11-13 DOI: 10.1016/j.jsbmb.2024.106635

Patrycja Dynarowicz-Latka , Anna Chachaj-Brekiesz , Anita Wnętrzak , Jan Kobierski , Andżelika Półtorak , Dawid Lupa , Ewelina W. Lipiec

Oxysterols are interesting molecules due to their dual nature, reflecting beneficial and harmful effects on the body. An issue that still needs to be solved is how slight modification of their structure owing to the location of the additional polar group in the molecules affects their biological activity. With this in mind, we selected three side chain-hydroxylated oxysterols namely: 20(S)-hydroxycholesterol (20(S)-OH), 24(S)-hydroxycholesterol (24(S)-OH), and 27-hydroxycholesterol (27-OH), and examined their behavior in mixtures with the bioactive sphingolipid – sphingomyelin (SM). Our research was based on the Langmuir monolayer technique supplemented with molecular dynamics (MD) and microscopic observation of the films texture (Brewster angle microscopy, BAM, and atomic force microscopy, AFM). Additionally, since 20(S)-hydroxycholesterol has not been studied so far, we thoroughly characterized this oxysterol in one-component monolayers. Our studies showed differences in the interactions of the studied oxysterols and sphingomyelin. Namely, it was found that 20(S)-OH binds to SM, unlike 24(S)-OH and 27-OH, which both weakly interact with SM. This distinct behavior was interpreted within the molecular dynamics as being due to weak intermolecular interactions between 20(S)-OH molecules, which allowed easy incorporation of SM into the 20(S)-OH monolayer. In contrast, the strong oxysterol-oxysterol interactions occurring in monolayers with 24(S)-OH or 27-OH make this process more difficult. This may be important in the process of bone formation/resorption. Other aspects derived from our study are: (i) the tendency of oxysterols to incorporate into lipid rafts (leading to their modification in structure and function), as well as (ii) the formation of multilayer structures, in which oxysterols are arranged in the characteristic forms of “strings of beads”, which may facilitate their transport across the membrane.

羟基甾醇是一种有趣的分子，因为它们具有双重性质，对人体既有益又有害。仍需解决的一个问题是，由于分子中附加极性基团的位置而对其结构进行的轻微改变如何影响其生物活性。有鉴于此，我们选择了三种侧链羟基化的氧基甾醇，即：20(S)-羟基胆固醇（20(S)-OH）、24(S)-羟基胆固醇（24(S)-OH）和 27-羟基胆固醇（27-OH），并研究了它们在与生物活性鞘脂--鞘磷脂（SM）的混合物中的行为。我们的研究以朗缪尔单层技术为基础，辅以分子动力学（MD）和薄膜纹理的显微观察（布鲁斯特角显微镜（BAM）和原子力显微镜（AFM））。此外，由于迄今为止尚未研究过 20(S)-羟基胆固醇，我们对单组分单层中的这种羟基甾醇进行了深入研究。我们的研究表明，所研究的羟基甾醇与鞘磷脂的相互作用存在差异。也就是说，我们发现 20(S)-OH 与鞘磷脂结合，而 24(S)-OH 和 27-OH 与鞘磷脂的相互作用较弱。分子动力学对这种不同行为的解释是，20(S)-OH 分子之间的分子间相互作用较弱，这使得 SM 很容易融入 20(S)-OH 单层中。与此相反，在含有 24（S）-OH 或 27-OH 的单层中，氧杂环醇与氧杂环醇之间会发生强烈的相互作用，从而使这一过程变得更加困难。这在骨形成/再吸收过程中可能很重要。我们的研究还得出了其他方面的结论(i)氧杂环醇融入脂质筏的倾向（导致其结构和功能的改变），以及(ii)多层结构的形成，其中氧杂环醇以 "串珠 "的特征形式排列，这可能会促进其跨膜运输。

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引用次数: 0

Steroid receptors in hormone dependent or sensitive cancers: The field of play now and looking forward 激素依赖性或敏感性癌症中的类固醇受体：现在和展望未来

IF 2.7 2区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Steroid Biochemistry and Molecular Biology

Pub Date : 2024-11-13 DOI: 10.1016/j.jsbmb.2024.106637

Donita Africander, Theresa Hickey

引用次数: 0

A study of the role of androgen receptor and androgen receptor variant 7 in TNBC patients and the effect of their targeting by Enzalutamide and EPI-001 in MDA-MB-231 一项关于雄激素受体和雄激素受体变异体 7 在 TNBC 患者中的作用以及恩杂鲁胺和 EPI-001 在 MDA-MB-231 中靶向它们的效果的研究。

IF 2.7 2区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Steroid Biochemistry and Molecular Biology

Pub Date : 2024-11-12 DOI: 10.1016/j.jsbmb.2024.106636

Belal M. Ali , Hanan S. El-Abhar , Ghada Mohamed , Hanan R. Nassar , Nelly Aliedin , Marwa Sharaky , Samia A. Shouman , Marwa Kamel

The lack of targeted therapy for triple-negative breast cancer (TNBC) is among the mainsprings of its poor prognosis. This study aimed to elucidate the role of the androgen receptor (AR) and its splice variant 7 (ARv7) in TNBC patients. Further, the molecular impact of their blockers, Enzalutamide and EPI-001, on the TNBC cell line MDA-MB-231 was investigated. Thereby, immunohistochemical expression of AR/ARv7 was assessed for TNBC Egyptian patients. Moreover, bioinformatics analysis of AR/ARv7 RNA status was carried out on TNBC patients from The Cancer Genome Atlas Breast Carcinoma project (TCGA-BRCA). Data from both groups was correlated with patients’ clinicopathological features. Besides, scratch wound healing assay and ELISA were employed to assess the effect of AR/ARv7 blockers on several metastasis markers in MDA-MB-231 cell line. In the Egyptian-TNBC patients, AR expression was associated with worse 7-year DFS (40.6 ± 18.6 %). In addition, ARv7 showed cytoplasmic and nuclear patterns, and both cytoplasmic and nuclear ARv7⁺ patients demonstrated a worse 7-year DFS (22.7 ± 17.7 % and 20 ± 17.9 %) and overall survival (63.6 ± 14.5 % and 40 ± 21.8 %). Importantly, 80 % of the nuclear ARv7⁺ patients developed distant metastasis. The data of the TCGA-TNBC patients showed a tendency for poor outcomes in the high ARv7-expressing patients. Molecularly, in MDA-MB-231, both inhibitors modulated metastasis and epithelial to mesenchymal transition (EMT) markers ROCK1, ROCK2, c-Myc, E-cadherin and N-cadherin, with EPI-001 downregulating NF-ĸB level as well. We concluded that ARv7 indicated poor prognosis in the studied cohorts and that blocking of AR/ARv7 abated metastasis and key regulators of EMT in MDA-MB-231, at least in part by targeting ROCK/NF-ĸB/c-Myc axis.

三阴性乳腺癌（TNBC）缺乏靶向治疗是其预后不良的主要原因之一。本研究旨在阐明雄激素受体（AR）及其剪接变体7（ARv7）在TNBC患者中的作用。此外，还研究了其阻断剂恩杂鲁胺和EPI-001对TNBC细胞系MDA-MB-231的分子影响。此外，还评估了TNBC埃及患者AR/ARv7的免疫组化表达。此外，还对癌症基因组图谱乳腺癌项目（TCGA-BRCA）中的 TNBC 患者进行了 AR/ARv7 RNA 状态的生物信息学分析。两组数据均与患者的临床病理特征相关。此外，还采用了划痕伤口愈合试验和酶联免疫吸附试验来评估AR/ARv7阻断剂对MDA-MB-231细胞系中几种转移标记物的影响。在埃及-TNBC患者中，AR表达与较差的7年DFS（40.6±18.6%）相关。此外，ARv7呈现细胞质和细胞核模式，细胞质和细胞核ARv7+患者的7年DFS（22.7±17.7%和20±17.9%）和总生存率（63.6±14.5%和40±21.8%）均较差。重要的是，80%的核ARv7+患者发生了远处转移。TCGA-TNBC患者的数据显示，ARv7高表达患者的预后倾向较差。分子方面，在MDA-MB-231中，两种抑制剂都能调节转移和上皮到间质转化（EMT）标志物ROCK1、ROCK2、c-Myc、E-钙粘蛋白和N-钙粘蛋白，EPI-001还能下调NF-ĸB水平。我们得出的结论是，ARv7表明研究组群的预后不佳，阻断AR/ARv7至少部分通过靶向ROCK/NF-ĸB/c-Myc轴，减轻了MDA-MB-231的转移和EMT的关键调节因子。

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引用次数: 0