Journal of Steroid Biochemistry and Molecular Biology最新文献_第4页

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

Panax notoginseng saponins improves lipid metabolism and prevents atherosclerosis in mice with steroid-resistant lupus nephritis via the SIRT1/PPARγ signaling pathway 三七皂苷通过 SIRT1/PPARγ 信号通路改善类固醇耐受性狼疮肾炎小鼠的脂质代谢并预防动脉粥样硬化。

IF 2.7 2区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Steroid Biochemistry and Molecular Biology

Pub Date : 2024-11-09 DOI: 10.1016/j.jsbmb.2024.106631

Zheng Xu , Jie Huang , Kaishun Shi , Ying Lu

Steroids serve as the primary medication for treating lupus nephritis (LN), however, steroid-resistance (SR) occurs sporadically in clinical practice, significantly affecting the therapeutic effect and long-term prognosis of patients. Our previous study found that panax notoginseng saponins (PNS) could partially reverse SR in LN. To further explore the role of PNS in reversing SR and reducing cardiovascular complications in LN, we conducted this study. Lupus mice were induced into SR while simultaneously receiving PNS. SIRT1-siRNA, SIRT1-siRNA NC, normal and lupus mice were used as control groups. Urine protein levels were measured at week 0, 4 and 8. Lipid metabolism-related biomarkers and renal function were assessed. The apoptosis rate of abdominal aortic endothelial cells was detected using flow-cytometry. The expression levels of PPARγ and SIRT1 were measured using RT-PCR and Western Blotting. Immunohistochemistry was performed to examine ACAT1 and VCAM-1 expressions. The results showed that compared to the SR lupus mice, the lupus mice treated with low/high dose PNS presented lower levels of urinary protein, serum creatinine, and blood lipids, a lower apoptosis rate of abdominal aortic endothelial cells, and decreased levels of ACAT1 and VCAM-1 PI in liver tissue, while the high-dose PNS exhibited more evidently. The PPARγ expression in SIRT1-siRNA group, as well as in low-dose and high-dose PNS groups was higher than that in the lupus and SR lupus group. In contrast, the expression of SIRT1 showed the opposite trend. Therefore, we conclude that PNS has the efficacy of reversing SR and ameliorating dyslipidemia in LN by modulating the SIRT1/PPARγ signaling pathway.

类固醇是治疗狼疮性肾炎（LN）的主要药物，但在临床实践中，类固醇耐药性（SR）时有发生，严重影响了患者的治疗效果和长期预后。我们之前的研究发现，三七皂苷（PNS）可部分逆转 LN 的类固醇抵抗。为了进一步探讨三七皂苷在逆转狼疮小鼠SR和减少心血管并发症方面的作用，我们进行了这项研究。在诱导狼疮小鼠进入 SR 的同时接受 PNS。SIRT1-siRNA、SIRT1-siRNA NC、正常小鼠和狼疮小鼠作为对照组。在第 0 周、第 4 周和第 8 周测量尿蛋白水平。对脂质代谢相关生物标志物和肾功能进行了评估。使用流式细胞仪检测腹主动脉内皮细胞的凋亡率。采用 RT-PCR 和 Western 印迹法测定 PPARγ 和 SIRT1 的表达水平。免疫组化法检测了 ACAT1 和 VCAM-1 的表达。结果显示，与SR狼疮小鼠相比，低/高剂量PNS治疗的狼疮小鼠尿蛋白、血清肌酐和血脂水平较低，腹主动脉内皮细胞凋亡率较低，肝组织中ACAT1和VCAM-1 PI水平下降，而高剂量PNS的表现更为明显。SIRT1-siRNA组、低剂量和高剂量PNS组的PPARγ表达高于狼疮组和SR狼疮组。相比之下，SIRT1 的表达却呈现出相反的趋势。因此，我们得出结论：PNS 通过调节 SIRT1/PPARγ 信号通路，具有逆转 SR 和改善 LN 血脂异常的功效。

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引用次数: 0

Calcitriol prevents SARS-CoV spike-induced inflammation in human trophoblasts through downregulating ACE2 and TMPRSS2 expression 骨化三醇通过下调 ACE2 和 TMPRSS2 的表达，防止 SARS-CoV 穗状病毒诱导的人滋养细胞炎症。

IF 2.7 2区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Steroid Biochemistry and Molecular Biology

Pub Date : 2024-11-06 DOI: 10.1016/j.jsbmb.2024.106625

Rafael Vargas-Castro , Janice García-Quiroz , Andrea Olmos-Ortiz , Euclides Avila , Fernando Larrea , Lorenza Díaz

SARS-CoV-2, the causative virus of COVID-19, increases the risk of pregnancy complications including hypertensive disorders and placental inflammation. The spike glycoprotein mediates viral cell entry by interacting with the angiotensin-converting enzyme (ACE)2 in conjunction with the transmembrane serine protease 2 (TMPRSS2). ACE1, ACE2 and renin are components of the renin-angiotensin system (RAS), which regulates blood pressure. As the placenta expresses all these proteins, it is a target for SARS-CoV-2 and a source of blood pressure modulators. Noteworthy, an ACE1/ACE2 ratio imbalance can lead to RAS dysregulation and a bad prognosis in COVID-19 patients. Calcitriol, the most active vitamin D metabolite, negatively regulates RAS, reduces inflammation, and enhances antiviral immunity, thereby protecting against COVID-19 severity. However, contrasting information exists on the regulatory role of calcitriol upon RAS components and SARS-CoV-2 receptors; while the impact of calcitriol on spike-induced inflammation in placental cells has not been explored. Thus, we studied the effects of calcitriol on these parameters using the trophoblast cell line HTR-8/SVneo and primary syncytiotrophoblasts. By RT-qPCR, ELISA, and immunocytochemistry, we found that the spike enhanced proinflammatory cytokines expression and secretion, while calcitriol significantly downregulated this effect. Calcitriol also diminished ACE1, ACE2, TMPRSS2, and renin gene expression, as well as ACE1/ACE2 mRNA ratio.

Conclusions

In the human placenta, calcitriol reduced the gene expression of main RAS components and TMPRSS2, resulting in the inhibition of spike-induced inflammation. This outcome suggest that vitamin D participates in restricting SARS-CoV-2 placental infection by rendering trophoblasts less permissive to infection while helping to regulate maternal blood pressure and decreasing inflammation.

SARS-CoV-2 是 COVID-19 的致病病毒，会增加妊娠并发症的风险，包括高血压和胎盘炎症。尖峰糖蛋白通过与血管紧张素转换酶（ACE）2 和跨膜丝氨酸蛋白酶 2（TMPRSS2）相互作用，介导病毒进入细胞。ACE1、ACE2 和肾素是调节血压的肾素-血管紧张素系统（RAS）的组成部分。由于胎盘表达所有这些蛋白，因此它是 SARS-CoV-2 的靶标，也是血压调节剂的来源。值得注意的是，ACE1/ACE2比例失调可导致RAS失调，并使COVID-19患者预后不良。骨化三醇是最活跃的维生素 D 代谢物，它能负向调节 RAS、减少炎症和增强抗病毒免疫力，从而防止 COVID-19 的严重性。然而，关于降钙素三醇对 RAS 成分和 SARS-CoV-2 受体的调节作用，存在着截然不同的信息；而降钙素三醇对尖峰诱导的胎盘细胞炎症的影响，则尚未得到探讨。因此，我们使用滋养层细胞系 HTR-8/SVneo 和原发性合胞滋养层细胞研究了降钙素三醇对这些参数的影响。通过 RT-qPCR、ELISA 和免疫细胞化学分析，我们发现穗状病毒会增强促炎细胞因子的表达和分泌，而降钙素三醇会显著降低这种效应。降钙素三醇还能降低 ACE1、ACE2、TMPRSS2 和肾素基因的表达以及 ACE1/ACE2 mRNA 的比值。结论：在人类胎盘中，降钙素三醇减少了RAS主要成分和TMPRSS2的基因表达，从而抑制了尖峰诱导的炎症。这一结果表明，维生素 D 通过降低滋养层细胞对感染的容许度，参与限制 SARS-CoV-2 胎盘感染，同时有助于调节母体血压和减少炎症。

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引用次数: 0

Causal influences of testosterone on brain structure change rate: A sex-stratified Mendelian randomization study 睾酮对大脑结构变化率的因果影响：性别分层孟德尔随机研究

IF 2.7 2区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Steroid Biochemistry and Molecular Biology

Pub Date : 2024-10-30 DOI: 10.1016/j.jsbmb.2024.106629

Xin Lian , Yaqi Bai , Pengyang Du , Zhinan Jing , Jimi Gao , Fan Liu , Jingjing Hu , Yujia Xi

The impact of testosterone levels on changes in brain structure has been reported. However, it is still unclear which specific brain region could be affected. This study approached Mendelian randomization method to reveal the causal relationship between testosterone levels and the rate of longitudinal structural changes in the brain. The testosterone-related GWAS data were determined from 425,097 European participants. The GWAS data on the rate of longitudinal structural changes in the brain came from the ENIGMA consortium, which included 15,640 all-age participants from 40 longitudinal cohorts. The inverse variance weighted was considered as the main estimate, MR Egger and weighted median methods were used to supplement IVW. A positive correlation was found between total testosterone levels and bioavailable testosterone levels in women and age-independent longitudinal changes in cerebral WM and surface area. The sex hormone-binding globulin levels were found a negative correlation with age-dependent longitudinal structural changes of cortical GM in men. Additionally, we also found that the bioavailable testosterone level in males was negatively associated with the quadratic age-dependent longitudinal change rate in the globus pallidum. We also found estradiol levels and sex hormone-binding globulin levels were negatively associated with the quadratic age-dependent longitudinal change rate of total brain in men. Moreover, we found a positive correlation between total testosterone levels and linear age-dependent longitudinal changes in the hippocampus in both males and females. The testosterone levels in different genders may have varying degrees of causal effects on the structural changes of brain regions. These findings provide evidence for the influence of the brain glandular axis on brain structure, particularly during female brain development.

睾酮水平对大脑结构变化的影响已有报道。然而，具体哪个脑区会受到影响仍不清楚。本研究采用孟德尔随机方法揭示睾酮水平与大脑纵向结构变化率之间的因果关系。与睾酮相关的 GWAS 数据来自 425 097 名欧洲参与者。关于大脑纵向结构变化率的基因组学分析数据来自ENIGMA联盟，其中包括来自40个纵向队列的15640名全年龄段参与者。反方差加权法被认为是主要的估计方法，MR Egger法和加权中位数法被用来补充反方差加权法。研究发现，女性的总睾酮水平和生物可利用睾酮水平与大脑WM和表面积的纵向变化呈正相关，且与年龄无关。性激素结合球蛋白水平与男性皮质基因组的纵向结构变化呈负相关。此外，我们还发现男性的生物可利用睾酮水平与球状苍白球随年龄变化的二次纵向变化率呈负相关。我们还发现，雌二醇水平和性激素结合球蛋白水平与男性全脑随年龄变化的二次纵向变化率呈负相关。此外，我们还发现男性和女性的总睾酮水平与海马的线性年龄依赖性纵向变化之间呈正相关。不同性别的睾酮水平可能对大脑区域的结构变化产生不同程度的因果影响。这些发现为脑腺轴对大脑结构的影响提供了证据，尤其是在女性大脑发育过程中。

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引用次数: 0

Synergistic inhibitory effects of tetramethylpyrazine and evodiamine on endometriosis development 四甲基吡嗪和依伏二胺对子宫内膜异位症发展的协同抑制作用

IF 2.7 2区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Steroid Biochemistry and Molecular Biology

Pub Date : 2024-10-30 DOI: 10.1016/j.jsbmb.2024.106630

Xiaohan Liu , Qingjun Shen , Liqin Cheng, Kailing Dai, Qiaozhu Wu, Xiaole Liu, Paul Yao, Liqin Zeng

Endometriosis (EMS) belongs to a gynecological disorder with inflammation and the existence of endometrial-like tissues beyond the uterus, often leading to infertility and pelvic pain. Estrogen receptor β (ERβ) is significantly expressed in endometriosis (EMS) and recognized as a promising therapeutic target for EMS treatment by inhibiting ERβ activity. In this study, we investigated the potential mechanisms for tetramethylpyrazine (TMP)-mediated ERβ suppression, and the synergistic inhibitory effect of TMP and evodiamine (EVO) on ERβ expression and EMS development. We found that TMP suppresses ERβ expression by reducing the association of Oct3/4 with the ERβ promoter and decreasing Oct3/4 protein levels without affecting Oct3/4 transcript levels. A minimum dosage of 10 µM TMP is required to inhibit ERβ expression. Neither TMP (5 µM) nor EVO (2 µM) alone had any effect, but their combination synergistically inhibited ERβ expression and modulated related cellular processes, including redox balance, mitochondrial function, inflammation, and proliferation. Additionally, the combination of TMP (10 mg/kg body weight) and EVO (5 mg/kg) synergistically inhibited ERβ expression and EMS development in the mouse model. In conclusion, TMP suppresses ERβ expression by reducing the association of Oct3/4 with the ERβ promoter. Neither TMP nor EVO alone effectively suppresses ERβ in both laboratory and live organism models. However, their combination synergistically inhibits ERβ expression and EMS development, suggesting a potential therapeutic strategy for EMS using TMP and EVO.

子宫内膜异位症（EMS）属于一种妇科疾病，其炎症和子宫内膜样组织存在于子宫腔之外，常常导致不孕和盆腔疼痛。雌激素受体β（ERβ）在子宫内膜异位症（EMS）中有显著表达，并被认为是通过抑制ERβ活性来治疗EMS的一个有前景的治疗靶点。本研究探讨了四甲基吡嗪（TMP）介导的ERβ抑制的潜在机制，以及TMP和依维地胺（EVO）对ERβ表达和EMS发展的协同抑制作用。我们发现，TMP通过减少Oct3/4与ERβ启动子的结合，降低Oct3/4蛋白水平而不影响Oct3/4转录本水平，从而抑制ERβ的表达。抑制 ERβ 表达至少需要 10 µM 的 TMP 剂量。单独使用 TMP（5 µM）或 EVO（2 µM）都没有任何效果，但它们的组合能协同抑制 ERβ 的表达，并调节相关的细胞过程，包括氧化还原平衡、线粒体功能、炎症和增殖。此外，在小鼠模型中，TMP（10 毫克/公斤体重）和 EVO（5 毫克/公斤）的组合能协同抑制 ERβ 的表达和 EMS 的发展。总之，TMP通过减少Oct3/4与ERβ启动子的结合来抑制ERβ的表达。在实验室和活体模型中，单独使用 TMP 或 EVO 都不能有效抑制 ERβ。然而，它们的组合能协同抑制ERβ的表达和EMS的发展，这表明使用TMP和EVO是一种潜在的EMS治疗策略。

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引用次数: 0

Biochemical classification diagnosis of polycystic ovary syndrome based on serum steroid hormones 根据血清类固醇激素对多囊卵巢综合征进行生化分类诊断。

IF 2.7 2区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Steroid Biochemistry and Molecular Biology

Pub Date : 2024-10-23 DOI: 10.1016/j.jsbmb.2024.106626

Min Wang , Shuhan Zhang , Jun He , Tianqi Zhang , Huaijun Zhu , Runbin Sun , Na Yang

Polycystic ovary syndrome (PCOS) is a metabolic disorder with clinical heterogeneity. PCOS women with non-hyperandrogenemia (NA) might be misdiagnosed due to a lack of diagnostic markers. This study aims to systematically analyze the differences in steroid hormones between PCOS women with hyperandrogenemia (HA) and NA, and to screen classification diagnosis models for PCOS. The serum samples from 54 HA-PCOS, 79 NA-PCOS and 60 control women (Non-PCOS) aged between 18 and 35 were measured by an integrated steroid hormone-targeted quantification assay using LC-MS/MS. The levels of serum androgens, corticosteroids, progestins and estrogens in the steroid hormone biosynthesis pathway were analyzed in PCOS and Non-PCOS women. Eight machine learning methods including Linear Discriminant Analysis (LDA), K-nearest Neighbors (KNN), Boosted Logistic Regression (LogitBoost), Naive Bayes (NB), C5.0 algorithm (C5), Random Forest (RF), Support Vector Machines (SVM), and Neural Network (NNET) were performed, evaluated and selected for classification diagnosis of PCOS. A 10-fold cross-validation on the training set was performed. The whole metabolic flux from cholesterol to downstream steroid hormones increased significantly in PCOS, especially in HA-POCS women. The RF model was chosen for the classification diagnosis of HA-PCOS, NA-PCOS, and Non-PCOS women due to the maximum average accuracy (0.938, p<0.001), AUC (0.989, p<0.001), and kappa (0.906, p<0.001), and the minimum logLoss (0.200, p<0.001). Five steroid hormones including testosterone, androstenedione, total 2-methoxyestradiol, total 4-methoxyestradiol, and free estrone were selected as the decision trees for the simplified RF model. A total of 37 women were included in the validation set. The diagnostic sensitivity for HA-PCOS, NA-PCOS, and Non-PCOS was 100 %, 93.3 % and 91.7 %, respectively. HA-PCOS, NA-PCOS, and Non-PCOS women showed obvious different steroid hormone profiles. The simplified RF model based on two androgens and three estrogens could be effectively applied to the classification diagnosis of PCOS, further reducing the missed diagnosis rate of NA-PCOS.

多囊卵巢综合征（PCOS）是一种代谢性疾病，具有临床异质性。由于缺乏诊断标志物，患有非高雄激素血症（NA）的多囊卵巢综合征女性可能会被误诊。本研究旨在系统分析高雄激素血症（HA）与非高雄激素血症 PCOS 女性之间类固醇激素的差异，并筛选 PCOS 的分类诊断模型。研究采用 LC-MS/MS 方法，对 54 名 HA-多囊卵巢综合征、79 名 NA-多囊卵巢综合征和 60 名对照组（非多囊卵巢综合征）18 至 35 岁女性的血清样本进行了综合类固醇激素靶向定量检测。分析了多囊卵巢综合征和非多囊卵巢综合征女性血清中雄激素、皮质类固醇、孕激素和类固醇激素生物合成途径中雌激素的水平。对线性判别分析（LDA）、K-近邻（KNN）、助推逻辑回归（LogitBoost）、Naive Bayes（NB）、C5.0 算法（C5）、随机森林（RF）、支持向量机（SVM）和神经网络（NNET）等八种机器学习方法进行了评估和选择，以对多囊卵巢综合征进行分类诊断。对训练集进行了 10 倍交叉验证。从胆固醇到下游类固醇激素的整个代谢通量在多囊卵巢综合征中显著增加，尤其是在 HA-POCS 妇女中。由于 RF 模型的平均准确率最高（0.938，p＜0.05），因此被选为 HA-PCOS、NA-PCOS 和非 PCOS 妇女的分类诊断模型。

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引用次数: 0

An optimized whole-body corticosteroid hormones quantification method by LC-MS/MS for assessing stress levels in European glass eels (Anguilla anguilla) 通过 LC-MS/MS 对皮质类固醇激素进行全身定量的优化方法，用于评估欧洲玻璃鳗（鳗鲡）的应激水平。

IF 2.7 2区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Steroid Biochemistry and Molecular Biology

Pub Date : 2024-10-23 DOI: 10.1016/j.jsbmb.2024.106627

Stellia Sebihi , Mathilde Monperrus , Pascale Coste , Emmanuel Huchet , Matthieu Lingrand , Stéphane Glise , Colin Bouchard , Maren Ortiz-Zarragoitia , Valérie Bolliet

The European eel (Anguilla anguilla) juvenile stage exhibits facultative estuarine migration. The causes of this behavior are yet unknown but it may have an impact on the population's fate by altering the sex ratio of the population. Recent studies have highlighted potential stress-related issues in glass eels settling in estuaries but studying stress response in small organisms requires sensitive, accurate and precise analytical methods. The aims of the present study are (i) to develop a whole-body Liquid Chromatography-Mass Spectrometry (LC-MS/MS) method for the simultaneous determination of several stress hormones in low-body mass fish; (ii) to apply this method to glass eels to study their responses to acute stress (iii) to test the effect of anxiolytics (diazepam) on these responses. Our results showed that enhanced LC-MS/MS analysis reduced detection limits and improved accuracy and precision for the quantification at the individual level. Following an acute stress, cortisol concentration significantly increased in glass eels and a 15 h diazepam exposure significantly reduced cortisol levels highlighting a marked anxiolytic effect on this species.

欧洲鳗鲡（Anguilla anguilla）的幼体阶段表现出亲河口洄游；这种行为的原因尚不清楚，但它可能会通过改变性别比例对种群的命运产生影响。最近的研究强调了在河口定居的玻璃鳗可能存在的应激相关问题，但研究小型生物的应激反应需要灵敏、准确和精确的分析方法。本研究的目的是：(i) 开发一种全身液相色谱-质谱法（LC-MS/MS），用于同时测定低体重鱼类体内的几种应激激素；(ii) 将该方法应用于玻璃鳗，研究它们对急性应激的反应；(iii) 测试抗焦虑药（地西泮）对这些反应的影响。我们的研究结果表明，增强型 LC-MS/MS 分析降低了检测限，提高了个体水平定量的准确性和精确性。急性应激后，玻璃鳗体内的皮质醇浓度明显升高，而 15 小时的地西泮暴露可明显降低皮质醇水平，这表明地西泮对该物种有明显的抗焦虑作用。

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引用次数: 0

Protopanaxadiol synergizes with glucocorticoids to enhance the therapeutic effect in adriamycin-induced nephrotic syndrome 原人参皂苷与糖皮质激素协同增强阿霉素诱导的肾病综合征的治疗效果

IF 2.7 2区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Steroid Biochemistry and Molecular Biology

Pub Date : 2024-10-22 DOI: 10.1016/j.jsbmb.2024.106628

Ming-Yan Yang , Dong Qi , Meng-Ying Wang , Da-Lei Li , Zhen-Yuan Li , Ya-Ping He , Ke Liu , Hua-Ying Fan

To date, glucocorticoids remain the mainstay of treatment of nephrotic syndrome (NS). However, serious side effects and development of drug-resistance following long-term use limit the application of glucocorticoids. Protopanaxadiol (PPD) possesses activity of dissociating transactivation from transrepression by glucocorticoid receptor (GR), which may serve as a potential selective GR modulator. However, steroid-like effects of PPD in vivo are unclear and not defined. How to translate PPD into clinical practice remains to be explored. The current study explored the renoprotection and potential mechanism of PPD and its combination with steroid hormones using adriamycin-induced NS rats. Adriamycin was given intravenously to rats to induce nephropathy. The determination of proteinuria, biochemical changes and inflammatory cytokines were performed, and pathological changes were examined by histopathological examination. Immunostaining and PCR were used to analyze the expression of interesting proteins and genes. The results showed that PPD, alone and in combination with prednisone, efficiently alleviate the symptoms of NS, attenuate nephropathy, improve adriamycin-induced podocyte injury by reducing desmin and increasing synaptopodin expression. In addition, the combined treatment reduced the expression of NF-κB protein and mRNA, as well as cytokine levels, and yet increased the expression of GR protein and mRNA. PPD modulated the transactivation of GR, manifested as repressing TAT, PEPCK and ANGPTL4 mRNA expressions mediated by GR. Meanwhile, PPD inhibited elevation of blood glucose and immune organ atrophy induced by prednisone. In summary, PPD increases the therapeutic effect of prednisone in NS while effectively prevents or decreases the appearance of side effects of glucocorticoids.

迄今为止，糖皮质激素仍是治疗肾病综合征（NS）的主要药物。然而，长期使用糖皮质激素会产生严重的副作用和耐药性，这限制了糖皮质激素的应用。原人参二醇（PPD）具有使糖皮质激素受体（GR）的反式激活与反式抑制分离的活性，可作为一种潜在的选择性GR调节剂。然而，PPD在体内的类固醇样作用尚不明确，也没有界定。如何将 PPD 转化为临床实践仍有待探索。本研究以阿霉素诱导的NS大鼠为研究对象，探讨了PPD及其与类固醇激素联用的肾保护作用和潜在机制。大鼠静脉注射阿霉素诱发肾病。对大鼠的蛋白尿、生化变化和炎性细胞因子进行测定，并通过组织病理学检查对病理变化进行检测。免疫染色和 PCR 被用来分析相关蛋白质和基因的表达。结果表明，PPD单独或与泼尼松联合使用可有效缓解NS的症状，减轻肾病，并通过减少desmin和增加突触素的表达来改善阿霉素诱导的荚膜细胞损伤。此外，联合治疗还能降低 NF-κB 蛋白和 mRNA 的表达以及细胞因子的水平，同时提高 GR 蛋白和 mRNA 的表达。PPD 可调节 GR 的转录活化，表现为抑制 GR 介导的 TAT、PEPCK 和 ANGPTL4 mRNA 的表达。同时，PPD 还能抑制泼尼松引起的血糖升高和免疫器官萎缩。总之，PPD能提高泼尼松对NS的治疗效果，同时有效预防或减少糖皮质激素副作用的出现。

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引用次数: 0