Steroids最新文献_第4页

Nutrient manipulation regulates growth and steroidal alkaloid production in plant cultures of Solanum viarum Dunal 营养调控对龙葵生长和甾体生物碱产生的影响。

IF 2.3 4区医学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY

Steroids

Pub Date : 2025-10-15 DOI: 10.1016/j.steroids.2025.109700

Archana Prasad , Preeti Patel , Abhishek Niranjan , Gauri Saxena , Debasis Chakrabarty

Solanum viarum is a valuable medicinal plant native to India and widely distributed throughout Asia. It serves as a commercially viable raw source for the steroidal drug industry, being the richest natural source of an important steroidal alkaloid- solasodine. Enhancement of solasodine content in in vitro plant cultures is always a keen interest for tissue culturists for the research and development in pharmaceutical industries. In the present study, a multiple linear regression (MLR) model was employed to investigate the synergistic effects of key nutrient components in the growth medium (Mg, Ca, Fe, N, and sucrose) for optimized growth and solasodine production in in vitro plant cultures of S. viarum. All the cultures were harvested after 35, 45, and 55 days of the culture cycle. The three models were designed to predict growth index, solasodine content, and solasodine yield in the plant cultures. The designed model was further evaluated by performing a validation experiment using ten different experimental setups, which showed a greater similarity between the predicted and experimental datasets. The results of the model-based experimental set showed that 1.4 mM Mg, 2.9 mM Ca, 1.9 µM Fe, 41.9 mM Nitrogen, and 4 % (w/v) sucrose resulted in achieving maximum solasodine yield (108.82 mg/g DW) in the plant culture of S. viarum after 54 days of harvest. The proposed MLR model offers a robust and reliable approach for predicting the optimal concentrations of micro- and macronutrients to maximize growth and solasodine accumulation in in vitro cultures of Solanum viarum. This study establishes a strategic framework that can be leveraged to enhance biomass production and secondary metabolite yield, contributing significantly to the large-scale cultivation and pharmaceutical exploitation of this valuable medicinal plant.

龙葵（Solanum viarum）是一种原产于印度的珍贵药用植物，在亚洲广泛分布。它作为一种商业上可行的甾体药物工业原料来源，是一种重要的甾体生物碱- solasodine的最丰富的天然来源。提高植物离体培养物中solasodine的含量一直是制药行业组织培养研究和开发的热点。本研究采用多元线性回归（MLR）模型，研究了生长培养基中关键营养成分（Mg、Ca、Fe、N和蔗糖）对紫葡萄（S. viarum）体外培养物生长和产茄碱的协同效应。在培养周期的35、45和55 天后收获所有的培养物。这三个模型被设计用来预测植物生长指数、茄碱含量和茄碱产量。通过使用10种不同的实验设置进行验证实验，进一步评估设计的模型，结果表明预测数据集与实验数据集之间具有更大的相似性。基于模型的实验结果表明，收获54 d后，1.4 mM Mg、2.9 mM Ca、1.9 µM Fe、41.9 mM Nitrogen和4 % （w/v）蔗糖的植株培养可获得最大的solasodine产量（108.82 Mg /g DW）。所提出的MLR模型提供了一种稳健可靠的方法来预测微量营养素和宏量营养素的最佳浓度，以最大限度地提高龙葵体外培养物的生长和茄碱积累。本研究建立了一个战略框架，可用于提高生物质产量和次生代谢物产量，为这种珍贵药用植物的大规模种植和药用开发做出重大贡献。

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引用次数: 0

Beta-Ecdysone protects osteocytes from excess glucocorticoids via Akt1-mediated regulation of Connexin43 β -蜕皮激素通过akt1介导的连接蛋白43的调节来保护骨细胞免受过量糖皮质激素的影响。

IF 2.3 4区医学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY

Steroids

Pub Date : 2025-10-04 DOI: 10.1016/j.steroids.2025.109693

Anna Xie , Libo Wang , Yu Zhang, Sunzhengyuan Zhang, Jinlong Cao, Chenglong Wang, Hongjin Wu, Weiwei Dai

Glucocorticoid-induced osteoporosis (GIOP) is a leading cause of secondary osteoporosis (OP). β-Ecdysone (βEcd), a naturally occurring estrogen analog, was evaluated for its ability to mitigate the effects of glucocorticoids (GCs) on osteocytes, the crucial cells in bone remodeling. In GIOP mouse model induced by dexamethasone (Dex), micro-CT, biomechanical testing, silver nitrate staining, and hematoxylin-eosin (HE) staining were employed, demonstrating that βEcd effectively attenuated Dex-induced decreases in bone mass and strength, and alleviated Dex induced reduction in osteocyte dendrite and viability. Network pharmacology analysis predicted that the therapeutic efficacy of βEcd against GIOP is mediated through the crucial targets such as protein kinase B (Akt1), with significant enrichment in pathways including apoptosis and phosphoinositide 3-kinase (PI3K)-Akt signaling. In vitro, the osteocyte-like MLO-Y4 cells were treated with 10 μM Dex for 48 h in the presence or absence of βEcd or the PI3K inhibitor LY294002 (LY). Crystal violet staining and connexin43 (CX43) immunofluorescence (IF) staining were employed, and western blot was used to assess the levels of Akt1, phospho (p)-Akt, CX43, p-CX43, and apoptosis-related factors. Hoechst staining and annexin V/PI apoptosis assays were also used to evaluate apoptosis. The results demonstrated that βEcd counteracted Dex-induced apoptosis by modulating Akt1 and CX43 expression in MLO-Y4 cells, while inhibition of Akt activity reversed these effects, suggesting that βEcd targets the Akt1 gene. The findings indicate that βEcd protects osteocytes from GC-induced apoptosis through Akt-mediated regulation of CX43, highlighting its potential as a therapeutic approach for the prevention and treatment of GIOP.

糖皮质激素性骨质疏松症（GIOP）是继发性骨质疏松症（OP）的主要原因。β-蜕皮激素（βEcd）是一种天然存在的雌激素类似物，其减轻糖皮质激素（GCs）对骨细胞（骨重塑的关键细胞）影响的能力被评估。在地塞米松（Dex）诱导的GIOP小鼠模型中，通过显微ct、生物力学测试、硝酸银染色和苏木精-伊红（HE）染色，表明βEcd能有效减弱Dex诱导的骨量和强度下降，减轻Dex诱导的骨细胞树突和活力下降。网络药理学分析预测，βEcd对GIOP的治疗作用是通过蛋白激酶B （Akt1）等关键靶点介导的，在细胞凋亡和磷酸肌肽3激酶(PI3K)-Akt信号通路中显著富集。体外，在βEcd或PI3K抑制剂LY294002 （LY）存在或不存在的情况下，用10 μM Dex处理骨细胞样MLO-Y4细胞48 h。采用结晶紫染色和连接蛋白43 （CX43）免疫荧光（IF）染色，western blot检测Akt1、phospho (p)-Akt、CX43、p-CX43及凋亡相关因子水平。采用Hoechst染色法和膜联蛋白V/PI法检测细胞凋亡。结果表明，βEcd通过调节MLO-Y4细胞中Akt1和CX43的表达来抵消dex诱导的细胞凋亡，而抑制Akt活性逆转了这些作用，表明βEcd靶向Akt1基因。研究结果表明，βEcd通过akt介导的CX43调节保护骨细胞免受gc诱导的凋亡，突出了其作为预防和治疗GIOP的治疗方法的潜力。

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引用次数: 0

Targeted metabolomics in PCOS mice identifies hippuric acid as a therapeutic metabolite. PCOS小鼠的靶向代谢组学鉴定马尿酸是一种治疗性代谢物。

IF 2.3 4区医学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY

Steroids

Pub Date : 2025-10-01 Epub Date: 2025-08-06 DOI: 10.1016/j.steroids.2025.109665

Hui Lan, Bin Meng, Jianbo Li, Chenjin Duan, Shuangqing Liu, Pengxiang Qu, Hongyu Qin

Polycystic ovary syndrome (PCOS) represents a complex endocrine disorder with profound detrimental effects on women's reproductive and metabolic health, yet the absence of specific pharmacotherapeutic interventions has resulted in a significant therapeutic gap. To elucidate the metabolic alterations in PCOS, we conducted a comprehensive targeted metabolomics analysis of plasma samples from healthy control mice and PCOS model mice, examining a panel of 197 metabolites spanning diverse metabolic classes. Our analysis revealed substantial metabolic differences between the groups, with organic acids, amino acids, and fatty acids emerging as the most abundant metabolite classes in both cohorts. Among the 197 metabolites analyzed, 86 demonstrated a Variable Importance in Projection (VIP) score > 1, with univariate analysis confirming 76 distinct metabolites showing significant alterations. Notably, the PCOS group exhibited marked increases in metabolites such as tartaric acid and docosapentaenoic acid, while hippuric acid showed the most pronounced reduction. Pathway enrichment analysis identified significant perturbations in key metabolic pathways, including amino acid metabolism, fatty acid oxidation, and the urea cycle in PCOS mice. The exogenous administration of hippuric acid led to a significant amelioration of ovarian pathology in PCOS mice, highlighting its promising therapeutic potential. These findings provide crucial insights into the altered metabolic landscape of PCOS, identifying potential biomarkers and therapeutic targets, with particular emphasis on the promising therapeutic role of hippuric acid in mitigating PCOS pathology, thereby offering a valuable avenue for further investigation and clinical translation.

多囊卵巢综合征（PCOS）是一种复杂的内分泌紊乱，对妇女的生殖和代谢健康有严重的有害影响，但由于缺乏特异性的药物治疗干预措施，导致治疗差距很大。为了阐明PCOS的代谢改变，我们对健康对照小鼠和PCOS模型小鼠的血浆样本进行了全面的靶向代谢组学分析，检查了跨越不同代谢类别的197种代谢物。我们的分析揭示了两组之间的代谢差异，有机酸、氨基酸和脂肪酸是两组中最丰富的代谢物类别。在分析的197种代谢物中，86种表现出预测变量重要性（VIP）评分 > 1，单变量分析证实76种不同的代谢物表现出显著的改变。值得注意的是，PCOS组的代谢产物如酒石酸和二十二碳五烯酸明显增加，而马尿酸的减少最为明显。途径富集分析发现，PCOS小鼠的氨基酸代谢、脂肪酸氧化和尿素循环等关键代谢途径存在显著扰动。外源性给药马尿酸可显著改善PCOS小鼠卵巢病理，显示其治疗潜力。这些发现为PCOS代谢景观的改变提供了重要的见解，确定了潜在的生物标志物和治疗靶点，特别强调了马尿酸在减轻PCOS病理方面的有希望的治疗作用，从而为进一步的研究和临床转化提供了有价值的途径。

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引用次数: 0

Kobochromone A, a polyphenol in Carex kobomugi, suppresses androgen signaling induced by 11-oxygenated androgens and enhances the efficacy of AKT inhibitors in triple-negative breast cancer cells kobomugi中的一种多酚Kobochromone A可抑制11-氧合雄激素诱导的雄激素信号，并增强AKT抑制剂在三阴性乳腺癌细胞中的作用。

IF 2.3 4区医学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY

Steroids

Pub Date : 2025-09-25 DOI: 10.1016/j.steroids.2025.109692

Masatoshi Tanio , Yuri Miyamoto , Tomofumi Saka , Yudai Kudo , Riri Hayashi , Shinya Kawano , Yuta Yoshino , Naohito Abe , Eiji Yamaguchi , Yuki Arai , Hirohito Kashiwagi , Masayoshi Oyama , Akichika Itoh , Akira Ikari , Satoshi Endo

Breast cancer is the most common cancer in women, with triple-negative breast cancer (TNBC) accounting for approximately 20% of cases. TNBC lacks estrogen receptors (ER), progesterone receptors (PR), and epidermal growth factor receptor 2 (HER2) expression, which makes targeted therapies ineffective. The luminal androgen receptor (LAR) subtype of TNBC expresses androgen receptor (AR), highlighting the need for treatment strategies that target androgen signaling. Recently, the role of 11-oxygenated androgens, in addition to conventional androgens such as testosterone and dihydrotestosterone, in androgen-related diseases in women has gained increased attention.

In this study, we investigated the involvement of 11-oxygenated androgens in LAR TNBC and explored the anti-androgenic effects of Kobochromone A (KC-A), a natural compound derived from Carex kobomugi. KC-A inhibits the androgen-synthesizing enzyme dehydrogenase/reductase short-chain dehydrogenase/reductase family member 11 (DHRS11) and suppresses AR expression. Using the AR-positive TNBC cell line MDA-MB-453, we demonstrated that 11-oxygenated androgens activate androgen signaling and promote cell proliferation. KC-A significantly inhibited androgen signaling by reducing nuclear AR localization and decreasing transmembrane protease, serine 2, and c-Myc expression. Furthermore, KC-A synergistically enhanced antiproliferative effects of the AKT inhibitor capivasertib (Cap), promoted apoptosis, and further suppressed AR expression. The primary therapeutic mechanisms of KC-A were identified as its dual actions: inhibition of DHRS11 and suppression of AR expression. These findings suggest that KC-A, either alone or in combination with AKT inhibitors, may offer a promising therapeutic strategy for LAR TNBC by targeting androgen signaling. Further studies are needed to confirm the efficacy and safety of KC-A in clinical applications.

乳腺癌是女性中最常见的癌症，三阴性乳腺癌（TNBC）约占病例的20%。TNBC缺乏雌激素受体（ER）、孕激素受体（PR）和表皮生长因子受体2 （HER2）的表达，这使得靶向治疗无效。TNBC的腔内雄激素受体（LAR）亚型表达雄激素受体（AR），强调了针对雄激素信号传导的治疗策略的必要性。最近，除了睾酮和双氢睾酮等传统雄激素外，11-氧合雄激素在女性雄激素相关疾病中的作用越来越受到关注。在这项研究中，我们研究了11-氧合雄激素在LAR TNBC中的作用，并探讨了Kobochromone A （KC-A）的抗雄激素作用。KC-A抑制雄激素合成酶脱氢酶/还原酶短链脱氢酶/还原酶家族成员11 (DHRS11)，抑制AR表达。利用ar阳性的TNBC细胞系MDA-MB-453，我们证明了11-氧合雄激素激活雄激素信号并促进细胞增殖。KC-A通过降低核AR定位和降低跨膜蛋白酶、丝氨酸2和c-Myc的表达，显著抑制雄激素信号传导。此外，KC-A协同增强AKT抑制剂capivasertib （Cap）的抗增殖作用，促进细胞凋亡，进一步抑制AR表达。KC-A的主要治疗机制被确定为其双重作用：抑制DHRS11和抑制AR表达。这些发现表明，KC-A单独或与AKT抑制剂联合，可能通过靶向雄激素信号通路，为LAR TNBC提供一种有希望的治疗策略。KC-A在临床应用中的有效性和安全性有待进一步研究证实。

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引用次数: 0

Steroidal scaffold dichotomy: pathogenic role of 7-ketocholesterol versus protective FXR-antagonistic actions of guggulsterone in metabolic regulation 甾体支架二分法：7-酮胆固醇的致病作用与谷固酮在代谢调节中的保护性fxr -拮抗作用

IF 2.3 4区医学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY

Steroids

Pub Date : 2025-09-24 DOI: 10.1016/j.steroids.2025.109691

Sarvesh Sabarathinam , Nila Ganamurali

Obesity-associated Dyslipidemia and inflammation are aggravated by the accumulation of toxic oxysterols, particularly 7-ketocholesterol (7-KC), which amplifies oxidative stress and metabolic dysfunction. The steroidal scaffold is a central determinant of whether such molecules exert protective or pathogenic effects. This review highlights the dichotomy between 7-KC, a cytotoxic oxysterol, and Guggulsterone, a Phytosteroids with therapeutic potential. Guggulsterone retains the tetracyclic steroid backbone, enabling it to mimic endogenous sterols while functioning as a farnesoid X receptor (FXR) antagonist. By relieving FXR-mediated suppression of CYP7A1, Guggulsterone enhances bile acid synthesis, promotes cholesterol clearance, and improves lipid profiles. Additionally, its structural features confer anti-inflammatory activity via NF-κB inhibition, contrasting with the pro-oxidant nature of 7-KC. The concept of steroid scaffold mimicry underscores the potential of Phytosteroids as blueprints for drug design, offering a path toward innovative therapies for obesity-linked metabolic disorders.

有毒的氧化固醇，尤其是7-酮胆固醇（7-KC）的积累会加剧肥胖相关的血脂异常和炎症，这会放大氧化应激和代谢功能障碍。甾体支架是这些分子是否发挥保护或致病作用的中心决定因素。这篇综述强调了7-KC（一种细胞毒性氧化固醇）和Guggulsterone（一种具有治疗潜力的植物类固醇）之间的对立。Guggulsterone保留了四环类固醇骨架，使其能够模拟内源性固醇，同时作为farnesoid X受体（FXR）拮抗剂发挥作用。通过缓解fxr介导的CYP7A1抑制，固谷酮增强胆汁酸合成，促进胆固醇清除，改善脂质谱。此外，它的结构特征通过抑制NF-κB赋予抗炎活性，与7-KC的促氧化性质形成对比。类固醇支架模拟的概念强调了植物类固醇作为药物设计蓝图的潜力，为肥胖相关代谢紊乱的创新疗法提供了一条途径。

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引用次数: 0

Duration of vitamin D supplementation modulates the association between cardiovascular disease and high-sensitivity C-reactive protein across body mass index strata 维生素D补充的持续时间调节了心血管疾病与高敏感性c反应蛋白之间的关系。

IF 2.3 4区医学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY

Steroids

Pub Date : 2025-09-23 DOI: 10.1016/j.steroids.2025.109690

Theocharis Koufakis , Theofylaktos Georgiadis , Areti Kourti , Katerina Thisiadou , Paraskevi Karalazou , Alexander Kokkinos , Michael Doumas , Kalliopi Kotsa , Kali Makedou

Background

Cardiovascular disease (CVD) and higher body mass index (BMI) are linked to chronic low-grade inflammation. It is unclear whether vitamin D modifies the association between CVD and inflammatory biomarkers uniformly across BMI strata. We therefore tested whether vitamin D status and supplementation modify the CVD–biomarker association and whether any modification differs by BMI category.

Methods

In a cross-sectional cohort of adults free of acute infection (N = 88; 20 with normal BMI, 34 with overweight, and 34 with obesity), four inflammatory biomarkers were assessed: high-sensitivity C-reactive protein (hs-CRP), presepsin, ferritin, and β-defensin-2. Outcomes were modeled on the natural-log scale with age and sex as covariates. We tested the interaction between BMI and CVD and evaluated whether vitamin D variables [25(OH)D concentrations, supplementation status, supplementation duration, sufficiency category] modified the CVD–biomarker relationship, including prespecified three-way interactions among CVD, vitamin D, and BMI.

Results

No interaction between BMI and CVD was detected for any biomarker. For hs-CRP, a significant three-way interaction among CVD, vitamin D supplementation duration, and BMI was observed (p = 0.008) and was robust to sensitivity analyses [duration capped at three or six months; additional adjustment for 25(OH)D and supplementation status]. With longer supplementation, the CVD–hs-CRP difference widened in the moderate-BMI category and attenuated in the higher-BMI category. Other biomarkers showed no comparable interactions.

Conclusion

Vitamin D exposure—particularly supplementation duration—may modulate CVD-related inflammation in a BMI-dependent manner. Replication in larger studies is warranted.

背景：心血管疾病（CVD）和较高的身体质量指数（BMI）与慢性低度炎症有关。目前尚不清楚维生素D是否能在BMI水平上均匀地改变心血管疾病和炎症生物标志物之间的关系。因此，我们测试了维生素D状态和补充是否会改变cvd生物标志物的关联，以及是否有任何改变因BMI类别而异。方法：在无急性感染的成人横断队列中（N = 88；20 BMI正常，34超重，34肥胖），评估四种炎症生物标志物：高敏c反应蛋白（hs-CRP）， presepsin，铁蛋白和β-防御素-2。结果采用自然对数量表，以年龄和性别为协变量。我们测试了BMI和CVD之间的相互作用，并评估了维生素D变量[25(OH)D浓度、补充状态、补充时间、充足类别]是否改变了CVD-生物标志物之间的关系，包括CVD、维生素D和BMI之间预先设定的三向相互作用。结果：没有检测到任何生物标志物在BMI和CVD之间的相互作用。对于hs-CRP，观察到CVD、维生素D补充时间和BMI之间显著的三向相互作用（p = 0.008），并且对敏感性分析具有稳健性[持续时间上限为3或6个月；额外调整25(OH)D和补充状态]。随着补充时间的延长，CVD-hs-CRP差异在中等bmi组中扩大，在高bmi组中减弱。其他生物标志物没有显示出类似的相互作用。结论：维生素D暴露-特别是补充时间-可能以bmi依赖的方式调节cvd相关炎症。在更大规模的研究中重复是有保证的。

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引用次数: 0

Design, synthesis and characterization of novel cholesterol derivatives: Anti-cancer activity, ADMET profiling and DFT insights 新型胆固醇衍生物的设计、合成和表征：抗癌活性、ADMET分析和DFT见解。

IF 2.3 4区医学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY

Steroids

Pub Date : 2025-09-15 DOI: 10.1016/j.steroids.2025.109687

Anmol Verma , Poonam Rawat , Sanyukta Shukla , Ranvijay Pratap Singh , Pratishtha Gupta , Shama Parveen , Monisha Banerjee , Arun Sethi , Saurabh Kumar Singh

In the present work, Steglich esterification and Mizoroki-Heck reaction have been carried out for the synthesis of novel cholesterol derivatives. The synthesized derivatives 2, 3, 4, 5 and 6 were purified through column chromatography and characterized by ¹H, ¹³C NMR, FT-IR spectroscopy, and mass spectrometry. The geometries of all the compounds were optimized in the ground state by the density function theory at the B3LYP/6-31G(d,p) level. The in vitro evaluation of compounds 2 (IC₅₀ 17), 3 (IC₅₀ 11), 4 (IC₅₀ 14) and 6 (IC₅₀ 20) for their anti-cancer activity against SiHa cells demonstrated an increased apoptotic activity in comparison to the parent compound 1 (IC₅₀ 24) i.e. cholesterol. The Molecular docking studies were carried out against two proteins bearing the protein data bank (PDB) ID 2B9D and 1R9W to investigate the inhibitory action of the derivatives. The result of molecular docking showed appreciable interactions of 2, 3, 4, 5 and 6 with the selected proteins as compared to 1. The in vitro and molecular docking studies show that the synthesized molecules can prove to be better anti-cancer agents on other cancer cells also. The computational analysis data and the experimental data were in conformation with each other. ADMET analysis was carried out using the admetSAR database and Swiss ADME.

本文采用Steglich酯化反应和Mizoroki-Heck反应合成了新型胆固醇衍生物。合成的衍生物2、3、4、5和6经柱层析纯化，并用1H、13C NMR、FT-IR和质谱对其进行了表征。利用密度泛函理论在B3LYP/6-31G（d,p）水平上优化了化合物的基态几何形状。体外评价化合物2 （IC50 17）、3 （IC50 11）、4 （IC50 14）和6 （IC50 20）对SiHa细胞的抗癌活性表明，与母体化合物1 (IC50 24)（即胆固醇）相比，它们的凋亡活性增加。以蛋白数据库（PDB）编号为2B9D和1R9W的两种蛋白为对象，进行分子对接研究，研究其衍生物的抑制作用。分子对接结果表明，与1相比，2、3、4、5和6与所选蛋白的相互作用明显。体外和分子对接研究表明，所合成的分子对其他癌细胞也有较好的抗癌作用。计算分析数据与实验数据吻合较好。ADMET分析采用admetSAR数据库和瑞士ADME进行。

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引用次数: 0

Mineralocorticoid receptor antagonism of vamorolone: Evidence from LIONHEART and VISION-DMD clinical trials 氨莫洛酮的矿皮质激素受体拮抗作用：来自LIONHEART和VISION-DMD临床试验的证据。

IF 2.3 4区医学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY

Steroids

Pub Date : 2025-09-14 DOI: 10.1016/j.steroids.2025.109689

Ana de Vera , Paula R Clemens , Utkarsh J Dang , Catherine Dutreix , Ekaterina Gresko , Michela Guglieri , Laura Hagerty , Shabir Hasham , Jesse Damsker , Yetrib Hathout , Aki Linden , Anders Berglund , Rebecca Tobin , Karim Wahbi , Eric P Hoffman

The effect of vamorolone, the first dissociative corticosteroid for Duchenne muscular dystrophy (DMD), at the mineralocorticoid receptor (MR) was investigated in the Phase 1 mechanistic LIONHEART study and using serum samples from boys with DMD in the pivotal VISION-DMD trial. In LIONHEART, 30 healthy adult males were randomized 1:1:1 to vamorolone 20 mg/kg, eplerenone 200 mg, or no treatment arms. A fludrocortisone challenge was administered between –9 h and 24 h after treatment. The LIONHEART primary outcome was urinary Na⁺/K⁺ ratio; additional outcomes were pharmacokinetics, urine Na⁺ and K⁺ concentrations, and safety. In VISION-DMD, boys with DMD aged 4–7 years were treated with vamorolone 2 or 6 mg/kg/d for 48 weeks or with prednisone 0.75 mg/kg/d or placebo for 24 weeks followed by vamorolone 2 or 6 mg/kg/d for 20 weeks following a 4-week washout. Serum sample analysis from VISION-DMD used the SomaScan® 7 K assay. In LIONHEART, vamorolone reversed the decrease in urinary Na⁺/K⁺ ratio induced by fludrocortisone, confirming vamorolone MR antagonism. The maximum MRA effect of vamorolone was observed at 4–6 h post dose and was detectable until approximately 10 h post dose. Vamorolone reversed fludrocortisone induced Na⁺ retention with no evidence of decreased potassium excretion. Vamorolone 20 mg/kg was well tolerated, and results were consistent with known PK parameters. The VISION-DMD results showed vamorolone-specific increases in renin serum levels, as well as klotho, and calcium carrier proteins fetuin A and B, consistent with an MR antagonist effect. The available data confirm the MR antagonistic effect of vamorolone in humans. LIONHEART: NCT06649409; VISION-DMD: NCT03439670.

第一种用于治疗杜氏肌营养不良症（DMD）的解离性皮质类固醇——氨莫洛酮对矿化皮质激素受体（MR）的影响在1期机械LIONHEART研究中进行了研究，并在关键的VISION-DMD试验中使用了患有DMD的男孩的血清样本。在LIONHEART研究中，30名健康成年男性按1:1:1的比例随机分配到氨莫洛酮20 mg/kg、依普利酮200 mg或无治疗组。在治疗后-9 h至24 h间给予氟化可的松刺激。LIONHEART的主要终点是尿Na+/K+比值；其他结果包括药代动力学、尿Na+和K+浓度以及安全性。在VISION-DMD中，4-7岁 岁的DMD男孩接受2或6 mg/kg/d的氨莫洛酮治疗48 周，或使用0.75 mg/kg/d的泼尼松或安慰剂治疗24 周，然后在4周的洗脱期后再使用2或6 mg/kg/d的氨莫洛酮治疗20 周。VISION-DMD的血清样本分析使用SomaScan®7 K检测。在LIONHEART中，氨莫洛酮逆转了氟可的松引起的尿Na+/K+比值的下降，证实了氨莫洛酮的MR拮抗作用。在给药后4-6 h观察到最大的MRA效应，并在给药后约10 h检测到。氨莫洛酮逆转了氟可的松诱导的Na+潴留，没有证据表明钾排泄减少。Vamorolone 20 mg/kg耐受性良好，结果与已知的PK参数一致。VISION-DMD结果显示，血清肾素水平、klotho和钙载体蛋白胎蛋白A和B均增加，与MR拮抗剂作用一致。现有的数据证实了人体内氨莫洛酮的MR拮抗作用。

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引用次数: 0

Quercetin-cyclodextrin combination effects on cytochrome P450 genes, oxidative stress and ovarian function in PCOS rats 槲皮素-环糊精联合对PCOS大鼠细胞色素P450基因、氧化应激及卵巢功能的影响。

IF 2.3 4区医学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY

Steroids

Pub Date : 2025-09-11 DOI: 10.1016/j.steroids.2025.109688

Fatemeh Taghipour , Hadi Samadian , Razieh Dalirfardouei , Sara Soleimani Asl , Nastaran Barati , Tayebe Artimani

This study investigates the effect of the quercetin/cyclodextrin (Que/β-CD) complex on oxidative stress, cytochrome P450 gene expression, and ovarian tissue structure in a rat polycystic ovary syndrome (PCOS) model. The Que/β-CD complexes were synthesized using the solvent evaporation method and characterized via scanning electron microscope (SEM) imaging and fourier transform infrared (FTIR) spectroscopy. Thirty female Wistar rats (6 weeks old, 160–180 g) with regular estrous cycles were randomly divided into six experimental groups: control, PCOS, PCOS treated with Que, PCOS adminstrated the β-CD, PCOS recivied metformin, and PCOS given Que/β-CD complex. Following model induction and treatments, tissue and gene expression analyses were performed. Characterization confirmed the successful synthesis of Que/β-CD complex. PCOS rats showed increased weight and higher number of atretic follicles compared to the controls (p < 0.01), which were effectively decreased after Que/β-CD treatment. Additionally, PCOS rats had reduced corpora lutea and CYP19A expression levels (p < 0.01), which were enhanced after Que/β-CD administration. Elevated CYP11A and CYP17A gene expression in PCOS rats markedly diminished with Que/β-CD treatment, indicating an improvement in disease symptoms. Oxidant levels, higher in PCOS rats (p < 0.01), meaningfully decreased after treatment with metformin, Que, or Que/β-CD (p < 0.0001, p < 0.001, and p < 0.001, respectively).

Overall, Que/β-CD treatment in the PCOS model resulted in to a significant decrease in body and ovary weights, number of cysts, atretic follicles, and oxidative stress markers, accompanied by a notable increase in corpora lutea, CYP19A expression, and antioxidant activity. These findings highlight Que/β-CD’s therapeutic potential in managing PCOS symptoms.

本研究探讨槲皮素/环糊精（Que/β-CD）复合物对多囊卵巢综合征（PCOS）模型大鼠氧化应激、细胞色素P450基因表达和卵巢组织结构的影响。采用溶剂蒸发法合成了Que/β-CD配合物，并通过扫描电镜（SEM）成像和傅里叶变换红外光谱（FTIR）对其进行了表征。选取雌性Wistar大鼠30只（6 周龄，160 ~ 180 g），月经周期正常，随机分为对照组、PCOS组、Que组、β-CD组、二甲双胍组和Que/β-CD复合物组。模型诱导和处理后，进行组织和基因表达分析。表征证实了Que/β-CD配合物的成功合成。与对照组相比，多囊卵巢综合征大鼠体重增加，闭锁卵泡数量增加(p

{"title":"Quercetin-cyclodextrin combination effects on cytochrome P450 genes, oxidative stress and ovarian function in PCOS rats","authors":"Fatemeh Taghipour , Hadi Samadian , Razieh Dalirfardouei , Sara Soleimani Asl , Nastaran Barati , Tayebe Artimani","doi":"10.1016/j.steroids.2025.109688","DOIUrl":"10.1016/j.steroids.2025.109688","url":null,"abstract":"<div><div>This study investigates the effect of the quercetin/cyclodextrin (Que/β-CD) complex on oxidative stress, cytochrome P450 gene expression, and ovarian tissue structure in a rat polycystic ovary syndrome (PCOS) model. The Que/β-CD complexes were synthesized using the solvent evaporation method and characterized via scanning electron microscope (SEM) imaging and fourier transform infrared (FTIR) spectroscopy. Thirty female Wistar rats (6 weeks old, 160–180 g) with regular estrous cycles were randomly divided into six experimental groups: control, PCOS, PCOS treated with Que, PCOS adminstrated the β-CD, PCOS recivied metformin, and PCOS given Que/β-CD complex. Following model induction and treatments, tissue and gene expression analyses were performed. Characterization confirmed the successful synthesis of Que/β-CD complex. PCOS rats showed increased weight and higher number of atretic follicles compared to the controls (p < 0.01), which were effectively decreased after Que/β-CD treatment. Additionally, PCOS rats had reduced corpora lutea and CYP19A expression levels (p < 0.01), which were enhanced after Que/β-CD administration. Elevated CYP11A and CYP17A gene expression in PCOS rats markedly diminished with Que/β-CD treatment, indicating an improvement in disease symptoms. Oxidant levels, higher in PCOS rats (p < 0.01), meaningfully decreased after treatment with metformin, Que, or Que/β-CD (p < 0.0001, p < 0.001, and p < 0.001, respectively).</div><div>Overall, Que/β-CD treatment in the PCOS model resulted in to a significant decrease in body and ovary weights, number of cysts, atretic follicles, and oxidative stress markers, accompanied by a notable increase in corpora lutea, CYP19A expression, and antioxidant activity. These findings highlight Que/β-CD’s therapeutic potential in managing PCOS symptoms.</div></div>","PeriodicalId":21997,"journal":{"name":"Steroids","volume":"223 ","pages":"Article 109688"},"PeriodicalIF":2.3,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058664","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Synthesis and preliminary biological evaluation of novel steroidal compounds as antibacterial agents 新型抗菌甾体化合物的合成及初步生物学评价。

IF 2.3 4区医学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY

Steroids

Pub Date : 2025-09-07 DOI: 10.1016/j.steroids.2025.109686

Anna Esposito , Maria Stabile , Antonella Migliaccio , Eliana De Gregorio , Stefano D’Errico , Annalisa Guaragna

Antimicrobial resistance is currently one of the most serious and alarming threats to human health; therefore, the identification of novel antimicrobial agents is a compelling need. Recently, we identified the heterocyclic steroid PYED-1 as a novel promising antibacterial and antibiofilm agent. In an effort to broaden the repertoire of active compounds and elucidate the structural features responsible for their antibacterial activity, two novel derivatives of PYED-1 have been conceived herein. The target compounds have been readily obtained in few steps and with very good yields. The antibacterial activity has been evaluated against S. aureus and A. baumannii strains, as examples of Gram-positive and -negative bacteria, by the broth microdilution method, while hemolysis assay has been used for the assessment of cytotoxicity. One of the two derivatives was able to inhibit the growth of S. aureus strains with lower MIC values (8 µg/mL) compared with those of PYED-1 (16 µg/mL) without showing hemolytic effect suggesting therefore a favorable safety profile. Overall, this study provides further indications on the functional groups required for the antibacterial activity of these novel steroidal derivatives.

抗微生物药物耐药性目前是对人类健康最严重和令人震惊的威胁之一；因此，鉴定新型抗菌药物是迫切需要的。近年来，我们发现杂环类固醇PYED-1是一种很有前景的新型抗菌和抗生物膜剂。为了扩大活性化合物的范围并阐明其抗菌活性的结构特征，本文构想了两种新的PYED-1衍生物。目标化合物在几个步骤中就可以很容易地得到，并且收率很高。以革兰氏阳性菌和阴性菌为例，用微量肉汤稀释法对金黄色葡萄球菌和鲍曼不动杆菌的抑菌活性进行了评价，同时用溶血试验对细胞毒性进行了评价。与PYED-1的MIC值（16 µg/mL）相比，其中一种衍生物能够抑制金黄色葡萄球菌菌株的生长，MIC值较低（8 µg/mL），而没有表现出溶血作用，这表明其具有良好的安全性。总之，本研究为这些新型甾体衍生物抗菌活性所需的官能团提供了进一步的指示。

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引用次数: 0