Steroids最新文献_第9页

Target-specific high-throughput screening of anti-inflammatory phytosteroids for autoimmune diseases: A molecular docking-dynamics simulation approach 靶向特异性抗炎植物类固醇对自身免疫性疾病的高通量筛选：分子对接动力学模拟方法

IF 2.1 4区医学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY

Steroids

Pub Date : 2025-05-01 Epub Date: 2025-03-20 DOI: 10.1016/j.steroids.2025.109601

Alaka Sahoo , Sudhir Kumar Paidesetty , Maitreyee Panda

Without proper pathophysiology and recommended therapy, synthetic steroids are widely used as a first-line option for the management of autoimmune diseases. However, their prolonged use often leads to severe side effects such as osteoporosis, hypertension, cardiovascular, gastrointestinal complications, etc. To search for potential and safer therapeutic options, the present study aims to explore the potency and drug-ability profiles of anti-inflammatory phytosteroids (PSs). In a target-specific approach, we have selected three key molecular targets: glucocorticoid receptor/GR (PDB ID: 4P6W), cyclooxygenase-2/COX2 (PDB ID: 5F1A), and inducible nitric oxide synthase/iNOS (PDB ID: 4NOS) for a docking study of 167) selected PSs. The drug-chemistry profiles (physicochemical, toxicity, pharmacokinetic, drug-ability, etc.) of PSs were also assessed using various bioinformatics and chemoinformatics tools. The above assessment suggested that withaminilide B (PS46) is a lead candidate with higher drug-ability properties. Further, the drug stability and kinetic behaviour of the lead with the GR target ‘GR-withaminilide B’ in comparison with the control drug, ‘GR-triamcinolone acetonide’ docking complex, were studied through molecular dynamics (MD) simulation at 200 nanosecond with free energy calculation (MM/PBSA). Overall findings suggested that PSs exhibit distinct drug-ability profiles based on their functional attachments with a steroidal core moiety, where withaminilide B is a lead PSs among all to be used as alternative/ complementary candidates expected with limited adverse effects. Further experimentation is essential before mainstream application, but the study provided a platform to select drug-able candidates with a higher chance of experimental success and accelerate the drug discovery process within limited resources.

没有适当的病理生理学和推荐的治疗方法，合成类固醇被广泛用作治疗自身免疫性疾病的一线选择。然而，它们的长期使用往往导致严重的副作用，如骨质疏松症、高血压、心血管、胃肠道并发症等。为了寻找潜在的和更安全的治疗选择，本研究旨在探索抗炎植物类固醇（PSs）的效力和药物能力概况。在靶向特异性方法中，我们选择了三个关键分子靶点：糖皮质激素受体/GR (PDB ID: 4P6W)，环氧化酶-2/COX2 （PDB ID: 5F1A）和诱导型一氧化氮合酶/iNOS (PDB ID: 4NOS)，用于167个选定的PSs的对接研究。利用多种生物信息学和化学信息学工具对PSs的药物化学特征（物理化学、毒性、药代动力学、药物能力等）进行了评估。上述评价表明，withaminilide B （PS46）是具有较高药性的主要候选药物。此外，通过分子动力学（MD）模拟，在200 ns下计算自由能（MM/PBSA），研究了铅与GR靶点“GR-withaminilide B”和对照药物“GR-曲安奈德”对接配合物的药物稳定性和动力学行为。总体研究结果表明，基于其与甾体核心部分的功能附着物，PSs表现出不同的药物能力特征，其中withaminilide B是所有PSs中首选的替代/补充候选药物，预期副作用有限。在主流应用之前，进一步的实验是必不可少的，但该研究提供了一个平台，可以选择具有更高实验成功机会的候选药物，并在有限的资源内加速药物发现过程。

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引用次数: 0

BSS-4, a diosgenin analogue, reduces carrageenan-induced paw inflammation in rat 薯蓣皂苷元类似物BSS-4可减轻卡拉胶诱导的大鼠足部炎症。

IF 2.1 4区医学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY

Steroids

Pub Date : 2025-05-01 Epub Date: 2025-03-22 DOI: 10.1016/j.steroids.2025.109602

Marisol Casimiro-Rosas , Irving Parra , Jesús Sandoval-Ramírez , María A. Fernández Herrera , Yousef Tizabi , Isabel Martínez-García , Liliana Mendieta

Inflammation is an adaptive response that ensures the survival of the organism in the face of injuries or trauma primarily via the immune system. However, overactivation of this process can be detrimental to the point of fatality. To overcome this overactivation, immunosuppressant agents such as steroids and non-steroidal anti-inflammatory drugs (NSAIDs) are used. Given the limitations of these drugs, including their side effects, an urgent need for development of potent and safer anti-inflammatory drugs is evident. Diosgenin, a steroidal saponin (a glycoside found in plants) and its analog, BSS-4 are gaining ground in this respect. Our objective in this study was to determine the effectiveness of BSS-4 in an established model of inflammation and provide clues on its mechanism of action. Carrageenan (Carr)-induced paw edema was used to evaluate the effectiveness of two doses of BSS-4 (0.5 and 1 mg/kg administered intraperitoneally) in adult male Wistar rats. Plantar edema was induced by subcutaneous injection of 50 µL of carrageenan (1 %) into the plantar aponeurosis of the right paw. Inflammatory cytokine markers, tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β) were quantified in this paw region using immunohistochemical assays. BSS-4 at 0.5 mg/kg dose, significantly reduced the paw edema up to three hours after administration. Concomitantly, TNF-α and IL-1β immunostaining were significantly reduced. BSS-4 also preserved the tissue architecture as assessed by hematoxylin and eosin (H&E) staining. These results indicate that BSS-4 can impart potent anti-inflammatory effects as well as reductions in TNF-α and IL-1β in an inflammatory rat model.

炎症是一种适应性反应，主要通过免疫系统确保生物体在面对损伤或创伤时的生存。然而，这个过程的过度激活可能是有害的，甚至是致命的。为了克服这种过度激活，免疫抑制剂如类固醇和非甾体抗炎药（NSAIDs）被使用。鉴于这些药物的局限性，包括它们的副作用，开发更有效和更安全的抗炎药物的迫切需要是显而易见的。薯蓣皂苷元，一种甾体皂苷（一种在植物中发现的糖苷）及其类似物BSS-4在这方面正在取得进展。我们的研究目的是确定BSS-4在已建立的炎症模型中的有效性，并为其作用机制提供线索。采用卡拉胶（Carrageenan, Carr）诱导的足跖水肿来评价两种剂量BSS-4（0.5和1 mg/kg腹腔注射）对成年雄性Wistar大鼠的有效性。右足跖腱膜皮下注射50 µL卡拉胶（1 %）诱导足底水肿。用免疫组织化学方法定量检测足部炎症细胞因子标志物、肿瘤坏死因子α (TNF-α)和白细胞介素-1β (IL-1β)。0.5 mg/kg剂量的BSS-4在给药后3小时显著减少足跖水肿。同时，TNF-α和IL-1β免疫染色明显降低。苏木精和伊红（H&E）染色显示，BSS-4也保留了组织结构。这些结果表明，BSS-4在炎症大鼠模型中具有有效的抗炎作用，并能降低TNF-α和IL-1β。

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引用次数: 0

Stress responses in blood donors: Oral fluid hormone dynamics and implications for donor support 献血者的应激反应：口服液激素动力学和对献血者支持的影响

IF 2.1 4区医学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY

Steroids

Pub Date : 2025-05-01 Epub Date: 2025-03-28 DOI: 10.1016/j.steroids.2025.109604

Agata Alterio , Matteo Feltracco , Giovanna Mazzi , Beatrice Rosso , llaria Prosdocimi , Andrea Gambaro

Glucocorticoids (cortisol and cortisone) hormones are potential biomarkers for monitoring physiological stress in humans. These hormones are released into the bloodstream but are also detectable in other biological matrixes such as oral fluid. Oral fluid hormone levels reflect those found in the blood, but oral fluid sampling is quicker and non-invasive, making it a viable alternative matrix for studying stress markers. This study investigates the stress response of blood donors at three different donation moments by analyzing cortisol and cortisone levels in oral fluid samples. To simultaneously detect these analytes, we developed and validated a new highly sensitive method using high-performance liquid chromatography coupled to a triple quadrupole mass spectrometer (HPLC-MS/MS). Glucocorticoid hormones were found in all samples with cortisone exhibiting higher concentrations than cortisol. Statistical results revealed a weakly negative trend over time for both analytes levels, indicating that the most crucial donation moment is upon donors’ arrival. A notable distinction was found in the evolution of the glucocorticoid hormones in different locations, suggesting that different environmental factors influence stress level more than the act of donation itself.

糖皮质激素（皮质醇和可的松）是监测人体生理压力的潜在生物标志物。这些激素会释放到血液中，但也能在口腔液等其他生物基质中检测到。口腔液中的激素水平反映了血液中的激素水平，但口腔液采样更快、无创伤，因此是研究压力标记物的一种可行的替代基质。本研究通过分析口腔液样本中的皮质醇和可的松水平，研究献血者在三个不同献血时刻的压力反应。为了同时检测这些分析物，我们开发并验证了一种新的高灵敏度方法，该方法采用高效液相色谱-三重四极杆质谱联用仪（HPLC-MS/MS）。在所有样本中都发现了糖皮质激素，其中可的松的浓度高于皮质醇。统计结果显示，这两种分析物的水平随时间呈微弱的负趋势，表明最关键的捐献时刻是在捐献者到达时。糖皮质激素在不同地点的变化有明显差异，这表明不同环境因素对压力水平的影响大于捐赠行为本身。

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引用次数: 0

Microbial steroid biotransformation: Regio- and stereo selective 17β-reduction by Priestia aryabhattai 微生物类固醇生物转化：紫花蓟马区域和立体选择性还原17β

IF 2.1 4区医学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY

Steroids

Pub Date : 2025-05-01 Epub Date: 2025-03-20 DOI: 10.1016/j.steroids.2025.109600

Yogeswari Sudhakar , Reddy Krishna Manasa , Dhanapal Priyadarshini , Sagar Chandrakant Dalsaniya , Gurrala Sheelu , Thenkrishnan Kumaraguru

The conversion of 17-oxosteroids to 17β-hydroxysteroids stands as a pivotal process in the synthesis of numerous steroidal drugs and intermediates. This study explored the potential of the strain Priestia aryabhattai (IICT-BC-1279) to catalyze the reduction of the C-17 carbonyl group in androst-4-ene-3,17-dione (AD), resulting in the exclusive production of testosterone (TS) through its 17β-hydroxysteroid dehydrogenase (17β-HSD) activity. Optimal conditions for this reduction were achieved at pH 7.0 and 25 °C, with supplementation of AD as an inducer (0.01 g/L), 1 % Tween 80 (w/v) and ethanol as co-solvent. Under these optimized parameters, 0.5 g/L AD was efficiently converted to TS as a sole product, achieving a yield of > 95 % and diastereomeric excess (d.e) of > 99 % within 48 h. The absence of by-products in this microbial 17β-reduction process simplifies product purification, highlighting the strain’s potential as a valuable biocatalyst for this essential transformation. Additionally, the conversion of androsta-1,4-diene-3,17-dione (ADD) to (+)-Boldenone (BD) was studied to explore substrate scope.

17-氧类固醇转化为17- β-羟基类固醇是合成许多类固醇药物和中间体的关键过程。本研究探讨了菌株Priestia aryabhattai （IICT-BC-1279）催化雄激素-4-烯-3,17-二酮（AD）中C-17羰基的还原，通过其17β-羟基类固醇脱氢酶（17β-HSD）活性产生睾酮（TS）的潜力。最佳还原条件为pH 7.0和25°C，添加AD作为诱导剂（0.01 g/L）， 1% Tween 80 （w/v）和乙醇作为共溶剂。在此优化条件下，0.5 g/L AD可高效转化为TS，产率为>；95%和非对映体过量（d.e）；在这个微生物17β还原过程中没有副产物简化了产物纯化，突出了菌株作为这一重要转化的有价值的生物催化剂的潜力。此外，还研究了androta -1,4-二烯-3,17-二酮（ADD）转化为(+)-Boldenone （BD）的过程，以探索底物范围。

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引用次数: 0

Unleashing the pharmacological potential of taste receptors in reproductive processes beyond their gustatory role 释放味觉感受器在生殖过程中超越味觉作用的药理学潜力

IF 2.1 4区医学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY

Steroids

Pub Date : 2025-05-01 Epub Date: 2025-03-26 DOI: 10.1016/j.steroids.2025.109603

Nourhan Magdy , Noha F. Abdelkader , Hala F. Zaki , Ahmed S. Kamel

Traditionally, taste receptors (TRs) have been understood to reside within the taste buds on the tongue, serving as initiators for different taste perceptions. However, recent research has expanded our understanding, revealing that TRs are found throughout the body and perform a wide range of functions beyond taste perception as non-tasting functions. These receptors, along with their genetic variations, have been linked to various human health conditions. They are activated by an array of substances, including hormones, nutrients, and toxins, indicating their involvement in numerous biological processes. Specifically, in males, TRs are notably present in the testes and epididymis, where they contribute to the hormonal production, spermatogenesis, and sperm maturation. In females, these receptors are found in the ovaries, uterus, and myometrium, playing crucial roles in ovulation, menstrual cycle regulation, and embryo implantation. There are a lot of missed areas regarding TRs research that imposes to fulfill the gaps in the current understanding of their role in reproduction. This review aims to provide a comprehensive overview of the emerging roles of extraoral TRs in reproductive health, highlighting their physiological and pathophysiological significance in various reproductive processes. As well, grabbing the attention towards the release of new pharmacological interventions to manage conception and contraception in male and female was considered.

传统上，味觉感受器（TRs）被认为存在于舌头上的味蕾中，作为不同味觉感知的启动器。然而，最近的研究扩大了我们的理解，揭示了TRs在整个身体中都有发现，并且作为非味觉功能发挥着广泛的功能。这些受体及其基因变异与各种人类健康状况有关。它们被一系列物质激活，包括激素、营养物质和毒素，表明它们参与了许多生物过程。具体来说，在男性中，TRs主要存在于睾丸和附睾，在那里它们有助于激素的产生、精子的发生和精子的成熟。在女性中，这些受体存在于卵巢、子宫和子宫肌层，在排卵、月经周期调节和胚胎着床中起着至关重要的作用。关于TRs的研究有很多被遗漏的领域，这些领域要求填补目前对它们在生殖中的作用的理解的空白。本文旨在全面概述口外TRs在生殖健康中的新作用，重点介绍其在各种生殖过程中的生理和病理生理意义。此外，还考虑了对新的药物干预措施的关注，以管理男性和女性的受孕和避孕。

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引用次数: 0

Isoxazolyl steroid blocks the Shh signaling pathway and the expression of MMP-2 and MMP-9 in cervical carcinoma cell lines 异恶唑基类固醇阻断宫颈癌细胞系Shh信号通路及MMP-2和MMP-9的表达。

IF 2.1 4区医学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY

Steroids

Pub Date : 2025-05-01 Epub Date: 2025-03-16 DOI: 10.1016/j.steroids.2025.109599

Olga Timoshenko , Elena Kugaevskaya , Tatiana Gureeva , Galina Morozevich , Alexey Lupatov , Arif Mekhtiev , Anton Rudovich , Vladimir Zhabinskii , Vladimir Khripach , Andrey Lisitsa

Cervical cancer is the fourth leading cause of cancer death among women worldwide. Matrix metalloproteinases MMP-2 and MMP-9 play a leading role in the processes of invasion and metastasis in cervical cancer. Research on the development of MMP inhibitors not yielded the expected results due to their serious side effects. Study of signaling pathways involved in regulation of MMPs expression is of great importance for search of new classes of therapeutic drugs. Aberrant activation of the Sonic Hedgehog (Shh) signaling pathway is associated with increased MMPs in many types of human cancer. This study investigated the inhibitory action of 17β-((3-butylisoxazol-5-yl)methyl)-androst-5-en-3β-ol on the Shh signaling pathway key genes (Ptch, Smo, Gli) expression and MMP-2, MMP-9 genes expression in human cervical carcinoma cell lines (SiHa and CaSki) and keratinocytes (HaCaT). Cyclopamine was used for comparative analysis. Gene expression analysis was performed using real-time PCR; the effects on survival and cell cycle were studied using the MTT test and flow cytometry method. 17β-((3-butylisoxazol-5-yl)methyl)-androst-5-en-3β-ol had higher cytotoxicity and more effectively blocked the Shh signaling pathway genes and MMP-2 and MMP-9 genes compared to cyclopamine in all cell lines. The results obtained demonstrate potential of 17β-((3-butylisoxazol-5-yl)methyl)-androst-5-en-3β-ol as the anticancer drug that simultaneously block the Shh signaling pathway and MMP expression. We are confident that the search for substances capable of simultaneously affecting several key components involved in tumor progression is of great importance for the creation of next-generation therapeutic agents.

宫颈癌是全世界妇女癌症死亡的第四大原因。基质金属蛋白酶MMP-2和MMP-9在宫颈癌的侵袭和转移过程中起主导作用。由于其严重的副作用，对MMP抑制剂的开发研究并未取得预期的效果。研究参与MMPs表达调控的信号通路对寻找新型治疗药物具有重要意义。在许多类型的人类癌症中，Sonic Hedgehog （Shh）信号通路的异常激活与MMPs的增加有关。本研究探讨了17β-((3-butylisoxazol-5-yl)methyl)-androst-5-en-3β-ol对人宫颈癌细胞系（SiHa和CaSki）和角质形成细胞（HaCaT） Shh信号通路关键基因（Ptch、Smo、Gli）表达和MMP-2、MMP-9基因表达的抑制作用。采用环巴胺进行对比分析。采用实时荧光定量PCR进行基因表达分析；采用MTT试验和流式细胞术研究其对细胞存活和细胞周期的影响。与环巴胺相比，17β-((3-丁基lisoxazol-5-yl)methyl)-androst-5-en-3β-ol具有更高的细胞毒性，更有效地阻断Shh信号通路基因和MMP-2和MMP-9基因。结果表明，17β-((3-丁基lisoxazol-5-yl)methyl)-androst-5-en-3β-ol可作为同时阻断Shh信号通路和MMP表达的抗癌药物。我们相信，寻找能够同时影响涉及肿瘤进展的几个关键成分的物质对于创造下一代治疗剂非常重要。

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引用次数: 0

Evaluation of the short-term stability of 6α-chloro-testosterone, 6β-bromo-androstenedione and 6-oxo-androstenedione in dimethylsulfoxide and methanol using liquid and gas chromatography − mass spectrometry 液相和气相色谱-质谱法评价6α-氯睾酮、6β-溴雄烯二酮和6-氧雄烯二酮在二甲亚砜和甲醇中的短期稳定性。

IF 2.1 4区医学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY

Steroids

Pub Date : 2025-05-01 Epub Date: 2025-03-09 DOI: 10.1016/j.steroids.2025.109597

Dayamin Martínez_Brito , Patrizia Leogrande , Xavier de la Torre , Francesco Botrè

This work studied the short-term stability of 6α-chloro-testosterone (6-CT), 6β-bromo-androstenedione (6-BrAED) and 6-oxo-androstenedione (6-oxo-AED) in methanol (MeOH) and dimethylsulfoxide (DMSO) solutions by gas and liquid chromatography coupled to mass spectrometry.

Solutions of 6-CT, 6-BrAED and 6-oxo-AED were prepared in MeOH and DMSO. They were stored at room temperature, +4°C and −20 °C. Measurements were made at 0, 7, 30, 60 and 90 days after solutions preparation, by liquid chromatography-tandem mass spectrometry and gas chromatography-high resolution mass spectrometry.

Although the degradation of 6-CT and 6-BrAED was extensive, the most notable result was that the higher degradation occurred in DMSO instead of MeOH. The interaction of DMSO with halogenated species and secondary hydroxyl groups favored the degradation of these compounds by forming chemically related species. No degradation of 6-oxo-AED in either MeOH or DMSO was observed.

Pronounced degradation of the 6-CT and 6-BrAED, during the derivatization reaction for the gas chromatography-mass spectrometry analysis was observed. Because of the acidic condition of the reaction and depending on the reactant, it was favored the loss of the halogen molecule or the dehydration reaction to form the unsaturated (Δ6) steroid derivative.

Our finding suggests to take duly into account the possibility of degradation processes when performing quantitative determination of 6-CT, 6-BrAED and 6-oxo-AED by chromatographic-spectrometric techniques based on the use of reference solutions stored for sufficiently long times.

采用气液相色谱联用质谱法研究了6α-氯睾酮（6-CT）、6β-溴雄烯二酮（6-BrAED）和6-氧-雄烯二酮（6-氧- aed）在甲醇（MeOH）和二甲基亚砜（DMSO）溶液中的短期稳定性。在MeOH和DMSO中制备6-CT、6-BrAED和6-oxo-AED溶液。分别保存于室温、+4°C和-20 °C。分别于溶液制备后0、7、30、60和90 d采用液相色谱-串联质谱法和气相色谱-高分辨率质谱法进行测定。虽然6-CT和6-BrAED的降解是广泛的，但最显著的结果是DMSO的降解率高于MeOH。DMSO与卤代物质和次生羟基的相互作用有利于这些化合物的降解，形成化学相关物质。在MeOH或DMSO中均未观察到6-oxo-AED的降解。在衍生化反应中，6-CT和6-BrAED明显降解，用于气相色谱-质谱分析。由于反应的酸性条件和根据反应物的不同，卤素分子的损失或脱水反应更有利于形成不饱和（Δ6）类固醇衍生物。我们的发现表明，在使用储存足够长时间的参比溶液进行6-CT、6-BrAED和6-oxo-AED定量测定时，色谱-光谱技术应充分考虑降解过程的可能性。

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引用次数: 0

New hydroxylated metabolite derived from the microbial biotransformation of 11α-acetoxyprogesterone by the endophytic fungus Phyllosticta sp. 16L1 and its cytotoxic activity 内生真菌Phyllosticta sp. 16L1对11α-乙酰氧基孕酮微生物转化的新羟基化代谢物及其细胞毒活性。

IF 2.1 4区医学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY

Steroids

Pub Date : 2025-04-01 Epub Date: 2025-02-28 DOI: 10.1016/j.steroids.2025.109584

Mufeda Ahmed Hazea Gazaem , Wan Nurul Nazneem Wan Othman , Syed Adnan Ali Shah , Mustapha Salihu , Azeana Zahari , Siti Hajar Sadiran , Fatimah Salim

Biotransformations catalysed by microbes are promising approach for producing a vast library of structurally diverse chemical molecules with applications in the pharmaceutical industry. The biotransformation of 11α-acetoxyprogesterone (1) by Phyllosticta sp. 16L1 has not been previously reported. In this study, the biotransformation of 11α-acetoxyprogesterone (1) was performed for the first time using the Phyllosticta sp. 16L1 strain. After an 8-day fermentation period, a new biotransformation metabolite, named as 11α-acetoxy-16α-hydroxyprogesterone (16α-hydroxy-3,20-dioxopregn-4-en-11α-yl acetate) (2) was isolated from the culture broth, along with its known isomer, 11α-acetoxy-15α-hydroxyprogesterone (3). The structure determination of the biotransformed products relied on comprehensive spectroscopic data, encompassing 1D and 2D-NMR, as well as LCMS analyses. The cytotoxic activity of the two biotransformed metabolites was assessed against selective human cancer cell lines, including hepatocellular carcinoma (HepG2), triple-negative breast cancer (MDA-MB-231), colorectal adenocarcinoma (Caco-2), and lung adenocarcinoma (A549). The results demonstrated that both metabolites 2 and 3 exhibited cytotoxic effects on the evaluated cell lines. Metabolite 2 showed stronger cytotoxic potential, with IC₅₀ values ranging from 6.65 to 27.75 μM, while metabolite 3 displayed lower potency, with IC₅₀ values between 38.20 and 162.53 μM. Notably, both metabolites exhibited minimal toxicity towards the normal liver Chang cells. Molecular docking studies were conducted to predict the binding modes and affinities of the metabolites against two targets (PDB: 5EM8 and 6V6O), both in 2D and 3D representations, with binding energies ranging from −8.5 to −7.2 kcal/mol. The results revealed that metabolites 2 and 3 interacted with key clinically significant amino acid residues, Lys745 and Met793, through conventional hydrogen bonding.

微生物催化的生物转化是一种很有前途的方法，可以产生大量结构多样的化学分子，并在制药工业中得到应用。Phyllosticta sp. 16L1对11α-乙酰氧基孕酮(1)的生物转化尚未见报道。本研究首次利用Phyllosticta sp. 16L1菌株进行了11α-乙酰氧基孕酮(1)的生物转化。经过8天的发酵，从培养液中分离出一种新的生物转化代谢物，命名为11α-乙酰氧基-16α-羟孕酮（16α-羟基-3,20-二氧opregn-4-烯-11α-乙酸酯）(2)，以及其已知的异构体11α-乙酰氧基-15α-羟孕酮(3)。生物转化产物的结构测定依赖于综合光谱数据，包括1D和2d nmr，以及LCMS分析。两种生物转化代谢物的细胞毒活性被评估针对选择性人类癌细胞系，包括肝细胞癌（HepG2）、三阴性乳腺癌（MDA-MB-231）、结直肠癌（Caco-2）和肺腺癌（A549）。结果表明，代谢产物2和3对所评价的细胞系均表现出细胞毒性作用。代谢物2的IC50值在6.65 ~ 27.75 μM之间，代谢物3的IC50值在38.20 ~ 162.53 μM之间，代谢物3的IC50值较低。值得注意的是，这两种代谢物对正常肝细胞的毒性很小。通过分子对接研究，预测代谢产物与两个靶标（PDB: 5EM8和6v60）的结合模式和亲和力，以2D和3D形式表示，结合能范围为-8.5至-7.2 kcal/mol。结果显示，代谢产物2和3通过常规氢键与临床重要的氨基酸残基Lys745、Met793和Leu745相互作用。

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引用次数: 0

Theoretical study of the pyridyl-cholestane formation pathway using DFT: A stepwise mechanistic approach 利用 DFT 对吡啶基-胆甾烷的形成途径进行理论研究：逐步机械方法。

IF 2.1 4区医学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY

Steroids

Pub Date : 2025-04-01 Epub Date: 2025-03-01 DOI: 10.1016/j.steroids.2025.109575

Kamlesh Sharma, Priyanka

The reaction mechanism of the formation of pyridyl-cholestane derivative 4 from a multi-component reaction involving cholestane-6-one, aromatic aldehyde, malononitrile, and ammonium acetate in presence of magnesium oxide nanoparticles (MgO NPs) as catalyst, was studied successfully by using DFT calculations. The mechanism involved condensation, cyclization, and aromatization steps which were investigated successfully theoretically. The theoretical calculations of physicochemical parameters, including Gibbs free energy, frontier molecular orbitals (FMOs), dipole moments, and hardness, of all the intermediates and transition states molecules. The study revealed the formation of key intermediates and transition states, with detailed analysis of their stability and electronic structures.

The reaction pathway begins with the formation of enamine I and α,β-unsaturated nitrile II, followed by Michael addition to produce intermediate B. The cyclization of A to intermediate B, which has the highest activation energy barrier was identified as slowest and the rate-determining step. The following steps, including cyclization (B to C) and proton transfer (C to D), exhibit progressively lower activation barriers and enhanced stability. Theoretical analysis indicates that the reaction is thermodynamically favorable, as the product is more stable than the initial reactants.

This study highlights the mechanistic insights contributing to the understanding of multi-component reactions in organic synthesis involved effectiveness of MgO NPs as a heterogeneous catalyst in enabling the efficient synthesis of pyridyl-cholestane derivative 4.

采用DFT计算方法，研究了在氧化镁纳米颗粒（MgO NPs）催化下，胆甾-6- 1、芳香醛、丙二腈、乙酸铵等多组分反应生成吡啶胆甾衍生物4的反应机理。反应机理包括缩合、环化和芳构化三个步骤，并在理论上进行了成功的研究。理论计算了所有中间态和过渡态分子的物理化学参数，包括吉布斯自由能、前沿分子轨道、偶极矩和硬度。该研究揭示了关键中间体和过渡态的形成，并详细分析了它们的稳定性和电子结构。该反应途径从形成烯胺I和α、β-不饱和腈II开始，然后经过Michael加成生成中间体B，其中A到中间体B的环化反应速度最慢，具有最高的活化能势垒。接下来的步骤，包括环化（B到C）和质子转移（C到D），表现出逐渐降低的激活障碍和增强的稳定性。理论分析表明，该反应在热力学上是有利的，因为产物比初始反应物更稳定。本研究强调了有助于理解有机合成中多组分反应的机理，包括MgO NPs作为多相催化剂在高效合成吡啶胆甾衍生物4中的有效性。

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引用次数: 0

17β-estradiol delays cardiac aging through suppressing the methylation of Beclin1 in a murine model 在小鼠模型中，17β-雌二醇通过抑制 Beclin1 的甲基化延缓心脏衰老。

IF 2.1 4区医学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY

Steroids

Pub Date : 2025-04-01 Epub Date: 2025-03-01 DOI: 10.1016/j.steroids.2025.109587

Lili Ye , Ruiyan Wang , Jun Zhao , Jingrong Chen , Feng Wang

Introduction

Cardiac endogenous senescence will gradually change and aggravate with age. Recent research showed that 17β-estradiol (17β-E2), an estrogen with numerous biological activities including the prevention of vascular senescence. However, how 17β-E2 against cardiac aging is still unknown. This work addressed the underlying mechanism with regard to Beclin1 and autophagy activity to better understand the anti-senescent effect of 17β-E2 on a well-established animal model of cardiac aging.

Material and methods

In this study, an aging model in female mice was established using d-galactose and ovariectomy. Cardiac function was evaluated by echocardiography, RNA-seq was performed to analyze the gene expression profiles of myocardial tissues from 17β-E2 treated mice. Additionally,The levels of Beclin1, LC3, P62, and ATG5 in myocardial tissues were assessed using qPCR and Western blotting. Methylation levels of the Beclin1 promoter region in myocardial tissues were determined by MSP and BSP.

Results

The findings demonstrated that cardiac aging mice treated with 17β-E2 had improved heart function. 17β-E2 restored EF(increase 1.25-fold) and FS(increase 1.2-fold) to near-normal levels. By RNA-sequencing and Gene Set Enrichment Analysis (GSEA) analysis, the autophagy signaling pathway was further enriched in the myocardial tissue of cardiac aging mice treated with 17β-E2, and we also discovered that 17β-E2 suppress the methylation of Beclin1 promoter region, which mediate the activation of autophagy signal.

Conclusions

Overall, our data showed that 17β-E2′s anti-senescent effect on cardiac aging mice was mediated by the crucial suppression of methylation in the Beclin1 promoter area and subsequent activation of the autophagy signal, which may present a possible therapeutic approach to prevent cardiac aging.

心脏内源性衰老会随着年龄的增长而逐渐改变和加剧。最近的研究表明，17β-雌二醇（17β-E2）是一种具有多种生物活性的雌激素，包括预防血管衰老。然而，17β-E2如何对抗心脏老化仍是未知的。为了更好地了解17β-E2在心脏衰老动物模型中的抗衰老作用，本研究探讨了Beclin1和自噬活性的潜在机制。材料与方法：本研究采用d-半乳糖和卵巢切除术建立雌性小鼠衰老模型。用超声心动图评价心脏功能，用RNA-seq分析17β-E2处理小鼠心肌组织的基因表达谱。采用qPCR和Western blotting检测心肌组织Beclin1、LC3、P62、ATG5的表达水平。心肌组织中Beclin1启动子区甲基化水平通过MSP和BSP检测。结果：心脏老化小鼠经17β-E2处理后，心脏功能得到改善。17β-E2恢复EF（增加1.25倍）和FS（增加1.2倍）至接近正常水平。通过rna测序和基因集富集分析（Gene Set Enrichment Analysis， GSEA）分析，我们发现17β-E2在心脏衰老小鼠心肌组织中进一步富集了自噬信号通路，并且我们还发现17β-E2抑制介导自噬信号激活的Beclin1启动子区甲基化。结论：总体而言，我们的数据表明，17β-E2对心脏衰老小鼠的抗衰老作用是通过关键的Beclin1启动子区甲基化抑制和随后的自噬信号激活介导的，这可能是一种可能的预防心脏衰老的治疗方法。

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引用次数: 0