无花果中的补骨脂素：分离、生物活性及与水飞蓟素的毒理药代动力学比较

Pharmacological Research - Modern Chinese Medicine Pub Date : 2025-09-11 DOI:10.1016/j.prmcm.2025.100690

Kiren Mustafa , Noreen Akhtar , Hina Khalid , Madiha Younas , Muhammad Tariq Saeed , Yuanda Song , Zhihe Li , Hassan Mohamed

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引用次数: 0

摘要

无花果（wúhuāguǒ）因其丰富的植物化学成分而具有重要的中药和营养价值。我们之前的研究表明，粗无花果提取物（FLA）在体外选择性地对抗肝癌细胞（HepG2），同时保留正常细胞。目的通过体外实验和计算研究，从黄芪多糖中分离出一种活性化合物，并分析其生物活性，特别是抗癌活性。方法采用真空液相色谱（VLC）和薄层色谱（TLC）相结合的方法，对肝癌细胞（HepG2）和胃癌细胞（SGC-7901）进行生物活性筛选和抑菌试验。采用Sephadex LH-20柱层析和薄层色谱对活性组分2 （Fr-2）进行反复亚分离，分离补骨脂素。以水飞蓟素为比较物，通过RT-qPCR、分子对接和ADMET药代动力学分析，评估其对关键肿瘤标志物的作用机制。结果FLA对HepG2（0.31±0.1）和SGC-7901（0.124±0.05）的IC50 (mg/mL)，得到Fr- 2（己烷：乙酸乙酯，50:50）。对黄曲霉FL（18±0.4 mm）、青霉菌FL（20±0.7 mm）和铜绿假单胞菌FL（17±0.8 mm）的抑制范围最大（mm）。Fr- 2的亚分离鉴定出补骨脂素，从而降低肿瘤抑制因子Tp53、抗凋亡（Bcl2）和细胞周期激酶（CDK1和CDK5）的基因表达。通过分子对接与关键癌症调节因子：Tp53、癌蛋白MDM2和Bcl2、CDK1/CDK5的分子相互作用也揭示了补骨脂素的强结合亲和力。补骨脂素通过双重靶向MDM2-p53轴显示了一种新的作用机制：它结合p53的N-TAD （Arg23, -8.8 kcal/mol）来减少泛素化，同时竞争性地抑制MDM2 （-5.8 kcal/mol）来稳定Tp53并诱导细胞凋亡。ADMET对比分析显示，补骨脂素的水溶性和口服生物利用度优于水飞蓟素（96.67%的吸收率）。结论具有补骨脂素特征的活性Fr-2具有广泛的抗菌和抗癌活性，可能通过抑制MDM2-p53通路诱导细胞凋亡，与水飞蓟素相比，其ADMET谱更优越。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Psoralen from Ficus carica: Fractionation, bioactivity, and toxicological-pharmacokinetic comparison with silymarin

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Psoralen from Ficus carica: Fractionation, bioactivity, and toxicological-pharmacokinetic comparison with silymarin

Background

Ficus carica (无花果 wúhuāguǒ) is valued in traditional Chinese medicine (TCM) and nutrition for its rich phytochemical content. Our prior research showed a crude fig extract (FLA) selectively fought liver cancer cells (HepG2) in vitro while sparing normal cells.

Purpose

We aimed to isolate an active compound from FLA and analyze the potent bioactivities, particularly anticancer potential, through in vitro and computational studies.

Method

An innovative strategy combined fractionation by vacuum liquid chromatography (VLC) on silica gel (using six non-polar to polar solvent gradients) with thin layer chromatography (TLC) and bioactivity screening on liver (HepG2) and gastric (SGC-7901) cancer cell lines, and antimicrobial assay. The active Fraction 2 (Fr-2) was repeatedly sub-fractionated using Sephadex LH-20 column chromatography and TLC to isolate psoralen. Its mechanism of action against key cancer markers was evaluated via RT-qPCR, molecular docking, and ADMET pharmacokinetic analysis, with silymarin as a comparator.

Results

Fractionation of FLA yielded Fr- 2 (Hexane: Ethyl acetate, 50:50) with the IC50 (mg/mL) against HepG2 (0.31 ± 0.1) and SGC-7901 (0.124 ± 0.05) among the six tested fractions. It also exhibited antimicrobial activity, showing maximum inhibition zones (mm) against Aspergillus flavus FL (18± 0.4 mm), Penicillium chrysogenum FL (20 ± 0.7 mm), and Pseudomonas aeruginosa (17 ± 0.8 mm). Sub-fractionation of Fr- 2 led to the identification of psoralen, which decreased the genetic expression of tumor suppressor Tp53, anti-apoptotic (Bcl2) and Cell cycle kinases (CDK1 and CDK5). Molecular interaction via molecular docking against critical cancer regulators: Tp53, oncoproteins MDM2 and Bcl2, and CDK1/CDK5 also revealed the strong binding affinity of Psoralen. Psoralen demonstrates a novel mechanism of action by dual targeting of the MDM2-p53 axis: it binds p53′s N-TAD (Arg23, -8.8 kcal/mol) to reduce ubiquitination, while competitively inhibiting MDM2 (-5.8 kcal/mol) to stabilize Tp53 and induce apoptosis. Comparative ADMET analysis revealed psoralen's superior water solubility and oral bioavailability (96.67 % absorption) versus silymarin.

Conclusion

The active Fr-2, featuring psoralen, demonstrates broad antimicrobial and anticancer activity by potentially inhibiting the MDM2-p53 pathway to induce apoptosis, and it exhibits a superior ADMET profile compared to silymarin.

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来源期刊

Pharmacological Research - Modern Chinese Medicine

CiteScore

1.60

自引率

0.00%

发文量