Alisol A, the Eye-Entering Ingredient of Alisma orientale, Relieves Macular Edema Through TNF-α as Revealed by UPLC-Triple-TOF/MS, Network Pharmacology, and Zebrafish Verification

IF 4.7 2区医学 Q1 CHEMISTRY, MEDICINAL Drug Design, Development and Therapy Pub Date : 2024-07-30 DOI:10.2147/dddt.s468119

Rui Shen, Kebin Cheng, Guanyi Li, Zhendong Pan, Xijier Qiaolongbatu, Yuting Wang, Cui Ma, Xucong Huang, Li Wang, Wenjing Li, Yuanyuan Wang, Lili Jing, Guorong Fan, Zhenghua Wu

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Abstract

Purpose: Alisma orientale (AO, Alisma orientale (Sam). Juzep) has been widely employed for the treatment of macular edema (ME) in traditional Chinese medicine due to its renowned water-relief properties. Nonetheless, the comprehensive investigation of AO in alleviating ME remained unexplored. This study aims to identify the active components of AO that target the eye and investigate its pharmacological effects and mechanisms on ME.
Methods: The study commenced with UPLC-Triple-TOF/MS analysis to identify the primary constituents of AO. Zebrafish eye tissues were then analyzed after a five-day administration of AO to detect absorbed components and metabolites. Subsequently, network pharmacology, molecular docking, and molecular dynamics simulations were employed to predict the mechanisms of ME treatment via biological target pathways. In vivo experiments were conducted to corroborate the pharmacological actions and mechanisms.
Results: A total of 7 compounds, consisting of 2 prototype ingredients and 5 metabolites (including isomers), were found to traverse the blood-eye barrier and localized within eye tissues. Network pharmacology results showed that AO played a role in the treatment of ME mainly by regulating the pathway network of PI3K-AKT and MAPK with TNF-α centered. Computational analyses suggested that 11-dehydro-16-oxo-24-deoxy-alisol A, a metabolite of alisol A, mitigates edema through TNF-α inhibition. Furthermore, zebrafish fundus confocal experiments and HE staining of eyes confirmed the attenuating effects of alisol A on fundus angiogenesis and ocular edema, representing the first report of AO’s ME-inhibitory effects.
Conclusion: In this study, computational analyses with experimental validation were used to understand the biological activity and mechanism of alisol A in the treatment of ME. The findings shed light on the bioactive constituents and pharmacological actions of AO, offering valuable insights and a theoretical foundation for its clinical application in managing ME.

Keywords: Alisma orientale, macular edema, network pharmacology, zebrafish, TNF-α

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通过 UPLC-Triple-TOF/MS、网络药理学和斑马鱼验证，东方曙光的入眼成分 Alisol A 可通过 TNF-α 缓解黄斑水肿

目的：东方泽泻（AO，Alisma orientale (Sam).Juzep）具有显著的利水作用，在传统中医中被广泛用于治疗黄斑水肿（ME）。然而，对东方鸢尾在缓解黄斑水肿方面作用的全面研究仍处于空白状态。本研究旨在确定 AO 中针对眼部的活性成分，并研究其对 ME 的药理作用和机制：研究首先通过UPLC-Triple-TOF/MS分析鉴定AO的主要成分。然后对斑马鱼眼组织进行为期五天的 AO 给药后分析，以检测吸收的成分和代谢物。随后，利用网络药理学、分子对接和分子动力学模拟来预测通过生物靶途径治疗 ME 的机制。为了证实药理作用和机制，还进行了体内实验：结果：共发现 7 种化合物（包括 2 种原型成分和 5 种代谢物（包括异构体））可穿过血眼屏障并在眼组织内定位。网络药理学结果表明，AO主要通过调节以TNF-α为中心的PI3K-AKT和MAPK通路网络在治疗ME中发挥作用。计算分析表明，秋水仙素A的代谢产物11-脱氢-16-氧代-24-脱氧-秋水仙素A可通过抑制TNF-α减轻水肿。此外，斑马鱼眼底共聚焦实验和眼球 HE 染色证实了泽泻醇 A 对眼底血管生成和眼部水肿的抑制作用，这是首次报道 AO 的 ME 抑制作用：本研究通过计算分析和实验验证，了解了泽泻醇 A 治疗 ME 的生物活性和机制。研究结果揭示了AO的生物活性成分和药理作用，为其临床应用于治疗ME提供了宝贵的见解和理论基础。关键词东方泽兰黄斑水肿网络药理学斑马鱼 TNF-α

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来源期刊

Drug Design, Development and Therapy CHEMISTRY, MEDICINAL-PHARMACOLOGY & PHARMACY

CiteScore

9.00

自引率

0.00%

发文量

382

审稿时长

>12 weeks

期刊介绍： Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications. The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas. Specific topics covered by the journal include: Drug target identification and validation Phenotypic screening and target deconvolution Biochemical analyses of drug targets and their pathways New methods or relevant applications in molecular/drug design and computer-aided drug discovery* Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes) Structural or molecular biological studies elucidating molecular recognition processes Fragment-based drug discovery Pharmaceutical/red biotechnology Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products** Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing) Preclinical development studies Translational animal models Mechanisms of action and signalling pathways Toxicology Gene therapy, cell therapy and immunotherapy Personalized medicine and pharmacogenomics Clinical drug evaluation Patient safety and sustained use of medicines.