夏枯草多酚通过S100A9-PP2A-AMPK通路调节酰基肉碱减轻肝损伤-葡萄膜炎共病

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-03-20 DOI:10.1016/j.phymed.2025.156675

Jingchen Xie , Suhui Xiong , Jiahui Yu , Xinyi Ma , Feng Xiang , Yang Chen , Bohou Xia , Yamei Li , Zhimin Zhang , Duanfang Liao , Limei Lin

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引用次数: 0

摘要

肝损伤和葡萄膜炎严重威胁着人类的健康。由于肝脏和眼睛之间的生理和病理关系密切，这两种情况同时发生的病例在临床环境中并不罕见，这大大增加了治疗的复杂性。然而，目前还没有合适的合并症动物模型的报道，并且缺乏对这种合并症的病理机制的研究。夏枯草，一种著名的中药，以清肝明目而闻名。夏枯草多酚（pvp）有望改善肝损伤和葡萄膜炎。然而，在单一生物体中探索其双重治疗作用的研究仍然缺乏，使关键活性成分和作用机制在很大程度上未被研究。目的建立大鼠肝损伤合并葡萄膜炎模型，探讨其病理机制，评价pvp对大鼠肝损伤合并葡萄膜炎的治疗效果。探索了pvp的作用机制，鉴定了其关键活性成分，为临床治疗药物的开发提供了潜在的新方向。方法通过腹腔注射d-GalN/LPS建立葡萄膜炎肝损伤大鼠模型。代谢组学和蛋白质组学应用于研究病理机制，随后使用酰基肉碱和S100A9抑制剂进行验证。我们使用pvp来评估治疗效果，并探讨其缓解肝损伤和葡萄膜炎的机制。网络药理学结合分子对接鉴定了pvp的关键活性成分。随后的动物实验证实了代表性成分对改善肝损伤和葡萄膜炎的疗效。结果：galn /LPS （150 mg/kg: 1 mg/kg）可引起大鼠肝损伤和葡萄膜炎。代谢组学分析指出酰基肉碱是关键的代谢物，其抑制作用减少了炎症。蛋白质组学分析表明S100A9与炎症和免疫有关。然后用S100A9抑制剂对模型大鼠进行干预。结果提示，d-GalN/LPS导致肝损伤和葡萄膜炎的病理机制涉及S100A9表达上调、PP2A活性升高、AMPK磷酸化抑制、CPT1A下调，导致酰基肉碱积累，促进肝脏和视网膜的炎症反应。此外，涉及pvp的实验表明，剂量依赖性改善了d-GalN/LPS引起的肝损伤和葡萄膜炎。其潜在的作用机制包括抑制S100A9表达，降低PP2A活性，激活AMPK，上调CPT1A，随后减少肝脏和视网膜中的酰基肉碱积累。该机制有效减轻了d-GalN/LPS诱导的炎症作用。网络药理学和分子对接分析确定了pvps的几个关键活性成分，即迷迭香酸、丹参苷、橙皮素、2-羟基肉桂酸、3,4-二羟基苯甲醛和7,8-二羟基香豆素，它们在减轻肝损伤和葡萄膜炎中发挥重要作用。代表性活性成分迷迭香酸在大鼠体内的后续实验证实其对d-GalN/ lps诱导的肝损伤和葡萄膜炎的症状有改善作用，进一步验证了这些关键活性成分的治疗潜力。结论本研究成功建立了大鼠肝损伤合并葡萄膜炎模型，证实了PVPs对该疾病的缓解作用。此外，研究确定其潜在机制涉及S100A9-PP2A-AMPK通路的调控，迷迭香酸被确定为关键活性化合物。这些发现为肝眼合并症的临床研究提供了基础，并为pvp清肝亮眼的进一步研究和药物开发提供了重要证据。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Prunella vulgaris polyphenols alleviate liver injury-uveitis comorbidity by regulating acylcarnitine via the S100A9-PP2A-AMPK pathway

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Prunella vulgaris polyphenols alleviate liver injury-uveitis comorbidity by regulating acylcarnitine via the S100A9-PP2A-AMPK pathway

Background

Liver injury and uveitis pose severe threats to human health. Owing to the close relationship of physiology and pathology between the liver and the eyes, cases in which both conditions occur simultaneously are not uncommon in clinical settings, significantly complicating treatment. However, no suitable comorbid animal model has been reported, and research on the pathological mechanisms of this comorbidity is lacking. Prunella vulgaris L., a well-known traditional Chinese medicine renowned for its liver-clearing and eye-brightening properties. Prunella vulgaris polyphenols (PVPs) hold promise for improving liver injury and uveitis. However, research exploring their dual therapeutic effects within a single organism remains lacking, leaving the key active components and mechanisms of action largely uninvestigated.

Purpose

This exploratory study aimed to establish a rat model of liver injury combined with uveitis and investigated its pathological mechanisms, evaluating the therapeutic efficacy of PVPs in alleviating liver injury combined with uveitis in rats. Additionally, it explored the mechanism of action and identified key active ingredients of PVPs, offering potential new directions for the development of clinical therapeutic drugs.

Methods

A rat model of liver injury with uveitis was established through intraperitoneal d-GalN/LPS injection. Metabolomics and proteomics were applied to investigate pathological mechanisms, followed by validation using acylcarnitine and S100A9 inhibitors. PVPs were administered to evaluate therapeutic effects and explore mechanisms involved in alleviating liver injury and uveitis. Network pharmacology combined with molecular docking identified critical active components in PVPs. Subsequent animal experiments verified the efficacy of the representative component in improving liver injury and uveitis.

Results

d-GalN/LPS (150 mg/kg : 1 mg/kg) induced significant liver injury and uveitis in rats. Metabolomics analysis pointed to acylcarnitine as a key metabolite, and its inhibition reduced inflammation. Proteomics analysis implicated S100A9 in inflammation and immunity. Then, we intervened with S100A9 inhibitors in the model rats. The results suggested that the pathological mechanism of liver injury and uveitis caused by d-GalN/LPS involved the upregulation of S100A9 expression, an increase in PP2A activity, the inhibition of AMPK phosphorylation, and the downregulation of CPT1A, leading to the accumulation of acylcarnitine and promoting the inflammatory response in the liver and retina. Further, experiments involving PVPs demonstrated dose-dependent improvements in liver injury and uveitis caused by d-GalN/LPS. The underlying mechanism of action involved suppression of S100A9 expression, reduction of PP2A activity, activation of AMPK, upregulation of CPT1A, and subsequent reduction in acylcarnitine accumulation in both the liver and retina. This mechanism effectively alleviated the inflammatory effects induced by d-GalN/LPS. Network pharmacology and molecular docking analyses pinpointed several key active components of PVPs—namely, rosmarinic acid, salviaflaside, esculetin, 2-hydroxycinnamic acid, 3,4-dihydroxybenzaldehyde, and 7,8-dihydroxycoumarin—that play significant roles in mitigating liver injury and uveitis. Follow-up experiments using the representative active component rosmarinic acid in rats confirmed its efficacy in improving symptoms of d-GalN/LPS-induced liver injury and uveitis, further validating the therapeutic potential of these key active components.

Conclusions

This study successfully established a rat model of liver injury combined with uveitis and confirmed the efficacy of PVPs in alleviating this condition. Furthermore, it determined that the underlying mechanism involves regulation of the S100A9-PP2A-AMPK pathway, with rosmarinic acid identified as a key active compound. These findings provide a basis for clinical studies on liver-eye comorbidities and offer critical evidence for further research and drug development of PVPs in liver-clearing and eye-brightening.

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来源期刊

Phytomedicine 医学-药学

CiteScore

10.30

自引率

5.10%

发文量

670

审稿时长

91 days

期刊介绍： Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.