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IF 4.8 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2025-01-03 Epub Date: 2024-12-12 DOI:10.1016/j.intimp.2024.113825

Xuelian Li, Xianjie Zhu, Shijiu Jiang, Wenling Yang, Fan Zhang, Xiaopeng Guo, Yumiao Wei

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引用次数: 0

摘要

背景：心脏纤维化是心肌梗塞（MI）后心肌重塑的一个关键因素，可导致心力衰竭恶化。从白术中提取的白术内酯 III（ATL-III）具有公认的抗氧化和抗炎作用，但其对心脏纤维化的影响仍不清楚：方法：通过永久性结扎左前降支（LAD）冠状动脉诱发小鼠心肌梗死，然后用ATL-III或二甲基亚砜（DMSO）治疗2周。通过超声心动图、组织学和心肌损伤血清生物标志物评估心脏纤维化。在体外，使用免疫荧光、5-乙炔基-2'-脱氧尿苷（EdU）和免疫印迹技术评估了ATL-III对心脏成纤维细胞（CF）增殖和胶原沉积的影响。网络药理学和分子对接确定了 ATL-III 的潜在靶点：结果：ATL-III治疗能明显改善心脏功能，表现为射血分数（EF）和分数缩短（FS）增加，左心室扩张减少。组织学分析显示，ATL-III治疗小鼠的纤维化区域减少，纤维化标志物α-SMA和胶原蛋白I的表达也有所降低。ATL-III还通过降低活性氧（ROS）和丙二醛（MDA）水平缓解氧化应激，同时提高超氧化物歧化酶（SOD）活性。此外，ATL-III 还能抑制炎症，降低 TNF-α、IL-6 和 IL-1β 蛋白及 mRNA 水平。在体外，ATL-III 可抑制 TGF-β1 诱导的 CF 增殖、迁移和分化，减少纤维化标志物的表达。分子对接和通路分析证实，ATL-III从机制上抑制了RhoA/ROCK1和ERK1/2信号通路：ATL-III通过减少氧化应激、炎症和CF激活，在减轻MI后心脏纤维化方面显示出治疗潜力。这些发现突出表明 ATL-III 是治疗心脏纤维化和相关心力衰竭的有希望的候选药物。

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Atractylenolide-III restrains cardiac fibrosis after myocardial infarction via suppression of the RhoA/ROCK1 and ERK1/2 pathway.

Background: Cardiac fibrosis, a critical factor in myocardial remodeling post-myocardial infarction (MI), can advance heart failure progression. Atractylenolide III (ATL-III), derived from Atractylodes lancea, has recognized antioxidant and anti-inflammatory effects; however, its influence on cardiac fibrosis remains unclear.

Methods: MI was induced in mice by permanent ligation of the left anterior descending (LAD) coronary artery, followed by 2 weeks of ATL-III or dimethyl sulfoxide (DMSO) treatment. Cardiac fibrosis was assessed by echocardiography, tissue histology, and serum biomarkers of myocardial injury. In vitro, the effects of ATL-III on cardiac fibroblast (CF) proliferation and collagen deposition were evaluated using immunofluorescence, 5-Ethynyl-2'-deoxyuridine (EdU), and western blot techniques. Network pharmacology and molecular docking identified potential ATL-III targets.

Results: ATL-III treatment significantly improved cardiac function, as evidenced by increased ejection fraction (EF) and fractional shortening (FS) and reduced left ventricular dilation. Histological analysis revealed decreased fibrotic areas in ATL-III-treated mice, along with reduced expression of fibrosis markers α-SMA and Collagen I. ATL-III also alleviated oxidative stress by reducing reactive oxygen species (ROS) and malondialdehyde (MDA) levels while increasing superoxide dismutase (SOD) activity. Furthermore, ATL-III suppressed inflammation, decreasing TNF-α, IL-6, and IL-1β protein and mRNA levels. In vitro, ATL-III inhibited TGF-β1-induced CF proliferation, migration, and differentiation, reducing the expression of fibrotic markers. Mechanistically, ATL-III suppressed the RhoA/ROCK1 and ERK1/2 signaling pathways, as confirmed by molecular docking and pathway analysis.

Conclusion: ATL-III demonstrates therapeutic potential in mitigating post-MI cardiac fibrosis by reducing oxidative stress, inflammation, and CF activation. These findings highlight ATL-III as a promising candidate for the treatment of cardiac fibrosis and associated heart failure.

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来源期刊

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

期刊介绍： International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.