Chelerythrine ameliorates Aspergillus fumigatus keratitis through suppressing the LOX-1/p38 MAPK signaling pathway

IF 3.7 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Cytokine Pub Date : 2024-07-26 DOI:10.1016/j.cyto.2024.156717
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Abstract

Purpose

Aspergillus fumigatus (A. fumigatus) keratitis is a type of infectious corneal disease that significantly impairs vision. The objective of this study is to evaluate the therapeutic potential of chelerythrine (CHE) on A. fumigatus keratitis.

Methods

The antifungal activity of CHE was assessed through various tests including the minimum inhibitory concentration test, scanning electron microscopy, transmission electron microscopy, propidium iodide uptake test and plate count. Neutrophil infiltration and activity were assessed using immunofluorescence staining and the myeloperoxidase test. RT-PCR, western blotting assay, and ELISA were performed to measure the expression levels of proinflammatory cytokines (IL-1β and IL-6), NF-E2-related factor (Nrf2), heme oxygenase-1 (HO-1), and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), as well as to determine the ratio of phosphorylated-p38 (p-p38) mitogen-activated protein kinase (MAPK) to p38 MAPK.

Results

In vitro, CHE inhibited the growth of A. fumigatus conidia, reduced fungal hyphae survival, and prevented fungal biofilm formation. In vivo, CHE reduced the severity of A. fumigatus keratitis and exhibited an excellent anti-inflammatory effect by blocking neutrophil infiltration. Furthermore, CHE decreased the expression levels of proinflammatory cytokines and LOX-1 at both mRNA and protein levels, while also decreasing the p-p38 MAPK/p38 MAPK ratio. Additionally, CHE increased the expression levels of Nrf2 and HO-1.

Conclusion

CHE provides protection against A. fumigatus keratitis through multiple mechanisms, including reducing fungal survival, inducing anti-inflammatory effects, enhancing Nrf2 and HO-1 expression, and suppressing the signaling pathway of LOX-1/p38 MAPK.

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白屈菜红碱通过抑制 LOX-1/p38 MAPK 信号通路改善曲霉菌角膜炎。
目的:曲霉菌角膜炎是一种严重损害视力的传染性角膜疾病。本研究旨在评估白屈菜红碱(CHE)对烟曲霉菌角膜炎的治疗潜力:方法:通过各种测试评估 CHE 的抗真菌活性,包括最小抑菌浓度测试、扫描电子显微镜、透射电子显微镜、碘化丙啶吸收测试和平板计数。使用免疫荧光染色和髓过氧化物酶试验评估了中性粒细胞的浸润和活性。通过 RT-PCR、Western 印迹检测和 ELISA 检测促炎细胞因子(IL-1β 和 IL-6)、NF-E2 相关因子(Nrf2)、血红素加氧酶-1(HO-1)和凝集素样氧化低密度脂蛋白受体-1(LOX-1)的表达水平,并测定磷酸化-p38(p-p38)丝裂原活化蛋白激酶(MAPK)与 p38 MAPK 的比率:结果:在体外,CHE能抑制烟曲霉分生孢子的生长,降低真菌菌丝的存活率,并阻止真菌生物膜的形成。在体内,CHE 可减轻烟曲霉菌角膜炎的严重程度,并通过阻断中性粒细胞浸润表现出良好的抗炎效果。此外,CHE 在 mRNA 和蛋白水平上降低了促炎细胞因子和 LOX-1 的表达水平,同时还降低了 p-p38 MAPK/p38 MAPK 比率。此外,CHE 还能提高 Nrf2 和 HO-1 的表达水平:结论:CHE可通过多种机制提供对烟曲霉菌角膜炎的保护,包括降低真菌存活率、诱导抗炎作用、提高Nrf2和HO-1的表达以及抑制LOX-1/p38 MAPK的信号通路。
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来源期刊
Cytokine
Cytokine 医学-免疫学
CiteScore
7.60
自引率
2.60%
发文量
262
审稿时长
48 days
期刊介绍: The journal Cytokine has an open access mirror journal Cytokine: X, sharing the same aims and scope, editorial team, submission system and rigorous peer review. * Devoted exclusively to the study of the molecular biology, genetics, biochemistry, immunology, genome-wide association studies, pathobiology, diagnostic and clinical applications of all known interleukins, hematopoietic factors, growth factors, cytotoxins, interferons, new cytokines, and chemokines, Cytokine provides comprehensive coverage of cytokines and their mechanisms of actions, 12 times a year by publishing original high quality refereed scientific papers from prominent investigators in both the academic and industrial sectors. We will publish 3 major types of manuscripts: 1) Original manuscripts describing research results. 2) Basic and clinical reviews describing cytokine actions and regulation. 3) Short commentaries/perspectives on recently published aspects of cytokines, pathogenesis and clinical results.
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