Department of Anesthesiology, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei, China.
Aging (Albany NY). 2024 May 3;16(9):7961-7978. doi: 10.18632/aging.205797.
This study combined bioinformatics and experimental verification in a mouse model of intestinal ischemia-reperfusion injury (IRI) to explore the protection mechanism exerted by butyrate against IRI.
GeneCards, Bioinformatics Analysis Tool for Molecular Mechanisms of Traditional Chinese Medicine and GSE190581 were used to explore the relationship between butyrate and IRI and aging. Protein-protein interaction networks involving butyrate and IRI were constructed via the STRING database, with hub gene analysis performed through Cytoscape. Functional enrichment analysis was conducted on intersection genes. A mouse model of IRI was established, followed by direct arterial injection of butyrate. The experiment comprised five groups: normal, sham, model, vehicle, low-dose butyrate, and high-dose butyrate. Intestinal tissue observation was done via transmission electron microscopy (TEM), histological examination via hematoxylin and eosin (H&E) staining, tight junction proteins detection via immunohistochemistry, and Western blot analysis of hub genes. Drug-target interactions were evaluated through molecular docking.
Butyrate protected against IRI by targeting 458 genes, including HMGB1 and TLR4. Toll-like receptor pathway was implicated. Butyrate improved intestinal IRI by reducing mucosal damage, increasing tight junction proteins, and lowering levels of HMGB1, TLR4, and MyD88. Molecular docking showed strong binding energies between butyrate and HMGB1 (-3.7 kcal/mol) and TLR4 (-3.8 kcal/mol).
According to bioinformatics predictions, butyrate mitigates IRI via multiple-target and multiple-channel mechanisms. The extent of IRI can be reduced by butyrate through the inhibition of the HMGB1-TLR4-MyD88 signaling pathway, which is related to senescence.
本研究通过建立小鼠肠缺血再灌注损伤（IRI）模型，结合生物信息学和实验验证，探讨丁酸盐对 IRI 的保护机制。
使用 GeneCards、中药分子机制生物信息学分析工具和 GSE190581 数据库探索丁酸盐与 IRI 和衰老的关系。通过 STRING 数据库构建涉及丁酸盐和 IRI 的蛋白质-蛋白质相互作用网络，利用 Cytoscape 进行枢纽基因分析。对交集基因进行功能富集分析。建立 IRI 小鼠模型，直接动脉注射丁酸钠。实验分为 5 组：正常组、假手术组、模型组、溶剂组、低剂量丁酸钠组和高剂量丁酸钠组。通过透射电子显微镜（TEM）观察肠组织，苏木精-伊红（H&E）染色进行组织学检查，免疫组化法检测紧密连接蛋白，Western blot 分析枢纽基因。通过分子对接评估药物-靶标相互作用。
丁酸盐通过靶向 458 个基因（包括 HMGB1 和 TLR4）来保护 IRI。涉及 Toll 样受体通路。丁酸钠通过减少黏膜损伤、增加紧密连接蛋白以及降低 HMGB1、TLR4 和 MyD88 的水平来改善肠道 IRI。分子对接显示丁酸盐与 HMGB1（-3.7 kcal/mol）和 TLR4（-3.8 kcal/mol）之间具有很强的结合能。
根据生物信息学预测，丁酸盐通过多靶点、多通道机制减轻 IRI。丁酸钠通过抑制 HMGB1-TLR4-MyD88 信号通路来减轻 IRI，这与衰老有关。
