目的 通過網絡藥理學和分子對接技術探究木糖-鄰苯三酚結合物（XP）改善膿毒癥相關急性腎損傷的潛在靶點，并采用動物實驗驗證其作用機制。方法 通過Swiss Target Prediction和PharmMapper數據庫篩選XP的作用靶點，GeneCards、DrugBank、OMIM數據庫檢索膿毒癥相關急性腎損傷的疾病靶點，將藥物靶點與疾病靶點取交集獲得潛在靶點。利用DAVID平臺對潛在靶點進行基因本體（GO）、京都基因和基因組百科全書（KEGG）富集分析；采用Cytoscape 3.9.1軟件繪制抗氧化劑XP改善脂多糖致膿毒癥相關急性腎損傷的蛋白相互作用（PPI）網絡圖，選取degree值排名前10位的核心靶點和抗氧化劑XP作為受體蛋白和配體小分子，使用Schrödinger軟件包進行受體和配體的分子對接，并開展核心靶點相關生物學通路的驗證實驗。結果 共篩選得到XP改善脂多糖致膿毒癥相關急性腎損傷的作用靶點111個，其中核心靶點為白蛋白（ALB）、蛋白激酶B1（Akt1）、甘油醛-3-磷酸脫氫酶（GAPDH）、半胱氨酸蛋白水解酶3（CASP3）、酪氨酸激酶C（SRC）、雌激素受體1（ESR1）、90kDa熱休克蛋白αA1（HSP90AA1）、V-Ha-Ras肉瘤病毒癌基因同源物（HRAS）、細胞周期素D1（CCND1）、絲裂原活化蛋白激酶1（MAPK1）。GO富集分析篩選出生物過程271條，細胞組成60條，分子功能100條；KEGG富集到生物學通路119條；分子對接結果顯示XP與核心靶點均能夠較好的結合。實驗結果表明，XP可以顯著改善脂多糖致膿毒癥相關急性腎損傷的腎功能指標升高和腎組織病理損傷，其作用機制與上調腎臟組織中p-磷脂酰肌醇-3-激酶（PI3K）和p-Akt蛋白的表達相關。結論 XP可通過激活PI3K/Akt信號通路，減輕膿毒癥相關急性腎損傷。

Objective To explore the potential targets of xylose-pyrogallol complexes (XP) in ameliorating sepsis associated acute kidney injury by network pharmacology and molecular docking methods, and to verify this mechanism in vivo. Methods The targets of XP were obtained by Swiss Target Prediction and PharMapper database, GeneCards, DrugBank and OMIM database searched the disease targets of sepsis associated acute kidney injury and the potential targets were obtained after the intersection of the drug targets and disease targets. DAVID platform was used for GO and KEGG enrichment analysis. Cytoscape 3.9.1 software was used to construct the PPI network of the intersection targets. Top ten core targets and XP were selected as receptors and small molecule ligand. Schrödinger software was used for molecular docking between receptors and ligand. Finally, the core targets and related biological pathway were confirmed by experiment. Results A total of 111 targets of XP were obtained for ameliorating sepsis associated acute kidney injury, and the core targets were ALB, Akt1, GAPDH, CASP3, SRC, ESR1, HSP90AA1, HRAS, CCND1, MAPK1. Items were screened by GO enrichment analysis, including 271 biological processes, 60 cellular components, and 100 molecular functions. KEGG was enriched to 119 gene pathways. Molecular docking results showed that XP had good affinity with the core targets. Animal experiment showed that XP could significantly alleviate the elevated levels of kidney function and the damage of kidney tissue in rats with sepsis associated acute kidney injury, and its mechanism was related to upregulate p-PI3K and p-Akt expression in kidney. Conclusion XP could alleviate sepsis associated acute kidney injury in rats by activating the PI3K/Akt signaling pathway.

R966

中國醫(yī)學科學院醫(yī)學與健康科技創(chuàng)新工程（2021-I2M-1-052）