背景:非酒精性脂肪性肝病(NAFLD)是全球范围内严重的公共卫生问题,目前,NAFLD的治疗仍在迷宫中。在早期阶段,食物方案和有利的肠道微生物群(GM)的组合应用被认为是一种替代疗法。因此,我们整合了转基因和被称为有效膳食谷物的Avenasativa(AS)的次级代谢产物(SMs),以通过网络药理学鉴定组合功效。
方法:我们通过天然产物活性和物种来源(NPASS)数据库浏览了AS的SM,并通过gutMGene数据库检索了GM的SM。然后,从与AS和GM的SM相关的目标中确定特定的相交目标。在NAFLD相关目标上选择最终目标,这被认为是关键目标。进行了蛋白质-蛋白质相互作用(PPI)网络和气泡图分析,以确定枢纽靶标和关键信号通路。分别。并行,我们通过RPackage将五个组分合并,分析了GM或AS的关系-关键信号通路-靶标-SMs(GASTM)。我们通过分子对接测定(MDA)鉴定了关键信号通路上的关键SM。最后,在硅平台上验证了确定的关键SM的理化性质和毒性。
结果:最后16个靶点被认为是抗NAFLD的关键蛋白,血管内皮生长因子A(VEGFA)是PPI网络分析的关键目标。PI3K-Akt信号通路是与作为拮抗模式的VEGFA相关的最主要的机制。GASTM网络代表122个节点(60GM,AS,PI3K-Akt信号通路,4个目标,和56个SM)和154个边缘。VEGFA-杨梅素,或者槲皮素,GSK3B-杨梅素,IL2皂苷元复合物形成最稳定的构象,这三种配体均来源于GM。相反,NR4A1-vestitol形成了具有最高亲和力的稳定构象,vestilol是从AS获得的。给定的四个SM没有障碍发展成为没有毒性的药物。
结论:结论:我们表明,AS和GM的组合应用可能会对NAFLD产生有效的协同作用,抑制PI3K-Akt信号通路。这项工作提供了饮食策略和有益的转基因对NAFLD的重要性,为进一步阐明联合应用(AS和GM)抗NAFLD的SM和药理机制奠定了数据挖掘基础。
Non-alcoholic fatty liver disease (NAFLD) is a serious public health issue globally, currently, the treatment of NAFLD lies still in the labyrinth. In the inchoate stage, the combinatorial application of food regimen and favorable gut microbiota (GM) are considered as an alternative therapeutic. Accordingly, we integrated secondary metabolites (SMs) from GM and
Avena sativa (AS) known as potent dietary grain to identify the combinatorial efficacy through network pharmacology.
We browsed the SMs of AS via Natural Product Activity & Species Source (NPASS) database and SMs of GM were retrieved by gutMGene database. Then, specific intersecting targets were identified from targets related to SMs of AS and GM. The final targets were selected on NAFLD-related targets, which was considered as crucial targets. The protein-protein interaction (PPI) networks and bubble chart analysis to identify a hub target and a key signaling pathway were conducted, respectively. In parallel, we analyzed the relationship of GM or AS─a key signaling pathway─targets─SMs (GASTM) by merging the five components via RPackage. We identified key SMs on a key signaling pathway via molecular docking assay (MDA). Finally, the identified key SMs were verified the physicochemical properties and toxicity in silico platform.
The final 16 targets were regarded as critical proteins against NAFLD, and Vascular Endothelial Growth Factor A (VEGFA) was a key target in PPI network analysis. The PI3K-Akt signaling pathway was the uppermost mechanism associated with VEGFA as an antagonistic mode. GASTM networks represented 122 nodes (60 GM, AS, PI3K-Akt signaling pathway, 4 targets, and 56 SMs) and 154 edges. The VEGFA-myricetin, or quercetin, GSK3B-myricetin, IL2-diosgenin complexes formed the most stable conformation, the three ligands were derived from GM. Conversely, NR4A1-vestitol formed stable conformation with the highest affinity, and the vestitol was obtained from AS. The given four SMs were no hurdles to develop into drugs devoid of its toxicity.
In conclusion, we show that combinatorial application of AS and GM might be exerted to the potent synergistic effects against NAFLD, dampening PI3K-Akt signaling pathway. This work provides the importance of dietary strategy and beneficial GM on NAFLD, a data mining basis for further explicating the SMs and pharmacological mechanisms of combinatorial application (AS and GM) against NAFLD.