Chamberlin Steve, Zweig Jonathan A, Neff Cody J, Marney Luke, Choi Jaewoo, Yang Liping, Maier Claudia S, Soumyanath Amala, McWeeney Shannon, Gray Nora E
Department of Medical Informatics and Clinical Epidemiology, Oregon Health & Science University, Portland, OR.
Department of Neurology, Oregon Health & Science University, Portland, OR.
bioRxiv. 2024 Nov 4:2024.11.04.621595. doi: 10.1101/2024.11.04.621595.
A water extract of the Ayurvedic plant (CAW) improves cognitive function in mouse models of aging and Alzheimer's disease, and affects dendritic arborization, mitochondrial activity and oxidative stress in mouse primary neurons. Triterpenes (TT) and caffeoylquinic acids (CQA) are constituents associated with these bioactivities of CAW although little is known about how interactions between these compounds contribute to the plant's therapeutic benefit.
Mouse primary cortical neurons were treated with CAW, or equivalent concentrations of four TT combined, eight CQA combined, or these twelve compounds combined (TTCQA). Treatment effects on the cell transcriptome (18,491 genes) and metabolome (192 metabolites) relative to vehicle control were evaluated using RNAseq and metabolomic analyses respectively.
Extensive differentially expressed genes (DEGs) were seen with all treatments, as well as evidence of interactions between compounds. Notably many DEGs seen with TT treatment were not observed in the TTCQA condition, possibly suggesting CQA reduced the effects of TT. Moreover, additional gene activity seen with CAW as compared to TTCQA indicate the presence of additional compounds in CAW that further modulate TTCQA interactions. Weighted Gene Correlation Network Analysis (WGCNA) identified 4 gene co-expression modules altered by treatments that were associated with extracellular matrix organization, fatty acid metabolism, cellular response to stress and stimuli, and immune function. Compound interaction patterns were seen at the eigengene level in these modules. Interestingly, in metabolomics analysis, the TTCQA treatment saw the highest number of changes in individual metabolites (20), followed by CQA (15), then TT (8) and finally CAW (3). WGCNA analysis found two metabolomics modules with significant eigenmetabolite differences for TT and CQA, and possible compound interactions at this level.
Four gene expression modules and two metabolite modules were altered by the four types of treatments applied. This methodology demonstrated the existence of both negative and positive interactions between TT, CQA and additional compounds found in CAW on the transcriptome and metabolome of mouse primary cortical neurons.
阿育吠陀植物的水提取物（CAW）可改善衰老和阿尔茨海默病小鼠模型的认知功能，并影响小鼠原代神经元的树突分支、线粒体活性和氧化应激。三萜类化合物（TT）和咖啡酰奎宁酸（CQA）是与CAW的这些生物活性相关的成分，尽管对于这些化合物之间的相互作用如何促成该植物的治疗益处知之甚少。
用CAW、四种TT的等效浓度组合、八种CQA的等效浓度组合或这十二种化合物的组合（TTCQA）处理小鼠原代皮质神经元。分别使用RNA测序和代谢组学分析评估相对于溶剂对照，处理对细胞转录组（18,491个基因）和代谢组（192种代谢物）的影响。
所有处理均观察到大量差异表达基因（DEG），以及化合物之间相互作用的证据。值得注意的是，在TT处理中观察到的许多DEG在TTCQA条件下未观察到，这可能表明CQA降低了TT的作用。此外，与TTCQA相比，CAW观察到的额外基因活性表明CAW中存在其他化合物，可进一步调节TTCQA的相互作用。加权基因共表达网络分析（WGCNA）确定了4个基因共表达模块因处理而改变，这些模块与细胞外基质组织、脂肪酸代谢、细胞对应激和刺激的反应以及免疫功能相关。在这些模块的特征基因水平上观察到化合物相互作用模式。有趣的是，在代谢组学分析中，TTCQA处理导致单个代谢物变化的数量最多（20个），其次是CQA（15个），然后是TT（8个），最后是CAW（3个）。WGCNA分析发现两个代谢组学模块，其特征代谢物在TT和CQA方面存在显著差异，并且在此水平上可能存在化合物相互作用。
所应用的四种处理改变了四个基因表达模块和两个代谢物模块。该方法证明了TT、CQA以及CAW中发现的其他化合物在小鼠原代皮质神经元的转录组和代谢组上存在正负相互作用。
