Maes Michael, Kubera Marta, Kotańska Magdalena
Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria.
Front Psychiatry. 2022 May 6;13:822382. doi: 10.3389/fpsyt.2022.822382. eCollection 2022.
There is evidence that chronic fatigue spectrum disorders (CFAS-Ds), including myalgic encephalomyelitis (ME), chronic fatigue syndrome (CFS), and chronic fatigue with physiosomatic symptoms including when due to comorbid medical disease, are characterized by neuroimmune and neuro-oxidative biomarkers. This study was performed to delineate the protein-protein interaction (PPI) network of CFAS-D and to discover the pathways, molecular patterns, and domains enriched in their PPI network. We performed network, enrichment, and annotation analyses using differentially expressed proteins and metabolics, which were established in patients with CFAS-D. The PPI network analysis revealed that the backbone of the highly connective CFAS-D network comprises , , , peroxides, , tumor necrosis factor (), and interleukin-6 () and that the network comprises interconnected immune-oxidative-nitrosative and Wnt/β-catenin subnetworks. Multiomics enrichment analysis shows that the CFAS-D network is highly significantly associated with cellular (antioxidant) detoxification, hydrogen peroxide metabolic process, peroxidase and oxidoreductase activity, interleukin-10 (IL-10) anti-inflammatory signaling and neurodegenerative canonical Wnt, the β-catenin complex, cadherin domains, cell-cell junctions and TLR2/4 pathways, and the transcription factors nuclear factor kappa B (NF-κB) and RELA. The top 10 DOID annotations of the CFAS-D network include four intestinal, three immune system disorders, cancer, and infectious disease. The custom Gene Ontology (GO) term annotation analysis revealed that the CFAS-D network is associated with a response to a toxic substance, lipopolysaccharides, bacterium, or virus. In conclusion, CFAS-D may be triggered by a variety of stimuli and their effects are mediated by aberrations in the cross-talks between redox, NF-κB, and Wnt/β-catenin signaling pathways leading to dysfunctions in multicellular organismal homeostatic processes.
有证据表明，慢性疲劳谱系障碍（CFAS-Ds），包括肌痛性脑脊髓炎（ME）、慢性疲劳综合征（CFS），以及伴有身心症状（包括由合并症引起时）的慢性疲劳，其特征为神经免疫和神经氧化生物标志物。本研究旨在描绘CFAS-D的蛋白质-蛋白质相互作用（PPI）网络，并发现其PPI网络中富集的途径、分子模式和结构域。我们使用在CFAS-D患者中确定的差异表达蛋白质和代谢物进行了网络、富集和注释分析。PPI网络分析显示，高度连接的CFAS-D网络的主干包括 、 、 、过氧化物、 、肿瘤坏死因子（ ）和白细胞介素-6（ ），并且该网络包括相互连接的免疫-氧化-亚硝化和Wnt/β-连环蛋白子网。多组学富集分析表明，CFAS-D网络与细胞（抗氧化剂）解毒、过氧化氢代谢过程、过氧化物酶和氧化还原酶活性、白细胞介素-10（IL-10）抗炎信号传导以及神经退行性经典Wnt、β-连环蛋白复合物、钙黏蛋白结构域、细胞间连接和TLR2/4途径，以及转录因子核因子κB（NF-κB）和RELA高度显著相关。CFAS-D网络的前10个疾病本体（DOID）注释包括四种肠道疾病、三种免疫系统疾病、癌症和传染病。定制的基因本体（GO）术语注释分析表明，CFAS-D网络与对有毒物质、脂多糖、细菌或病毒的反应相关。总之，CFAS-D可能由多种刺激引发，其效应由氧化还原、NF-κB和Wnt/β-连环蛋白信号通路之间的串扰异常介导，导致多细胞生物体稳态过程功能障碍。
