Nguyen Hai Duc, Kim Min-Sun
Department of Pharmacy, College of Pharmacy and Research Institute of Life and Pharmaceutical Sciences, Sunchon National University, Suncheon 57922, Republic of Korea.
Department of Pharmacy, College of Pharmacy and Research Institute of Life and Pharmaceutical Sciences, Sunchon National University, Suncheon 57922, Republic of Korea.
Toxicology. 2022 Apr 15;471:153164. doi: 10.1016/j.tox.2022.153164. Epub 2022 Mar 25.
Converging evidence demonstrates that microRNAs (miRNAs) play an important role in the etiology of cognitive impairment. Thus, we aim to: (i) identify the molecular mechanisms of heavy metals, particularly miRNAs involved in the development of cognitive impairment; and (ii) generate miRNA sponges to prevent them from binding with their target messenger RNAs. The Comparative Toxicogenomics Database (CTD; http://ctd.mdibl.org), MicroRNA ENrichment TURned NETwork (MIENTURNET, http://userver.bio.uniroma1.it/apps/mienturnet/) and the microRNA sponge generator and tester (miRNAsong, http://www.med.muni.cz/histology/miRNAsong) were used as the core data-mining approaches in the current study. We observed that lead acetate, arsenic, gold, copper, iron, and aluminum, as well as their mixtures, had significant effects on the development of cognitive impairment. Although prevalent genes obtained from investigated heavy metals of cognitive impairment were different, the "PI3K-Akt signaling pathway", "pathways of neurodegeneration-multiple diseases", "apoptosis", "apoptosis-multiple species", "p53 signaling pathway", "NF-kappa B signaling pathway", and "Alzheimer's disease pathway" were highlighted. The mixed heavy metals altered the genes BAX, CASP3, BCL2, TNF, and IL-1B, indicating the significance of apoptosis and pro-inflammatory cytokines in the pathogenesis of cognitive impairment and the possibility of targeting these genes in future neuroprotective therapy. In addition, we used a network-based approach to identify key genes, miRNAs, pathways, and diseases related to the development of cognitive impairment. We also found 16 significant miRNAs related to cognitive impairment (hsa-miR-1-3p, hsa-let-7a-5p, hsa-miR-9-5p, hsa-miR-16-5p, hsa-miR-17-5p, hsa-miR-20a-5p, hsa-miR-26a-5p, hsa-miR-26b-5p, hsa-miR-34a-5p, hsa-miR-101-3p, hsa-miR-106a-5p, hsa-miR-128-3p, hsa-miR-144-3p, hsa-miR-199a-3p, hsa-miR-204-5p, and hsa-miR-335-5p). Finally, we created and evaluated miRNA sponge sequences for these miRNAs in silico. Further studies, including in vivo and in vitro, are needed to assess the link between these genes, miRNAs, pathways, and cognitive impairment.
越来越多的证据表明，微小RNA（miRNA）在认知障碍的病因中起着重要作用。因此，我们旨在：（i）确定重金属的分子机制，特别是参与认知障碍发展的miRNA；以及（ii）生成miRNA海绵以防止它们与其靶信使RNA结合。比较毒理基因组学数据库（CTD；http://ctd.mdibl.org）、微小RNA富集转化网络（MIENTURNET，http://userver.bio.uniroma1.it/apps/mienturnet/）和微小RNA海绵生成器及测试器（miRNAsong，http://www.med.muni.cz/histology/miRNAsong）被用作本研究的核心数据挖掘方法。我们观察到醋酸铅、砷、金、铜、铁和铝及其混合物对认知障碍的发展有显著影响。尽管从所研究的认知障碍重金属中获得的普遍基因不同，但“PI3K-Akt信号通路”、“神经退行性变-多种疾病通路”、“凋亡”、“凋亡-多种物种”、“p53信号通路”、“NF-κB信号通路”和“阿尔茨海默病通路”被突出显示。混合重金属改变了BAX、CASP3、BCL2、TNF和IL-1B基因，表明凋亡和促炎细胞因子在认知障碍发病机制中的重要性以及在未来神经保护治疗中靶向这些基因的可能性。此外，我们使用基于网络的方法来识别与认知障碍发展相关的关键基因、miRNA、通路和疾病。我们还发现了16种与认知障碍相关的重要miRNA（hsa-miR-1-3p、hsa-let-7a-5p、hsa-miR-9-5p、hsa-miR-16-5p、hsa-miR-17-5p、hsa-miR-20a-5p、hsa-miR-26a-5p、hsa-miR-26b-5p、hsa-miR-34a-5p、hsa-miR-101-3p、hsa-miR-106a-5p、hsa-miR-128-3p、hsa-miR-144-3p、hsa-miR-199a-3p、hsa-miR-204-5p和hsa-miR-335-5p）。最后，我们在计算机上创建并评估了这些miRNA 的miRNA海绵序列。需要进一步的研究，包括体内和体外研究，以评估这些基因、miRNA、通路与认知障碍之间的联系。
