■自COVID-19爆发以来,青少年抑郁和焦虑的发病率一直在增加,目前尚无有效的治疗药物。四尼散是中医常用的治疗抑郁样行为和焦虑样行为,但其治疗青春期抑郁合并焦虑的机制尚不清楚。
■网络药理学用于探索潜在的药物分子和相关靶标,分子对接和分子动力学(MD)模拟,评价潜在药物分子与相关靶点的相互作用,并建立了青少年大鼠焦虑合并抑郁模型以及以下行为测试和分子生物学测试来验证网络药理学和分子对接的结果。
■因此,筛选出Si-niSan的256种活性成分和1128种潜在靶标。其中,槲皮素,木犀草素,山奈酚,7-甲氧基-2-甲基异黄酮,Formonoetin被证明是最有潜力的成分;而STAT3,IL6,TNF,AKT1,AKT1,TP53,IL1B,MAPK3,VEGFA,CASP3、MMP9显示为最有潜力的靶点。AGE-RAGE信号通路在糖尿病并发症中的作用,IL-17信号通路,HIF-1信号通路,PI3K-Akt信号通路和TNF信号通路,参与抗炎过程,显示是Si-niSan调控的最可能的途径。化合物与炎症相关靶标之间的分子对接和MD模拟显示槲皮素具有良好的结合能力,木犀草素,山奈酚,景别素和Formononetin对PTGS2和PPARγ的影响。在青春期大鼠的实验中,Si-niSan显着抑制了早期产妇分离(MS)与青少年慢性不可预测的轻度压力(CUMS)引起的抑郁和焦虑。qPCR结果进一步表明Si-niSan调节氧化应激和炎症反应。
■这项研究表明,通过靶向TNF通路和Nrf2通路改善海马炎症,Si-niSan可以改善MS联合CUMS诱导的青少年焦虑和抑郁样行为,有助于揭示四逆散治疗青少年抑郁合并焦虑的作用机制。
UNASSIGNED: The incidence rate of adolescent depression and anxiety has been increasing since the outbreak of COVID-19, which there are no effective therapeutic drugs available. Si-ni San is commonly used in traditional Chinese medicine for the treatment of depression-like as well as anxiety-like behavior, but its mechanism for treating depression combined with anxiety during adolescence is not yet clear.
UNASSIGNED: Network pharmacology was used to explore potential drug molecules and related targets, molecular docking and molecular dynamics (MD) simulation were used to evaluate the interaction between the potential drug molecules and related targets, and a model of anxiety combined with depression in adolescent rats as well as the following behavioral tests and molecular biology tests were used to verify the results from network pharmacology and molecular docking.
UNASSIGNED: As a result, 256 active ingredients of Si-ni San and 1128 potential targets were screened out. Among them, quercetin, Luteolin, kaempferol, 7-Methoxy-2-methyl isoflavone, formononetin showed to be the most potential ingredients; while STAT3, IL6, TNF, AKT1, AKT1, TP53, IL1B, MAPK3, VEGFA, CASP3, MMP9 showed to be the most potential targets. AGE-RAGE signaling pathway in diabetic complications, IL-17 signaling pathway, HIF-1 signaling pathway, PI3K-Akt signaling pathway and TNF signaling pathway, which are involved in anti-inflammation processes, showed to be the most probable pathways regulated by Si-ni San. Molecular docking and MD simulation between the compounds to inflammation-associated targets revealed good binding abilities of quercetin, Luteolin, kaempferol, nobiletin and formononetin to PTGS2 and PPARγ. In the experiment with adolescent rats, Si-ni San markedly suppressed early maternal separation (MS) combined with adolescent chronic unpredictable mild stress (CUMS)-induced depression combined with anxiety. The qPCR results further indicated that Si-ni San regulated the oxidative stress and inflammatory response.
UNASSIGNED: This study demonstrates that adolescent anxiety- and depression-like behavior induced by MS combined CUMS can be ameliorated by Si-ni San by improved inflammation in hippocampus via targeting TNF pathway and Nrf2 pathway, helping to reveal the mechanism of Si-ni San in treating adolescent depression combined with anxiety.