Yuan Ruixue, Li Yaojing, Li Xiangyi, Fu Yingmei, Ning Ailing, Wang Dongxiang, Zhang Ran, Yu Shunying, Xu Qingqing
Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
958 Hospital of PLA ARMY, Chongqing, China.
Front Pharmacol. 2024 Aug 23;15:1431923. doi: 10.3389/fphar.2024.1431923. eCollection 2024.
Risperidone is one of the most reliable and effective antipsychotics for schizophrenia treatment. However, the mechanism of action of risperidone is not yet fully understood. Traf2 and Nck-interacting protein kinase (), a schizophrenia susceptibility gene, is associated with risperidone treatment response. Our previous experiments confirmed that downregulated TNIK affected the effect of risperidone on downstream targets. However, the effect of downregulated TNIK on risperidone-induced molecular expression remains to be further explored.
Transcriptome analysis was performed on U251 cells subjected to risperidone, siRNA, and no treatment, respectively. Compared to the no-treatment group, two groups of DEGs were screened out and then intersected with the schizophrenia-related genes to screen the cross-talk genes. Those DEGs were analyzed using GO and KEGG. STRING and Cytoscape were used to construct a protein-protein interaction (PPI) network for the cross-talk gene.
The results showed that the parathyroid hormone synthesis, secretion, and action were significantly enriched after risperidone treatment. Downregulated TNIK could have an impact on the collagen-containing extracellular matrix, signaling receptor activator activity, and PI3K-Akt signaling pathway. Interestingly, bone mineralization function and calcium signaling pathway were enriched in the cross-talk genes. Additionally, FGFR2, FGF1, and FGFR might be the potential targets for affecting the effects of risperidone.
The study indicated that risperidone primarily influences functions and/or pathways associated with bone metabolism, potentially contributing to the adverse effect of osteoporosis. Our study may offer a novel perspective on investigating the mechanisms underlying the adverse effects of risperidone.
利培酮是治疗精神分裂症最可靠且有效的抗精神病药物之一。然而，利培酮的作用机制尚未完全明确。Traf2和Nck相互作用蛋白激酶（TNIK）作为一种精神分裂症易感基因，与利培酮治疗反应相关。我们之前的实验证实，TNIK表达下调会影响利培酮对下游靶点的作用。然而，TNIK表达下调对利培酮诱导的分子表达的影响仍有待进一步探究。
分别对接受利培酮、TNIK小干扰RNA（siRNA）处理及未处理的U251细胞进行转录组分析。与未处理组相比，筛选出两组差异表达基因（DEGs），然后与精神分裂症相关基因进行交集分析以筛选相互作用基因。使用基因本体论（GO）和京都基因与基因组百科全书（KEGG）对这些DEGs进行分析。利用STRING和Cytoscape构建相互作用基因的蛋白质-蛋白质相互作用（PPI）网络。
结果显示，利培酮治疗后甲状旁腺激素合成、分泌及作用显著富集。TNIK表达下调会对含胶原蛋白的细胞外基质、信号受体激活剂活性及PI3K-Akt信号通路产生影响。有趣的是，骨矿化功能和钙信号通路在相互作用基因中富集。此外，FGFR2、FGF1和FGFR可能是TNIK影响利培酮作用的潜在靶点。
该研究表明，利培酮主要影响与骨代谢相关的功能和/或通路，这可能是其导致骨质疏松不良反应的原因。我们的研究可能为探究利培酮不良反应的潜在机制提供新的视角。
