Postoperative neurocognitive disorder (PND) is one of the most common postoperative neurological complications in aged patients, characterized by mental disorder, anxiety, personality changes, and impaired memory. At present, the molecular mechanism of PND remains largely unclear, and the ideal biomarker for clinical diagnosis and prognosis are lacking. Circular RNA (circRNA) and microRNA (miRNA), as unique non-coding RNAs, affecting the regulation of miRNAs on genes and further intervening in the progression of diseases through the sponge action between the two. Besides, it could be served as novel biomarkers in various diseases. In order to detect the differential expression profiles of genes caused by PND, a total of 26 18-month-old male C57BL/6 mice were randomly assigned to control group and PND group. Behavioral tests showed that mice in the PND group had impaired cognitive function compared with the control group. Three mice in each group were randomly selected to harvest the brain for analysis the expressions of circRNAs, miRNAs, and mRNAs in the prefrontal cortex by next-generation sequencing (NGS) technology. Differentially expressed genes, including 1192 circRNAs, 27 miRNAs, and 266 mRNAs were identified, and its accuracy was further confirmed by qRT-PCR. Bioinformatics analysis results suggested that neuroinflammation was the main pathological mechanism of PND. The construction of competitive endogenous RNA (ceRNA) networks and the identification of hub genes provided possible therapeutic targets for PND. Cinnarizine and Clemastine were predicted to have the potential therapeutic effects on PND. This is the first study to explore the differential expression profiles of genes and their regulation mechanisms in PND, our results provided new clues and targets for the treatment of this refractory disease.
Perioperative neurocognitive disorder (PND) leads to progressive deterioration of cognitive function, especially in aged patients. Demyelination is closely associated with cognitive dysfunction. However, the relationship between PND and demyelination remains unclear. Here we showed that demyelination was related to the pathogenesis of PND. Clemastine, an antihistamine with potency in remyelination, was predicted to have a potential therapeutic effect on PND by next-generation sequencing and bioinformatics in our previous study. In the present study, it was given at 10 mg/kg per day for 2 weeks to evaluate the effects on PND in aged mice. We found that clemastine ameliorated PND and reduced the expression levels of inflammatory factors such as tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β). Further investigation suggested clemastine increased the expression of oligodendrocyte transcription factor 2 (OLIG2) and myelin basic protein (MBP) to enhance remyelination by inhibiting the overactivation of the WNT/β-catenin pathway. At the same time, the expression of post-synaptic density protein 95 (PSD95, or DLG4), brain-derived neurotrophic factor (BDNF), synaptosomal-associated protein 25 (SNAP25) and neuronal nuclei (NEUN) were also improved. Our results suggested that clemastine might be a therapy for PND caused by anesthetic and surgical factors in aged patients.
To identify the molecular mechanisms and novel therapeutic agents of late-onset Alzheimer’s disease (AD), we performed integrative network analysis using multiple transcriptomic profiles of human brains. With the hypothesis that AD pathology involves the whole cerebrum, we first identified co-expressed modules across multiple cerebral regions of the aging human brain. Among them, two modules (M3 and M8) consisting of 1,429 protein-coding genes were significantly enriched with AD-correlated genes. Differential expression analysis of microarray, bulk RNA-sequencing (RNA-seq) data revealed the dysregulation of M3 and M8 across different cerebral regions in both normal aging and AD. The cell-type enrichment analysis and differential expression analysis at the single-cell resolution indicated the extensive neuronal vulnerability in AD pathogenesis. Transcriptomic-based drug screening from Connectivity Map proposed Gly-His-Lys acetate salt (GHK) as a potential drug candidate that could probably restore the dysregulated genes of the M3 and M8 network. Pretreatment with GHK showed a neuroprotective effect against amyloid-beta-induced injury in differentiated human neuron-like SH-SY5Y cells. Taken together, our findings uncover a dysregulated network disrupted across multiple cerebral regions in AD and propose pretreatment with GHK as a novel neuroprotective strategy against AD.
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