Vascular dementia (VaD) is a common cause of cognitive decline and dementia of vascular origin, but the precise pathological mechanisms are unknown, and so effective clinical treatments have not been established. Tilianin, the principal active compound of total flavonoid extract from Dracocephalum moldavica L., is a candidate therapy for cardio-cerebrovascular diseases in China. However, its potential in the treatment of VaD is unclear. The present study is aimed at investigating the protective effects of tilianin on VaD and exploring the underlying mechanism of the action. A model of VaD was established by permanent 2-vessel occlusion (2VO) in rats. Human neurons (hNCs) differentiated from human-induced pluripotent stem cells were used to establish an oxygen-glucose deprivation (OGD) model. The therapeutic effects and potential mechanisms of tilianin were identified using behavioral tests, histochemistry, and multiple molecular biology techniques such as Western blot analysis and gene silencing. The results demonstrated that tilianin modified spatial cognitive impairment, neurodegeneration, oxidation, and apoptosis in rats with VaD and protected hNCs against OGD by increasing cell viability and decreasing apoptosis rates. A study of the mechanism indicated that tilianin restored p-CaMKII/ERK1/2/CREB signaling in the hippocampus, maintaining hippocampus-independent memory. In addition, tilianin inhibited an ox-CaMKII/p38 MAPK/JNK/NF-κB associated inflammatory response caused by cerebral oxidative stress imbalance in rats with VaD. Furthermore, specific CaMKIIα siRNA action revealed that tilianin-exerted neuroprotection involved increase of neuronal viability, inhibition of apoptosis, and suppression of inflammation, which was dependent on CaMKIIα. In conclusion, the results suggested the neuroprotective effect of tilianin in VaD and the potential mechanism associated with dysfunction in the regulation of p-CaMKII-mediated long-term memory and oxidation and inflammation involved with ox-CaMKII, which may lay the foundation for clinical trials of tilianin for the treatment of VaD in the future.

Existing studies have revealed that microRNAs (miRNAs) have a role in cognitive deficits in Alzheimer’s disease (AD). However, the function and pathophysiological mechanism of deregulated miRNAs underlying AD pathology remain to be investigated. The present study aimed to clarify the role and mechanism of miR-148a-3p in AD. RNA sequencing, qRT-PCR, and western blot analysis were used to identify the aberrant expression and signaling of miR-148a-3p within cells, mice, and patients with AD. Molecular biology techniques involving luciferase reporter assays, gene overexpression and silencing, chromatin immunoprecipitation, and adeno-associated virus-based miRNA overexpression were used to explore the biological function and mechanisms of miR-148a-3p. Downregulation of miR-148a-3p was identified in AD. Upregulation of miR-148a-3p was found to protect neuronal cells against Aβ-associated tau hyperphosphorylation by directly targeting p35/CDK5 and PTEN/p38 mitogen-activated protein kinase (MAPK) pathways. A mutual regulatory link between miR-148a-3p and PTEN using a feedforward arrangement was confirmed via promotion of transcription and expression of miR-148a-3p by way of the PTEN/Akt/CREB pathway. Significantly, in vivo targeting of miR-148a-3p signaling ameliorated cognitive deficits by decreasing p35/PTEN-elicited tau hyperphosphorylation, accompanied by feedforward transduction of the PTEN/Akt/CREB pathway. In conclusion, the present study implicated the miR-148a-3p/p35/PTEN pathway as an essential contributor to tau hyperphosphorylation and feedforward regulation in AD.

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Background Radiotherapy-associated secondary cancer is an important issue for the treatment of breast cancer (BCa). This study aimed to investigate the molecular mechanism and genetic risk factors for radiation-associated secondary diseases in BCa. Methods The differentially expressed genes (DEGs) between preradiation and postradiation BCa samples in the GSE65505 dataset were obtained. The pathways related to the radiation-associated DEGs in the protein–protein interaction (PPI) network modules were identified. miRNAs targeted to the key genes in the PPI network were identified, and their association with BCa prognosis was analyzed. Results A total of 136 radiation-associated DEGs preradiation and postradiation BCa samples were screened out. The PPI network consisted of a significant module that consisted of 21 upregulated DEGs that were associated with “hsa04512: ECM–receptor interaction,” “hsa04151: PI3K-Akt signaling pathway,” and “hsa04115: p53 signaling pathway.” Sixteen DEGs, including three collagen genes collagen type I alpha 1 chain (COL1A1), COL3A1, and COL1A2, were enriched in 17 radiation-associated pathways. The three genes were upregulated in BCa tissues compared with controls and were also elevated by radiation. They were targeted by hsa-miR-29a/c, and the expression levels of hsa-miR-29a/c were associated with a poor prognosis of BCa. Conclusions The upregulation of COL1A1, COL3A1, and COL1A2 might be genetic risk factors for radiation-associated secondary diseases in BCa.

Vascular dementia (VaD) is the second most common form of dementia with uncertain mechanisms and no effective treatments. microRNAs (miRNAs) and transcription factors (TFs) are considered regulatory factors of genes involved in many diseases. Therefore, this work investigated the aberrantly expressed miRNAs, TFs, corresponding target genes, and their co-regulatory networks in the cortex of rats with bilateral common carotid artery occlusion (2VO) to uncover the potential mechanism and biomarkers of VaD. Differentially expressed genes (DEGs), miRNAs (DEMs), and TFs (DETFs) were identified using RNA sequencing, and their interaction networks were constructed using Cytoscape. The results showed that rats with 2VO had declined cognitive abilities and neuronal loss in the cortex than sham rats. DEGs, DEMs, and DETFs were discriminated between rats with 2VO and sham rats in the cortex, as shown by the 13 aberrantly expressed miRNAs, 805 mRNAs, and 63 TFs. The miRNA-TF-target gene network was constructed, showing 523 nodes and 7237 edges. Five miRNAs (miR-5132-5p, miR-764-3p, miR-223-3p, miR-145-5p, and miR-122-5p), ten TFs (Mxi1, Nfatc4, Rxrg, Zfp523, Foxj2, Nkx6-1, Klf4, Klf5, Csrnp1, and Prdm6), and seven target genes (Serpine1, Nedd4l, Pxn, Col1a1, Plec, Trip12, and Tpm1) were chosen as the significant nodes to construct feed-forward loops (FFLs). Gene Ontology and pathway enrichment analysis revealed that these miRNA and TF-associated genes are mostly involved in the PI3K/Akt, neuroactive ligand–receptor interaction, calcium signaling, and Wnt signaling pathways, along with central locations around the cell membrane. They exert functions such as growth factor binding, integrin binding, and extracellular matrix structural constituent, with representative biological processes like vasculature development, cell–substrate adhesion, cellular response to growth factor stimulus, and synaptic transmission. Furthermore, the expression of three miRNAs (miR-145-5p, miR-122-5p, and miR-5132-5p), six TFs (Csrnp1, Klf4, Nfatc4, Rxrg, Foxj2, and Klf5), and five mRNAs (Serpine1, Plec, Nedd4l, Trip12, and Tpm1) were significantly changed in rats with VaD, in line with the outcome of RNA sequencing. In the potential FFL, miR-145-5p directly bound Csrnp1 and decreased its mRNA expression. These results might help the understanding of the underlying regulatory mechanisms of miRNA-TF-genes, providing potential therapeutic targets in VaD.