Cromolyn prevents cerebral vasospasm and dementia by targeting WDR43.

Background: Cerebral vasospasm (CV) can cause inflammation and damage to neuronal cells in the elderly, leading to dementia. Purpose: This study aimed to investigate the genetic mechanisms underlying dementia caused by CV in the elderly, identify preventive and therapeutic drugs, and evaluate their efficacy in treating neurodegenerative diseases. Methods: Genes associated with subarachnoid hemorrhage and CV were acquired and screened for differentially expressed miRNAs (DEmiRNAs) associated with aneurysm rupture. A regulatory network of DEmiRNAs and mRNAs was constructed, and virtual screening was performed to evaluate possible binding patterns between Food and Drug Administration (FDA)-approved drugs and core proteins. Molecular dynamics simulations were performed on the optimal docked complexes. Optimally docked drugs were evaluated for efficacy in the treatment of neurodegenerative diseases through cellular experiments. Results: The study found upregulated genes (including WDR43 and THBS1) and one downregulated gene associated with aneurysm rupture. Differences in the expression of these genes indicate greater disease risk. DEmiRNAs associated with ruptured aortic aneurysm were identified, of which two could bind to THBS1 and WDR43. Cromolyn and lanoxin formed the best docking complexes with WDR43 and THBS1, respectively. Cellular experiments showed that cromolyn improved BV2 cell viability and enhanced Aß42 uptake, suggesting its potential as a therapeutic agent for inflammation-related disorders. Conclusion: The findings suggest that WDR43 and THBS1 are potential targets for preventing and treating CV-induced dementia in the elderly. Cromolyn may have therapeutic value in the treatment of Alzheimer's disease and dementia.

Analysis of co-expression gene network associated with intracranial aneurysm and type 2 diabetes mellitus.

To screen for common target genes in intracranial aneurysms (IA) and type 2 diabetes mellitus (T2DM), construct a common transcriptional regulatory network to predict clusters of candidate genes involved in the pathogenesis of T2DM and IA, and identify the common neurovascular markers and pathways in T2DM causing IA. Microarray datasets (GSE55650, GSE25462, GSE26969, GSE75436, and GSE13353) from the GEO database were analyzed in this research. Screening of the IA and the T2DM datasets yielded a total of 126 DEGs, among which 78 were upregulated and 138 were downregulated. Functional enrichment analysis revealed that these DEGs were enriched for a total of 68 GO pathways, including extracellular matrix composition, coagulation regulation, hemostasis regulation, and collagen fiber composition pathways. We also constructed transcriptional regulatory networks, and identified key transcription factors involved in both the conditions. Univariate logistic regression analysis showed that ARNTL2 and STAT1 were significantly associated with the development of T2DM and IA, acting as the common neurovascular markers for both the diseases. In cellular experiments, hyperglycemic microenvironments exhibited upregulated STAT1 expression. STAT1 may be involved in the pathogenesis of IA in T2DM patients. Being the common neurovascular markers, STAT1 may acts as novel therapeutic targets for the treatment of IA and T2DM.

Neurovascular alterations of muscularis propria in the human anterior vaginal wall in pelvic organ prolapse.

In the pathophysiology and progression of pelvic organ prolapse (POP), it has been demonstrated that there is a reorganisation of the muscularis propria of the anterior vaginal wall due to a phenotypic smooth muscle cell to myofibroblast switch. An abnormal deposition of collagen type III seems to be influenced by the involvement of advanced glycation end-products. The aim of the present study was to evaluate the hypothesis that this connective tissue remodelling could also be associated with neurovascular alterations of the muscularis in women with POP compared with control patients. We examined 30 women with POP and 10 control patients treated for uterine fibromatosis. Immunohistochemical analysis, using glial fibrillary acidic protein, S-100 protein, receptor tyrosine kinase, neurofilament and α-smooth muscle actin antibodies, was performed. S-100, receptor tyrosine kinase and neurofilament were also evaluated using Western blot analysis. We observed a decrease in all neurovascular-tested markers in nerve bundles, ganglia and interstitial cells of Cajal from POP samples as compared with controls. Even if the processes responsible for these morphological alterations are still not known, it is conceivable that collagen III deposition in the anterior vaginal wall affects not only the architecture of the muscle layer but could also modify the intramuscular neurovascularisation and account for an alteration of the neuromuscular plasticity of the layer.