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Differential Multigenomic Effect of Soluble Epoxide Hydrolase Inhibition on the Hippocampal Brain Microvasculature of FeFemale Mice on Low and High Glycemic Diets.

ABSTRACT: Microvascular dysfunction is central to the development of dementia. The effect of high glycemic diet (HGD), independent from dietary fat, on brain microvasculature is crucial, yet an understudied research topic, especially in feFemales. Our study aimed to determine the transcriptomic changes in feFemale brain hippocampal microvasculature induced by a HGD and characterize the response to soluble epoxide hydrolase inhibitor (sEHI). We demonstrated for the first time in feFemales that the HGD had an opposite gene expression profile compared to the LGD and differentially expressed 506 genes, primarily downregulated, with functions related to cell signaling, cell adhesion, cellular metabolism, and neurodegenerative diseases. Surprisingly, the sEHI modified the transcriptome of feFemale mice consuming the LGD more than the HGD, by modulating genes involved in metabolic pathways that synthesize neuroprotective epoxyeicosatrienoic acids (EETs) and associated with a higher EETs/ dihydroxyeicosatrienoic acids (DHETs) ratio.

ORGANISM(S): Mus musculus

PROVIDER: GSE195975 | GEO | 2022/11/16

REPOSITORIES: GEO

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Project description:Introduction: The identification of biomarkers in Barrett’s oesophagus (BO) that stratify groups at risk of progressing to oesophageal adenocarcinoma (OAC) would allow tailored surveillance strategies. We have applied a novel high throughput RNA sequencing analysis characterizing the BO mRNA transcriptome across the metaplasia-dysplasia sequence to identify potential markers of progression in an unbiased fashion and functionally validated these at the protein level. Methods: Matched biopsy samples for histology and RNA extraction were taken from BO patients of known histological grade. RNA was extracted from matched samples and sequenced to 60bp length (paired-end).21 samples were sequenced (HGD,7; LGD, 7 and SIM, 7). Reads obtained were mapped to NCBI build37.2 using TopHat. Read count generation, normalisation and differential expression (DE) analysis was performed using the HTSeq-DESeq pipeline. Significantly DE genes (>2 fold change in expression with B-H adjusted p-value <0.1) were further assessed for network and biological relevance using Ingenuity Pathway analysis. Candidate genes were selected and validated in a larger cohort (n=64) using RT-PCR. Targets were further validated (by ELISA and immunohistochemistry) in independent cohorts of patients using serum and tissue microarrays. Results: DE analysis was performed in 3 groups with 2 conditions at a time using the lower grade cohort as control and the higher grade as comparator: SIM vs. LGD (demonstrated 218 DE genes, 131 up-regulated in LGD, 87 down-regulated compared to SIM), SIM vs. HGD (49 DE, 27 up, 22 down) and LGD vs. HGD (317 DE, 81 up, 216 down). Six network-central candidate genes (FOSB, IL-1B, SERPINA3, KLK7, GSTM5 &SCUBE2) were selected for RT-PCR validation following network and functional analysis. Circulating IL-1β and SERPINA-3 demonstrated progressive significant increases in expression across the dysplasia sequence to OAC (p<0.005)). This was confirmed at the tissue level showing significant differences between SIM and dysplastic BO (p<0.05). Conclusion: The use of RNA-sequencing as a detailed and unbiased analysis method identifies IL-1β and SERPINA-3 as novel candidates differentially expressed along the metaplasia-dysplasia-cancer sequence in BO.