scholarly journals Inhibition of Soluble Epoxide Hydrolase Is Protective against the Multiomic Effects of a High Glycemic Diet on Brain Microvascular Inflammation and Cognitive Dysfunction

Nutrients ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 3913
Author(s):  
Saivageethi Nuthikattu ◽  
Dragan Milenkovic ◽  
Jennifer E. Norman ◽  
John Rutledge ◽  
Amparo Villablanca
Keyword(s):  
Gene Expression ◽  
Differential Expression ◽  
Gene Networks ◽  
Epoxide Hydrolase ◽  
Soluble Epoxide Hydrolase ◽  
Wild Type ◽  
Protein Coding ◽  
Wild Type Male ◽  
Molecular Effects ◽  
Microvascular Inflammation

Diet is a modifiable risk factor for cardiovascular disease (CVD) and dementia, yet relatively little is known about the effect of a high glycemic diet (HGD) on the brain’s microvasculature. The objective of our study was to determine the molecular effects of an HGD on hippocampal microvessels and cognitive function and determine if a soluble epoxide hydrolase (sEH) inhibitor (sEHI), known to be vasculoprotective and anti-inflammatory, modulates these effects. Wild type male mice were fed a low glycemic diet (LGD, 12% sucrose/weight) or an HGD (34% sucrose/weight) with/without the sEHI, trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB), for 12 weeks. Brain hippocampal microvascular gene expression was assessed by microarray and data analyzed using a multi-omic approach for differential expression of protein and non-protein-coding genes, gene networks, functional pathways, and transcription factors. Global hippocampal microvascular gene expression was fundamentally different for mice fed the HGD vs. the LGD. The HGD response was characterized by differential expression of 608 genes involved in cell signaling, neurodegeneration, metabolism, and cell adhesion/inflammation/oxidation effects reversible by t-AUCB and hence sEH inhibitor correlated with protection against Alzheimer’s dementia. Ours is the first study to demonstrate that high dietary glycemia contributes to brain hippocampal microvascular inflammation through sEH.

scholarly journals The Western Diet Regulates Hippocampal Microvascular Gene Expression: An Integrated Genomic Analyses in Female Mice

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Saivageethi Nuthikattu ◽  
Dragan Milenkovic ◽  
John Rutledge ◽  
Amparo Villablanca
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Differential Expression ◽  
Differential Gene Expression ◽  
Gene Networks ◽  
Molecular Mechanisms ◽  
Western Diet ◽  
Protein Coding ◽  
Female Mice ◽  
Differential Gene

AbstractHyperlipidemia is a risk factor for dementia, and chronic consumption of a Western Diet (WD) is associated with cognitive impairment. However, the molecular mechanisms underlying the development of microvascular disease in the memory centers of the brain are poorly understood. This pilot study investigated the nutrigenomic pathways by which the WD regulates gene expression in hippocampal brain microvessels of female mice. Five-week-old female low-density lipoprotein receptor deficient (LDL-R−/−) and C57BL/6J wild type (WT) mice were fed a chow or WD for 8 weeks. Metabolics for lipids, glucose and insulin were determined. Differential gene expression, gene networks and pathways, transcription factors, and non-protein coding RNAs were evaluated by genome-wide microarray and bioinformatics analysis of laser captured hippocampal microvessels. The WD resulted in differential expression of 2,412 genes. The majority of differential gene expression was attributable to differential regulation of cell signaling proteins and their transcription factors, approximately 7% was attributable to differential expression of miRNAs, and a lesser proportion was due to other non-protein coding RNAs, primarily long non-coding RNAs (lncRNAs) and small nucleolar RNAs (snoRNAs) not previously described to be modified by the WD in females. Our findings revealed that chronic consumption of the WD resulted in integrated multilevel molecular regulation of the hippocampal microvasculature of female mice and may provide one of the mechanisms underlying vascular dementia.

scholarly journals Lipotoxic Injury Differentially Regulates Brain Microvascular Gene Expression in Male Mice

Nutrients ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1771
Author(s):  
Saivageethi Nuthikattu ◽  
Dragan Milenkovic ◽  
John C. Rutledge ◽  
Amparo C. Villablanca
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Differential Expression ◽  
Gene Networks ◽  
Molecular Mechanisms ◽  
Differentially Expressed Gene ◽  
Density Lipoprotein ◽  
Male Mice ◽  
Protein Coding ◽  
A Genome

The Western diet (WD) and hyperlipidemia are risk factors for vascular disease, dementia, and cognitive impairment. However, the molecular mechanisms are poorly understood. This pilot study investigated the genomic pathways by which the WD and hyperlipidemia regulate gene expression in brain microvessels. Five-week-old C57BL/6J wild type (WT) control and low-density lipoprotein receptor deficient (LDL-R−/−) male mice were fed the WD for eight weeks. Differential gene expression, gene networks and pathways, transcription factors, and non-protein coding RNAs were evaluated by a genome-wide microarray and bioinformatics analysis of laser-captured hippocampal microvessels. The WD resulted in the differential expression of 1972 genes. Much of the differentially expressed gene (DEG) was attributable to the differential regulation of cell signaling proteins and their transcription factors, approximately 4% was attributable to the differential expression of miRNAs, and 10% was due to other non-protein coding RNAs, primarily long non-coding RNAs (lncRNAs) and small nucleolar RNAs (snoRNAs) not previously described to be modified by the WD. Lipotoxic injury resulted in complex and multilevel molecular regulation of the hippocampal microvasculature involving transcriptional and post-transcriptional regulation and may provide a molecular basis for a better understanding of hyperlipidemia-associated dementia risk.

scholarly journals Genetic variation in soluble epoxide hydrolase: association with outcome after aneurysmal subarachnoid hemorrhage

2014 ◽  
Vol 121 (6) ◽  
pp. 1359-1366 ◽  
Author(s):  
Ross P. Martini ◽  
Jonathan Ward ◽  
Dominic A. Siler ◽  
Jamie M. Eastman ◽  
Jonathan W. Nelson ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Scale Score ◽  
Glasgow Outcome Scale ◽  
Epoxide Hydrolase ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Delayed Cerebral Ischemia ◽  
Soluble Epoxide Hydrolase ◽  
Neurological Deterioration ◽  
Wild Type ◽  
Functional Polymorphisms

Object Patients with aneurysmal subarachnoid hemorrhage (SAH) are at high risk for delayed cerebral ischemia (DCI) and stroke. Epoxyeicosatrienoic acids (EETs) play an important role in cerebral blood flow regulation and neuroprotection after brain injury. Polymorphisms in the gene for the enzyme soluble epoxide hydrolase (sEH), which inactivates EETs, are associated with ischemic stroke risk and neuronal survival after ischemia. This prospective observational study of patients with SAH compares vital and neurologic outcomes based on functional polymorphisms of sEH. Methods Allelic discrimination based on quantitative real-time polymerase chain reaction was used to differentiate wild-type sEH from K55R heterozygotes (predictive of increased sEH activity and reduced EETs) and R287Q heterozygotes (predictive of decreased sEH activity and increased EETs). The primary outcome was new stroke after SAH. Secondary outcomes were death, Glasgow Outcome Scale score, and neurological deterioration attributable to DCI. Results Multivariable logistic regression models adjusted for age at admission and Glasgow Coma Scale scores revealed an increase in the odds of new stroke (OR 5.48 [95% CI 1.51–19.91]) and death (OR 7.52 [95% CI 1.27–44.46]) in the K55R group, but no change in the odds of new stroke (OR 0.56 [95% CI 0.16–1.96]) or death (OR 3.09 [95% CI 0.51–18.52]) in patients with R287Q genotype, compared with wild-type sEH. The R287Q genotype was associated with reduced odds of having a Glasgow Outcome Scale score of ≤ 3 (OR 0.23 [95% CI 0.06–0.82]). There were no significant differences in the odds of neurological deterioration due to DCI. Conclusions Genetic polymorphisms of sEH are associated with neurological and vital outcomes after aneurysmal SAH.

scholarly journals Intraspecific sequence and gene expression variation contribute little to venom diversity in sidewinder rattlesnakes ( Crotalus cerastes )

2019 ◽  
Vol 286 (1906) ◽  
pp. 20190810 ◽  
Author(s):  
Rhett M. Rautsaw ◽  
Erich P. Hofmann ◽  
Mark J. Margres ◽  
Matthew L. Holding ◽  
Jason L. Strickland ◽  
...  
Keyword(s):  
Gene Expression ◽  
Differential Expression ◽  
Complex Traits ◽  
Sequence Divergence ◽  
Protein Sequences ◽  
Venom Gland ◽  
Stabilizing Selection ◽  
Protein Coding ◽  
Standing Variation ◽  
Crotalus Cerastes

Traits can evolve rapidly through changes in gene expression or protein-coding sequences. However, these forms of genetic variation can be correlated and changes to one can influence the other. As a result, we might expect traits lacking differential expression to preferentially evolve through changes in protein sequences or morphological adaptation. Given the lack of differential expression across the distribution of sidewinder rattlesnakes ( Crotalus cerastes ), we tested this hypothesis by comparing the coding regions of genes expressed in the venom gland transcriptomes and fang morphology. We calculated Tajima's D and F ST across four populations comparing toxin and nontoxin loci. Overall, we found little evidence of directional selection or differentiation between populations, suggesting that changes to protein sequences do not underlie the evolution of sidewinder venom or that toxins are under extremely variant selection pressures. Although low-expression toxins do not have higher sequence divergence between populations, they do have more standing variation on which selection can act. Additionally, we found significant differences in fang length among populations. The lack of differential expression and sequence divergence suggests sidewinders—given their generalist diet, moderate gene flow and environmental variation—are under stabilizing selection which functions to maintain a generalist phenotype. Overall, we demonstrate the importance of examining the relationship between gene expression and protein-coding changes to understand the evolution of complex traits.

scholarly journals Analysis of uterine gene expression in interleukin-15 knockout mice reveals uterine natural killer cells do not play a major role in decidualization and associated angiogenesis

Reproduction ◽  
2012 ◽  
Vol 143 (3) ◽  
pp. 359-375 ◽  
Author(s):  
Brent M Bany ◽  
Charles A Scott ◽  
Kirsten S Eckstrum
Keyword(s):  
Gene Expression ◽  
Natural Killer ◽  
Differential Expression ◽  
Knockout Mice ◽  
Implantation Site ◽  
Wild Type ◽  
Rt Pcr ◽  
Unk Cells ◽  
Interleukin 15 ◽  
Uterine Natural Killer

During decidualization, uterine natural killer (uNK) cells are the most abundant immune cell types found in the uterus. Although it is well known that they play key roles in spiral arteriole modification and the maintenance of decidual integrity seen after mid-pregnancy, their roles in the differentiation of decidual cells and accompanying angiogenesis during the process of decidualization is less well characterized. To address this, we used whole-genome Illumina BeadChip analysis to compare the gene expression profiles in implantation segments of the uterus during decidualization on day 7.5 of pregnancy between wild-type and uNK cell-deficient (interleukin-15-knockout) mice. We found almost 300 differentially expressed genes and verified the differential expression of ∼60 using quantitative RT-PCR. Notably, there was a lack of differential expression of genes involved in decidualization and angiogenesis and this was also verified by quantitative RT-PCR. Similar endothelial cell densities and proliferation indices were also found in the endometrium between the implantation site tissues of wild-type and knockout mice undergoing decidualization. Overall, the results of this study reveal that uNK cells likely do not play a major role in decidualization and accompanying angiogenesis during implantation. In addition, the study identifies a large number of genes whose expression in implantation-site uterine tissue during decidualization depends on interleukin-15 expression in mice.

scholarly journals Soluble Epoxide Hydrolase Inhibition Modulates Gene Expression of Anti‐Apoptotic and Apoptotic Factors

2008 ◽  
Vol 22 (S1) ◽  
Author(s):  
Alexis N Simpkins ◽  
Ahmed A. Elmarakby ◽  
Jeffery E. Quigley ◽  
Derek A. Schreihofer ◽  
Bruce D. Hammock ◽  
...  
Keyword(s):  
Gene Expression ◽  
Epoxide Hydrolase ◽  
Soluble Epoxide Hydrolase ◽  
Apoptotic Factors

scholarly journals Cis-regulatory mutations associate with transcriptional and post-transcriptional deregulation of the gene regulatory program in cancers

2020 ◽  
Author(s):  
Jaime A. Castro-Mondragon ◽  
Miriam Ragle Aure ◽  
Ole Christian Lingjærde ◽  
Anita Langerød ◽  
John W. M. Martens ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Networks ◽  
Regulation Of Gene Expression ◽  
Functional Enrichment ◽  
Protein Coding ◽  
Mirna Genes ◽  
Regulatory Program ◽  
Regulatory Mutations ◽  
Gene Regulatory ◽  
Pan Cancer

ABSTRACTBackgroundMost cancer alterations occur in the noncoding portion of the human genome, which contains important regulatory regions acting as genetic switches to ensure gene expression occurs at correct times and intensities in correct tissues. However, large scale discovery of noncoding events altering the gene expression regulatory program has been limited to a few examples with high recurrence or high functional impact.ResultsWe focused on transcription factor binding sites (TFBSs) that show similar mutation loads than what is observed in protein-coding exons. By combining cancer somatic mutations in TFBSs and expression data for protein-coding and miRNA genes, we evaluated the combined effects of transcriptional and post-transcriptional alteration on the dysregulation of the regulatory programs in cancer. The analysis of seven cancer cohorts culminated with the identification of protein-coding and miRNA genes linked to mutations at TFBSs that were associated with a cascading trans-effect deregulation on the cells’ regulatory program. Our analyses of cis-regulatory mutations associated with miRNAs recurrently predicted 17 miRNAs as pan-cancer-associated through deregulation of their target gene networks. Overall, our predictions were enriched for protein-coding and miRNA genes previously annotated as cancer drivers. Functional enrichment analyses highlighted that cis-regulatory mutations are associated with the dysregulation of key pathways associated with carcinogenesisConclusionsThese pan-cancer results suggest that our method predicts cis-regulatory mutations related to the dysregulation of key gene regulatory networks in cancer patients. It highlights how the gene regulatory program is disrupted in cancer cells by combining transcriptional and post-transcriptional regulation of gene expression.

scholarly journals Genomic modules and intramodular network concordance in susceptible and resilient male mice across models of stress

2021 ◽  
Author(s):  
Salvatore G. Caradonna ◽  
Tie-Yuan Zhang ◽  
Nicholas O’Toole ◽  
Mo-Jun Shen ◽  
Huzefa Khalil ◽  
...  
Keyword(s):  
Gene Networks ◽  
Anxiety And Depression ◽  
Stress Coping ◽  
Housing Conditions ◽  
Male Mice ◽  
Wild Type ◽  
Genomic Signatures ◽  
Gene Coding ◽  
Chronic Social Defeat Stress ◽  
Wild Type Male

AbstractThe multifactorial etiology of stress-related disorders necessitates a constant interrogation of the molecular convergences in preclinical models of stress that use disparate paradigms as stressors spanning from environmental challenges to genetic predisposition to hormonal signaling. Using RNA-sequencing, we investigated the genomic signatures in the ventral hippocampus common to mouse models of stress. Chronic oral corticosterone (CORT) induced increased anxiety- and depression-like behavior in wild-type male mice and male mice heterozygous for the gene coding for brain-derived neurotrophic factor Val66Met, a variant associated with genetic susceptibility to stress. In a separate set of male mice, chronic social defeat stress (CSDS) led to a susceptible or a resilient population, whose proportion was dependent on housing conditions, namely standard housing or enriched environment. Rank-rank-hypergeometric overlap (RRHO), a threshold-free approach that ranks genes by their p value and effect size direction, was used to identify genes from a continuous gradient of significancy that were concordant across groups. In mice treated with CORT and in standard-housed susceptible mice, differentially expressed genes (DEGs) were concordant for gene networks involved in neurotransmission, cytoskeleton function, and vascularization. Weighted gene co-expression analysis generated 54 gene hub modules and revealed two modules in which both CORT and CSDS-induced enrichment in DEGs, whose function was concordant with the RRHO predictions, and correlated with behavioral resilience or susceptibility. These data showed transcriptional concordance across models in which the stress coping depends upon hormonal, environmental, or genetic factors revealing common genomic drivers that embody the multifaceted nature of stress-related disorders.

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