A systems biology network analysis of nutri(epi)genomic changes in endothelial cells exposed to epicatechin metabolites

Abstract

Although vasculo-protective effects of flavan-3-ols are widely accepted today, their impact on endothelial cell functions and molecular mechanisms of action involved is not completely understood. The aim of this study was to characterize the potential endothelium-protective effects of circulating epicatechin metabolites and to define underlying mechanisms of action by an integrated systems biology approach. Reduced leukocyte rolling over vascular endothelium was observed following epicatechin supplementation in a mouse model of inflammation. Integrative pathway analysis of transcriptome, miRNome and epigenome profiles of endothelial cells exposed to epicatechin metabolites revealed that by acting at these different levels of regulation, metabolites affect cellular pathways involved in endothelial permeability and interaction with immune cells. In-vitro experiments on endothelial cells confirmed that epicatechin metabolites reduce monocyte adhesion and their transendothelial migration. Altogether, our in-vivo and in-vitro results support the outcome of a systems biology based network analysis which suggests that epicatechin metabolites mediate their vasculoprotective effects through dynamic regulation of endothelial cell monocyte adhesion and permeability. This study illustrates complex and multimodal mechanisms of action by which epicatechin modulate endothelial cell integrity.

Acute Effects of the Consumption of Passiflora setacea Juice on Metabolic Risk Factors and Gene Expression Profile in Humans

“…Literature lacks data about the effect of Passiflora on miRNA expression. However, it has been suggested that plant food bioactives can modulate the expression of miRNA [85,86]. Among the miRNA identified from bioinformatic analysis as potentially involved in the post-transcriptional regulation of identified differentially expressed genes by PS juice consumption, we can list miRNA-16, -26, and -124. miRNA-16 has shown to play a role in inflammation [87] and hypertension [88], whereas miRNA-124 mediates anti-inflammatory effects and is involved in neuroprotective mechanisms [89].…”

Dietary intakes of flavan-3-ols and cardiometabolic health: systematic review and meta-analysis of randomized trials and prospective cohort studies

“…The molecular mechanisms by which dietary flavan-3-ols mediate these effects on vascular health include nitric oxide–dependent arterial function (51, 52), anti-inflammatory effects (53), and effects on glucose metabolism, β-cell function, and inhibition of glucose transporters (54–57). However, early mechanistic studies did not consider the absorption, distribution, metabolism, and excretion of the flavan-3-ols.…”

Standardized Echinacea purpurea extract primes an IFN specific innate immune monocyte response via JAK1-STAT1 dependent gene expression and epigenetic control of endogenous retroviral sequences

“…In contrast to pharmacological drugs (for example glucocorticoids (GC)) which can trigger drastic expression changes of GC-responsive genes (typically, log 2 fold > 1), many bioactive phytochemicals rather induce moderate transcriptional changes (typically log 2 fold > 0,4) of multiple genes converging on the same pathway [44][45][46]. Genes differentially expressed (DEG) by Echinaforce® treatment were enriched for IPA canonical pathways related to innate immune responses including interferon signaling, interferon regulatory factor (IRF) activation and the role of pattern recognition receptors, among others ( Figure 1B-C and Supplementary table 2).…”

“…A total of 1,875 CpG sites was found differentially methylated (FDR < 0.1) with a methylation difference of at least 5%. Typically, DNA methylation changes after short (24-72h) exposure to phytochemicals and nutrients are much smaller than cancer associated DNA methylation changes in oncogenes or tumor suppressor genes which accumulate for many years in response to the microenvironment [46,68,69]. However, similar DMR effects sizes and cutoff (<5%) were found to be biologically meaningful in various disease etiologies [40,70,71].…”