Grapefruit Juice Flavanones Modulate the Expression of Genes Regulating Inflammation, Cell Interactions and Vascular Function in Peripheral Blood Mononuclear Cells of Postmenopausal Women

Abstract

Grapefruit is a rich source of flavanones, phytochemicals suggested excreting vasculoprotective effects. We previously showed that flavanones in grapefruit juice (GFJ) reduced postmenopausal women’s pulse-wave velocity (PWV), a measure of arterial stiffness. However, mechanisms of flavanone action in humans are largely unknown. This study aimed to decipher molecular mechanisms of flavanones by multi-omics analysis in PBMCs of volunteers consuming GFJ and flavanone-free control drink for 6 months. Modulated genes and microRNAs (miRNAs) were identified using microarrays. Bioinformatics analyses assessed their functions, interactions and correlations with previously observed changes in PWV. GFJ modified gene and miRNA expressions. Integrated analysis of modulated genes and miRNA-target genes suggests regulation of inflammation, immune response, cell interaction and mobility. Bioinformatics identified putative mediators of the observed nutrigenomic effect (STAT3, NF-κB) and molecular docking demonstrated potential binding of flavanone metabolites to transcription factors and cell-signaling proteins. We also observed 34 significant correlations between changes in gene expression and PWV. Moreover, global gene expression was negatively correlated with gene expression profiles in arterial stiffness and hypertension. This study revealed molecular mechanisms underlying vasculoprotective effects of flavanones, including interactions with transcription factors and gene and miRNA expression changes that inversely correlate with gene expression profiles associated with cardiovascular risk factors.Clinical Trial Registration[ClinicalTrials.gov], identifier [NCT01272167].

Citrus flavanone metabolites protect pancreatic β-cells against cholesterol stress through a multi-proteomic mechanism

“…5 and 9). Previous studies have reported that flavanones naringenin-4′ O -glucuronide (−7.5 kcal mol −1 ) and naringenin-7- O -glucuronide (−7.9 kcal mol −1 ) present potential probability of binding to STAT3, 19 comparable to the result that we found in our study for H7G (−8.66 kcal mol −1 ) and PA (−6.81 kcal mol −1 ). Furthermore, it has been suggested that haringenin-4′ O -glucuronide presents a potential probability of interacting with the ERK1-MAPK signaling protein (−7.6 kcal mol −1 ), 19 also similar to that we found in our study on H7G (−8.55 kcal mol −1 ) and PA (−6.60 kcal mol −1 ).…”

“…Previous studies have reported that flavanones naringenin-4′ O -glucuronide (−7.5 kcal mol −1 ) and naringenin-7- O -glucuronide (−7.9 kcal mol −1 ) present potential probability of binding to STAT3, 19 comparable to the result that we found in our study for H7G (−8.66 kcal mol −1 ) and PA (−6.81 kcal mol −1 ). Furthermore, it has been suggested that haringenin-4′ O -glucuronide presents a potential probability of interacting with the ERK1-MAPK signaling protein (−7.6 kcal mol −1 ), 19 also similar to that we found in our study on H7G (−8.55 kcal mol −1 ) and PA (−6.60 kcal mol −1 ). These in silico results suggest that H7G and PA may interact with these transcription factors and cell signaling proteins, but do not allow us conclude whether these result in the activation or inhibition of the proteins identified as differentially expressed in our study.…”

“…17 Regarding flavanones, it has been shown that flavanones exert their health properties through multigenomic modification at the molecular level. 18,19 It has been shown that hesperetin increased superoxide dismutase and glutathione peroxidase and down-regulated the expression of glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP), endoplasmic reticulum stress marker proteins in the pancreas of diabetic rats. 20 In humans, orange juice ingestion altered protein expression involved in signal transduction, DNA replication, and the cell cycle 21 and upregulated miR-375, important for the pancreatic β-cell survival.…”

Integrated Analysis of Genomic and Genome-Wide Association Studies Identified Candidate Genes for Nutrigenetic Studies in Flavonoids and Vascular Health: Path to Precision Nutrition for (Poly)phenols

“…However, here we have only included the studies that demonstrated positive effects of flavonoids on vascular function and analyzed their genomic effects using microarray methods [26][27][28]. In addition, two recent studies of relevance for our analyses [29,30] were also included. In all of these studies, the analyses of global gene expression were conducted in samples of peripheral blood.…”

“…Based on our previously reported strategy for the systematic literature search [25], we identified five human intervention studies with flavonoids that analyzed global gene expression in peripheral blood cells and demonstrated at least one positive effect on vascular function. General information about each of these studies, referred to as Paper 1 to Paper 5 (Paper 1 [26]; Paper 2 [27]; Paper 3 [28]; Paper 4 [30]; Paper 5 [29]) is presented in Table 1. In these studies, flavonoids of different subclasses were studied: Hesperidin displays relevant role in the nutrigenomic effect of orange juice on blood leukocytes in human volunteers: a randomized controlled cross-over study [26] Healthy, middleaged, moderately overweight men…”