Effect of Pomegranate Extract in Mesenchymal Stem Cells by Modulation of microRNA-155, microRNA-21, microRNA-23b, microRNA-126a, and PI3K\AKT1\NF-κB Expression

Abstract

Today, mesenchymal stem cells (MSCs) are candidates for various autoimmune disease treatments due to immunomodulatory activity in these cells. Much research has recently been done to improve the immunomodulatory activity of MSCs. Genetic variation is one of these methods. microRNAs (miRNAs) are small noncoding RNAs that control most of the cell's biological activities. Recent studies have shown that miRNAs play a significant role in the regulation of MSC immunomodulatory activity. Pomegranate is a fruit that has antioxidant, anti-inflammatory, and anticancer properties and has been used for many years for therapeutic purposes. The objective of this research is to evaluate the immunoregulatory-related miRNAs level of adiposederived MSCs (Ad-MSCs) obtained from adipose tissue in the presence or lack of pomegranate (Punica granatum) extract (PGE). Our results showed that miRNA-23 and miRNA-126 were upregulated by PGE treatment in MSCs, and in contrast, miRNA-21 and miRNA-155 were downregulated by PGE treatment in MSCs. In addition this research shows that PGE can downregulate the expression of PI3K\AKT1\NF-jB in Ad-MSCs. Our bioinformatics data have shown that the target of these four miRNAs and the signaling pathways, in which these targets are involved, can play an important role in regulating the immunomodulation function of stem cells. In conclusion, PGE can inhibit the expression of PI3K\AKT1\NF-jB genes involved in inflammatory pathways via miRNA-23 and miRNA-126 overexpression or miRNA-21 and miRNA-155 downregulation that plays a role in the pathways of immune modulation in Ad-MSCs. These results may provide insight into the mechanism underlying the regulation of the immunomodulatory activity of Ad-MSCs by PGE.

Immunomodulatory effects of phytosomal curcumin on related‐micro RNAs, CD200 expression and inflammatory pathways in dental pulp stem cells

“…In fact, it has already been proven that these pathways are the target genes of four miRs and are linked to the immunomodulatory properties of MSCs. 47 Similar to our findings, consistently, curcumin reduces nuclear factor-kappa B (NF-κB) and inhibits the phosphorylation of AKT via phosphatidylinositol-3-kinase (PI3K), which reduces the level of proinflammatory cytokines, chemokines and adhesion molecules. [37][38][39] On the other hand, these pathways are involved in the immunoregulatory activity of hDPSCs and PC can be highly effective in this regard.…”

“…Procedures for the integrated analyses of miRNAs and target genes have been previously reported. 47 The three steps were: miRNA target prediction using the TargetScan algorithm, data compilation for identi-…”

“…Various experiments have been undertaken to optimize the immunomodulatory function of MSCs through diverse methods and mechanisms. 47,57 Sinjari et al studied the effect of curcumin/liposome on 2-hydroxyethyl methacrylate (HEMA)-treated hDPSCs and showed that this agent inhibits the secretion of inflammatory cytokines by inhibiting the NFkB/ERK/pERK pathway after HEMA treatment compare to HEMA untreated group, while there was no significant difference between the untreated group and the curcumin/liposome treated group. 58 Even a study on another form of nanoparticle called nanomicelle showed that nanocurcuminoids increases the population of Tregs and elevates the expression of TGFβ and FOXP3 genes.…”

“…Total RNA (1 μg) was reverse transcribed into miR's and target gene's cDNA using the miRNAs first-strand cDNA synthesis kit (Zist Royesh, Tehran, Iran) and the universal cDNA kit (Parstus, Mashhad, Iran), respectively. Next, the quantitative real-time polymerase chain reaction (qPCR) was conducted by using special primers, 47 2 μL of cDNA and SYBR Green Supermix (Amplicon) with ABI step one (Carlsbad, CA). The sequence of primers was designed using Primer3Plus (www.primer3plus.…”

The Role of miR-155 in Nutrition: Modulating Cancer-Associated Inflammation

“…Interestingly, in vitro and in vivo studies have revealed that a pomegranate extract reduces miR-155 expression while it induces expression of SHIP-1, inhibition of pAkt, and expression of pPI3K [ 152 ]. In fact, miR-155 downregulation plays an important role in pathways of immune modulation in adipose-derived mesenchymal stem cells treated with a pomegranate extract (Ad-MSCs) [ 153 ]. On the other hand, genistein inhibits breast cancer cell proliferation and down-regulates miR-155 expression thereby inducing caspase-mediated cell death [ 154 ].…”