Effects of Resveratrol on the Expression and DNA Methylation of Cytokine Genes in Diabetic Rat Aortas

Abstract

This paper studies the expression of proinflammatory cytokines such as IL-1β, IL-6, TNF-α, and IFN-γ and anti-inflammatory cytokines such as IL-10 in diabetic rat aortas, the effects of resveratrol on these cytokines, and the potential epigenetic mechanisms involved. The experiment was performed on rats divided into four groups: normal group (NC), normal interventional group (NB), diabetic group (DM), and diabetic interventional group (DB). The NB and DB groups were treated with resveratrol. After more than 3 months, the rats' aortas were removed and analyzed for cytokines by using immunohistochemistry, Western blotting, real-time PCR, and methylation-specific PCR. Histological localization of these cytokines was mainly found in the arterial intima of diabetic rats. The protein and mRNA expression levels of IL-1β, IL-6, TNF-α, and IFN-γ were significantly higher in the DM group than in the NC group (p < 0.05), whereas in the resveratrol-treated groups (NB and DB), the levels were relatively lower than those in the corresponding groups. The DM group showed reduced levels of DNA methylation at the specific cytosine phosphate guanosine sites of IL-1β, IL-6, TNF-α, and IFN-γ, relative to those in the NC group (p < 0.01), and these levels were increased by resveratrol. In contrast, IL-10 was dramatically methylated and showed decreased expression in response to high glucose, and resveratrol reversed this effect. These results demonstrate that the inflammatory response is involved in diabetic macroangiopathy. Resveratrol inhibits the expression of proinflammatory cytokines and thus may have a protective effect on the aorta in hyperglycemia. Thus, DNA methylation, an epigenetic gene silencing signal, may be responsible for these two phenomena.

Stilbenoid‐Mediated Epigenetic Activation of Semaphorin 3A in Breast Cancer Cells Involves Changes in Dynamic Interactions of DNA with DNMT3A and NF1C Transcription Factor

“…Briefly, RSV treatment reversed methylation‐mediated silencing of TSGs, BRCA1 , PTEN , APC , and RARbeta2 , in breast cancer . Furthermore, both RSV and PTS were shown to increase methylation at specific CpG loci located in pro‐inflammatory cytokines and fatty acid synthase gene, respectively, which resulted in gene suppression . In our recent genome‐wide study using methylation microarray technology, we further confirmed hyper‐ and hypomethylation upon treatment with stilbenoids and epigenetic silencing of oncogenic pathways in response to the compounds .…”

“…Stilbenoids were shown to exert anti‐cancer effects in cell lines and in vivo models, however, without a clear molecular mechanism demonstrated . There are a few reports by us and others on the involvement of epigenetics and specifically DNA methylation in the action of stilbenoids . Briefly, RSV treatment reversed methylation‐mediated silencing of TSGs, BRCA1 , PTEN , APC , and RARbeta2 , in breast cancer .…”

Novel insights into DNA methylation and its critical implications in diabetic vascular complications

“…However, these increases were abolished in losartan-treated mice, accompanied with decreased blood pressure, mesangial hypertrophy and proteinuria [46]. Lou et al [47] aimed to investigate the effects of resveratrol (trans-3,5,40-trihydroxystilbene) on the expression of pro-inflammatory cytokines such as IL-1β, IL-6, TNF-α and IFN-γ in diabetic rat aortas and the potential epigenetic mechanisms involved. It showed that the expression levels of pro-inflammatory cytokines were significantly lower in the resveratrol-treated diabetic group.…”

“…It showed that the expression levels of pro-inflammatory cytokines were significantly lower in the resveratrol-treated diabetic group. Furthermore, the untreated group showed reduced levels of DNA methylation at the specific cytosine phosphate guanosine sites of IL-1β, IL-6, TNF-α and IFN-γ and these levels were reversed by resveratrol [47]. Thus, although the studies were limited, they implicated that epigenetic modifications may be one of the protective mechanisms and it can be reversible, which may be used as a therapeutic tool targeting diabetic vascular complications.…”

Antidiabetic Effects of Resveratrol: The Way Forward in Its Clinical Utility

“…RSV also demonstrated inhibitory effect on NF- κ B activity and ameliorated the elevated levels of inflammatory proteins, TNF- α (tumour necrosis factor- α ), interleukin- (IL-) 6, and COX-2 (cyclooxygenase 2), thus contributing to reduction in neuroinflammation and protection against functional and behavioural deficits in diabetic neuropathy [106]. The anti-inflammatory property of RSV has been confirmed in diabetic animals by the downregulation of proinflammatory genes and proteins like TNF- α , IL-1 β , IL-6, IL-4, IL-17, COX-2 intercellular adhesion molecule 1 (ICAM), and vascular cell adhesion protein 1 (VCAM1) [14, 19, 22, 24, 107, 108] which are downstream targets of NF- κ B. In addition, RSV significantly decreased the activation and recruitment of macrophages thereby retarding the inflammation process in diabetic rats [22, 109].…”