DNA methylation is an epigenetic mechanism that is essential for regulating gene transcription. However, aberrant DNA methylation, which is a nearly universal finding in cancer, can result in disturbed gene expression. DNA methylation is modified by environmental factors such as diet that may modify cancer risk and tumor behavior. Abnormal DNA methylation has been observed in several cancers such as colon, stomach, cervical, prostate, and breast cancers. These alterations in DNA methylation may play a critical role in cancer development and progression. Dietary nutrient intake and bioactive food components are essential environmental factors that may influence DNA methylation either by directly inhibiting enzymes that catalyze DNA methylation or by changing the availability of substrates required for those enzymatic reactions such as the availability and utilization of methyl groups. In this review, we focused on nutrients that act as methyl donors or methylation co-factors and presented intriguing evidence for the role of these bioactive food components in altering DNA methylation patterns in cancer. Such a role is likely to have a mechanistic impact on the process of carcinogenesis and offer possible therapeutic potentials.

The glycocalyx is crucial for normal endothelial function. It also tethers extracellular superoxide dismutase (SOD3), which protects the endothelium against oxidative damage. Proteolytic enzymes [matrix metalloproteinases (MMPs)] are capable of disrupting endothelial cell surface proteins, such as syndecans, resulting in derangements of the endothelial glycocalyx. We sought to test the role of MMPs in oxidative stress-mediated disruption of the endothelial glycocalyx and examine the effect of pharmacological inhibition of MMPs on mitigating this detrimental effect. We also examined the role of histone deacetylase (HDAC) in the oxidative stress-mediated MMP induction and glycocalyx remodeling. Oxidative stress was experimentally induced in human adipose microvascular endothelial cells using H₂O₂ and buthionine sulfoximine in the presence and absence of potent MMP and HDAC inhibitors. H₂O₂ and buthionine sulfoximine resulted in a notable loss of the endothelial glycocalyx; they also increased the expression and proteolytic activity of MMP-2 and MMP-9 and subsequently increased the shedding of syndecan-1 and SOD3 from the endothelial cell surface. MMP upregulation was accompanied by a decline in mRNA and protein levels of their inhibitors, tissue inhibitors of metalloproteinase (TIMPs; TIMP-1 and TIMP-3). Furthermore, oxidative stress induced HDAC activity. Inhibition of MMPs and HDAC reversed syndecan-1 and SOD3 shedding and maintained endothelial glycocalyx integrity. HDAC inhibition increased TIMP expression and reduced MMP expression and activity in endothelial cells. Our findings shed light on MMPs and HDAC as therapeutically targetable mechanisms in oxidative stress-induced glycocalyx remodeling. NEW & NOTEWORTHY Oxidative stress, a hallmark of many diseases, damages the endothelial glycocalyx, resulting in vascular dysfunction. Studying the mechanistic link between oxidative stress and endothelial glycocalyx derangements might help discover new therapeutic targets to preserve vascular function. In this study, we investigated the involvement of matrix metalloproteinases and histone deacetylase in oxidative stress-induced endothelial glycocalyx degradation.

Insulin resistance promotes vascular endothelial dysfunction and subsequent development of cardiovascular disease. Previously we found that skeletal muscle arteriolar flow-induced dilation (FID) was reduced following a hyperinsulinemic clamp in healthy adults. Therefore, we hypothesized that hyperinsulinemia, a hallmark of insulin resistance, contributes to microvascular endothelial cell dysfunction via inducing oxidative stress that is mediated by NADPH oxidase (Nox) system. We examined the effect of insulin, at levels that are comparable with human hyperinsulinemia on 1) FID of isolated arterioles from human skeletal muscle tissue in the presence and absence of Nox inhibitors and 2) human adipose microvascular endothelial cell (HAMECs) expression of nitric oxide (NO), endothelial NO synthase (eNOS), and Nox-mediated oxidative stress. In six lean healthy participants (mean age 25.5±1.6 y, BMI 21.8±0.9), reactive oxygen species (ROS) were increased while NO and arteriolar FID were reduced following 60min of ex vivo insulin incubation. These changes were reversed after co-incubation with the Nox isoform 2 (Nox2) inhibitor, VAS2870. In HAMECs, insulin-induced time-dependent increases in Nox2 expression and P47^phox phosphorylation were echoed by elevations of superoxide production. In contrast, phosphorylation of eNOS and expression of superoxide dismutase (SOD2 and SOD3) isoforms showed a biphasic response with an increased expression at earlier time points followed by a steep reduction phase. Insulin induced eNOS uncoupling that was synchronized with a drop of NO and a surge of ROS production. These effects were reversed by Tempol (SOD mimetic), Tetrahydrobiopterin (BH4; eNOS cofactor), and VAS2870. Finally, insulin induced nitrotyrosine formation which was reversed by inhibiting NO or superoxide generation. In conclusions, hyperinsulinemia may reduce FID via inducing Nox2-mediated superoxide production in microvascular endothelial cells which reduce the availability of NO and enhances peroxynitrite formation. Therefore, the Nox2 pathway should be considered as a target for the prevention of oxidative stress-associated endothelial dysfunction during hyperinsulinemia.

Cardiovascular disease (CVD) is a leading cause of preventable death among young women in the United States. Habitual resistance exercise training is known to have beneficial effects on endothelial function and CVD risk factors, including obesity; however, previous studies show that acute resistance exercise impairs endothelial function in obese adults who are sedentary, a response that may be linked to inflammation. We sought to determine if circuit-based resistance training (CRT) attenuates acute resistance exercise-induced reductions in endothelial function in a population of young, obese, sedentary women and whether or not inflammation plays a role in this response. Eighteen obese [body mass index (BMI) 30.0-40.0 kg · m(-2)] young premenopausal women were randomly assigned to either a CRT group or a no-exercise control group (CON). Conduit artery endothelial function was assessed using brachial artery flow-mediated dilation (FMD) determined by ultrasound before and after a single bout of strenuous weightlifting (SWL). In addition, circulating inflammatory mediators (tumor necrosis factor-α and C-reactive protein), blood pressure, fasting blood lipids, glucose, waist circumference, body composition, and aerobic capacity were assessed. Among participants randomized to the CRT group, 8 weeks of training led to considerable increases in FMD after SWL (P=0.001) compared to the CON group. However, no significant differences between the groups were observed in circulating inflammatory mediators, blood pressure, fasting blood lipids, or other physical and physiological characteristics. This study shows that CRT alleviates acute exertion-induced reductions in endothelial function among obese sedentary women in the absence of changes in inflammation.

Vitamin D (VD) deficiency is a hallmark of obesity and vascular dysfunction. We sought to test the hypothesis that VD deficiency may contribute to obesity-related vascular dysfunction by inducing adipokine hypomethylation and augmented expression. To this end, we collected blood and adipose tissues (ATs) from a cohort of 77 obese participants who were classified as having mild, moderate, or severe VD deficiency. The body composition, vascular reactivity, cardiometabolic profiles, and DNA methylation of 94 inflammation-related adipokines were measured. Our results show that higher degrees of VD deficiency were associated with lower DNA methylation and induced the expression of inflammatory adipokines such as B-cell lymphoma 6 (BCL6), C-X-C Motif Chemokine Ligand 8 (CXCL8), histone deacetylase 5 (HDAC5), interleukin 12A (IL12A), and nuclear factor κB (NFκB) in the ATs. They were also associated with higher BMI and total and visceral fat mass, impaired insulin sensitivity and lipid profiles, AT hypoxia, and higher concentrations of circulating inflammatory markers. Moderate and severe VD deficiency correlated with impaired vasoreactivity of the brachial artery and AT-isolated arterioles, reduced nitric oxide generation, and increased arterial stiffness. In a multivariate regression analysis, the VD deficiency level strongly predicted the adipokine methylation score, systemic inflammation, and microvascular dysfunction. In conclusion, our findings suggest that VD deficiency is a possible contributor to obesity-related adipokine hypomethylation, inflammation, and vascular dysfunction.