Resveratrol is the most well-known polyphenolic stilbenoid, present in grapes, mulberries, peanuts, rhubarb, and in several other plants. Resveratrol can play a beneficial role in the prevention and in the progression of chronic diseases related to inflammation such as diabetes, obesity, cardiovascular diseases, neurodegeneration, and cancers among other conditions. Moreover, resveratrol regulates immunity by interfering with immune cell regulation, proinflammatory cytokines’ synthesis, and gene expression. At the molecular level, it targets sirtuin, adenosine monophosphate kinase, nuclear factor-κB, inflammatory cytokines, anti-oxidant enzymes along with cellular processes such as gluconeogenesis, lipid metabolism, mitochondrial biogenesis, angiogenesis, and apoptosis. Resveratrol can suppress the toll-like receptor (TLR) and pro-inflammatory genes’ expression. The antioxidant activity of resveratrol and the ability to inhibit enzymes involved in the production of eicosanoids contribute to its anti-inflammation properties. The effects of this biologically active compound on the immune system are associated with widespread health benefits for different autoimmune and chronic inflammatory diseases. This review offers a systematic understanding of how resveratrol targets multiple inflammatory components and exerts immune-regulatory effects on immune cells.

Influence of Resveratrol on the Immune Response

Atherosclerosis is a chronic inflammatory disease promoted by hyperlipidemia. Several studies support FOXP3-positive regulatory T cells (Tregs) as inhibitors of atherosclerosis; however, the mechanism underlying this protection remains elusive. To define the role of FOXP3-expressing Tregs in atherosclerosis, we used the DEREG mouse, which expresses the diphtheria toxin (DT) receptor under control of the Treg-specific Foxp3 promoter, allowing for specific ablation of FOXP3+ Tregs. Lethally irradiated, atherosclerosis-prone, low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice received DEREG bone marrow and were injected with DT to eliminate FOXP3(+) Tregs. Depletion of Tregs caused a 2.1-fold increase in atherosclerosis without a concomitant increase in vascular inflammation. These mice also exhibited a 1.7-fold increase in plasma cholesterol and an atherogenic lipoprotein profile with increased levels of VLDL. Clearance of VLDL and chylomicron remnants was hampered, leading to accumulation of cholesterol-rich particles in the circulation. Functional and protein analyses complemented by gene expression array identified reduced protein expression of sortilin-1 in liver and increased plasma enzyme activity of lipoprotein lipase, hepatic lipase, and phospholipid transfer protein as mediators of the altered lipid phenotype. These results demonstrate that FOXP3(+) Tregs inhibit atherosclerosis by modulating lipoprotein metabolism.

Depletion of FOXP3(+) regulatory T cells promotes hypercholesterolemia and atherosclerosis

Cancer onset and progression have been linked to oxidative stress by increasing DNA mutations or inducing DNA damage, genome instability, and cell proliferation and therefore antioxidant agents could interfere with carcinogenesis. It is well known that conventional radio-/chemotherapies influence tumour outcome through ROS modulation. Since these antitumour treatments have important side effects, the challenge is to develop new anticancer therapeutic strategies more effective and less toxic for patients. To this purpose, many natural polyphenols have emerged as very promising anticancer bioactive compounds. Beside their well-known antioxidant activities, several polyphenols target epigenetic processes involved in cancer development through the modulation of oxidative stress. An alternative strategy to the cytotoxic treatment is an approach leading to cytostasis through the induction of therapy-induced senescence. Many anticancer polyphenols cause cellular growth arrest through the induction of a ROS-dependent premature senescence and are considered promising antitumour therapeutic tools. Furthermore, one of the most innovative and interesting topics is the evaluation of efficacy of prooxidant therapies on cancer stem cells (CSCs). Several ROS inducers-polyphenols can impact CSCs metabolisms and self-renewal related pathways. Natural polyphenol roles, mainly in chemoprevention and cancer therapies, are described and discussed in the light of the current literature data.

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Polyphenols as Modulator of Oxidative Stress in Cancer Disease: New Therapeutic Strategies

In the past, numerous methods have been developed to predict MHC class II binders or T-helper epitopes for designing the epitope-based vaccines against pathogens. In contrast, limited attempts have been made to develop methods for predicting T-helper epitopes/peptides that can induce a specific type of cytokine. This paper describes a method, developed for predicting interleukin-10 (IL-10) inducing peptides, a cytokine responsible for suppressing the immune system. All models were trained and tested on experimentally validated 394 IL-10 inducing and 848 non-inducing peptides. It was observed that certain types of residues and motifs are more frequent in IL-10 inducing peptides than in non-inducing peptides. Based on this analysis, we developed composition-based models using various machine-learning techniques. Random Forest-based model achieved the maximum Matthews's Correlation Coefficient (MCC) value of 0.59 with an accuracy of 81.24% developed using dipeptide composition. In order to facilitate the community, we developed a web server "IL-10pred", standalone packages and a mobile app for designing IL-10 inducing peptides (http://crdd.osdd.net/raghava/IL-10pred/).

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Computer-aided designing of immunosuppressive peptides based on IL-10 inducing potential.

Objective—Hyperlipidemia-induced endothelial cell (EC) activation is considered as an initial event responsible for monocyte recruitment in atherogenesis. However, it remains poorly defined what is the mechanism underlying hyperlipidemia-induced EC activation. Here, we tested a novel hypothesis that mitochondrial reactive oxygen species (mtROS) serve as signaling mediators for EC activation in early atherosclerosis. Approach and Results—Metabolomics and transcriptomics analyses revealed that several lysophosphatidylcholine (LPC) species, such as 16:0, 18:0, and 18:1, and their processing enzymes, including Pla2g7 and Pla2g4c, were significantly induced in the aortas of apolipoprotein E knockout mice during early atherosclerosis. Using electron spin resonance and flow cytometry, we found that LPC 16:0, 18:0, and 18:1 induced mtROS in primary human aortic ECs, independently of the activities of nicotinamide adenine dinucleotide phosphate oxidase. Mechanistically, using confocal microscopy and Seahorse XF mi...

Mitochondrial Reactive Oxygen Species Mediate Lysophosphatidylcholine-Induced Endothelial Cell Activation

Endothelial dysfunction is a pathological status of the vascular system, which can be broadly defined as an imbalance between endothelium-dependent vasoconstriction and vasodilation. Endothelial dysfunction is a key event in the progression of many pathological processes including atherosclerosis, type II diabetes and hypertension. Previous reports have demonstrated that pro-inflammatory/immunoeffector cytokines significantly promote endothelial dysfunction while numerous novel anti-inflammatory/immunosuppressive cytokines have recently been identified such as interleukin (IL)-35. However, the effects of anti-inflammatory cytokines on endothelial dysfunction have received much less attention. In this analytical review, we focus on the recent progress attained in characterizing the direct and indirect effects of anti-inflammatory/immunosuppressive cytokines in the inhibition of endothelial dysfunction. Our analyses are not only limited to the importance of endothelial dysfunction in cardiovascular disease progression, but also expand into the molecular mechanisms and pathways underlying the inhibition of endothelial dysfunction by anti-inflammatory/immunosuppressive cytokines. Our review suggests that anti-inflammatory/immunosuppressive cytokines serve as novel therapeutic targets for inhibiting endothelial dysfunction, vascular inflammation and cardio- and cerebro-vascular diseases.

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Immunosuppressive/anti-inflammatory cytokines directly and indirectly inhibit endothelial dysfunction--a novel mechanism for maintaining vascular function.

As the population ages and lifestyles change in concordance, the number of patients suffering from ischemic stroke and its associated disabilities is increasing. Studies on determining the relationship between endothelial progenitor cells (EPCs) and ischemic stroke have become a new hot spot and have reported that EPCs may protect the brain against ischemic injury, promote neurovascular repair, and improve long-term neurobehavioral outcomes. More importantly, they introduce a new perspective for prognosis assessment and therapy of ischemic stroke. However, EPCs’ origin, function, influence factors, injury repair mechanisms, and cell-based therapy strategies remain controversial. Particularly, research conducted to date has less clinical studies than pre-clinical experiments on animals. In this review, we summarized and analyzed the current understanding of basic characteristics, influence factors, functions, therapeutic strategies, and disadvantages of EPCs as well as the regulation of inflammatory factors involved in the function and survival of EPCs after ischemic stroke. Identifying potential therapeutic effects of EPCs in ischemic stroke will be a challenging but an incredibly important breakthrough in neurology, which may bring promise for patients with ischemic stroke.

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Endothelial progenitor cells in ischemic stroke: an exploration from hypothesis to therapy

To determine whether the expression of histone modification enzymes is regulated in physiological and pathological conditions, we took an experimental database mining approach pioneered in our labs to determine a panoramic expression profile of 164 enzymes in 19 human and 17 murine tissues. We have made the following significant findings: (1) Histone enzymes are differentially expressed in cardiovascular, immune, and other tissues; (2) our new pyramid model showed that heart and T cells are among a few tissues in which histone acetylation/deacetylation, and histone methylation/demethylation are in the highest varieties; and (3) histone enzymes are more downregulated than upregulated in metabolic diseases and regulatory T cell (Treg) polarization/ differentiation, but not in tumors. These results have demonstrated a new working model of "Sand out and Gold stays," where more downregulation than upregulation of histone enzymes in metabolic diseases makes a few upregulated enzymes the potential novel therapeutic targets in metabolic diseases and Treg activity.

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Metabolic Diseases Downregulate the Majority of Histone Modification Enzymes, Making a Few Upregulated Enzymes Novel Therapeutic Targets--"Sand Out and Gold Stays".

Valeria Chernaya

Papers

Immunosuppressive/anti-inflammatory cytokines directly and indirectly inhibit endothelial dysfunction--a novel mechanism for maintaining vascular function.

Endothelial progenitor cells in ischemic stroke: an exploration from hypothesis to therapy

Metabolic Diseases Downregulate the Majority of Histone Modification Enzymes, Making a Few Upregulated Enzymes Novel Therapeutic Targets--"Sand Out and Gold Stays".

Epigenetic enzymes are the therapeutic targets for CD4+CD25+/highFoxp3+ regulatory T cells