Table 2.
The role of antioxidants in MetS and endothelial dysfunction.
| Antioxidants | Sources | Functions | |||||
|---|---|---|---|---|---|---|---|
| Antioxidant Function | Anti-Inflammatory Role | Obesity, Dyslipidemia, Adipose Tissue Remodeling | Hyperglycemia, Insulin Resistance, Hyperinsulinemia | Hypertension | Endothelial Dysfunction | ||
| Vitamin E | Vegetable oils, safflower seed oil, soy oil, palm oil [52] | Scavenging free radicals [53] ↑ NO bioavailability ↓ NOX activity [54] Inhibition of lipid peroxidation [54] |
↓ CRP level ↓ Pro-inflammatory cytokines (IL-1 and 6, TNF) ↓ PGE2 synthesis ↓ Chemokine IL-8, PAI-1 levels [52] |
Inhibition of cholesterol synthesis ↓ LDL oxidation [55] |
Improving insulin sensitivity ↓ Plasma glucose [56] ↓ HbA1c [57] |
↓ Blood pressure | ↓ Monocyte adhesion to endothelium ↓ E-selectin, ICAM-1, and VCAM-1 ↓ Platelet aggregation [52] ↓ Risk of CVD morbidity and mortality [54] protecting endothelial cells from chromatin damage protecting endothelial cells from telomere shortening [6] |
| Vitamin C | Cherries, wild rose, blackcurrant, guava, peppers, brussels, broccoli, grapefruit, pomelo, lemon, orange, lime [58] |
↓ ROS production ↑ NO bioavailability [54] ↓ XO activity ↓ NOX activity ↑ SOD activity ↑ GPx activity ↑ GR activity ↑ TrxR activity Preventing lipid peroxidation [58] |
↓ IL-2,6,12, IFN-γ Activation of Nrf2 Suppressing NF-κB, TNF-α pathway ↓ CRP [58] |
↑ HDL ↓ Cholesterol, LDL and TG [59] |
↓ Plasma insulin ↓ Plasma TGL ↓ HbA1c ↓ FBS [60] |
↓ Systolic blood pressure [61] | ↓ Endothelial dysfunction [62] ↓ Risk of CVD morbidity and mortality [54] |
| Zinc | Milk, cheese, red meat, or liver [61] | ↑ CuZn-SOD activity [63] ↑ eNOS expression levels ↑ NO availability [64] |
Suppression of the NF-B pathway ↑ PPAR-α expression [65] |
↑ Leptin synthesis Improve leptin sensitivity [66] |
↓ Glucagon secretion ↓ Insulin resistance ↑ Insulin sensitivity ↑ GLUT4 Translocation [63] |
↓ Systolic blood pressure [67] | Prevention of endothelial dysfunction [64] |
| Copper | Milk, meat, seafood, vegetables, fruits [68] | Scavenging free radicals ↑ CuZn-SOD activity [69] |
Activation of PPAR-α signaling [68] |
↓ Total cholesterol ↓ LDL [69] |
↓ Plasma glucose [69] ↓ Intramuscular fat accretion [68] |
↓ Diastolic blood pressure [69] | Benefited the fibers of the blood vessel wall by maintaining its toughness and suppleness [70] |
| Selenium | Fish, such as tuna and mackerel, animal foods, cereals, plant sources, such as garlic, onions, and broccoli [71] | ↑ NO bioavailability ↓ Lipid peroxidation ↑ Antioxidant capacity in liver and kidney [72] ↑ GSH in the RBCs and liver ↑ Antioxidant enzyme activities (↑ GPx activity) [73] ↓ MDA [74] |
↓ TNF-α, IL-1β, PGE2 [68] ↓ Leukocyte and neutrophil count in circulation ↓ CRP, IL-6 ↓ MDA Inhibition of NF-B [74] |
↓ Leptin resistance Improving hyperlipidemia [73] ↑ HDL ↓ LDL ↓ TG ↓ Ratio of total cholesterol to HDL cholesterol [71] |
↓ Blood glucose ↓ Diabetes prevalence [71] ↑ Insulin secretion ↓ Insulin resistance [73] |
High levels of selenium: ↑ incidence of hypertension |
Inhibition of platelet aggregation [72] |
| Melatonin | Eggs and fish, nuts, some cereals, germinated legumes or seeds, mushrooms [75] | Scavenging of free radicals ↓ Lipid peroxidation ↑ NO synthesis ↓ MDA Activation of SOD, CAT, and GR [74] Activation of SIRT1/Nrf2 signaling pathway ↓ Oxidative stress damage [75] |
Down-regulation of chemokine expression Inhibition of the NF-κB phosphorylation of PI3K/Akt, p38, ERK, JNK and MAPK [75] ↓ NOX ↓ Pro-inflammatory mediators (COX-2, TNF-α, iNOS) [76] |
↓ LDL ↑ HDL [74] ↓ Leptin resistance [77] ↓ Total cholesterol, TG, and ox-LDL ↓ Body weight ↓ Intra-abdominal visceral fat deposition [76] |
Improvement in insulin resistance ↓ Hyperinsulinemia ↓ Hyperglycemia ↓ HbA1c ↓ Incidence of T2D [77] |
↓ Blood pressure [74] |
Prevention of endothelial dysfunction [76] ↓ E-selectin, ICAM-1, and VCAM-1 [76] Inhibition of platelet aggregation Alteration of levels/activity of proteins involved in the coagulation cascade [77] |
| L-arginine | Seafood, watermelon juice, nuts, seeds, algae, meats, rice protein concentrate, and soy protein isolate [78] | ↑ ↓ ROS production ↑ SOD activity ↓ Lipid peroxidation [79] NO bioavailability ↓ MDA [80] |
↓ TNF-α, IL-1β, and IL-6 secretion [78] |
↓ Total cholesterol, LDL and TG ↑ HDL ↑ Adiponectin ↓ Body fat ↓ FFA ↓ Leptin [80] |
↓ Risk of diabetes ↑ Insulin secretion ↓ Blood glucose ↑ Insulin sensitivity [80] |
↓ Blood pressure [80] | Improvement in endothelial function [80] |
| Quercetin (Flavonol) | Citrus fruits, apples, grapes, dark cherries and dark berries, onions, parsley and sage, tea, olive oil, red wine [53], mangoes, buckwheat, plums, and tomatoes [6] |
ROS scavenger Inhibition of lipid peroxidation Inhibition of ROS production up-regulating the expression of SOD, CAT, and GSH ↑ TAC and GPX ↓ MDA Prevention of ROS production by inhibition of NOX2 Cu2+ and Fe2+ chelation [6] |
Inhibition of neutrophil infiltration Inhibition of NLRP3 pathways Inhibition of NF-κB pathways Inhibition of ROS/AMPK pathways ↓ IL-6 and TNFα [6] |
↓ Inflammation in BAT Promoting thermogenesis and browning of WAT [6] ↓ Ox-LDL ↓ Body weight [53] ↓ TG ↓ Cholesterol ↑ Adiponectin ↓ Leptin ↑ HDL [81] ↓ Waist circumference [82] |
↓ Blood glucose ↓ Insulin resistance ↑ Insulin ↓ HbA1c [81] ↑ β-cell number [82] |
↓ Systolic blood pressure [53] | Removal of endothelial cells aging Vasodilatory effect due to up-regulation of eNOS Anti-atherosclerosis effects Reduction in CVD [6] |
| Flavones | Dried oregano, dried parsley [53] | ↑ Activation of PPARs ↓ MCP-1 ↓ TNF-α ↓ INF-γ ↓ IL-1β ↓ IL-6 [83] |
↑ Adiponectin ↓ Body weight ↓ TG ↓ Cholesterol ↓ LDL ↓ V-LDL ↓ Apo-B [83] |
↑ Glucose tolerance glycemic control improvement ↓ Insulin resistance Regulation of GLUT4 expression [83] |
Blockage of macrophage foam cell formation [83] | ||
| Flavanones | Grapefruit juice and cooked tomato [53] | Stimulation of the antioxidant defense system and apoptosis [84] ↑ Antioxidant Capacity [82] |
↓ CRP ↓ TNF-α ↓ IL-6 [82] |
↓ LDL ↑ HDL ↓ TG ↓ Cholesterol ↓ ApoB ↑ Adiponectin [82] |
↑ Insulin sensitivity ↑ Insulin signaling [53] ↓ Blood glucose ↓ Insulin resistance ↓ C-peptide ↓ Glucose intolerance ↓ HbA1c ↑ GLUT4 [82] |
↓ Blood pressure [82] | ↑ Endothelium-dependent vasodilation ↑ NO production ↓ IL-6 ↓ E-selectin ↓ P-selectin ↓ VCAM-1 ↓ ICAM-1 [82] |
| Catechins (Flavanol) | Brewed green tea, black tea, blueberries, fava beans, cocoa, and dark chocolate [53] | ↓ ROS formation and NOX activity ↑Phosphorylation of eNOS and ↑ NOS production using the PI3k-dependent pathway ↑ GSH [53] ↑ NO and consequently decrease in formation of reactive oxygen and nitrogen species [24] |
Inhibition TNF-α- mediated NF-κB, and MAPKs activation [85] |
↓ Body weight ↓ BMI ↓ Cholesterol ↓ LDL ↓ TG [53] |
↓ Blood glucose ↓ Glucose intolerance ↑ Insulin sensitivity [53] |
↓ Blood pressure [53] | ↓ Endothelial dysfunction [53] |
| Anthocyanins | Blueberries, strawberries, pomegranates, wine, asparagus, elderberry juice concentrate [53] |
Inhibition of lipid peroxidation [21] Suppressing protein levels of NOX1 and NOX4 Up-regulating Nrf2 [86] ↓MDA [85] |
↓ CRP ↓ IL-1β [82] Up-regulation of the PPARα ↓ Serum leptin and resistin ↓ TNF-α ↓ IL-6 ↓ IL-12 Suppressing iNOS and COX-2 Inhibition of signaling pathway of MAPK and NF-κB [86] ↓ MCP-1 [87] |
↓ BMI ↓ Body weight [88] ↓ ApoB [82] ↑ HDL ↓ LDL ↓ Cholesterol ↓ TG ↓ Hypertrophy of the adipocytes in epididymal WAT [86] |
↓ Insulin resistance GLUT4 and GLUT1, and thereby Improvement in insulin sensitivity |
↓ Systolic blood pressure [53] | ↑ Von Willebrand factor ↓ Endothelial dysfunction ↓ P-selectin [82] Inhibition of ICAM-1 and VCAM-1 ↑ eNOS expression and NO release [87] |
| Genistein (Isoflavones) | Soy and fava beans, green bean, kudzu root, and alfalfa sprouts [53] | Preventing phosphorylation of JNK Activation of Akt /ERK 1,2 pathway [89] ↑ eNOS activity and blocking NADPH-stimulated ROS production Suppression of superoxide production and NOX4 expression ↓ MDA [90] |
↓ CRP [53] ↓ TNF-α [82] Activation of PPARs and AMPK ↓ IL-6 [89] |
↓ TG ↓ Cholesterol ↓ Visfatin ↓ LDL and ox-LDL ↑ HDL ↑ Adiponectin [53] ↑ β-oxidation of FA ↓ Lipogenesis Preventing de-novo lipid synthesis [89] Promotion of browning of white adipocytes [90] |
↓ Insulin resistance [82] ↑ Proliferation of βcells [89] ↓ HbA1c ↓ Blood glucose [90] |
↓ Blood pressure [53] | ↓ Circulating ICAM ↓ Endothelial dysfunction [53] ↓ ET-1 NO production via PKA/eNOS/NO signaling ↑ Expression of E-selectin, P-selectin, MCP-1, and IL-8 [90] |
| Carotenoids | Fruits (tangerines, cantaloupes, papayas, and oranges) and vegetables (carrot, pumpkin, spinach, sweet potato, tomato, broccoli, and green peas) [53] | ↓ Production of free radicals [91] Serve as precursors for retinol (vitamin A), retinaldehyde, and retinoic acid, among other substances; retinoid conversion products that play important roles as transcriptional regulators in the visual cycle and gene regulation link [92] |
Down-regulation of NF-κB and MAPK signaling pathways, Reducing the release of pro-inflammatory cytokines [93] | ↑ Adiponectin ↓ Body weight ↓ Visceral fat ↓ Lipid storage ↓ LDL [53] ↓ TG ↑ HDL [91] Reversing cholesterol transport by HDL [93] |
↑ Insulin sensitivity ↓ Insulin resistance [53] ↓ Blood glucose [91] |
↓ Blood pressure [53] | ↓ Endothelial dysfunction ↓ PAI-1 [53] Delay the progression of cardiovascular diseases ↑ NO bioavailability ↓ Accumulation of cholesterol in foam cells and the formation of atherosclerotic plaques [93] |
| Resveratrol | Grapes, apples, blueberries, plums, wine, peanuts [6], and dark chocolate [53] | ↓ H2O2
production ↑ Level of regulatory T cells ↓ ROS by inhibiting the MAPK pathways [6] |
Inhibition of PKA and Akt/PKB pathway [6] |
Acting as a WAT remodeling to BAT ↓ Accumulation of glycerol in adipose tissue Promoting thermogenesis by activation of SIRT1 and suppressing white adipogenesis [6] |
↑ Insulin production ↓ Insulin resistance [87] ↓ Blood glucose [94] |
↓ Blood pressure ↑ Na+ excretion (renal) [53] |
↑ NO production Up-regulation of eNOS expression Suppressing the synthesis of ET-1 [6] |
| N-acetylcysteine | Allium plant [87] | ↑ Endogenous concentrations of total glutathione Scavenging free radicals Suppressing ROS generation [95] ↑ Intracellular cysteine levels Replenishing systemic pools of (LMW) thiols and reduced protein sulfhydryl groups, which are implicated in the regulation of the redox stats [96] |
↓ CRP [97] Blocking NF-κB Inhibition of the release of IL-1, IL-6, and TNF [96] ↓ Gene expression of pro-inflammatory cytokines [33] |
↓ TG ↑ HDL [97] ↓ Cholesterol ↓ LDL ↓ VLDL Preventing lipid accumulation in BAT [96] |
↑ Insulin secretion [96] ↓ Blood glucose ↓ Insulin resistance [95] |
↓ Blood pressure [87] | ↑ NO [97] Stabilizing the production of atherosclerotic plaque [96] |
NADPH oxidase (NOX), C-reactive protein (CRP), tumor necrosis factor (TNF), triglyceride (TG), low-density lipoprotein (LDL), oxidized low-density lipoprotein (ox-LDL), very low-density lipoprotein (VLDL), high-density lipoprotein (HDL), reactive oxygen species (ROS), interferon gamma (IFN-γ), nuclear factor erythroid 2–related factor 2 (Nrf2), endothelial NOS (eNOS), inducible nitric oxide synthase (iNOS), peroxisome proliferator-activated receptor α (PPAR-α), prostaglandin E2 (PGE2), plasminogen activator inhibitor-1 (PAI-1), intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1(VCAM-1), glutathione (GSH), xanthine oxidase (XO), superoxide dismutase (SOD), glutathione peroxidase (GPx) glutathione reductase (GR), thioredoxin reductase (TrxR), catalase (CAT), triglyceride lipase (TGL), glycosylated hemoglobin (HbA1c), malondialdehyde (MDA), cyclooxygenase-2 (COX-2), free fatty acids (FFA), white adipose tissue (WAT), brown adipose tissue (BAT), monocyte chemoattractant protein 1 (MCP-1), apolipoprotein B (ApoB), endothelin 1 (ET-1), total antioxidant capacity (TAC), glucose transporters (GLUTs), body mass index (BMI), ↑: increase, ↓: decrease.