Table 1.

Summary of the researches from the last ten years that have studied the effect of the combination between polyphenols and fish oils for improving Metabolic Syndrome features.

Bioactive	Dose	Model	Health Effects of the Combination	Reference
In vitro studies
Epigallocatechin-3-gallate (EGCG) from green tea and DHA.	EGCG, DHA or EGCG + DHA (50 µM) 1 h.	FaO cells (H4-11-E-C3 rat hepatoma).	Less lipid peroxidation levels More GSH/GSSG and less catalase EGCG impairs DHA-related Nrf2 nuclear translocation and decreases HO-1 protein levels.	[39]
Resveratrol and EPA.	Resveratrol (25 mg/mL); EPA (30 mM); 19 h.	RAW 264.7 murine macrophage.	Enhanced anti-inflammatory effect Decreased NO levels; Modulating P-SAPK/JNK; Down-regulation of proinflammatory; genes (IL, chemokines, transcription factors); Up-regulation antioxidant genes.	[40]
Resveratrol and EPA.	Resveratrol(25 µmol/L); EPA (20 µmol/L).	Human peripheral blood leukocytes (PBLs); Normal human articular chondrocytes from knee (NHAC-kn).	Synergistic effects on CCL5/RANTES; Additive effects on IL-6 or CXCL8/IL-8.	[41]
In vivo studies
Resveratrol and fish oil.	20 mg resveratrol/kg/day; 0·4 g fish oil (54% EPA, 10% DHA)/kg per day; 2 months.	Obese male Wistar rats.	Activation of the Nrf2/Keap1 pathway; Increases survival of obese rats because of less oxidative stress in the aorta and myocardium.	[42]
Grape seed proanthocyanidins extract and fish oil.	Proanthocyanidin rich grape seed extract (GSPE, 0.8 g kg−1 feed) EPA/DHA 1:1 (16.6 g kg−1 feed); 24-weeks.	Prediabetic female Wistar–Kyoto rats.	Both additive and synergistic effects on total and specific protein carbonylation in liver; Effects strongly depended on the background diet; Results correlated with improved insulin sensitivity and antioxidant status.	[43]
Grape seed proanthocyanidins extract and oil rich in DHA.	GSPE (25 mg/kg body weight); 500 mg oil-rich DHA (38.8%)/kg body weight; 21 days.	Obese male Wistar rats.	Activation of muscle β-oxidation More mitochondrial functionality and oxidative capacity; Up-regulation of AMPK phosphorylation, PPARα and Ucp2.	[44]
Apple polyphenols and fish oil.	1.5% apple polypheno l10% fish oil (27% EPA, 11% DHA); 4 weeks.	Male Sprague–Dawley rats.	Synergistic effects: lower posterior abdominal fat wall and testicle peripheral fat; Additive effects: lower cholesterol and FFA; lower adiponectin than in fish oil and more than in polyphenols; less oxidative stress than in polyphenols but more than in fish oil.	[45]
Grape seed proanthocyanidins extract and fish oil.	GSPE(0.8 g kg−1 feed) EPA/DHA 1:1 (16.6 g kg−1 feed); 24-weeks.	Prediabetic female Wistar–Kyoto rats.	Complementary effects: Lower omega-6/-3 ratio; Lower production of ARA proinflammatory lipid mediators; Up-regulation desaturases towards omega-3. Additive effects: Down-regulation Δ5D and COX activities on ARA; Enhancing the antioxidant enzymes decreasing total FFA in plasma.	[46]
Grape seed proanthocyanidins extract and fish oil.	GSPE(0.8 g kg−1 feed) EPA/DHA 1:1 (16.6 g kg−1 feed); 24 weeks.	Prediabetic female Wistar–Kyoto rats.	Synergistic effect of GPx activity; Higher amount of MUFA and PUFA-containing DAG and long-chain fatty acid-containing ceramides.	[47]
Grape seed proanthocyanidins extract and fish oil.	GSPE(0.8 g kg−1 feed) EPA/DHA 1:1 (16.6 g kg−1 feed). 24 weeks.	Prediabetic female Wistar–Kyoto rats.	Additive effects on the regulation of proteins involved in insulin signaling, glycolysis, fatty acid beta-oxidation, and endoplasmic reticulum stress.	[48]
Grape seed proanthocyanidins extract and fish oil.	GSPE(0.8 g kg−1 feed) EPA/DHA 1:1 (16.6 g kg−1 feed); 24 weeks.	Prediabetic female Wistar–Kyoto rats.	Additive effect on insulin, leptin, and triglycerides levels in prediabetic rats.	[49]
Plant oil extracts (tocopherols, cholecalciferol, retinol, lignans, coumarins and dicyclo esters) and fish oil.	Daily oral gavage of salmon oil (1365 mg/kg body weight) supplemented with Schisandra chinensis oil extract and Matricaria chamomilla oil extract at growing doses of plant extract from 1365, 2730 to 5460 mg/kg body weight; 21 days.	Male Balb/c mice.	Synergistic antioxidant effect as free radical scavengers; Better immunomodulatory activity at highest plant extract doses without any toxicity.	[50]
Brown seaweed lipids.	0.5% or 2.0% seaweed lipids; 4 weeks.	Female KK-Ay mice.	Less lipid peroxidation in the liver; Hepatic enrichment in DHA and ARA.	[51]
Anti-inflammatory dietary mixture (AIDM) (resveratrol, lycopene, catechin, vitamins E and C, and fish oil)	AIDM; 6 weeks.	Female ApoE*3Leiden transgenic mice.	Decreased CRP and fibrinogen expression. Decreased plasma cholesterol, TG, serum amyloid Aβ, vascular inflammation markers, and adhesion molecules	[52]
Biologically active substances-enriched diet (BASE-diet) (polyphenols, b-carotene, probiotics, and omega-3 and -6 PUFAs).	BASE-diet; 3 vs. 14 months	Adult male Sprague–Dawley rats.	Regulation of gonadotrope cell activation pathway and guanylate cyclase pathway, mast cell activation, gap junction regulation, melanogenesis, and apoptosis.	[53]
Functional food of salmon oil (omega-3 and omega-6 PUFAs, vitamins A, E and D3) with oil extract of motherwort (flavonoids and iridoids).	Daily intragastric administration of functional food (salmon oil:motherwort oil extract in 8:2 ratio) at the doses of 2340 and 1170 mg/kg body weight; 14 days.	Rats.	Increased left ventricular pressure after ischemia; Normalized contraction/relaxation of left ventricle; Decreased aspartate amino transferase and creatine kinase activity; Cardioprotective effect without any toxicity.	[54]
Human studies
Polyphenols from green tea and coffee, vegetables, fruits, dark chocolates, and extra-virgin olive oil; Omega-3 PUFAs from salmon, dentex, and anchovies.	Diet naturally rich/or not in omega-3 PUFAs (4 g/day) and/or polyphenols (2.861 mg/day); 8 weeks	Humans at high metabolic risk.	Reduction of the postprandial lipid VLDL; Increases IDL; LDL richer and HDL poorer in TG.	[55]
Polyphenols from green tea and coffee, vegetables, fruits, dark chocolates, and extra-virgin olive oil; Omega-3 PUFAs from salmon, dentex, and anchovies.	Diet naturally rich/or not in omega-3 PUFAs (4 g/day) and/or polyphenols (2.861 mg/day); 8 weeks.	Humans at high metabolic risk.	Additive effects of polyphenols (less TG, large VLDL, and urinary 8-isoprostanes) and of fish oils (less postprandial chylomicron cholesterol and VLDL apolipoprotein B-48); Correlation lipoprotein changes and 8-isoprostanes.	[56]
Polyphenols from green tea and coffee, vegetables, fruits, dark chocolates, and extra-virgin olive oil; Omega-3 PUFAs from salmon, dentex, and anchovies.	Diet naturally rich/or not in omega-3 PUFAs (4 g/day) and/or polyphenols (2.861 mg/day); 8 weeks	Humans at high metabolic risk.	Additive effects of polyphenols (less plasma glucose and increased early insulin secretion) and of fish oils (reduced beta-cell function and GLP-1).	[57]
Polyphenols from green tea and coffee, vegetables, fruits, dark chocolates, and extra-virgin olive oil; Omega-3 PUFAs from salmon, dentex, and anchovies.	Diet naturally rich/or not in omega-3 PUFAs (4 g/day) and/or polyphenols (2.861 mg/day); 8 weeks.	Humans at high metabolic risk.	Lipid rearrangements (in phospholipids fatty acid profiles of HDL).	[58]
Cranberry polyphenols; EPA and DHA.	200 mL of the cranberry; 1 g omega-3 fatty acid capsule, 180 mg EPA and 120 mg DHA, twice daily; 8 weeks.	Humans with diabetes and periodontal disease.	Decreased glycated hemoglobin; Increased HDL-C; Improve periodontal status.	[59]
Polyphenols from green tea and coffee, vegetables, fruits, dark chocolates, and extra-virgin olive oil; Omega-3 PUFAs from salmon, dentex, and anchovies.	Diet naturally rich/or not in omega-3 PUFAs (4 g/day) and/or polyphenols (2.861 mg/day); Blood samples taken before and up to 6 h after the test meal.	Humans at high metabolic risk.	Change in levels of chylomicron cholesterol and triglycerides due to omega-3; Response to nutraceuticals depends on acute or chronic supplementation.	[60]
Diet rich in polyphenols and omega-3; PUFAs.	Retrospective study; June 2017 to December 2018; Łódź, Poland.	Middle-age patients after percutaneous coronary intervention.	PLR and NLR depending on the omega-6/omega-3 ratio.	[61]
Polyphenols from green tea and coffee, vegetables, fruits, dark chocolates, and extra-virgin olive oil; Omega-3 PUFAs from salmon, dentex, and anchovies.	Diet naturally rich/or not in omega-3 PUFAs (4 g/day) and/or polyphenols (2.861 mg/day); 8 weeks.	Human at high metabolic risk.	Change in gut microbiota associated with changes in glucose/lipid metabolism.	[62]
Fish oil; Chocolate containing plant sterols and green tea.	Fish oil (1.7 g EPA + DHA/day); Chocolate containing plant sterols (2.2 g/day); Green tea (two sachets/day); 6 weeks.	Patients suffering from type 2 diabetes.	Both nutraceuticals combined with statin therapy significantly reduced LDL-C and CRP.	[63]
Mix of phytosterols, antioxidants, probiotics, fish oil, berberine, and vegetable proteins (PROG) + proprietary lifestyle.	PROG plan daily; 13 weeks.	Healthy overweight people with cardiometabolic syndrome.	Less body and fat mass; Improved plasma lipid profiles and inflammation markers.	[64]
Nutraceutical cocktail (polyphenols, omega-3 fatty acids, vitamin E, and selenium).	Nutraceutical cocktail daily; 10–20 days.	People with sedentary behaviors and fructose overfeeding.	Less alterations on lipid metabolism; No effect in preventing insulin resistance.	[65]
Aterofisiol® (EPA, DHA, oligomeric proanthocyanidinsand resveratrol, vitamins K2, B6, and B12).	Aterofisiol®; 1 tablet every 24 h starting 30 days before the surgery and stopping 5 days before it.	Patients with carotid stenosis who underwent endarterectomy.	Alteration of atherosclerotic plaque composition; More prevention from neurological events associated.	[66]