Polyphenols and omega-3 as nutriceuticals: Comparison
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PolypThenols and omega-3 polyunsaturated fatty acids from fish oils, i.e., eicosapentaenoic and docosahexaenoic acids, are adequate combination of the well-recognized nuindividual nutraceuticals, and their single antioxidant and anti-inflammatory properties have been demonstrated in several studies found in the literature. It has been reported that the combination of these nutraceuticals can lead to three-fold increases in glutathione peroxidase activity, two-fold increases in plasma antioxidant capacity, decreases of 50–100% in lipid peroxidation, protein carbonylation, and urinary 8-isoprotanes, as well as 50–200% attenuation of common inflammation biomarkers, among other effects, as compared to their individual capacities. Therefore, the adequate combination of those bioactive food compounds and their single of polyphenols and omega-3 polyunsaturated fatty acids from fish oils (eicosapentaenoic and docosahexaenoic acids), particularlly their single antioxidant and anti-inflammatory properties should, may offer a powerful tool for the design of successfully nutritional interventions for the prevention and palliation of a plethora of human metabolic diseases, frequentlyoften diet-inducrelated, whose etiology and progression are characterized by redox homeostasis disturbances and a low-grade of chronic inflammation. However, the certain mechanisms behind their biological activities, in vivo interaction (both between them and other food compounds), and their optimal doses and consumption are not well-known yet. Therefore, we review here the recent evidence accumulated during the last decade aboutevidence in both preclinical and clinical trials, of the cooperative action between polyphenols and fish oils against diet-related metabolic alterationss nutraceuticals on human health, focusing on the mechanisms and pathways described and the effects reported. The final objective is to provide useful information for developing effective strategies forof personalized nutrition based on these nutraceutical combined used of these bioactive food compounds. 

  • eicosapentaenoic acid
  • docosahexaenoic acid
  • omega-3 polyunsaturated fatty acids
  • plant bioactives
  • oxidative stress
  • inflammation
  • metabolic disorders
  • nutraceuticals

1. Introduction

Nutraceuticals, defined as “any substance that is food or part of a food and provide medical or health benefits, including the prevention and treatment of disease” [1], are currently considered a viable strategy for the prevention and palliation of several human diseases, including those inducred by the consumption of “obesogenic” diets.

Tlated to the widespread c“onsumption of diets high in saturated fat and sugar and low in polyunsaturated fatty acids (PUFAs) and antioxidants, togetbesogenic” lifestyle.

Ther with a more sedentary“obesogenic” lifestyle, have notably increased the prevalence of metabolic alterations such as the so-called Metabolic Syndrome (MetS) [2]., MetS is a pathological condition defined by the simultaneous presence of different combinations of three or more of the following metabolic alterations: abdominal obesity, blood hypertension, hyperglycemia, and serum dyslipidemia [3]. It has been estimated that MetS affects over a billion people worldwide [4] and iis considered a risk factor for noncommunicable diseases such as type 2 diabetes and cardiovascular diseases (CVD) [54]. Other main chronic illnesses promoted by obesity are cancer and neurodegenerative pathologies, both[5]. affectiIng a great number of people worldwide and whose incidence grows in parallel with the dramatic increase in the aging population around the world [6].

All the metabterestingly, all these pathololgic alterations of MetS and its derived diseases are es are characterized by an increase in oxidative stress and a proinflammatory status [76]. Interestingly, it seems that oxidative stress and inflammation also are both the cause and the consequence of MetS and associated diseases [8]. For this reason, bioactive compounds naturally present in food with antioxidant and/or anti-inflammatory properties have attracted the attention of the scientific community for the development of successful nutritional interventions. Among those, dietary polyphenols are often considered because they are one of the most important groups of natural antioxidants and anti-inflammatory agents found in human diets, including fruits, vegetables, grains, tea, essential oils, and their derived foods and beverages [97]. On the Habitualother hand, regular intake of fish-derived omega-3 has , i.e., eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids, has also been reported to be involved in the prevention of several of those metabolic alterations and diseases [8], because of theincluding autoimmune disorders,r biological functions and bioactivities. Interestingly, EPA and DHA play an important role in anti-inflammatory processes because they are substrates for cyclooxygenase, lipoxygenase, cytochrome P450, and several other enzymes [9]. As a MretS, diabetes, CVD, neurodegensult, numerous lipid mediators involved in inflammatory processes are generated, including specialized pro-resolving lipid mediators (SPMs), which actively resolve inflammation [10].

Several stive diseases, cancer, and otherudies have pointed out that fish oils can also improve the antioxidant defense, mainly via nuclear factor erythroid 2 (Nrf2)-dependent mechanisms [11][1012][13][14]. However, the influence of highly unsaturated fatty acids on redox homeostasis remains controversial. The high consumption of these omega-3 causes an enriched in PUFAs of cell membranes and tissues, which could make them more vulnerable to suffering from lipid peroxidation under oxidative stress insults, because of the presence of those high unsaturated structures carrying many “fragile” double bonds [1115]. There combinafore, a good strategy for preventing potentially detrimental health effects of the high PUFAs intake regarding oxidation may be the simultaneous consumption of omega-3 PUFAs and polyphenols in food may not only be useful for retaining their bioactive value. Nevertheless, it is necessary to unequivocally identify the molecular processes and bioavailability but also may eliminate, or at least limiting, the deleterious chemical pathways that can be modulated by the combination of those nutrients, determine the optimal consumption in the context of several metabolic alterations and describe potential eadverse or antagonist effects of the high PUFAs intake regarding oxidation, that could exist, among other concerns.

Therefore, we review the recent epreclinical and clinical evidence that supports the combined use of fish-derived omega-3 PUFAs and polyphenols as nutraceuticals, for the prevention and treatment of metabolic disturbances characterizgoverned by high oxidative stress and inflammation, was to s. We aim to provide solid scientific evidence for the optimum design of nutritional strategies. The studies that have addressed this topic during the last decade are summarize bellowd in Table 1 and will be discussed more in detail in the following sections.

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 MetS features, neurodegenerative pathologies, cancer, and other health effects.

Bioactive´s Combination

Model

Health Effects of the Combination

Reference

MetS features

  • In vitro studies

Epigallocatechin-3-gallate (EGCG) and 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.

[16]

Resveratrol (2·5 mg/mL) and 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.

[17]

Resveratrol (25 ?mol/L) and EPA (20 ?mol/L)

Human peripheral blood leukocytes (PBLs) and normal human articular chondrocytes from knee (NHAC-kn).

Synergistic effects on CCL5/RANTES; additive effects on IL-6 or CXCL8/IL-8.

[18]

  • In vivo studies

Resveratrol (20 mg/kg/day) and fish oil (0.4 g (54% EPA, 10% DHA)/kg/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.

[19]

Proanthocyanidin rich grape seed extract (0.8 g/kg feed) and EPA/DHA 1:1 (16.6 g /kg 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.

[20]

Proanthocyanidin rich grape seed extract (25 mg/kg body weight) and oil-rich DHA (500 mg (38.8% DHA)/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.

[21]

1.5% apple polyphenol and 10% 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.

[22]

Proanthocyanidin rich grape seed extract (0.8 g/kg feed) and EPA/DHA 1:1 (16.6 g /kg 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.

[23]

Proanthocyanidin rich grape seed extract (0.8 g/kg feed) and EPA/DHA 1:1 (16.6 g /kg 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.

[24]

Proanthocyanidin rich grape seed extract (0.8 g/kg feed) and EPA/DHA 1:1 (16.6 g /kg 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.

[25]

Proanthocyanidin rich grape seed extract (0.8 g/kg feed) and EPA/DHA 1:1 (16.6 g /kg feed); 24-weeks.

Prediabetic female Wistar–Kyoto rats.

Additive effect on insulin, leptin, and triglycerides levels in prediabetic rats.

[26]

Salmon oil (1365 mg/kg body weight/day) supplemented tocopherols, cholecalciferol, retinol, lignans, coumarins and dicyclo esters at 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.

[27]

Brown seaweed lipids (0.5% or 2.0%); 4 weeks.

Female KK-Ay mice.

Less lipid peroxidation in the liver; hepatic enrichment in DHA and ARA.

[28]

Biologically active substances-enriched (BASE) diet (polyphenols, b-carotene, probiotics, and salmon fat);;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.

[29]

Anti-inflammatory dietary mixture (AIDM) (resveratrol, lycopene, catechin, vitamins E and C, and fish oil); 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

[30]

Salmon oil/motherwort oil extract in 8:2(2340 and 1170 mg/day/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.

[31]

  • Human studies

Diet naturally rich/or not in fish 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.

[32]

Diet naturally rich/or not in fish 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.

[33]

Diet naturally rich/or not in fish 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 omega-3 (reduced beta-cell function and GLP-1).

[34]

Diet naturally rich/or not in fish 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).

[35]

Cranberry polyphenols (200 mL) and 1 g capsule EPA (180 mg) and DHA (120 mg) twice daily; 8 weeks.

Humans with diabetes and periodontal disease.

Decreased glycated hemoglobin; increased HDL-C;improve periodontal status.

[36]

Diet naturally rich/or not in fish 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.

[37]

Diet rich in polyphenols and omega-3 (retrospective study from 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.

[38]

Diet naturally rich/or not in fish 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.

[39]

Fish oil (1.7 g EPA + DHA/day) and chocolate containing plant sterols (2.2 g/day) and 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.

[40]

PROG plan daily; 13 weeks.

Healthy overweight people with cardiometabolic syndrome.

Less body and fat mass; improved plasma lipid profiles and inflammation markers.

[41]

Nutraceutical cocktail (polyphenols, omega-3 fatty acids, vitamin E, and selenium) daily; 10–20 days.

People with sedentary behaviors and fructose overfeeding.

Less alterations on lipid metabolism; no effect in preventing insulin resistance.

[42]

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.

[43]

Neurodegenerative Diseases

  • In vitro studies

EPA (0.125 µM), lyc-O-mato (0.1 µM), carnosic acid (0.2 µM) and lutein (0.2 µM).

BV-2 immortalized murine microglial cell line.

Synergistic inhibition of the production of proinflammatory mediators: inhibition redox-sensitive NF-κB activation; inhibition of superoxide production; upregulation COX-2 and iNOS; more release of PGE2 and NO; attenuation IL-6 and CD40.

[44]

Resveratrol, quercetin, and apigenin (1.5 to 6.25 µM), α-ALA, EPA, DHA, and OA (6.25 to 50 µM) and α-Tocopherol.

N2a Neuronal cells.

Cytoprotective against 7-Ketocholesterol-induced neurotoxicity.

[45]

  • In vivo studies

Resveratrol and DHA (50 mg/kg/day); 6 weeks.

Adult C57Bl/6 mice.

Modulation of steroid hormone biosynthesis, JAK-STAT signaling pathway, ribosome, graft-versus-host disease pathways in the hippocampus;

Decreased IL-6 and Apolipoprotien E (ApoE) expression.

[46]

LMN diet; 5 months.

Tg2576 male and female mice as a model of AD.

Delays the Aβ plaque formation and decreases Aβ1–40 and Aβ1–42 plasma levels in adult mice.

[47]

LMN diet; 10, 20, 30, or 40 days.

129S1/SvImJ adult male mice.

Enhancement of cholinergic and catecholaminergic transmissions; Nrf2 activation and increased protein levels of SOD-1 and GPx.

[48]

Multivitamins, zinc, polyphenols, omega-3 fatty acids, and probiotics mixture; 48 days.

Crickets.

A combination of multivitamins, zinc, and omega-3 fatty acids was the most effective for improving memory and cognitive performance.

[49]

Resveratrol (50 mg/L drinking water) and DHA (300 g) and prebiotics (100 g) of prebiotic in powdered food; from post-natal day 21 to 43.

Adolescent male and female Sprague–Dawley rats suffering from mild traumatic brain injury.

Modify premorbid characteristics; prevented injury-related deficits in longer-term behavior measures, medial prefrontal cortex spine density, and levels of Aqp4, Gfap, Igf1, Nfl, and Sirt1 expression in the prefrontal cortex.

[50]

  • Human studies

Smartfish® (200 mL/day) ; 4–17 months.

Patients with minor cognitive impairment (MCI), with pre-MCI, or with Alzheimer disease (AD).

Increase amyloid-β phagocytosis and resolvin D1 in patients with MCI.

[51]

Smartfish® (200 mL/day); 6 months.

Older adults (68–83 years) without any specific pathology.

Limited beneficial effects improving cognitive function.

[52]

NEWSUP; 23 weeks.

Children aged 15 months to 7 years; primary population: children younger than 4.

Increased working memory, hemoglobin concentration among children with anemia, decreased body mass index z score gainm, and increased lean tissue accretion with less fat; increased index of cerebral blood flow (CBFi).

[53]

Cancer

  • In vivo studies

Curcumin (1% w/w) and menhaden fish oil (4% w/w); 3 weeks.

Lgr5-EGFP-IREScreERT2 knock-in mice.

Only fish oils+curcumin reduced nuclear β-catenin in aberrant crypt foci and synergistically increased targeted apoptosis in DNA damaged Lgr5+ stem cells; only fish oils+curcumin up-regulated p53 signaling in Lgr5+ stem cells from mice exposed to a carcinogen.

[54]

  • Human studies

PureVida™ (3 capsules/day); 1 month.

Post-menopausal breast cancer patients.

Decrease in CRP; reduction of pain from aromatase inhibitors of hormonal therapies.

[55]

Mediterranean-type dietary pattern (population-based case–control study, January 2015 to December 2016, Catania, Italy).

Prostate cancer (PCa) cases and controls.

High adherence to diet inversely associated with the likelihood of prostate cancer: PCa cases consume a lower amount of vegetables, legumes, and fish.

[56]

Exercise and physical activity

  • In vivo studies

5% fish oil (13.2% EPA, 8.6% DHA, 4.9%DPA) and 1% curcumin in diet;10 days.

C57BI/6 mice.

Decreased loss of muscle cross-sectional area; an enhanced abundance of HSP70 and anabolic signaling (Akt phosphorylation, p70S6K phosphorylation) while reducing Nox2.

[57]

  • Human studies

1 L daily supplementation of almond and olive oil and α-tocopherol based beverage enriched with a DHA functional beverage five days a week; 5 weeks.

Young/senior male athletes.

Increased PUFAs and reduced SFAs in plasma; increased DHA in erythrocyte; increased blood cell polyphenol concentration in senior athletes; protects against oxidative damage but enhances nitrative damage in young athletes; gene expression of antioxidant enzymes in peripheral blood mononuclear cells after exercise in young athletes (GPx, CAT, and Cu–Zn SOD).

[58]

1 L daily supplementation of almond and olive oil and α-tocopherol based beverage enriched with a DHA functional beverage five days a week; 5 weeks.

Young/senior male athletes.

Increased TNFα levels depending on age and exercise; attenuated the increase in plasma NEFAs, sICAM3 and sL-Selectin induced by exercise; exercise increased PGE2 plasma levels in supplemented young athletes; exercise increased NFkβ-activated levels in PBMCs mainly in supplemented young athletes.

[59]

Polyphenols (741 mg), vitamin E (138 mg), selenium (80 μg), and omega-3 (2.1 g); 60 days of hypoactivity.

Healthy, active male subjects.

Ineffectiveness regarding oxidative muscle damage, mitochondrial content, and protein balance and a disturbance of essential signaling pathways (protein balance and mitochondriogenesis) during the remobilization period.

[60]

Age-related eye disease

  • In vitro studies

288 ng of Resvega (30 mg of trans resveratrol and 665 mg of omega-3 EPA and DHA, among other nutrients);48 h.

ARPE-19 cells.

Induced autophagy by increased autolysosome formation and autophagy flux; change p62 and LC3 protein levels Cytoprotection under proteasome inhibition

[61]

  • In vivo studies

Resvega (100 µL/day); 38 days.

C57BL6/J mice.

Less vascular endothelial growth factor (VEGF) protein expression levels and less MMP-9 activity; mitigate choroidal neovascularization and retinal disease.

[62]

Others

Dermatologic food (EPA+DHA+polyphenols); 8 weeks.

Adult atopic dog.

Reductions in clinical scores of atopic dermatitis.

[63]

Olive oil polyphenols and fish oil (Prospective birth cohort Assessment of Lifestyle and Allergic Disease During INfancy (ALADDIN); September 2004–November 2007, Stockholm area, Sweden).

Placentas.

Altered histone acetylation in placentas.

[64]

Omega-3 fatty acids, polyphenols, and fiber (mother–neonate pairs from the prospective and observational MAMI birth cohort; 18 months, 2015–2017,Spanish–Mediterranean area).

Gut microbiota from mother–neonate pairs.

Higher abundance of the Ruminococcus species in maternal gut microbiota; higher relative abundance of Faecalibacterium prausnitzii considered as a biomarker of colonic health, associated with anti-inflammatory properties; modulation of neonatal microbiota.

[65]

2. Combined Polyphenols and Fish Oils Intake for Improving Metabolic HSyndrome Fealthtures. Preclinical and Clinical Evidence.

DSeveral sturing the last decade, several researchers have investigated the synergistic, additive, and complementary effects between fish oils (EPAdies in both cell and animal models addressed the effects of the combination between fish oil and polyphenols in restoring the redox homeostasis that is broken in MetS. Additive effects on the activation of the nuclear factor Nrf2 p45-related factor 2/Kelch-like ECH-associated protein 1 (Keap1) pathway were found after the treatment with a mix of the epigallocatechin-3-gallate (EGCG) and DHA) and polypheno in hepatic cells [16], and in pthe myocareventing and palliatingdium and aorta of obese male Wistar rats [19], after the supplemetabolic alterations and other physiological situations governed by oxidative stress and inflammation processes to provide solid scientific evidence for the optimum design of nutritional strategiesntation with resveratrol and fish oil. Moreover, the combined intake of proanthocyanidins from grape seed extract and fish oils showed relevant additive and even synergistic effects on liver redox homeostasis, especially on the modulation of carbonylation of specific liver proteins, lowering lipid peroxidation levels and improving oxygen radical absorbance capacity (ORAC) and the glutathione peroxidase (GPx) activity in plasma, while lowering cholesterol, tumor necrosis factor-alpha (TNFα) and plasma insulin levels in female Wistar–Kyoto rats fed an obesogenic diet [20].

2.1. Combined Polyphenols and Fish Oils Intake for Improving Metabolic Syndrome Features

S Theve coadministration of gral studies, both preclinical and clinical ones, have evaluated the effects thatpe seed proanthocyanidins and an oil-rich in DHA improve muscle status as well, because activated muscle β-oxidation, increased the mitochondrial functionality and oxidative capacity, and up-regulated fatty acid uptake gene expressions in obese male Wistar rats [21]. Also, the combination of apple polyphenols andwith fish oils would exert on MetS issues, and they are in male Sprague–Dawley rats fed a high cholesterol diet improved serum and liver lipid profiles and oxidative stress markers su[22].

Regarding inflammation, synerized in Table 1.

Table 1. Sugistic and additive anti-inflammatory of the researches froeffects between resveratrol and EPA were detected in macrophages in macrophages [17], human the last ten yperipheral blood leukocytes (PBLs), and articular chondrocytes from knee (NHAC-kn) [18]. In femars that have studied the effect of le Wistar–Kyoto rats fed an obesogenic, the combination between polyphenolof grape proanthocyanidins and fish oil [23] caused an 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 at 50 µM for 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.

[12]

Resveratrol and EPA

Res (2·5 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.

[13]

Resveratrol and EPA

25 ?mol/L RV;

20 ?mol/L EPA.

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.

[14]

  • In vivo studies

Resveratrol and fish oil

20 mg resveratrol/kg/day;

0·4 g Fish oil (54% EPA, 10% DHA)/kg per d;

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.

[15]

Grape proanthocyanidins and fish oil

Proanthocyanidin rich grape seed extract (GSE, 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.

[16]

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.

[17]

Apple polyphenols and fish oil

1.5% apple polyphenol

10% 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.

[18]

Grape proanthocyanidins and fish oil

Proanthocyanidin rich grape seed extract (GSE, 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.

[19]

Grape proanthocyanidins and fish oil

Proanthocyanidin rich grape seed extract (GSE, 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.

[20]

Grape proanthocyanidins and fish oil

Proanthocyanidin rich grape seed extract (GSE, 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.

[21]

Grape proanthocyanidins and fish oil

Proanthocyanidin rich grape seed extract (GSE, 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.

[22]

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.

[23]

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.

[24]

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

[25]

Biologically active substances-enriched diet (BASE-diet) (polyphenols, b-carotene, probiotics, and omega-3 and -6 PUFAs).

BASE-diet 3 for 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.

[26]

Functional food of salmon oil (omega-3 and omega-6 PUFAs, vitamins A, E and D3) with oil extract of motherwort (flavonoids and iridoids).

Functional food;

Daily intragastric administration (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.

[27]

  • 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.

[28]

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.

[29]

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 omega-3 (reduced beta-cell function and GLP-1).

[30]

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).

[31]

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.

[32]

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.

[33]

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.

[34]

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

[35]

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.

[36]

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.

[37]

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.

[38]

Aterofisiol® (EPA, DHA, oligomeric proanthocyanidins

and 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.

[39]

2.2. Fish Oils Intake in Neurodegenerative Pathologies, Cancer, and Other Health Effects

Benrichment in omega-3 PUFAs while decreasing omega-6 in membranes and tissues, resultides MetS disorders, during the last decade, the combination of polyphenolng in more favorable inflammatory and redox status, which was defined by a shift in the 12/15-lipoxygenases activities towards omega-3 PUFAs, enhanced GPx activities, and significant modulation of the cyclooxygenase (COX)-dependent synthesis of proinflammatory lipid mediators and fish oils has been studied forthe down-regulation of de novo synthesis of arachidonic acid (ARA) leaded by Δ5 desaturase. Moreover, the development of nutritional strategies that would result inouble supplemention increased monounsaturated fatty acid and polyunsaturated fatty acid-containing diacylglycerols (DAG) and long-chain fatty acid-containing ceramides abundances compared to the control an[24]. Theseffective method lipidomic profiles were correlated with the up-regulation of preventing and treatingoteins involved in improving insulin signaling, and lipid and glucose metabolism [25]. Biother diseases. In all the cases, these diseaschemical and biometric parameters confirmed that only the nutraceutical combination could restore insulin, leptin, and triglyceride levels to normal values [26].

Polyphenols, and also and marine omega-3 PUFAs in combination with other physbiological situations addressed, were alsoly active substances were also evaluated in some preclinical studies. Fish oil supplemented with plant oil extracts from chSchisandra chinensis and Matricaria chamomilla [27] demonstrated synergisticterized by the disruption/chan effects as free radical scavengers compared to controls in mice. Brown seaweed lipids extracts resulting in less lipid peroxidation in the liver of female KK-Ay mice, even if the hepatic percentage of the redoxPUFAs increased [28]. Thomeostasis and/or inflammatory status, ande long-term intake of the BASE diet modulated the expression of relevant genes associated with chronic disorders in the liver of male Sprague–Dawley rats, suggesting a link between diet, reproductive system function, and aging h[29]. Morencove, they ar, the anti-inflammatory AIDM mixture [30] was effectrongly influenced by diet aive in improving lipid and inflammatory CVD risk factors in rodents, and a fish oil combined with motherwort oil demonstrated superior cardioprotective properties in rats w[31].

Thell. Many of them are age-related diseases, such as brain damages, cognition alterationeffects of diets rich in fish-derived omega-3 and polyphenols in subjects at high CV risk have been studied in several human trials, which reported a reduction in the postprandial lipid content of large very low-density lipoprotein (VLDL) and increases intermediate-density lipoprotein (IDL) cholesterol; LDL particles richer in triglycerides, and HDL poorer [32][33] while decreasing oxidativeur stress [33], and bloodegenerative glucose, insulin secretion and postprandial glucagon-like peptide 1 levels [34]. Other lipid rearrangements iseasen HDL were also reported [35]. Diets, which have been gained increasing inteenriched in proanthocyanidins from cranberry juice and fish oil also improved both insulin and lipoprotein metabolisms in patients suffering from diabetes and periodontal disease [36]. Neverthest in parallel with the extension of lifespless, it has been reported that the postprandial chylomicron response to these nutraceuticals depends on supplementation time [37], and and the dramaticshould also be considered in this kind of nutrition strategies. The omega-6/omega-3 ratio [38] rate of agingnd the modulation of the worldwide population.microbiota composition The[39] sueemmary of also critical in the studies addressing these issues from the last decade is shown iny of their cardioprotective properties. Interestingly, the statin therapy of patients suffering from CVD could be efficiently complemented with a combination of fish oils and polyphenols Table 2[40].

Table 2. Several mixtummaryres of bioactive substances and nutraceutical cocktails, all of the researches from the lm especially rich in polyphenols and fish oils, were also tested in human trials [41][42][43], demonstrast ten years that have studied ting effectiveness in ameliorating lipid profiles, inflammation and atheroscerotic events, but less action on insulin sensitivity.

3. Combined Polyphenols and Fish Oils Intake for Improving Neurodegenerative Diseases. Preclinical and Clinical Evidence.

The benefitial effect of the s of combination between ing polyphenols and fish oils for improvingon cognition alteration and neurodegenerative pathologies, cancer, and other health effectsrocesses have been also investigated. Thus, resveratrol and DHA significantly altered hippocampal expression of gene associated with inflammatory responses [46].

Bioactive

Dose

Model

Health Effects of the Combination

Reference

Neurodegenerative Diseases

  • In vitro studies

EPA, Lyc-O-mato, Carnosic acid, and Lutein.

0.125 µM EPA, 0.1 µM Lyc-O-mato, 0.2 µM Carnosic acid and 0.2 µM Lutein.

BV-2 immortalized murine microglial cell line.

Synergistic inhibition of the production of proinflammatory mediators:

Inhibition redox-sensitive NF-κB activation;

Inhibition of superoxide production;

Upregulation COX-2 and iNOS;

More release of PGE2 and NO;

Attenuation IL-6 and CD40.

[40]

Polyphenols (Resveratrol, Quercetin, and Apigenin), omega-3 and omega-9 Fatty

Acids (α-ALA, EPA, DHA, and OA) and α-Tocopherol.

Polyphenols: 1.5 to 6.25 µM;

Fatty acids: 6.25 to 50 µM.

α-Tocopherol: 400 µM.

N2a Neuronal cells.

Cytoprotective against 7-Ketocholesterol-induced neurotoxicity.

[41]

  • In vivo studies

Resveratrol and docosahexaenoic acid

50 mg/kg/day of each supplement;

6 weeks.

Adult C57Bl/6 mice.

Modulation of steroid hormone biosynthesis, JAK-STAT signaling pathway, ribosome, graft-versus-host disease pathways in the hippocampus;

Decreased IL-6 and Apolipoprotien E (ApoE) expression.

[42]

LMN diet rich in polyphenols and PUFAs.

LMN diet;

5 months.

Tg2576 male and female mice as a model of AD.

Delays the Aβ plaque formation and decreases Aβ1–40 and Aβ1–42 plasma levels in adult mice.

[43]

LMN diet rich in polyphenols and PUFAs.

LMN diet;

10, 20, 30, or 40 days.

129S1/SvImJ adult male mice.

Enhancement of cholinergic and catecholaminergic transmissions;

Nrf2 activation and increased protein levels of SOD-1 and GPx.

[44]

Resveratrol, prebiotic fiber, and DHA.

Resveratrol 50 mg/L drinking water;

DHA and prebiotics in powdered food (100 g of prebiotic, 300 g of DHA, and 600 g of standard diet per 1 kg of food);

Administration from post-natal day 21 to 43.

Adolescent male and female Sprague–Dawley rats suffering from mild traumatic brain injury.

Modify premorbid characteristics

Prevented injury-related deficits in longer-term behavior measures, medial prefrontal cortex spine density, and levels of Aqp4, Gfap, Igf1, Nfl, and Sirt1 expression in the prefrontal cortex.

[45]

Multivitamins, zinc, polyphenols, omega-3 fatty acids, and probiotics.

Bioactive mixture for 2 two weeks;

48 days.

Crickets.

A combination of multivitamins, zinc, and omega-3 fatty acids was the most effective for improving memory and cognitive performance.

[46]

  • Human studies

Smartfish® (omega-3 EPA and DHA, and resveratrol, vitamin D).

200 mL/day Smartfish drink containing 1000 mg DHA, 1000 mg EPA, pomegranate and chokeberry, 10 mg vitamin D3 and resveratrol, whey protein, fiber, and fruit juice;

4–17 months.

Patients with minor cognitive impairment (MCI), with pre-MCI, or with Alzheimer disease (AD).

Increase amyloid-β phagocytosis and resolvin D1 in patients with MCI.

[47]

Smartfish® (omega-3 EPA and DHA, and resveratrol, vitamin D).

200 mL/day Smartfish drink containing 1500 mg DHA and 1500 mg EPA, 10 μg vitamin D3, 150 mg resveratrol, and 8 g whey protein isolate;

6 months.

Older adults (68–83 years) without any specific pathology.

Limited beneficial effects improving cognitive function.

[48]

NEWSUP (high in plant polyphenols and omega-3 fatty acids, high fortification of micronutrients, and high protein content).

NEWSUP;

23 weeks.

Children aged 15 months to 7 years; primary population: children younger than 4.

Increased working memory, hemoglobin concentration among children with anemia, decreased body mass index z score gainm, and increased lean tissue

accretion with less fat;

Increased index of cerebral blood flow (CBFi).

[49]

Cancer

  • In vivo studies

Curcumin and fish oil.

1% (w/w) curcumin;

4% (w/w) menhaden fish oil;

3 weeks nutraceutical supplementation + genotoxic carcinogen injections + 17 weeks.

Lgr5-EGFP-IREScreERT2 knock-in mice.

Only fish oils+curcumin reduced nuclear β-catenin in aberrant crypt foci and synergistically increased targeted apoptosis in DNA damaged Lgr5+ stem cells;

Only fish oils+curcumin up-regulated p53 signaling in Lgr5+ stem cells from

mice exposed to a carcinogen.

[50]

  • Human studies

PureVida™ (EPA/DHA/hydroxytyrosol/curcumin).

3 capsules of PureVida™/day;

Each capsule: 460 mg of fish oil (EPA and DHA), 125 mg of Hytolive® powder (12.5 mg of natural hydroxytyrosol), and 50 mg extract of curcumin (47.5 mg curcuminoids);

1 month.

Post-menopausal breast cancer patients.

Decrease in CRP;

Reduction of pain from aromatase inhibitors of hormonal therapies.

[51]

Mediterranean diet.

Mediterranean-type dietary pattern;

Population-based case–control study;

January 2015 to December 2016;

Catania, Italy.

Prostate cancer (PCa) cases and controls.

High adherence to diet inversely associated with the likelihood of prostate cancer:

PCa cases consume a lower amount of vegetables, legumes, and fish.

[52]

Exercise and physical activity

  • In vivo studies

Fish oil and curcumin.

5% fish oil (EPA: 13.2%; DHA: 8.6%; DPA: 4.9%), 1% curcumin in diet;

10 days supplement + 7 day hindlimb unloading.

C57BI/6 mice.

Decreased loss of muscle cross-sectional area;

An enhanced abundance of HSP70 and anabolic signaling (Akt phosphorylation, p70S6K phosphorylation) while reducing Nox2.

[53]

  • Human studies

Beverages based on almonds and olive oil and enriched with α-tocopherol and DHA.

1 L daily supplementation of almond and olive oil and α-tocopherol based

beverage enriched with a DHA functional beverage five days a week;

5 weeks.

Young/senior male athletes.

Increased PUFAs and reduced SFAs in plasma;

Increased DHA in erythrocyte;

Increased blood cell polyphenol concentration in senior athletes;

Protects against oxidative damage but enhances nitrative damage in young athletes.

Gene expression of antioxidant enzymes in peripheral blood mononuclear cells after exercise in young athletes (GPx, CAT, and Cu–Zn SOD).

[54]

Beverages based on almonds and olive oil and enriched with α-tocopherol and DHA.

1 L daily supplementation of almond and olive oil and α-tocopherol based

beverage enriched with a DHA functional beverage five days a week;

5 weeks.

Young/senior male athletes.

Increased TNFα levels depending on age and exercise;

Attenuated the increase in plasma NEFAs, sICAM3 and sL-Selectin induced by exercise;

Exercise increased PGE2 plasma levels in supplemented young athletes;

Exercise increased NFkβ-activated levels in PBMCs mainly in supplemented young athletes.

[55]

Antioxidant/anti-inflammatory cocktail (polyphenols, vitamin E, selenium, and omega-3).

Daily antioxidant/anti-inflammatory cocktail (741 mg of polyphenols, 138 mg of vitamin E, 80 μg of selenium, and 2.1 g of omega-3);

60 days of hypoactivity.

Healthy, active male subjects.

Ineffectiveness regarding oxidative muscle damage, mitochondrial content, and protein balance and a disturbance of essential signaling pathways (protein balance and mitochondriogenesis) during the remobilization period.

[56]

Age-related eye disease

  • In vitro studies

Resvega (30 mg of trans resveratrol and 665 mg of omega-3 EPA and DHA, among other nutrients).

288 ng of Resvega (30 mg of trans resveratrol and 665 mg of omega-3, among other nutrients);

48 h.

ARPE-19 cells.

Induced autophagy by increased autolysosome formation and autophagy flux

Change p62 and LC3 protein levels Cytoprotection under proteasome inhibition

[57]

  • In vivo studies

Resvega (30 mg of trans resveratrol and 665 mg of omega-3, among other nutrients).

100 µL of Resvega once a day;

38 days.

C57BL6/J mice.

Less vascular endothelial growth factor (VEGF) protein expression levels and less MMP-9 activity;

Mitigate choroidal neovascularization and retinal disease.

[58]

Others

    

Dermatologic food

(EPA+DHA+polyphenols).

Dermatologic food;

8 weeks.

Adult atopic dog.

Reductions in clinical scores of atopic dermatitis.

[59]

Olive oil polyphenols and fish oil.

Prospective birth cohort Assessment of Lifestyle

and Allergic Disease During INfancy (ALADDIN)

Families recruited: September 2004–November 2007;

Stockholm area, Sweden.

Placentas.

Altered histone acetylation in placentas.

[60]

Omega-3 fatty acids, and polyphenols, fiber.

Mother–neonate pairs from the prospective and observational MAMI birth cohort.

Recruited: 2015–2017

Spanish–Mediterranean area;

18 months.

Gut microbiota from mother–neonate pairs.

Higher abundance of the Ruminococcus species in maternal gut microbiota;

Higher relative abundance of Faecalibacterium prausnitzii considered as a biomarker of colonic health, associated with anti-inflammatory properties;

Modulation of neonatal microbiota.

[61]

2.3. Omega-3 Lipophenols Derivatives: the Combined Properties of Omega-3 PUFAs and Polyphenols in a Single Molecule

This anti-inflammatory action was furthe successfulr investigated and it was reported that low concentrations of a combination of the biological activities of polyphenols and omega-3 PUFAs on oxidEPA-rich oil and phytonutrients prevented the transformation of microglia to proinflammatory M1 phenotype and the redox-sensitive NF-κB activation, inwhile the anti-inflammationory IL-10 secretion [44]. In N2a neural cell, the main Mediet-related diseases, cancer,terranean diet nutrients demonstrated to be potent cytoprotective agents against neurotoxicity [45] and other diets like human pathologies the LMN, also rich in polyphenols and PUFAs, decreased the behavioral deterioration and delayed the amyloid plaques formation [47], and caused an enhavnce been reportd modulatory effect on both cholinergic and catecholaminergic transmissions [48] in animal modedls of in several studies, as we showed in this revieaging and Alzheimer’s disease. Similar conclusions on the improvement of memory and cognitive performance were also reached in animal models feeding diets rich in those compounds and other bioactive nutrients [49]. How.ever, As a consequeresults were more inconsistent in clinical trials. For instance, the intsupplementation with Smartfish® increased amyloid-β phagocytosis and rest in the solvin D1 in patients with minor cognitive impairments [51], but it had o-nly a limited beneficalled omega-3ial impact in older adults without any other pathology l[52].

Mixtures between polyphenol derivatives or sphingolipids hs and omega-3 were tested in young subjects to find beneficial effects over the post-mild traumatic brain injury function in adolescent rats [50], and s grown during the last decadeeemed to improve executive function, brain health, and nutritional status in vulnerable young children at risk of undernutrition living in low-income countries [53].

4. Combined Polyphenols and Fish Oils Intake for Improving Cancer. Preclinical and Clinical Evidence.

The Ibioactivit has been described a heterogeneous group of different chemical structures obtained fromy of the combination between polyphenols and PUFAs was also tested against some types of cancers. In colonic leucine-rich repeat-containing G-protein-coupled receptor 5-positive (Lgr5+) stem cells in mice, which are the cells of origin of colon cancer, the chemical bonding between polyphenols and omega-3 PUFAs and someombination between fish oil and curcumin synergistically increased targeted apoptosis in DNA damaged Lgr5+ stem cells, maximally reduced their damaged, drop to the level measured in saline-treated mice. Moreover, p53 signaling in Lgr5+ stem cells from natural sourcesmice exposed to a genotoxic carcinogen (azoxymethane) was uniquely up-regulated only following fish oil plus curcumin cotreatment [6254][63][64]. ThIntere are alsostingly, some esterified phenols with fatty acids different from omega-3 PUFAs, omega-3 PUFAs (so-called lipophenols), particularly quercetin bound to ALA, EPA and DHA reported antioxidant, anti-inflammatory, and anticarcinogenic properties in lung cells exposure to H2O2 insult [66] or chigarette smoke atoxicants [67].

A recent study reported thaprylic acit hydroxytyrosol combined with omega-3 and curcumin reduced inflammation and [65],pain in patients with aromatase-induced musculoskelmitoyl acidetal symptoms, as one of the side effects of the hormonal therapies for breast cancer [6655]. Remarkably, or oleic acidseveral DHA and phenols conjugated increase the bioactivity of the individual compounds against breast cancer [6768], and also mainly investigated because ofight prevent or inhibit the progression of triple-negative breast cancer (TNBC) [69] and inhibit the geir protectilatinolytic matrix metalloproteinase MMP-9 [70]. Morever, effect in lipid-based food matrthe high adherence to diets rich in polyphenols and fish oils, such as the Mediterranean diet, was found inversely associated with the likelihood of suffering from prostate cancer [56].

5. Combined Polyphenols and Fish Oils Intake for Improving Other Pathologies and Physiological Processes. Preclinical and Clinical Evidence.

Physiologices from al processes concomitant with oxidation, and more recently as functional food ingredientsve stress and/or inflammation were also addressed to test the effects of polyphenols and fish oils. As a consequence, it has been found that fish oil and curcumin mayprevent skeletal muscle atrophy [6857]. EFunctional beven if they are also very relrages containing these nutraceuticals seemed to protect against oxidative damage [58] and evnhant and showed imporce the gene expression of antioxidant enzymes in peripheral blood mononuclear cells [59] in young atanhletes, but propertiesincreasing nitrative damage [58] and the proinfunctions, they arlammatory circulating environment in response to the exercise o[59]. Furt of the scope of this review, andhermore, an antioxidant/anti-inflammatory cocktail did not cause any significant effect in the prevention of muscle deconditioning induced by long-term inactivity in healthy men [60]. These heteronly the last studgeneous results reflect the extremely complexyty of the redox homeostasis in skeletal muscle and the need for more investigation.

Likes abouwise, it has been reported that omega-3 lipophenol derivatives will be considered anand resveratrol could prevent aged retinal pigment epithelial (RPE) cells damage and age-related macular degeneration [61], choroidal summarizneovascularization [62] and they can be used in for designed Table 3.

Table 3.dermatologic diets to Suimmary of the mosprove skin barrier function for the treatment of dermatitis [63]. Int erecent researches thatstingly, several esterified phenols with DHA have studied the potential of lipophenols for their use inhown powerful antioxidant properties and high protection activities against reactive aldehyde all-trans-retinal toxicity and photo-oxidative toxicity and constitute highly promising strategies for the prevention and treatmentof retinal degeneration [71][72][73][74][75][76].

Finally, sofme several humtudies revealed that immune priming [64] and dmicrobiota [65] isn the neases and pathologies.wborn are tightly regulated by maternal diet composition, particularly polyphenols and omega-3, affecting the infant health.

Lipophenol

Dose

Model

Health Effects of the Combination

Reference

• In vitro studies

Isopropyl-phloroglucinol (IP)-DHA; IP–D2-DHA; IP–D4-DHA.

0–80 µM for 1 h.

ARPE-19 cells.

Reduced radical lipid peroxidation status on cells under oxidative conditions as a model of age-related macular degeneration and Stargardt’s disease.

[69]

IP-DHA.

0–80 µM for 1 h.

Primary rat RPE, mouse neural retina and human ARPE-19 cells.

Both polyphenol and PUFAs are needed for anti-carbonyl and anti-oxidative capacities;

Protection against a lethal dose of all-trans-retinal;

Long term protection effects.

[70]

Quercetin conjugated to DHA (Q-3-DHA).

0–80 µM for 1 h.

ARPE-19 cells.

Less toxicity that quercetin alone and better anti-carbonyl capacity.

[71]

Q-3-DHA-7OiP (quercetin-isopropyl DHA).

0–80 µM for 1 h.

ARPE-19 cells.

Highly capacity against carbonyl and oxidative stresses.

[72]

Quercetin-3-O-glucoside (Q3G)-EPA and -DHA.

1 mM for 48 h at 37 °C.

Normal diploid human fetal lung fibroblast cell line (WI-38);

Fresh human normal primary hepatocytes (h-NHEPS™).

Greater cell viability upon H2O2 exposure in lung and liver;

Lower production of lipid hydroperoxides under induced oxidative stress.

[73]

Quercetin-3-O-glucoside (Q3G)-EPA and -DHA.

1 mM for 48 h at 37 °C.

Normal diploid human fetal lung fibroblast cell line (WI-38).

Protection against nicotine- and Cr(VI)-induced cell death and membrane lipid peroxidation;

A less inflammatory response (lesser COX-2 and PGE2).

[74]

DHA linked to resveratrol (RES-DHA).

10, 20, 40, or 80 μM for 72 h.

THP-1 monocytes.

Capacity for inhibiting MMP-9.

[75]

• In vivo studies

IP-DHA.

An intravenous injection at doses from 5 to 30 mg/kg body weight;

An orally gavaged administration at doses from 40 to 150 mg/kg body weight.

Albino Abca4−/− mice.

A dose-dependently decreased light-induced photoreceptor degeneration and preserved visual sensitivity by reducing carbonyl stress in the retina;

Long term protection effects.

[76]

Acylated phloridzin-DHA (PZ-DHA).

In vitro: 10, 50, 100 µM for 24 h at 37 °C;

In vivo: 5 intra-tumoral injections of PZ-DHA: 0.75 mg/kg;

15-days.

Mammary carcinoma (MDA-MB-231, MDA-MB-468, 4T1, MCF-7 and T-47D) cells;

Female non-obese diabetic severe combined immunodeficient (NOD-SCID) mice.

Selectively cytotoxic to breast cancer cells in vitro and in vivo.

[77]

Acylated phloridzin-DHA (PZ-DHA).

In vitro: 10 µM for 24 h at 37 °C;

In vivo: Intraperitoneal injection of PZ-DHA (100 mg/kg body weight) every second day for 9 days;

17-days.

Mammary carcinoma (MDA-MB-231, MDA-MB-468, 4T1, MCF-7 and T-47D) cells;

BALB/c and NOD-SCID female mice.

Potential prevention or inhibition of triple-negative breast cancer (TNBC).

[78]

36. Conclusions

The health benefits of the combination of the bioactive properties of the polyphenols and fish oils have demonstrated important beneficial effects, especially as abeen largely supported by a growing amount of scientific evidence. Several synergistic, additive, or complementary antioxidant and anti-inflammatory agents, because of several synergistic, additive, or complementaryeffects have been consistently reported, as well as modulation of lipid and lipoprotein metabolism. Modulation of insulin signaling and gut microbiota were also found. Nevertheless, some bioactive cocktails failed in reproducing the beneficial effects between both nin clinical trials. This fact might be explained by the complexity of the interaction of nutraceuticals, as is evidenced in the majority of the studies already published. However, more information is needed to u-metabolism and mechanisms of action, as well as the strongly influence that multiple factors exert on their bioactivity (chemical structure of polyphenols, diet EPA/DHA ratio, dietary framework, presence of other bioactive substances pathophysiological condition, physical activity of patients, age, etc). The adoption of multiomic and system biology strategies, and increasing the number of clinical trials would help fully understanding how theose nutraceuticals interact withto each other in vivo and also how they actually interact witwith the metabolism of a certain organism, and if it is wanted to use those nutraceuticals. This knowledge is neccessary for the correct use of polyphenols and fish oil as part of personalized nutrition.

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