Polyphenols and Fish Oils | Encyclopedia MDPI

Polyphenols and Fish Oils: History

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Polyphenols and omega-3 polyunsaturated fatty acids from fish oils, i.e., eicosapentaenoic and docosahexaenoic acids, are well-recognized 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 properties should offer a powerful tool for the design of successfully nutritional interventions for the prevention and palliation of a plethora of human metabolic diseases, frequently diet-induced, 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 about the cooperative action between polyphenols and fish oils against diet-related metabolic alterations, focusing on the mechanisms and pathways described and the effects reported. The final objective is to provide useful information for strategies for personalized nutrition based on these nutraceuticals.

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 induced by the consumption of “obesogenic” diets.

The widespread consumption of diets high in saturated fat and sugar and low in polyunsaturated fatty acids (PUFAs) and antioxidants, together with a more sedentary 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 is considered a risk factor for noncommunicable diseases such as type 2 diabetes and cardiovascular diseases (CVD) ^[5]. Other main chronic illnesses promoted by obesity are cancer and neurodegenerative pathologies, both affecting 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 metabolic alterations of MetS and its derived diseases are characterized by an increase in oxidative stress and a proinflammatory status ^[7]. 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 ^[9]. Habitual intake of fish-derived omega-3 has been reported to be involved in the prevention of several metabolic alterations and diseases, including autoimmune disorders, MetS, diabetes, CVD, neurodegenerative diseases, cancer, and others ^[10]. 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 ^[11]. The combination of omega-3 PUFAs and polyphenols in food may not only be useful for retaining their bioactive value and bioavailability but also may eliminate, or at least limiting, the deleterious potential effects of the high PUFAs intake regarding oxidation. Therefore, the recent evidence that supports the combined use of fish-derived PUFAs and polyphenols as nutraceuticals for the prevention and treatment of metabolic disturbances characterized by oxidative stress and inflammation, was to summarize bellow.

2. Combined Polyphenols and Fish Oils Intake for Improving Metabolic Health

During the last decade, several researchers have investigated the synergistic, additive, and complementary effects between fish oils (EPA and DHA) and polyphenols in preventing and palliating metabolic alterations and other physiological situations governed by oxidative stress and inflammation processes to provide solid scientific evidence for the optimum design of nutritional strategies.

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

Several studies, both preclinical and clinical ones, have evaluated the effects that the combination of polyphenols and fish oils would exert on MetS issues, and they are summarized in Table 1.

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 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

Besides MetS disorders, during the last decade, the combination of polyphenols and fish oils has been studied for the development of nutritional strategies that would result in an effective method of preventing and treating other diseases. In all the cases, these diseases, and also other physiological situations addressed, were also characterized by the disruption/change of the redox homeostasis and/or inflammatory status, and hence, they are strongly influenced by diet as well. Many of them are age-related diseases, such as brain damages, cognition alterations, and neurodegenerative diseases, which have been gained increasing interest in parallel with the extension of lifespan and the dramatic rate of aging of the worldwide population. The summary of the studies addressing these issues from the last decade is shown in Table 2.

Table 2. Summary of the researches from the last ten years that have studied the effect of the combination between polyphenols and fish oils for improving neurodegenerative pathologies, cancer, and other health effects.

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 Aβ_1–40 and Aβ_1–42 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-IRES^creERT2 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

The successful combination of the biological activities of polyphenols and omega-3 PUFAs on oxidation, inflammation, diet-related diseases, cancer, and other human pathologies have been reported in several studies, as we showed in this review. As a consequence, the interest in the so-called omega-3 lipophenol derivatives or sphingolipids has grown during the last decade. It has been described a heterogeneous group of different chemical structures obtained from the chemical bonding between polyphenols and omega-3 PUFAs and some from natural sources ^[62]^[63]^[64]. There are also esterified phenols with fatty acids different from omega-3 PUFAs, such as caprylic acid ^[65], palmitoyl acid ^[66], or oleic acid ^[67], mainly investigated because of their protective effect in lipid-based food matrices from oxidation, and more recently as functional food ingredients ^[68]. Even if they are also very relevant and showed important properties and functions, they are out of the scope of this review, and only the last studies about omega-3 lipophenol derivatives will be considered and summarized in Table 3.

Table 3. Summary of the most recent researches that have studied the potential of lipophenols for their use in the prevention and treatment of several human diseases and pathologies.

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]

3. Conclusions

The combination of the bioactive properties of the polyphenols and fish oils have demonstrated important beneficial effects, especially as antioxidant and anti-inflammatory agents, because of several synergistic, additive, or complementary effects between both nutraceuticals, as is evidenced in the majority of the studies already published. However, more information is needed to understand how these nutraceuticals interact with each other in vivo and also how they actually interact with the metabolism of a certain organism, and if it is wanted to use those nutraceuticals as part of personalized nutrition.

This entry is adapted from the peer-reviewed paper 10.3390/molecules26092438

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