Table 2.
Effects of n-3 PUFA supplementation in oxidative stress in healthy subjects or in population with cardiometabolic disorders.
| Reference | Study Design | Population | Intervention | Outcome Measurements | Comments |
|---|---|---|---|---|---|
| Meydani et al., 1991 [170] | Randomized intervention before and after comparison | Young females, aged 51–71; n = 14. Old females, aged 51–71. n = 9 | 1680 mg EPA + 720 mg DHA per day for 3 months | Plasma MDA level | ↑Plasma MDA level |
| Harats et al., 1991 [171] | Randomized parallel clinical trial | Study A: Smokers: Control: BMI: 23.5 ± 1.2, age: 42.6, n = 5 Fish oil: 23.8 ± 0.8, age: 37.4, n = 6 Study B: Smokers Control: BMI: 24.5 ± 1.2, age: 31, n = 3 Fish oil: BMI: 25.0 ± 1.3, age: 29.1, n = 3 Fish oil + VitE: BMI: 23.5 ± 1.2, age: 35.2, n = 4 Study C: Non-smokers, normolipidemic: Control: BMI: 23.7, age: 36.8, n = 8 Fish oil: BMI: 24.7 ± 1.3, age: 41, n = 6 Fish oil + VitE: BMI: 24.5 ± 1.9, age: 38.8, n = 6 |
Study A: Fish oil: concentrate (MaxEPA), 10 g/d for 4 weeks. Study B and C, Fish oil: (MaxEPA), 10 g/d for 4 weeks Fish oil (10 g/day) + Vit E (400 mg/d) for 4 weeks |
Plasma and LDL TBARS level | 10 g/d of fish oil consumption ↑plasma LDL TBARS level in smokers and non-smokers Vitamin E counteracted the effect of fish oil more effectively in non-smokers |
| Nenseter et al., 1992 [176] | Randomized placebo-controlled parallel clinical trial | Normolipidemic subjects Treatment: women and men, BMI not reported, age: 27–63, n = 12 Control: women and men, BMI not reported, age: 23–70, n = 11 |
Treatment: 6 g capsules/d of n-3 PUFA (highly concentrated ethyl esters). Control: 6 g of corn oil Duration: 4 months |
Susceptibility of LDL to Lipid peroxides formation | ↔ Lipid peroxides formation |
| Frankel et al., 1994 [177] | Randomized, double-blind, clinical trial | Hypertriglycemic men and women, age, BMI, smoking status not reported. n = 9/group | Control group: fish oil absent from the diet. Supplemented group: 5.1 g of fish oil per day for 6 weeks |
LDL oxidative susceptibility | ↔ LDL oxidative susceptibility |
| Brude et al., 1997 [178] | Randomized, double-blind, placebo-controlled parallel clinical trial | Male smokers, hyperlipidemia, aged 40–60, BMI not mentioned. n-3 PUFA capsule group (n = 11), antioxidant group (n = 11), n-3 PUFAS + antioxidants group (n = 11), control oil group (n = 9) |
n-3 PUFAS group: 5 g DHA and EPA/d Antioxidants capsule, 75 mg Vit E, 150 mg Vit C, 15 mg β-carotene, and 30 mg coenzyme Q10 per day Control group: 8 g of oil with an FA pattern similar to an ordinary Norwegian diet Lasted for 6 weeks |
LDL oxidative susceptibility, lipid peroxides | ↔ LDL oxidative susceptibility, ↔ lipid peroxides |
| Mori et al., 1999 [159] | Randomized, controlled parallel study | 49 untrained and sedentary NIDDM patients. Age: 30–65 y. BMI < 36 kg/m2 |
Study 1: Group 1: Low-fat diet (30% of daily energy) (n = 14) Group 2: Low-fat diet + one daily fish meal (3.6 g n-3 PUFA/day) (n = 12) Group 3: Low-fat diet + Moderate exercise (n = 11) Group 4: Low-fat diet + Fish meal + moderate exercise (n = 12) for 8 weeks. |
Urine F2- isoprostanes | Urine F2- isoprostanes |
| Higdon et al., 2000 [160] | Randomized blinded, crossover study | Post-menopausal women, aged between 50–75, BMI < 30 kg/m2, non-smokers, n = 15 | Fish oil group: 15 g/d (2.0 g EPA/d and 1.4 g DHA/d) Safflower oil group: 15g/d (10.5 g linoleate/d); Sunflower oil: 15g/d (12.3 g oleate/d) in a 3-treatment crossover trial (5 weeks with a 7-wk washout interval) |
Plasma F2-isoprostanes, MDA, and TBARS | In fish oil group: ↓plasma F2-isoprostanes ↓MDA ↑TBARS |
| Wander and Du, 2000 [172] | Randomized crossover study | Post-menopausal women, aged 45–75, BMI < 30 kg/m2, smoking status not reported. n = 46 | Group 1: fish oil (2.5 g EPA and 1.8 g DHA) Group 2: fish oil (2.5 g EPA and 1.8 g DHA) + 100 mg α-tocopheryl acetate Group 3: fish oil (2.5 g EPA and 1.8 g DHA) + 200 mg α-tocopheryl acetate Group 4: fish oil (2.5 g EPA and 1.8 g DHA) + 400 mg α-tocopheryl acetate for 5 weeks (4-period crossover design) |
TBARS, protein oxidation | ↑TBARS. Protein oxidation not changed |
| Mori et al., 2000 [162] | Randomized, placebo-controlled parallel study | Overweight, mildly hyperlipidemic men, age: 20–65 y, BMI: 25–30 kg/m2 | Group 1: 4 g/d of purified EPA (n = 19) Group 2: 4 g/d of purified DHA (n = 17) Group 3: 4 g/d of olive oil (n = 20) for 6 weeks |
Urine F2- isoprostanes | ↓Urine F2- isoprostanes in the EPA, DHA treatment groups |
| Wu et al., 2006 [179] | Randomized, single-blind, placebo-controlled parallel clinical trial | Post-menopausal vegetarian women, aged <60. Corn oil: n = 13 DHA: n = 14 |
Corn oil group: 6 g corn oil/day DHA-rich algae oil group: 2.14 g of DHA/day for 6 weeks |
Plasma α-tocopherol, urine F2-isoprostanes | ↔Plasma α-tocopherol, urine F2-isoprostanes |
| Egert et al., 2007 [173] | Randomized parallel controlled study | Healthy men and women, aged: 25.9 ± 6.82; BMI: 22.2 ± 2.95, non-smokers. n = 48 | ALA group: Rapeseed oil +1% of energy of ALA (n = 15) EPA group: Rapeseed oil + 1% of energy of EPA (n = 17) DHA group: Rapeseed oil + 1% of energy of DHA (n = 16) |
Ex vivo LDL oxidative susceptibility | EPA and DHA group: ↑ ex vivo LDL oxidative susceptibility |
| Cazzola et al., 2007 [163] | Randomized parallel placebo-controlled intervention | Healthy young men (age: 14–42 y, BMI: 24.1 ± 0.3). n = 93 Healthy old men (age: 53-70 y. BMI: 27.6 ± 0.0). n = 62 |
4 young and 4 older groups: 1: 1.35 g EPA + 0.27 g DHA per day; 2: 2.7 g EPA + 0.54 g DHA per day; 3: 4.05 g EPA + 0.81 g DHA per day; 4: corn oil group Lasted for 12 weeks |
Plasma lipid hydroperoxides Lag time of lipoprotein peroxidation |
↓Plasma lipid hydroperoxides ↓Lag time of lipoprotein peroxidation and ↓GSH/Gluthatione in olders |
| Hanwell et al., 2009 [180] | Randomized, double-blind, placebo-controlled crossover clinical trial | Hyper-triglyceridemic, overweight, and obese men; aged > 45, smoking status not reported. n = 10 in total | High-fat, high-fructose meal in all groups: Fish oil group: 7 g of fish oil concentrate (2.8 g EPA and 1.4 g DHA) Isoflavone group: 336 mg NovaSoy (150 mg glycoside isoflavones). Fish oil + isoflavone: 7 g fish oil + 336 mg NovaSoy Placebo group: 7 g corn oil Consumed 4 days separated by 1week wash out. |
Lipid peroxides, oxidized LDL, total antioxidant status |
↔ Lipid peroxides, ↔ oxidized LDL, ↔ total antioxidant status |
| Bloomer et al., 2009 [174] | Randomized, double-blind crossover study | Subjects are exercise trained man, non-smokers, no history of cardiometabolic diseases. Age: 25.5 ± 4.8 y. BMI: 24.1 ± 1.6 n = 14 |
Intervention group: 2.224 g EPA and 2.208 g DHA per day Control group: same quantity of soybean oil Duration: 6 weeks (with 8-week washout) Supplementation were prior to performing a 60 min treadmill climb using a weighted pack |
Blood was collected pre and post exercise and analyzed for a variety of oxidative stress (Protein carbonyls, IgG-autoantibodies, low-density lipoprotein, Malondialdehyde, Hydrogen peroxide and xanthine oxidase activity, Nitric oxide, Whole blood lactate and inflammatory biomarkers | Resting levels: ↓ CRP, ↓TNF- α, ↔ MDA, ↔ Nitric oxide. Exercise: ↑ oxidative biomarkers (mild) |
| Mas et al., 2010 [164] | Randomized, Placebo-controlled intervention | Study A: placebo-controlled intervention (BMI: 25–30), dyslipidemic men, age: 20–54 y, n = 17–20 per group. Study B: hypertensive type 2 diabetic and post-menopausal women, age: 40–75 y, n = 16–18 |
In both studies, n-3 PUFA group: 4 g/day of EPA or DHA Control group: Olive oil placebo lasted for 6 weeks |
Plasma F2-isoprostanes | ↓ Plasma F2-isoprostanes with n-3 PUFAS supplementation |
| Petersson et al., 2010 [181] | Randomized parallel study | Participants with metabolic syndrome, age: 35–70 y, BMI: 20–40 kg/m2, smokers or non-smokers. Saturated high-fat diet: n = 100 Monosaturated high-fat diet: n = 111 Low-fat diets with n-3 PUFA: n = 100 Low-fat diets with sunflower oil: n = 106 |
Saturated high-fat diet (38% E fat): (HSFA: 16% SFA, 12% MUFA and 6% PUFA), Monosaturated high-fat diet (38% E fat): (HMUFA: 8% SFA, 20% MUFA and 6% PUFA) Low-fat (28% E) high-complex carbohydrate diets (LFHCC: 8% SFA, 11% MUFA and 6% PUFA) with 1.24 g/d n-3 PUFA Low-fat (28% E)-high-complex carbohydrate diets (LFHCC: 8% SFA, 11% MUFA and 6% PUFA) with 1g/d high-oleic acid sunflower oil For 12 weeks |
Urinary levels of 8-iso-PGF2α and 15-keto-dihydro-PGF2α Serum CRP |
↔ 8-iso-PGF2α ↔ 15-keto-dihydro-PGF2α ↔ Serum CRP |
| Ulven et al., 2011 [182] | Randomized parallel study | Participants with normal or slightly elevated total blood cholesterol and/or triglyceride levels, age: 30–50 y, BMI > 30 kg/m2 | Krill oil group: 3 g/day (EPA + DHA= 543 mg/day) in 6 capsules (n = 36) Fish oil group: 1.8 g/day (EPA + DHA= 864 mg/day) in 3 capsules (n = 40) Control group: no supplementation (n = 37) Duration: 7 weeks |
Urine F2-isoprostanes, plasma α-tocopherol | ↔ Urine F2-isoprostanes, ↔ plasma α-tocopherol |
| Egert et al., 2012 [184] | Randomized single-blind parallel | Men and premenopausal women; Age: 19–43 y; BMI < 28 kg/m2, non-smokers | Margarines fortified with 10% weight of EPA, DHA, or ALA EPA group: 2.2 g/day (n = 25). DHA group: 2.3 g/day (n = 25) ALA group: 4.4 g/day (n = 24) For 6 weeks |
Antioxidant capacity, plasma MDA, RBC-MDA, linoleic acid hydroperoxides (LA-OOH) in RBC | ↔ Antioxidant capacity ↑Plasma MDA in EPA and DHA groups. ↔ RBC-MDA ↓ RBC-LA-OOH |
| Kirkhus et al., 2012 [185] | Open, randomized parallel study | 159 healthy men and women. Age: 18–70 y, BMI < 30 kg/m2, moderate smokers | 1g/day of EPA + DHA as: - fish pâté (34 g). n = 44 - n-3 PUFA-enriched fruit juice (500 mL). n = 38 - 3 capsuled of fish oil. n = 40 - Control: non-supplemented. n = 37 Duration: 7weeks |
Urine F2-isoprostanes and plasma α-tocopherol | ↓Plasma α-tocopherol in fish pâté group when calculated in relation to the level of serum TG ↔ F2-isoprostanes |
| Ottestad et al., 2012 [183] | Randomized, double-blind, placebo-controlled parallel study | 54 Healthy men and women, age: 18–50 y, BMI < 30 kg/m2, non-smokers | Group 1: 8 g/d of fish oil (EPA/DHA) n = 17 Group 2: 8 g/d of oxidized fish oil (EPA/DHA) n = 18 Group 3: 8 g/d of high-oleic sunflower oil n = 19 For 7 weeks |
Urine F2-isoprostanes and plasma oxidation products from n-3 PUFA and n-6 PUFA oxidation 4-HHE and 4-HNE; plasma α-tocopherol, enzymatic activity of GR, GPx, and CAT | ↔ Urine F2-isoprostanes and ↔ plasma oxidation products from n-3 PUFA and n-6 PUFA oxidation ↔ 4-HHE and ↔ 4-HNE; ↔ plasma α-tocopherol, ↔ enzymatic activity of GR, GPx, and CAT |
| Schimidt et al., 2012 [165] | Randomized, controlled, parallel intervention | 10 normo and 10 dyslipidemic men; Age: 29–51, BMI: 35 kg/m2. n = 20 | 6 Fish oil capsules, providing 1.14 g DHA and 1.56 g EPA per day, for 12 weeks | GST, GR, and antioxidative enzymes SOD3, CAT, and HMOX2 expression in whole blood cells, GPx, MMPs, cyrochrome P450 (CYP) enzymes expression in whole blood | ↑GST, ↑GR and antioxidative enzymes ↑SOD3, ↑CAT and HMOX2 expression, ↓GPx, ↓MMPs, ↓cytochrome P450 (CYP) enzymes expression |
| Kiecolt-Glaser et al., 2013 [166] | Randomized, double-blind, controlled parallel trial | Healthy sedentary overweight middle-aged and older adults Age: 48–85 y, BMI: 22.5–40 kg/m2. Non-smokers |
Group 1: 2.5 g/day n-3 PUFA (n = 35), Group 2: l.25 g/day n-3 PUFA (n = 40) Group 3: placebo capsules that mirrored the proportions of fatty acids in the typical American diet (n = 31) Duration: 4 months |
Plasma F2-isoprostanes | ↓Plasma F2-isoprostanes with n-3 PUFAS supplementation |
| Haijianfar et al., 2013 [167] | Randomized double-blind placebo-controlled clinical trial | Type 2 diabetic women. Age: 45–65 y BMI: 27.7 ± 3.4 (n-3 PUFA group). BMI: 28 ± 3.8. (Control group) |
n-3 PUFA group: 2000 mg/d in 2 capsules: each contained 1,000 mg n-3PUFA (65% EPA, 360 mg and 35% DHA, 240 mg) (n = 37) Control group: 2 placebo capsules, each contains 1 g of cornstarch (n = 34) Duration: 8 weeks |
Serum antioxidant capacity | ↑Antioxidant capacity in the n-3 PUFA supplemented group |
| Véricel et al. 2015 [168] | Randomized, double-blind, placebo-controlled, two-period crossover trial | Post-menopausal women with type 2 diabetes, age: 59.8 ± 4.7 y, BMI: 34.1 ± 5 kg/m2. n = 11 | Intervention: 400 mg/day of DHA (in 2 capsules/d) Control: 2 placebo (same amount of sunflower oil) Duration: 2 weeks |
Plasma and platelet vitamin E, alpha- and gamma-tocopherol concentrations, plasma MDA, 8-iso-PGF2α | ↑ Platelet alpha-tocopherol, gamma-tocopherol tend to increase. ↓MDA, ↓8-iso-PGF2α. n-3 PUFAS supplementation ↓ oxidative stress associated with diabetes |
| Alves Luzia et al. (2015) [175] | Randomized, double-blind, placebo-controlled trial | Women (40 to 70 years) with low habitual fatty fish and seafood intake, who met at least two of the following criteria: total cholesterol > 200 mg/dL, LDL-C > 140 mg/dL, HDL-C < 50 mg/dL, and triglycerides >150 mg/dL | The fish oil group: daily consumption of 1 g n-3 PUFA (540 mg EPA + 360 mg DHA) and 1 capsule of placebo (n = 22) Fish+VitE group: 1 g n-3 PUFA, 400 mg vitamin E/ alpha-tocopherol (n = 19). Placebo group: 2 capsules/d mineral oil (n = 18) Duration: 3 months |
Biomarkers of oxidative stress at baseline, 45 and 90 days | ↑ TBARS in the group supplemented with fish oil alone, but not in the fish oil + vitamin E group |
| Berge et al., (2015) [169] | Randomized, clinical interventional pilot study | Healthy female and male, mean age: 23 ± 4 y. BMI: 20.9 kg/m2, n=17 | 17 subjects received dietary supplementation with krill oil (832.5 mg EPA and DHA per day) for 28 days | Plasma total antioxidant capacity (AOC) | ↑AOC after krill oil intake. AOC positively correlated with plasma EPA concentration and RBC EPA concentration |
| Fayh et al., 2018 [161] | Randomized, double-blind, placebo-controlled trial | Male and female with T2DM, Age: 50–57 y. Mean BMI: 28.2 kg/m2 in n-3 PUFAS group and 28.8 kg/m2 in control group. n = 15/group | Control group: 3 capsules/day that contains 500 mg gelatin Intervention group: 3 capsules/d (each capsule contains 180 mg EPA, 120 mg DHA, 2 mg Vit E) For 8 weeks At the beginning and at the end of protocol, an acute exercise was performed (treadmill) |
TBARS; Plasma F2-isoprostanes, TRAP, SOD activity, hs-CRP | n-3 PUFA supplementation: ↓ TG, ↓TRAP levels after exercise, without a significant effect on inflammatory and oxidative-stress markers |
Abbreviations: NAFLD, non-alcoholic fatty liver disease; AST, aspartate transaminase; ALT, alanine transaminase; GGT, gamma-glutamyl transpeptidase; ↑, increased; ↓, decreased; ↔, not changed; TG, triglycerides; US, ultrasonography; DPI, doppler perfusion index; TNF-alpha, tumor necrosis factor-alpha; HOMA-IR, homeostasis model assessment-estimated IR; HDL, high density lipoprotein; FBG, fasting blood glucose; NS, not significant; CRP, C-reactive protein; MDA, malondialdehyde; EPA-E, ethyl-eicosapentanoic acid; MRI, magnetic resonance imaging; NAS, NASH activity score; ApoB, apolipoprotein B, FGF21, fibroblast growth factor 21; PGE2, prostaglandin E2; Hb1C, Hemoglobin A1c.