Abstract
The health benefits of plant food-based diets could be related to both integrated antioxidant and anti-inflammatory mechanisms exerted by a wide array of phytochemicals present in fruit, vegetables, herbs and spices. Therefore, there is mounting interest in identifying foods, food extracts and phytochemical formulations from plant sources which are able to efficiently modulate oxidative and inflammatory stress to prevent diet-related diseases. This paper reviews available evidence about the effect of supplementation with selected fruits, vegetables, herbs, spices and their extracts or galenic formulation on combined markers of redox and inflammatory status in humans.
Keywords: Antioxidants, human, functional foods, inflammation, oxidative stress, plant foods
1. INTRODUCTION
The regulation of endogenous antioxidant defences, including superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX), involves the interaction with antioxidant responsive elements (ARE) which are present in the promoter regions of most of the genes inducible by oxidative stress [1]. In particular, nuclear factor-erythroid 2-related factor 2 (Nrf2) is the transcription factor responsible for both constitutive and inducible expression of ARE-regulated genes [2]. Under physiological conditions, Nrf2 is bound to kelch-like protein-1 (KEAP1) and is thereby sequestered in the cytoplasm; however, in the presence of oxidative stress, Nrf2 dissociates from KEAP1, translocates into the nucleus and induces the transcription of antioxidant enzymes. Oxidative stress represents also a key stimulus for the activation of nuclear factor- kappa B (NF-κB), which appears in the cytoplasm of non-stimulated cells forming a complex with its inhibitor IκB. Following stimulation, NF-κB is activated by phosphorylation and degradation of IκB, thus migrating to the nucleus, stimulating gene expression and inducing the synthesis of inflammatory cytokines. The close link between oxidative and inflammatory stress in the mechanisms of body defences against stress, is further highlighted in the oxidative burst of leucocytes, the innate immune response involving the activation of NADPH-oxidase (NOX) and myeloperoxidase (MPO) yielding a massive production of Reactive Oxygen Species (ROS) and Reactive Nitrogen Species (RNS) [3]. However, the presence of an excessive and uncontrolled ROS and cytokines production, a condition defined as “low-grade chronic inflammation” takes place and is associated with pre-pathological conditions such as obesity and degenerative diseases [4, 5].
Inflammatory and oxidative stress can rise also as a direct consequence of unbalanced dietary life style, such as the ingestion of high fat and high carbohydrate meals [6, 7]. Increase in postprandial lipopolysaccharide (LPS) and Toll-like receptor-4 (TLR4) is associated with increased levels of inflammatory cytokines, such as interleukin (IL)-6, IL-17 and tumor necrosis factor-alpha (TNF-α) [8], which in turn activate oxidative burst [9]. Given these premises, the importance of the diet, as inducer or preventer of inflammatory and oxidative stress, is paramount.
A large body of epidemiological and clinical evidence provides a solid rationale for the health benefits of diets based on foods of vegetable origin [10], thanks to their content of bioactive ingredients such as vitamins and flavonoids. In fact, flavonoids and their metabolites, in addition to their direct free radical scavenging capacity [11], impair the production of ROS and RNS by neutrophils and other phagocytic cells through the inhibition of NOX, MPO and inducible-Nitric Oxide Synthases (iNOS) [3]. However, herbs and spices used for culinary purposes also represent an excellent, source of phytochemicals [12, 13]. Antioxidant and anti-inflammatory activities have been reported in vitro and in animal models for ginger (Zingiber officinale) [14], milk thistle (Silybum marianum) [15], hawthorn (Crataegus monogyna) [16, 17], passion flower (Passiflora edulis) [18] and chamomile (Matricaria chamomilla) [19, 20]. Therefore the health benefits of plant food-based diets could be related to both integrated antioxidant and anti-inflammatory mechanisms exerted by a wide array of phytochemicals present in fruit, vegetables, herbs and spices [21-24]. On this basis, there is mounting interest in identifying foods, food extracts and phytochemicals formulations from plant sources which are able to efficiently modulate oxidative and inflammatory stress to prevent diet-related diseases [25]. This paper reviews available evidence about the effect of supplementation with selected fruits, vegetables, herbs, spices, cocoa, beverages with mixed plant food composition as well as extracts and galenic formulation, on combined markers of redox and inflammatory status in humans.
2. Overview of identified studies
We performed a search on MEDLINE and Google Scholar Databases for literature of human studies by using the search terms: (fruit* OR vegetable* OR herb* OR spice* OR cocoa) AND antioxidant AND (cytokines OR CRP) AND (subjects OR patients).
A total of 88 interventions from 74 studies reporting both markers of redox/oxidative and inflammatory status after consumption of plant-derived products were collected. Dietary interventions were grouped according to different categories, specifically vegetables (Table 1) [26-31], fruits (Table 2) [32-54], grape seeds (Table 3) [55-59], herbs (Table 4) [60-65], green tea (Table 5) [66-70], spices (Table 6) [71-78], beverages with mixed composition (Table 7) [8, 79-82] extracts with mixed composition (Table 8) [83-93] and cocoa products (Table 9) [66, 94-97]. Selection of the plant foods was performed on the basis of available human data on both oxidative and inflammatory markers: for example, raspberry, blackberry and olives were not included due to the lack of combined information. Of these interventions, 69 were given over a long-term (from five days to 1 year). Studies were extremely variable in their experimental design: 44 were parallel, 17 were cross-over and 13 were longitudinal studies. The number of participants enrolled in individual trials ranged from 8 [29, 45] to 121 [73], and enrolled subjects were characterized by extremely variable features and health status: either healthy subjects or patients with asthma, cancer, infections, hemodialysis, rheumatoid arthritis, sepsis, acute respiratory distress syndrome, cardiovascular disease (CVD, hypertension, diabetes, dyslipidemia and metabolic syndrome and subjects with risk factors for CVD (i.e. smoking habit, overweight/obesity, old age). A limited number of studies evaluated the effect of the tested product in acute models of oxidative stress such as postprandial status (high energy meal, two studies) or physical exercise (five studies).
Table 1.
Treatment |
Dose/day
Standardization |
Subjects (healthy status and no.) | Study design and duration | Markers of red-ox/ oxidative status | Markers of inflammatory status | Refs. |
---|---|---|---|---|---|---|
Carrot (juice) | 16 fl oz | Healthy 17 |
Longitudinal, 3 months | NEAC↑ MDA↓ |
CRP and IL-1↔ | [26] |
Tomato (juice) | 280 ml (11.6 mg of lycopene/100 ml) |
Healthy women 25 |
Longitudinal, 2 months | TBARS ↓ NEAC ↔ |
Adiponectin ↑ | [27] |
Tomato-derived Lyc-O-Mato (capsules) | 45 mg lycopene | Asthmatic 79 |
Parallel, 14 weeks | IsoP↔ | CRP ↑ IL-6, IL-8 and TNF-α ↔ |
[28] |
Tomato-derived Lyc-O-Mato (capsules). | 30 mg lycopene | Obese 8 |
Longitudinal, 4 weeks | Dienes ↔ | CRP, TNF-α and IL-6 ↔ | [29] |
Tomato-derived Lyc-O-Mato (drink). | 250 ml (5.7 mg of lycopene, 3.7 mg of phytoene, 2.7 mg of phytofluene, 1 mg of β-carotene, and 1.8 mg α-tocopherol) |
Healthy 26 |
Crossover, 26 days | IsoP↔ | TNF-α and IFN-γ ex vivo ↓ | [30] |
Tomato-derived Lyc-O-Mato (extract) | 80 mg lycopene | Healthy 18 males |
Longitudinal, 1 week; postprandial (3h) |
MDA ↔ MDA ↔ |
CRP↔ CRP↔ |
[31] |
CRP: C reactive protein; IFN-γ: interferon gamma; IL: interleukin; IsoP: isoprostanes; MDA: malondialdehyde; NEAC: non-enzymatic antioxidant capacity; TBARS: thiobarbituric acid reactive substances; TNF-α: tumor necrosis factor alfa.
Table 2.
Treatment |
Dose/day
Standardization |
Subjects (healthy status and no.) | Study design and Duration | Markers of red-ox/ oxidative status | Markers of inflammatory status | Refs. |
---|---|---|---|---|---|---|
Bilberry (juice) | 330 ml | At least one risk factor for cardiovascular disease 62 |
Parallel, 4 weeks | NEAC, lipid peroxidation and GSH ↔ | CRP and IL-6 ↓ IL-1, IL-2, IL-12, IL-17 and IFN-γ ↔ TNF-α ↑ |
[32] |
Cranberries (dried powder) | 1500 mg | Men with urinary tract infection 42 |
Parallel, 6 months | NEAC, SOD, MDA, GSH, GPX, CAT and AOPP ↔ | CRP ↔ | [33] |
Cranberry (juice) | 480 ml (polyphenols 458 mg) |
Metabolic syndrome 31 |
Parallel, 8 weeks | NEAC ↑ MDA ↓ oxLDL,↓ |
CRP↔ IL6↔ |
[34] |
Cranberry (juice) | 0,7 litres (polyphenols 104mg/100ml) |
Metabolic syndrome 56 |
Parallel, 60 days | Lipid peroxidation and AOPP ↓ | Adiponectin ↑ CRP, TNF-α, IL-1 and IL-6 ↔ |
[35] |
Fermented papaya (sachets) | 9 g | Type 2 diabetic obese 17 |
Longitudinal, 2 and 6 weeks | 4-HNE ↔ Carbonils ↔ |
Oxidative burst ↑ | [36] |
Fermented papaya (supplement). | 9 g | Elderly 40 |
Crossover, 3 months | SOD, GPX and GSH ↔ | TNF-α and IL-6 ↓ CRP ↔ Hsp-70 ↑ |
[37] |
Fermented papaya (supplement). | 9 g | HCV-related cirrhosis 50 |
Longitudinal, 6 months | GSH and GPX↑ MDA and 8-OHdG↓ |
TNF-α↓ | [38] |
Fermented papaya (supplement). | 6 g | HCV-related cirrhosis 32 |
Parallel, 6 months | 4-HNE ↓ GSH ↑ |
TNF-α ex vivo ↓ | [39] |
Freeze-dried Strawberry | 50g (polyphenols 2.0g) |
Women with metabolic syndrome 16 |
Longitudinal, 4 weeks | 4-HNE, MDA ↓ oxLDL ↔ |
CRP and adiponectin ↔ | [40] |
Freeze-dried strawberry | 25 g (low) (polyphenols 1.0g) 50g (high) (polyphenols 2.0g) |
Obese with elevated serum lipids 60 |
Parallel, 12 weeks | MDA and HNE ↓ MDA and HNE ↓ |
CRP ↔ CRP ↔ |
[41] |
Freeze-dried strawberry | 50g (polyphenols 2.0g) |
Type 2 diabetic 36 |
Parallel, 6 weeks | NEAC ↑ MDA ↓ |
CRP ↓ | [42] |
Freeze-dried whole grape (powder) | 46 g (polyphenols 580 mg/100 g) |
Dyslipidemia 11 Non-dyslipidemia 13 |
Crossover, 4 weeks | oxLDL, IsoP, SOD and GPX↔ oxLDL, IsoP, SOD and GPX↔ |
TNF-α, IL-6, IL-8 and NOX↔ adiponectin↑ iNOS↓ TNF-α, IL-6, IL-8 and NOX↔ adiponectin↓ iNOS↑ |
[43] |
Treatment |
Dose/day Standardization |
Subjects (healthy status and no.) |
Study design and Duration |
Markers of red-ox/ oxidative status | Markers of inflammatory status | Refs. |
Pomegranate (concentrated juice) | 50 g (polyphenols 6.3 mg/100 g). |
Type 2 diabetic 31 |
Longitudinal, 4 weeks | NEAC ↑ | IL-6 and adiponectin ↓ TNF-α and CRP ↔ |
[44] |
Pomegranate (capsules) | 2 capsules (1.5g polyphenol). | obese with type 2 diabetes 8 healthy 9 |
Longitudinal, 4 weeks | 4-HNE, MDA ↓ oxLDL ↔ 4-HNE, MDA, oxLDL ↔ |
CRP ↔ CRP ↔ |
[45] |
Pomegranate (extract) | 1g (600–755 mg of gallic acid equivalents) |
Hemodialysis 33 |
Parallel, 6 months | NEAC, AOPP, 8-OHdG and ox-LDL↔ | IL-6 and CRP ↔ | [46] |
Pomegranate (extract) | 2 capsules (500 mg, 40% ellagic acid) | Rheumatoid arthritis 55 |
Parallel, 8 weeks | MDA ↔ GPX ↑ |
CRP ↔ | [47] |
Pomegranate (extract) | 100mg | Overweight/obese 42 |
Parallel, 30 days | MDA ↓ | CRP and IL-6 ↓ | [48] |
Pomegranate juice + pomegranate (extract) | 100 mL Juice 1,050 mg extract |
Hemodialysis 20 |
Crossover 4 weeks juce followed by 4 weeks extract or 4 weeks extract followed by 4 weeks juice), immediately before each dialysis treatment |
IsoP ↔ | CRP and IL-6 ↔ | [49] |
Pomegranate (juice) | 100ml (polyphenols 0.7mmol/100 cc juice). |
Hemodialysis 27 |
Parallel, during the first hour of a dialysis session | AOPP ↓ | MPO ↓ | [50] |
Pomegranate (juice) | 100 cc (polyphenols 0.7mmol/100 cc juice). |
Hemodialysis 49 |
Parallel, during each dialysis (3 times/ week), 1 year | MDA, AOPP and carbonyls ↓ | TNF-α, IL-6 and MPO ↓ | [51] |
Red grape (concentrated juice) | 100ml (polyphenols 0.64 g) |
Hemodialysis 38 Healthy 15 |
Parallel, 2 weeks | NEAC ↑ oxLDL ↓ NEAC ↑ oxLDL ↓ |
CRP ↔ CRP ↔ |
[52] |
Red grape (concentrated juice) | 100ml (polyphenols 0.64 g) |
Hemodialysis 16 |
Parallel, 2 weeks | oxLDL ↓ | CRP ↔ ROS ↓ |
[53] |
Rio red grapefruit | Half 3 times/day | Obese 74 Metabolic syndrome 29 |
Parallel, 6 weeks | IsoP ↔ IsoP ↔ |
CRP ↔ CRP ↔ |
[54] |
4-HNE: 4-hydroxynonenal; 8-OHdG: 8-hydroxy-2' –deoxyguanosine; AOPP: advanced oxidation protein products; CAT: catalase; CRP: C reactive protein; GPX: glutathione peroxidase; GSH: reduced glutathione; Hsp-70: heat shock protein 70; IFN-γ: interferon gamma; IL: interleukin; iNOS: inducible nitric oxide synthase; IsoP: isoprostanes; MDA: malondialdehyde; NEAC: non-enzymatic antioxidant capacity; NOX: NADPH-oxidase; oxLDL: oxidized low density lipoproteins; ROS: reactive oxygen species; SOD: superoxide dismutase; TNF-α: tumor necrosis factor alfa; HCV: Hepatitis C Virus.
Table 3.
Treatment |
Dose/day
Standardization |
Subjects (healthy status and no.) | Study design and duration | Markers of red-ox/ oxidative status | Markers of inflammatory status | Refs. |
---|---|---|---|---|---|---|
Grape seeds (capsules) | 1300 mg | CVD risk factors 50 |
Crossover, 1 month | NEAC, MDA and IsoP↔ | CRP and IL-6 ↔ | [55] |
Grape seed extract (added in yoghurt) | 2 g | CVDrisk factors 35 |
Crossover, 4 weeks | oxLDL and IsoP↔ | CRP↔ | [56] |
Grape seed extract (capsules) | 2 g | Overweight/obese first degree relatives of type 2 diabetic patients 38 |
Parallel, 8 weeks + 6d fructose |
week 8: carbonils ↓ IsoP and TBARS ↔ after fructose: IsoP and TBARS↓ |
week 8: CRP ↔ after fructose: CRP ↔ |
[57] |
Grape seed extract (tablets) | 600 mg | Type 2 diabetes 32 |
Crossover, 4 weeks | NEAC ↔ GSH ↑ |
CRP ↓ | [58] |
Monomeric and oligomeric flavanols from grape seeds (capsules) | 200 mg | Male smokers 25 |
Parallel, 8 weeks | NEAC, SOD, CAT, GPX and IsoP↔ GSH/GSSG ↑ |
CRP ↔ TNF-α ↓ |
[59] |
CAT: catalase; CRP: C reactive protein; CVD: cardiovascular; GPX: glutathione peroxidase; GSH: reduced glutathione; GSSG: oxidized glutathione; IL: interleukin; IsoP: isoprostanes; MDA: malondialdehyde; NEAC: non-enzymatic antioxidant capacity; oxLDL: oxidized low density lipoproteins; SOD: superoxide dismutase; TBARS: thiobarbituric acid reactive substances; TNF-α: tumor necrosis factor alfa.
Table 4.
Treatment |
Dose/day
Standardization |
Study design and duration |
Study design and
duration |
Markers of red-ox/ oxidative status | Markers of inflammatory status | Refs. |
---|---|---|---|---|---|---|
Ginseng based steroid Rg1 (capsule) | 5 mg Rg1 | Healthy 12 |
Crossover, one night and one hour before exercise | TBARS ↓ | IL6 ↔ TNF- α ↓ |
[60] |
Ginseng extract (capsule) | 250 mg, four capsules/day (7 mg ginsenosides) |
Hyperlipidemic 36 |
Parallel, 8 weeks | PAB ↔ | CRP↔ | [61] |
Ginsenosides (intravenously) | 1.5 mL/kg (equal to 1.35 mg/kg ginsenosides and 0.15 mg/kg aconite alkaloid). | Children undergoing heart surgery for congenital heart defects 24 |
Parallel, 2 minutes before the start of cardiopulmonary bypass (CPB) and throughout the course of CPB. | MDA (1 and 2h after reperfusion) ↓ | IL-6 and LPS (1 and 2h after reperfusion)↓ | [62] |
Silybum marianum (L.) Gaertn. (silymarin) extract (tablets) | 140 mg silymarin three times/day | Type 2 diabetes 40 |
Parallel, 45 days | SOD↑ GPX↑ NEAC ↑ MDA↓ |
CRP↓ | [63] |
Nettle (Urtica dioica) (extract) | 100 mg /kg of body weight | 50 type 2 diabetes |
Parallel, 8 weeks | NEAC ↑ SOD ↑ MDA↔ GPX↔ |
CRP and IL-6↓ TNF-α ↔ |
[64, 65] |
CRP: C reactive protein; GPX: glutathione peroxidase; IL: interleukin; NEAC: non-enzymatic antioxidant capacity; LPS: lipopolysaccharide; MDA: malondialdehyde; PAB: Pro-oxidant- Antioxidant Balance; SOD: superoxide dismutase; TBARS: thiobarbituric acid reactive substances; TNF-α: tumor necrosis factor α.
Table 5.
Treatment |
Dose/day
Standardization |
Subjects (healthy status and no.) | Study design and duration | Markers of red-ox/ oxidative status | Markers of inflammatory status | Refs. |
---|---|---|---|---|---|---|
Green tea (Beverage) | 2.4 g instant green tea (297.9 mg catechins) |
Obese 19 |
Crossover, 5 days | IsoP ↓ | CRP and IL6 ↔ | [66] |
Green tea extract (Beverage) | 159 mg total catechins in 450ml | Male cyclists 9 |
Crossover, 21 days, After exercise (2h) |
oxLDL and TBARS ↔ After exercise: oxLDLand TBARS ↔ |
CRP ↓ IL6 ↔ After exercise: CRP and IL6 ↔ |
[67] |
Green tea extract (capsule) | 379 mg (208 mg EGCG) | Obese, hypertensive patients 9 |
Parallel, 3 months | NEAC ↑ | TNF-α ↓ CRP ↓ |
[68] |
Green tea extract (capsule) | 1 g (483 mg of Camelia Sinensis powder and 100 mg of leaf extracts for a total of 68 mg catechins) | Chronic dialysis 20 |
Longitudinal, 3 and 6 months | oxLDL ↓ (only in 9 patients) | P22phox ↓ | [69] |
Green tea extract (Tablets) | 455 and 910 mg of catechins during a single hemodialysis session. | Haemodialysis patients 44 |
Crossover, bolus, 1 and 3h post-dialysis Parallel, 7 months |
peroxides ↓ peroxides ↓ |
IL-8 and TNF-α receptor↓ CRP and TNF-α↓ |
[70] |
CRP: C reactive protein; EGCG: epigallocatechingallate; IL: interleukin; IsoP: isoprostanes; NEAC: non-enzymatic antioxidant capacity; oxLDL: oxidized low density lipoproteins; TBARS: thiobarbituric acid reactive substances; TNF-α: tumor necrosis factor alfa.
Table 6.
Treatment |
Dose/day
Standardization |
Subjects (healthy status and no.) | Study design and duration | Markers of red-ox/ oxidative status | Markers of inflammatory status | Refs. | |
---|---|---|---|---|---|---|---|
Curcumin (phytosome) | 200 mg | Healthy 19 |
Parallel, 48 hours prior and 24 hours after running test | NEAC↔ CAT ↔ GPX ↔ |
CRP ↓ (24h) IL-8 ↓ (2h) MPO ↔ |
[71] | |
Curcumin extracts (powder) | 400 mg (80 mg curcumin) | Healthy 38 |
Parallel, 4 weeks | NEAC↑ CAT↑ SOD ↔ |
CRP ↔ MPO↑ |
[72] | |
Curcuminoids (capsules) | 4 g | Undergoing coronary artery bypass grafting 121 |
Parallel, 3 days before the surgery and 5 days after surgery | MDA↓ | CRP↓ | [73] | |
Turmeric (capsules) | 2 g | Type 2 diabetes on metformin therapy 60 |
Parallel, 4 weeks. | NEAC ↑ MDA↓ GSH, GPX, CAT and carbonyls ↔ |
CRP↓ | [74] | |
Turmeric (capsules) | 2.8 g | Overweight and obese women 98 |
Parallel, 4 weeks | IsoP and oxLDL↔ | CRP, IL-6, IL-8 and TNF-α ↔ | [75] | |
Ginger (capsule) | 1000 mg | Peritoneal dialysis 36 |
Parallel, 10 weeks | MDA↔ | CRP↔ | [76] | |
Treatment |
Dose/day Standardization |
Subjects (healthy status and no.) |
Study design and duration |
Markers of red-ox/ oxidative status | Markers of inflammatory status | Refs. | |
Ginger (capsules) | 3 g | Type 2 diabetes 45 |
Parallel, 3 months | NEAC↑ MDA↓ |
CRP↓ | [77] | |
Ginger extract (enteral feeding) | 120 mg | Acute respiratory distress syndrome 32 |
Parallel, 5 and 10 days | GSH (day 5)↑ | IL-1 ↔ IL-6 (day 5)↓ TNF-α ↔ |
[78] |
CAT: catalase; CRP: C reactive protein; GPX: glutathione peroxidase; GSH: reduced glutathione; IL: interleukin; IsoP: isoprostanes; MDA: malondialdehyde; MPO: myeloperoxidase; NEAC: non-enzymatic antioxidant capacity; oxLDL: oxidized low density lipoproteins; SOD: superoxide dismutase; TNF--α: tumor necrosis factor alfa.
Table 7.
Treatment |
Dose/day
Standardization |
Subjects (healthy status and no.) |
Study design and
duration |
Markers of
red-ox/ oxidative status |
Markers of inflammatory status | Refs. |
---|---|---|---|---|---|---|
Mixed fruit beveragea | 120 ml | Healthy 14 |
Longitudinal, 12 weeks | TBARS ↔ | CRP↔ | [79] |
Citrus-based juice with melanocarpab. | 300 ml | Metabolic syndrome 33 |
Parallel, 6 months | oxLDL↓ | CRP↓ | [80] |
Mixed fruit and vegetable beverageb | 360 mg/L polyphenols; 170 mg total proanthocyanidins and 9 mg anthocyanins in single dose | Healthy 20 |
Parallel, acute (0-4h) | IsoP↓ NEAC↑ |
CRP↔ | [81] |
Pineapple, black currant and plum. | 500 ml (32 mg anthocyanins, 2.5 mg flavan-3-ols and 20 mg flavonols) | Overweight 14 |
Crossover, acute, post-prandial with high fat and carbohydrates meal (0-8h) | IsoP↔ NEAC↔ |
TNF- α, IL-6 and IL-17↓ | [8, 82] |
CRP: C reactive protein; IFN: interferon; IL: interleukin; IsoP: isoprostanes; MDA: malondialdehyde; NEAC: non-enzymatic antioxidant capacity; TBARS: thiobarbituric acid reactive substances; TNF- α: tumor necrosis factor alfa. Mixed fruit beveragea: Acai pulp, pomegranate, wolfberry, camu camu, passion fruit, aronia, acerola, bilberry, apricot, purple grape, white grape, lychee, banana, kiwi, pear, cranberry, blueberry and prune. Citrus-based juiceb. juice citrus (95%) with 5% of A. melanocarpa extract. Mixed fruit and vegetable beveragec: Coffee fruit extract, grape seed, North American wild blueberry, quercetin, resveratrol, bilberry, raspberry, cranberry, prune, tart cherry, strawberry, grape seed extract, broccoli sprouts, broccoli, tomato, carrot, spinach, kale, brussels sprout, pomegranate extract and acai pulp) dissolved in a blend of juices (grape, pomegranate, pear, apple, strawberry, chiloensis; acai, yumberry, rubra; cupuacu and camu and a standardized extract of Ashwagandha).
Table 8.
Treatment |
Dose/day
Standardization |
Subjects (healthy status and no.) |
Study design and
Duration |
Markers of red-ox/ oxidative status | Markers of inflammatory status | Refs. | |
---|---|---|---|---|---|---|---|
Capsule containing antioxidants, plant-food extracts and PUFA | Four capsules (resveratrol 6.3 mg, tomato extract (3.75 mg lycopene), green tea extract 94.5 mg, a-tocopherol 90.7 mg, vitamin C 125 mg, eicosapentaenoic acid (EPA) 380 mg, docosahexaenoic acid(DHA) 260 mg, other PUFA 60 mg) |
Overweight 36 |
Crossover, 5 weeks | IsoP↓ | CRP ↔ IL-18 ↓ MPO ↑ |
[83] | |
CHOLACTIV (capsule) |
Two capsule Leucoselect® Phytosome® 250 mg; policosanol 15 mg; tomato extract (lycopene≥ 10%) 75mg; Oenothera biennis oil (cis-γ-linolenic acid≥9%) 250 mg) |
Dyslipidemia 60 |
Parallel, 6 weeks | SOD ↔ GPX ↔ MDA ↔ |
CRP ↓ | [84] | |
Fruits and vegetables capsules (FV)a FVB: FV with the addition of mixed berry juice powderb |
Three twice a day with meal | Healthy 117 |
Parallel, 60 days | SOD↑ SOD↑ |
CRP↔ CRP↔ |
[85] | |
Capsule containing: ginseng roots, mulberry leaf water extract and banana leaf water extract. | 6 g | Impaired glucose tolerance or mild T2D 94 |
Parallel, 24 weeks | oxLDL↓ | CRP↔ | [86] | |
Capsule containing powder concentrate derived from fruits and vegetablesc | Three twice a day with meal (6 capsules) (7.5mg β-carotene, 200mg vitamin C, 60 mg α-tocopherol) |
Overweight and obese pre-menopausal women 42 |
Parallel, 8 weeks Pre- and post-30 min exercise |
8 weeks: Carbonyls and oxLDL↓ MDA↔ Post-exercise: Carbonyls, oxLDL and MDA↔ |
8 weeks: TNF- α and IL-6↔ Post-exercise: TNF- α ↓ IL-6↔ |
[87] | |
Vitamins, minerals and mixed plant extractsd (Tablets) | 2 tablets | Healthy 42 |
Longitudinal, 4 weeks | oxLDL↓ IsoP↔ |
CRP↔ | [88] | |
Infusion of IMOD (urtica, carotenoids, urea, and selenium) | 125 mg of IMOD* | Severe sepsis 16 |
Parallel, 14 days | NEAC, lipid peroxidation and SH ↔ | TNF-α↓ IL-1, IL-2, IL-6↔ |
[89] | |
Powder containing: green tea extract, blueberry pomace extract, Soy protein complex | Soy protein complex 40 g. 2, 136 mg GAE. |
Healthy 31 |
Parallel, 2 weeks 2.5-h exercise (3-day exercise period). |
NEAC, carbonyls and IsoP↔ NEAC, carbonyls and IsoP↔ |
CRP, TNF-α IL-6 and IL-8 ↔ CRP, TNF-α IL-6 and IL-8 ↔ |
[90] | |
Treatment |
Dose/day Standardization |
Subjects (healthy status and no.) |
Study design and Duration |
Markers of red-ox/ oxidative status | Markers of inflammatory status | Refs. | |
Curcuminoids + piperine (capsules) | curcuminoids (1g) + piperine (10mg) | Metabolic syndrome 100 |
Parallel, 8 weeks | SOD↑ MDA↓ |
CRP↓ | [91] | |
Mixed plant extracts and fish oil capsules) | One each supplement/day 100 mg of resveratrol, a complex of 800 mg each of green, black, and white tea extract, 250 mg of pomegranate extract, 650 mg of quercetin, 500 mg of acetyl-l-carnitine, 600 mg of lipoic acid, 900 mg of curcumin, 1 g of sesamin, 1.7 g of cinnamon bark extract, and 1.0 g fish oil |
Healthy 54 |
Parallel, 6 months | Carbonyls ↔ | CRP, TNF- α and IL-6↔ | [92] | |
Powder containing green tea extract (1g) + vitamin C and E | Twice/day and one hour before surgery‡ | Cancer patients 36 |
Parallel, three doses† | NEAC ↑ IsoP↔ |
CRP ↔ | [93] |
CRP: C reactive protein; GPX: glutathione peroxidase; IL: interleukin; IsoP: isoprostanes; MDA: malondialdehyde; MPO: myeloperoxidase; NEAC: non-enzymatic antioxidant capacity; oxLDL: oxidized low density lipoproteins; PUFA: polyunsaturated fatty acids; SH: sulphydrils; SOD: superoxide dismutase; TNF- α: tumor necrosis factor alfa; T2D: Type 2 diabetes. a: capsules blended fruit and vegetable juice powder concentrate derived from acerola cherry, apple, beet, broccoli, cabbage, carrot, cranberry, kale, orange, peach, papaya, parsley, pineapple, spinach, and tomato; b: bilberry, blackberry, black currant, blueberry, cranberry, Concord grape, elderberry, raspberry and red currant; c: acerola cherry, apple, bilberry, blackberry, black currant, blueberry, beetroot, broccoli, cabbage, carrot, Concord grape, cranberry, elderberry, kale, orange, peach, papaya, parsley, pineapple, raspberry, red currant, spinach and tomato; d: Citrus bioflavonoids, green coffee bean extract, pomegranate whole fruit extract, grape seed extract, blueberry fruit extract, green tea leaf extract, bitter melon fruit extract, prune skin extract, watercress herb 4:1 extract, Chinese cinnamon bark powder, Indian gum Arabic tree bark and heart wood extract, rosemary extract and artichoke leaf extract; *: in 100 ml of DW5% infused over 1 hour on the first day, then 8 ml of IMOD in 100 ml/d; ‡ pancreaticoduodenectomy; †: 2 the day before the operation and the third the day of surgery 3 h before the anaesthesia.
Table 9.
Treatment |
Dose/day
Standardization |
Subjects (healthy status and no.) | Study design and duration | Markers of red-ox/ oxidative status | Markers of inflammatory status | Refs. |
---|---|---|---|---|---|---|
Dark chocolate + Cocoa beverage |
36.9 g (Procyanidin 4.56mg/g) + 30.9 g (Procyanidin 15.6mg/g) |
Healthy 25 |
Longitudinal, 6 weeks treatment and 6-weeks washout period | NEAC, IsoP ↔ . oxLDL ↓ |
CRP ↔ Ex vivo IL-1β, IL-6, TNF-α ↔ |
[94] |
Cocoa beverages |
180 mg flavanols (low), 400 mg flavanols (medium) 900 mg flavanols (high) |
Obese 19 |
Crossover, 5 days | IsoP ↔ . IsoP ↓ IsoP ↔ . |
CRP↔, IL-6 ↑ CRP ↓, IL6↓ CRP ↔, IL-6 ↑ |
[66] |
Cocoa cream products |
78 g of: A: cocoa; B: cocoa + hazelnut (30 g); C: cocoa + hazelnuts + phytosterols (2 g); D:cocoa+hazelnuts+phytosterols+ fiber (20 g). |
Pre-hypertensive or stage-1 hypertensive, high cholesterol 113 |
Parallel, 4 weeks | oxLDL ↔ oxLDL ↔ oxLDL ↔ oxLDL ↓ |
CRP and IL-6 ↔ CRP and IL-6 ↔ CRP and IL-6 ↔ CRP ↓, IL-6 ↔ |
[95] |
Cocoa powder | 45.3 mg flavanols / 400 mL semi-skimmed milk |
Moderately hypercholesterolaemic 20 Healthy 24 |
Cross-over, 4 wks | NEAC, MDA, Carbonyls ↔ NEAC, MDA, Carbonyls ↔ |
IL-10 ↓ IL-1β, IL-6, IL-8, TNF-α ↔ IL-10 ↓ IL-1β, IL-6, IL-8, TNF-α ↔ |
[96, 97] |
CRP: C reactive protein; IL: interleukin; IsoP: isoprostanes; MDA: malondialdehyde; NEAC: non-enzymatic antioxidant capacity; oxLDL: oxidized low density lipoproteins; TNF-α: tumor necrosis factor alfa.
As expected, multiple biomarkers were used to monitor different aspects of redox/oxidative and inflammatory status in biological fluids and cells. Markers of redox status included non- enzymatic antioxidant capacity (NEAC, n=29), reduced glutathione (GSH, n=8) or ratio of reduced/oxidized glutathione (GSH/GSSG) (n=1), antioxidant enzymes (n=29) (e.g. SOD, CAT and GPX), markers of lipid peroxidation (n=77) [i.e. oxidized low density lipoproteins (oxLDL), isoprostanes (IsoP), malondialdehyde (MDA), thiobarbituric acid reactive substances (TBARS), peroxides, 4-hydroxy-nonenal (4-HNE) and conjugated dienes], pro-oxidant- antioxidant balance (PAB, n=1), 8-hydroxy-2'–deoxyguanosine (8-OHdG, n=2) and markers of protein oxidation (n=15). Inflammatory markers included C-reactive protein (CRP, n=69), heat shock protein 70 (HSP70, n=1), inflammatory cytokines (n=49), adiponectin (n=8) and markers of innate immunity-mediated ROS generation (n=10) [i.e. the oxidative burst, subunit p22phox of the NOX, iNOS and MPO].
3. Studies on combined antioxidant and anti-inflammatory effect of vegetables and vegetable extracts
Table 1 describes the reviewed intervention studies on the combined antioxidant and anti-inflammatory effects of vegetables and vegetable extracts.
Three months of supplementation with carrot [26] juice decrease marker of lipid oxidation, increase plasma antioxidant defenses but did not show any effect on inflammatory markers in healthy subjects. On the contrary, drinking 280 mL of tomato juice for two months [27] decreased markers of lipid oxidation, without affecting antioxidant capacity status, but increasing the anti-inflammatory adiponectin in healthy subjects. On the other hand, tomato-derived Lyc-o-Mato supplement did not affect peroxidation markers, neither in the form of drink [30] nor as supplement [28, 31]. Besides Lyc-o-Mato increased CRP production in asthmatic subjects [28] without affecting plasma cytokines concentration in obese and asthmatic subjects [28, 29], but decreasing the ex-vivo production of interferon (IFN)-γ and TNF-α in healthy subjects [30].
Although only 28.6% (2/7) of the interventions improved the markers of red-ox or inflammatory status, however it must be taken into account that some of the intervention studies were not controlled for placebo [26, 27, 29, 31] and 4 studies out of seven were conducted on healthy subjects, supposedly not affected by oxidative/inflammatory chronic conditions.
4. Studies with fruits, fruit juices, grape seeds and their extracts
Within juice (Table 2), pomegranate juice (100cc/day, 1 year) [48] and concentrated juice (50g/day, four weeks) [44] decreased IL-6 [44, 48, 51] or MPO [50, 51], concomitantly increasing NEAC [44] or decreasing lipo-peroxidation and protein oxidation markers [48, 50] in type 2 diabetic patients [44], hemodialysis subjects [50, 51] and overweight/obese subjects [48].
Cranberry juice (0.7 liters for 60 days in parallel design) significantly reduced markers of protein and lipid oxidation and increased the anti-inflammatory adiponectin in patients with metabolic syndrome [35].
In the study by Basu et al. [34], 480 mL of cranberry juice, in a similar period of time (8 weeks) and in patients with metabolic syndrome, decreased oxidative stress markers (oxLDL and MDA), increase plasma NEAC and in agreement with results from Simao’s [35], the juice did not affect CRP and IL-6 levels, while adiponectin levels were not measured in this study. On the contrary, when cranberry was given as dried powder for 6 months, it neither affected the markers of redox/oxidative status nor CRP in men with urinary tract infections [33]. Bilberry juice, in a parallel study on subjects with at least one risk factor for CVD was effective in modulating inflammatory markers without any impact on redox status or lipid oxidation [32]. On the contrary, in type 2 diabetic patients, freeze-dried strawberry 50g/day consumption for 6 weeks decreased CRP and MDA and increased NEAC [42].
One and half rio red grapefruit consumption for 6 weeks in parallel design, failed to display any effect on isoprostanes and CRP levels neither in obese nor in subjects with metabolic syndrome [54]. However, it is extremely interesting to notice that subjects with high baseline isoprostanes levels experienced a significant reduction in response to grapefruit consumption, highlighting once more the importance of a detectable oxidative/inflammatory stress for a significant effect [54, 98]. Marotta et al. [38, 39] showed that supplementation with 9 and 6 g of fermented papaya for 6 months in patients with HCV-related cirrhosis translated in an improvement of marker of redox status, in a decrease in marker of oxidative stress and in a parallel anti-inflammatory effect on TNF-α and TNF-α ex vivo production. In a different group of subjects, chronic consumption of 9 g of fermented papaya for 3 months decreased TNF-α and IL-6, increase Hsp-70 without changes in antioxidant enzymes in elderly subjects [37]. A quite surprising increase of oxidative burst in PBMN was described in Type 2 diabetic obese after supplementation with 9 g of sachets of fermented papaya [36]. Barona et al. [43] observed an increase of iNOS in subjects without dyslipidemia and a decrease in those individuals with dyslipidemia after 4 weeks of consumption of 46 g of freeze-dried whole grape powder. Also plasma adiponectin concentrations followed opposite outcomes based on dyslipidemia category (Table 2), whereas IL-6, IL-8, TNF-α, SOD, GPX, oxLDL and IsoP did not differ significantly between treatment periods regardless of dyslipidemia classification. On the contrary GPX increased in patients with Rheumatoid Arthritis after the consumption of pomegranate extract (500 mg) for 8 weeks [50].
Table 3 describes intervention trials with grape seeds in different forms: as capsules [55, 57], tablets [58] or added in yoghurt [56].
In the study by Kar et al. [58] where 600 mg of grape seeds extract was given to 32 diabetics for 4 weeks, showed a combined effect in increasing antioxidant status (GSH), and decreasing inflammation (CRP). In agreement with Kar’s findings, 200 mg of monomeric and oligomeric flavanols from grape seeds increased the GSH/GSSG ratio and decreased TNF-α in smokers. Higher doses of grape seed extract, 1300 mg and 2 g, did not show any effect on selected markers of redox, oxidative and inflammatory status [55, 56]. Nevertheless, two grams of grape seeds extracts displayed an antioxidant effect, decreasing isoprostanes and lipid oxidation, after fructose ingestion in overweight obese patients [57].
5. Studies with herbs, green tea and their extracts
Overall, herb extracts are extremely effective in modulating oxidative and inflammatory status as shown in four studies out of the five identified (Table 4).
Ginseng-based steroid Rg1 (5 mg) decreased lipid oxidation and inflammatory TNF-α in healthy subjects after exercise [60] and ginsenosides, intravenously injected, decreased lipid oxidation and IL-6 and LPS production [62].
On the contrary, capsules of ginseng extracts did not affect CRP levels and antioxidant status [61]. Between the selected herbs, extracts of Silybum marianum (milk thistle) decreased CRP in subjects with Type 2 diabetes in concomitance with an increase in NEAC and antioxidant enzymes (SOD and GPX), as well as with decreases in MDA levels [63]. Also the hydro alcoholic nettle (Urtica dioica) extract, 100 mg/kg of body weight for 8 weeks supplementation, increased NEAC and decreased IL-6 and CRP in patients with type 2 diabetes [64, 65].
Green tea extracts modulate both markers of oxidation and inflammation, as shown in three studies out of the four identified; at least one marker of inflammation was actively improved in all studies (Table 5).
In particular, in hemodialysis patients the decrease in peroxides levels of two different doses of green tea extract (455 and 910 mg) was associated with the reduction of markers of inflammation IL8 and TNF-α receptor, CRP and TNF-α both after acute and chronic consumption [70]. Similar results were obtained with 1 g of green tea extract in a longitudinal study of 3 and 6 months with a decline in oxLDL and of p22phox [69]. Furthermore green tea extract (379 mg) increased NEAC, concomitantly with a reduction of TNF-α and CRP after 3 months of supplementation in obese and hypertensive patients [68].
6. Studies with spices extracts
Spices often used for culinary purposes, namely curcumin and ginger, showed the capability to improve both oxidative stress and inflammatory status (Table 6).
Capsules of curcuminoids decreased lipid oxidation and CRP levels in patients undergoing coronary artery bypass [73]. Decrease of CRP and IL-8 concentration but with no antioxidant effect, was obtained with 200 mg of curcumin in healthy subjects [71].
Studies conducted with ginger involved patients with Type 2 diabetes [77], subjects on peritoneal dialysis [76], or patients with acute respiratory distress syndrome [78]. In two of these studies, ginger consumption improved redox and inflammatory markers. In another 4-week study on diabetic patients, with a randomized, controlled design, turmeric (2g) as an adjunct to standard metformin therapy determined a significant reduction in lipid peroxidation and MDA, reduced CRP and enhanced total antioxidant status [74].
7. Studies with beverages and extracts with mixed plant food composition
Among different beverages, a mixed fruits juice did not affect neither TBARS nor CRP levels in healthy subjects after 12 weeks of 120 ml daily [79], whereas ingestion of 300 mL of citrus-based juice with added A. melanocarpa extract for 6 months reduced both oxLDL and CRP in patients with metabolic syndrome [80] (Table 7).
On the other hand, after acute consumption of a polyphenol-rich beverage containing an extremely variegate variety of mixed fruit and vegetable extracts improve redox markers without affecting CRP levels in healthy subjects [81].
On the contrary, half liter of a mixed fruit-based drink decreased the postprandial inflammatory stress induced by a high fat meal (1361 calories) without affecting redox markers in overweight subjects [8, 82] as displayed in Table 7.
As described in Table 8, when supplements with mixed composition were administered as capsules, tablets, powder or by infusion, three studies showed a combined effect on both markers of redox/oxidative and inflammatory status.
In particular, five weeks of supplementation with capsules containing resveratrol, tomato extract, green tea extract, antioxidant vitamins, fish oil and polyunsaturated fatty acids (PUFA), decreased isoprostanes concentration concomitantly with a reduction of IL-18 in overweight subjects [83]. After 8 weeks of consumption of capsules containing powder concentrate derived from acerola cherry, apple, bilberry, blackberry, black currant, blueberry, beetroot, broccoli, cabbage, carrot, Concord grape, cranberry, elderberry, kale, orange, peach, papaya, parsley, pineapple, raspberry, red currant, spinach and tomato, were found a decrease in protein (carbonyls) and lipid (oxLDL) oxidative damage, as well as the exercise-induced increase of TNF-α [87]. Furthermore, 8 weeks of supplementation with capsule containing curcuminoids (1g) + piperine (10 mg) was able to modulate SOD in conjunction with a decrease in lipid peroxidation (MDA) and the inflammatory CRP [91]. In the study from Soare et al. [92] providing an extremely variegate composition of functional ingredients, ranging from resveratrol, to fish oil to green, black and white tea etc. for 6 months failed to show any results on redox/oxidative and inflammatory status. Negative results were also obtained by Nieman et al. [90], with green tea, blueberry and soy protein extracts, and by Braga et al. [93] with green tea extracts and vitamin C and E, in healthy and
cancer patients, where only an effect on plasma NEAC was observed in Braga’s study. However, all these three studies suffered from potential bias due to lack or improper placebo. In particular, placebo was prepared from Soy protein isolate containing 1.38 mg/g gallic acid equivalents (GAE) in the study of Nieman et al. [90], it was a concentrate orange juice in the study of Braga et al. [93] and, in the study from Soare et al. [92] placebo was lacking and both groups received a daily multivitamin/mineral supplement. Studies from Gupta et al. [84] and Mahmoodpoor et al. [89] failed to display any effect on antioxidant status but showing a decrease of levels of CRP in patients with dyslipidaemia and TNF-α in patients with sepsis, respectively. A limited effect on SOD and LDL oxidation was observed after two months of supplementation with capsules containing a wide array of fruit and vegetables [85] or 24 weeks with capsules containing ginseng roots, mulberry and banana extracts [86] in healthy subjects and type 2 diabetes patients, respectively.
8. Studies with cocoa products
Table 9 describes the reviewed intervention studies with cocoa products, including dark chocolate, beverages and creams. Within these interventions decreases in peroxidation markers were observed in healthy [94], obese [66] and pre-hypertensive or stage-1 hypertensive subjects with high cholesterol [95]. In particular, the consumption of a cocoa beverage with a medium content of flavanols (400mg /day) for 5 days decreased IsoP, CRP and IL-6 levels in obese subjects, whereas beverages with lower (180mg/day) or higher (900mg/day) flavanols content increased IL-6 levels [66]. IL-6 did not decrease [95] after the consumption of a cocoa cream product (78g of cocoa + 30g hazelnuts + 2g phytosterols + 20 g fiber) that decreased levels of oxLDL and CRP [95]. Furthermore, others reported decreased levels of the anti-inflammatory IL-10 after the consumption of a cocoa powder (45.3mg flavanols) with 400 mL of semi-skimmed milk in both normo- and moderate hyper-cholesterolaemic subjects [96, 97].
9. DISCUSSION
In this paper, for the first time, we reviewed available evidence about the effect of supplementation with selected fruits, vegetables, herbs, spices and their extracts or galenic formulations on combined markers of redox and inflammatory status in humans. Overall, 30.7% (27/88) of the interventions did not show any positive effect on any markers, while in the remaining 69.3% (61/88) there was an improvement of at least one of the two category markers. Among the 61 interventions showing an effect on the selected markers, 44.2% (27/61) improved both markers of redox and inflammatory status. More specifically, markers of red-ox and oxidative status change after the interventions as follows: NEAC increased in 48.3% (14/29), GSH in the 50.0% (4/8), antioxidant enzymes in the 31.0% (9/29), whereas marker of protein oxidation and markers of lipid peroxidation decreased in the 33.3% (5/15) and 48.0% (37/77), respectively. For what concerning markers of inflammatory stress, CRP decreased after intervention in 24.6% of the studies (17/69), the 44.9% (22/49) of the interventions reported decreases in at least one inflammatory cytokines, whereas 40.0% of the interventions (4/10) reported increased in markers of ROS generation [i.e. the oxidative burst, iNOS and MPO].
Some considerations are essential for a more comprehensive evaluation of these findings. First, the high heterogeneity of the reviewed studies should be taken into account, as they involved not only wide and very different sources of food, food extracts and supplements, but also different doses, length of supplementation and characteristics of the subjects. Moreover, identified studies presented different robustness and designs, and sometimes a limited sample size. For what concerns the length of the study, in one-day trial it is possible having a clear experimental window of the investigated phenomenon, free of any interference from diet, physical activity and homeostatic controls. On the other hand, when dealing with long-term intervention studies, all the potential bias due to subjects variability, selection criteria, study design, food/extract/ galenic composition must be taken into account. The choice of the biomarkers and the type of measurements also represent an enormous source of variability: markers of redox status can include assessment of endogenous antioxidant (NEAC, single antioxidants, enzymes etc.), while markers of oxidative stress status might involve lipid peroxidation (oxLDL, MDA, isoprostanes, and others) and markers for inflammatory stress are mainly CRP and cytokines. All these markers respond differently to the different types of supplementation, providing different physiological meanings. In our view, in order to obtain a clearer picture of the phenomenon, it is preferable to assess a battery of biomarkers for three interconnected but different responses. For lipid oxidation, despite isoprostane levels being considered a gold standard, it will be also useful to assess other markers such as LDL oxidation or hydro-peroxides levels in order to obtain more complete information. At the same time, the assessment of antioxidant status should include markers for NEAC [Ferric Reducing Antioxidant Potential (FRAP), Total-radical Trapping Antioxidant Parameter (TRAP) and oxygen radical absorbance capacity (ORAC)], endogenous antioxidants (GSH, uric acid and thiols) and endogenous enzymes, preferably in cellular systems (CAT, SOD, GPX). With respect to the inflammatory response it is crucial to understand the role that every single cytokine plays in the different type of pathology or metabolic conditions, keeping in mind that their supposedly low or undetectable levels in healthy and young people could be raised by specific stressors such as post-prandial stress or strenuous physical exercise.
In long term studies we need to consider the existence of physiological mechanism of homeostatic control for both oxidative and inflammatory stress, aimed to tune the antioxidant network and to optimize inflammatory response to the stress. As we showed in previous works [98, 99], in healthy condition such as the absence of specific risk factors for oxidative stress (smoking, obesity, old age etc.), the body require a minimum dose of nutritional antioxidant to maintain physiological red-ox homeostasis, translating in a lack of effect on markers of antioxidant status following long term supplementation. We showed that 58% of the intervention studies conducted with fruit, vegetables, tea, wine, cocoa-products, olive oil and galenic flavonoids, reported a lack of effect in healthy subjects [99] with an effect size of 0.367 (p<0.001;n=1450) [98]. On the contrary when the studies were conducted on subjects characterized by different CVD risk factors (smoking, hypercholesterolemia, metabolic syndrome, hypertension etc.) involving the existence of an oxidative/inflammatory stress, the percentage of efficiency rise to 70% of the intervention studies and effect size of 0.937 (p<0.001;n=526) [98, 99].
A detailed description of the nutritional, antioxidant as well as bioactive ingredient composition of the tested food or extracts is crucial for characterizing the tested matrix and for defining the “effective dose” able to display an antioxidant/anti-inflammatory effect in humans. However, most of the studies lack this information and the majority of the compounds present in the food or in the extracts were not identified. However, between the different ingredients, flavonoids, with their considerable in vitro antioxidant capacity [100-102], might play a role in the modulation of redox-regulated genes as well as in the anti-inflammatory activity of plant foods [103, 104]. Flavonoids, such as catechins from green tea, curcumin from turmeric and grape seed procyanidins [1, 104-106] exert their anti-inflammatory and antioxidant effects through the activation of Nrf2, inducing the antioxidant enzymes transcription, and the inhibition of NF-kB, key transcription factors in inflammatory responses. In this framework, it must be taken into account that not only flavonoids, but also other bioactive phytochemicals like triterpenes, centella saponin, asiaticoside, and sceffoleoside, asiatic acid, madecassic acid, phenolic acid avenanthramides and others can affect Nrf2 and/or NF-κB pathways [107-109]. The mechanism suggested for Nrf2 and/or NF-κB modulation by polyphenols, phenolic acids, saponins and triterpenoids is the interaction of electrophiles with cysteine residues of KEAP1 I-κB and/or I-kappa kinases (IKK) [110-119].
However, due to the extensive metabolic activity during digestion, leading to different metabolites endowed with different bioactive ingredients from parental compounds, it is still unclear which are the bioactive ingredients or metabolites responsible of the effect and their relevance in humans [98, 99, 120].
CONCLUSION
In this review, we have shown that some fruits, vegetables, herbs, spices, cocoa and their extracts display a perceived functional activity increasing antioxidant status and at the same time modulating oxidative and inflammatory stress in humans. Interestingly, the modulatory effect of plant foods seems much more efficient in subjects characterized by different risk factors and high level of inflammatory and oxidative stress. In order to fully identify the food items, their functional ingredients as well as the mechanism of action able to display mutual antioxidant/anti-inflammatory activities, more evidence in humans is needed. Meanwhile, it is highly recommended to fully utilize the “functional heritage“ of the wide array of different phytochemicals with multi-factorial synergistic interactions contained in fruits, vegetables, herbs and spices and their extracts to efficiently prevent the raise of oxidative and inflammatory stress, major determinants of degenerative diseases.
ACKNOWLEDGEMENTS
Editorial assistance was provided by Luca Giacomelli, PhD, on behalf of Content Ed Net; this assistance was funded by PGT Healthcare.
LIST OF ABBREVIATIONS
- 4-HNE
4-hydroxynonenal
- 8-OHdG
8-hydroxy-2'–deoxyguanosine
- ARE
Antioxidant responsive elements
- CAT
catalase
- CRP
C-reactive protein
- CVD
cardiovascular disease
- FRAP
ferric Reducing Antioxidant Potential
- GAE
gallic acid equivalents
- GPX
glutathione peroxidase
- GSH
glutathione
- GSH/GSSG
ratio of reduced/oxidized glutathione
- HSP70
heat shock protein 70
- IFN
interferon
- IkB
inhibitor of NF-kB
- IKK
I-kappa kinases
- IL
interleukin
- iNOS
inducible nitric oxide synthases
- IsoP
isoprostanes
- KEAP1
kelch-like protein-1
- LPS
lipopolysaccharide
- MDA
malondialdehyde
- MPO
myeloperoxidase
- NEAC
non-enzymatic antioxidant capacity
- NF-kB
nuclear factor- kappa B
- NFR2
nuclear factor-erythroid 2-related factor 2
- NOX
NADPH-oxidase
- ORAC
oxygen radical absorbance capacity
- oxLDL
oxidized low density lipoproteins
- PAB
pro-oxidant- antioxidant balance
- PUFA
polyunsaturated fatty acids
- RNS
reactive nitrogen species
- ROS
reactive oxygen species
- SOD
superoxide dismutase
- TBARS
thiobarbituric acid reactive substances
- TLR4
toll-like receptor-4
- TNF-α
tumour necrosis factor-alpha
- TRAP
total-radical trapping antioxidant parameter
CONFLICT OF INTEREST
The authors confirm that this article content has no conflict of interest.
REFERENCES
- 1.Serafini M., Del Rio D., Yao D.N., Bettuzzi S., Peluso I. Health Benefits of Tea. In: Benzie I.F., Wachtel-Galor S., editors. Herbal Medicine: Biomolecular and Clinical Aspects. 2nd ed. Boca Raton, FL: CRC Press; 2011. [Google Scholar]
- 2.Hu R., Saw C.L., Yu R., Kong A.N. Regulation of NF-E2-related factor 2 signaling for cancer chemoprevention: antioxidant coupled with antiinflammatory. Antioxid. Redox Signal. 2010;13(11):1679–1698. doi: 10.1089/ars.2010.3276. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Halliwell B., Cross C.E. Oxygen-derived species: their relation to human disease and environmental stress. Environ. Health Perspect. 1994;102(Suppl. 10):5–12. doi: 10.1289/ehp.94102s105. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Guarner V., Rubio-Ruiz M.E. Low-grade systemic inflammation connects aging, metabolic syndrome and cardiovascular disease. Interdiscip. Top. Gerontol. 2015;40:99–106. doi: 10.1159/000364934. [DOI] [PubMed] [Google Scholar]
- 5.Magrone T., Jirillo E. Mechanisms of neutrophil-mediated disease: innovative therapeutic interventions. Curr. Pharm. Des. 2012;18(12):1609–1619. doi: 10.2174/138161212799958512. [DOI] [PubMed] [Google Scholar]
- 6.Burton-Freeman B. Postprandial metabolic events and fruit-derived phenolics: a review of the science. Br. J. Nutr. 2010;104(Suppl. 3):S1–S14. doi: 10.1017/S0007114510003909. [DOI] [PubMed] [Google Scholar]
- 7.Morabito G., Kucan P., Serafini M. Prevention of postprandial metabolic stress in humans: role of fruit-derived products. Endocr. Metab. Immune Disord. Drug Targets. 2015;15(1):46–53. doi: 10.2174/1871530314666141021114325. [DOI] [PubMed] [Google Scholar]
- 8.Peluso I., Raguzzini A., Villano D.V., et al. High fat meal increase of IL-17 is prevented by ingestion of fruit juice drink in healthy overweight subjects. Curr. Pharm. Des. 2012;18(1):85–90. doi: 10.2174/138161212798919020. [DOI] [PubMed] [Google Scholar]
- 9.Deopurkar R., Ghanim H., Friedman J., et al. Differential effects of cream, glucose, and orange juice on inflammation, endotoxin, and the expression of Toll-like receptor-4 and suppressor of cytokine signaling-3. Diabetes Care. 2010;33(5):991–997. doi: 10.2337/dc09-1630. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Trichopoulou A., Bamia C., Trichopoulos D. Anatomy of health effects of Mediterranean diet: Greek EPIC prospective cohort study. BMJ. 2009;338:b2337. doi: 10.1136/bmj.b2337. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Kumar S., Pandey A.K. Free Radicals: Health Implications and their Mitigation by Herbals. Br. J. Med. Med. Res. 2015;7:438–457. [Google Scholar]
- 12.Opara E.I., Chohan M. Culinary herbs and spices: their bioactive properties, the contribution of polyphenols and the challenges in deducing their true health benefits. Int. J. Mol. Sci. 2014;15(10):19183–19202. doi: 10.3390/ijms151019183. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Bower A., Marquez S., De Mejia E.G. The health benefits of selected culinary herbs and spices found in the traditional mediterranean diet. Crit. Rev. Food Sci. Nutr. 2016;56(16):2728–2746. doi: 10.1080/10408398.2013.805713. [DOI] [PubMed] [Google Scholar]
- 14.Mashhadi N.S., Ghiasvand R., Askari G., Hariri M., Darvishi L., Mofid M.R. Anti-oxidative and anti-inflammatory effects of ginger in health and physical activity: review of current evidence. Int. J. Prev. Med. 2013;4(Suppl. 1):S36–S42. [PMC free article] [PubMed] [Google Scholar]
- 15.Vaid M., Katiyar S.K. Molecular mechanisms of inhibition of photocarcinogenesis by silymarin, a phytochemical from milk thistle (Silybum marianum L. Gaertn.). Int. J. Oncol. 2010;36(5):1053–1060. doi: 10.3892/ijo_00000586. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Hatipoğlu M., Sağlam M., Köseoğlu S., Köksal E., Keleş A., Esen H.H. The Effectiveness of Crataegus orientalis M Bieber. (Hawthorn) Extract Administration in Preventing Alveolar Bone Loss in Rats with Experimental Periodontitis. PLoS One. 2015;10(6):e0128134. doi: 10.1371/journal.pone.0128134. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Zhang J., Liang R., Wang L., et al. Effects of an aqueous extract of Crataegus pinnatifida Bge. var. major N.E.Br. fruit on experimental atherosclerosis in rats. J. Ethnopharmacol. 2013;148(2):563–569. doi: 10.1016/j.jep.2013.04.053. [DOI] [PubMed] [Google Scholar]
- 18.Silva R.O., Damasceno S.R., Brito T.V., et al. Polysaccharide fraction isolated from Passiflora edulis inhibits the inflammatory response and the oxidative stress in mice. J. Pharm. Pharmacol. 2015;67(7):1017–1027. doi: 10.1111/jphp.12399. [DOI] [PubMed] [Google Scholar]
- 19.Drummond E.M., Harbourne N., Marete E., Jacquier J.C., O'Riordan D., Gibney E.R. An in vivo study examining the antiinflammatory effects of chamomile, meadowsweet, and willow bark in a novel functional beverage. J. Diet. Suppl. 2013;10(4):370–380. doi: 10.3109/19390211.2013.830680. [DOI] [PubMed] [Google Scholar]
- 20.Kolodziejczyk-Czepas J., Bijak M., Saluk J., et al. Radical scavenging and antioxidant effects of Matricaria chamomilla polyphenolic-polysaccharide conjugates. Int. J. Biol. Macromol. 2015;72:1152–1158. doi: 10.1016/j.ijbiomac.2014.09.032. [DOI] [PubMed] [Google Scholar]
- 21.Georgiev V., Ananga A., Tsolova V. Recent advances and uses of grape flavonoids as nutraceuticals. Nutrients. 2014;6(1):391–415. doi: 10.3390/nu6010391. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Serban C., Sahebkar A., Antal D., Ursoniu S., Banach M. Effects of supplementation with green tea catechins on plasma C-reactive protein concentrations: A systematic review and meta-analysis of randomized controlled trials. Nutrition. 2015;31(9):1061–1071. doi: 10.1016/j.nut.2015.02.004. [DOI] [PubMed] [Google Scholar]
- 23.Ghosh S., Banerjee S., Sil P.C. The beneficial role of curcumin on inflammation, diabetes and neurodegenerative disease: A recent update. Food Chem. Toxicol. 2015;83:111–124. doi: 10.1016/j.fct.2015.05.022. [DOI] [PubMed] [Google Scholar]
- 24.Goya L., Martín M.Á., Sarriá B., Ramos S., Mateos R., Bravo L. Effect of cocoa and its flavonoids on biomarkers of inflammation: studies of cell culture, animals and humans. Nutrients. 2016;8(4):212. doi: 10.3390/nu8040212. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Magrone T., Perez de Heredia F., Jirillo E., Morabito G., Marcos A., Serafini M. Functional foods and nutraceuticals as therapeutic tools for the treatment of diet-related diseases. Can. J. Physiol. Pharmacol. 2013;91(6):387–396. doi: 10.1139/cjpp-2012-0307. [DOI] [PubMed] [Google Scholar]
- 26.Potter A.S., Foroudi S., Stamatikos A., Patil B.S., Deyhim F. Drinking carrot juice increases total antioxidant status and decreases lipid peroxidation in adults. Nutr. J. 2011;10:96. doi: 10.1186/1475-2891-10-96. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Li Y.F., Chang Y.Y., Huang H.C., Wu Y.C., Yang M.D., Chao P.M. Tomato juice supplementation in young women reduces inflammatory adipokine levels independently of body fat reduction. Nutrition. 2015;31(5):691–696. doi: 10.1016/j.nut.2014.11.008. [DOI] [PubMed] [Google Scholar]
- 28.Wood L.G., Garg M.L., Smart J.M., Scott H.A., Barker D., Gibson P.G. Manipulating antioxidant intake in asthma: a randomized controlled trial. Am. J. Clin. Nutr. 2012;96(3):534–543. doi: 10.3945/ajcn.111.032623. [DOI] [PubMed] [Google Scholar]
- 29.Markovits N., Ben Amotz A., Levy Y. The effect of tomato-derived lycopene on low carotenoids and enhanced systemic inflammation and oxidation in severe obesity. Isr. Med. Assoc. J. 2009;11(10):598–601. [PubMed] [Google Scholar]
- 30.Riso P., Visioli F., Grande S., et al. Effect of a tomato-based drink on markers of inflammation, immunomodulation, and oxidative stress. J. Agric. Food Chem. 2006;54(7):2563–2566. doi: 10.1021/jf053033c. [DOI] [PubMed] [Google Scholar]
- 31.Denniss S.G., Haffner T.D., Kroetsch J.T., Davidson S.R., Rush J.W., Hughson R.L. Effect of short-term lycopene supplementation and postprandial dyslipidemia on plasma antioxidants and biomarkers of endothelial health in young, healthy individuals. Vasc. Health Risk Manag. 2008;4(1):213–222. doi: 10.2147/vhrm.2008.04.01.213. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Karlsen A., Paur I., Bøhn S.K., et al. Bilberry juice modulates plasma concentration of NF-kappaB related inflammatory markers in subjects at increased risk of CVD. Eur. J. Nutr. 2010;49(6):345–355. doi: 10.1007/s00394-010-0092-0. [DOI] [PubMed] [Google Scholar]
- 33.Vidlar A., Vostalova J., Ulrichova J., et al. The effectiveness of dried cranberries (Vaccinium macrocarpon) in men with lower urinary tract symptoms. Br. J. Nutr. 2010;104(8):1181–1189. doi: 10.1017/S0007114510002059. [DOI] [PubMed] [Google Scholar]
- 34.Basu A., Betts N.M., Ortiz J., Simmons B., Wu M., Lyons T.J. Low-energy cranberry juice decreases lipid oxidation and increases plasma antioxidant capacity in women with metabolic syndrome. Nutr. Res. 2011;31(3):190–196. doi: 10.1016/j.nutres.2011.02.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Simão T.N., Lozovoy M.A., Simão A.N., et al. Reduced-energy cranberry juice increases folic acid and adiponectin and reduces homocysteine and oxidative stress in patients with the metabolic syndrome. Br. J. Nutr. 2013;110(10):1885–1894. doi: 10.1017/S0007114513001207. [DOI] [PubMed] [Google Scholar]
- 36.Dickerson R., Banerjee J., Rauckhorst A., et al. Does oral supplementation of a fermented papaya preparation correct respiratory burst function of innate immune cells in type 2 diabetes mellitus patients? Antioxid. Redox Signal. 2015;22(4):339–345. doi: 10.1089/ars.2014.6138. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Marotta F., Koike K., Lorenzetti A., et al. Nutraceutical strategy in aging: targeting heat shock protein and inflammatory profile through understanding interleukin-6 polymorphism. Ann. N. Y. Acad. Sci. 2007;1119:196–202. doi: 10.1196/annals.1404.011. [DOI] [PubMed] [Google Scholar]
- 38.Marotta F., Yoshida C., Barreto R., Naito Y., Packer L. Oxidative-inflammatory damage in cirrhosis: effect of vitamin E and a fermented papaya preparation. J. Gastroenterol. Hepatol. 2007;22(5):697–703. doi: 10.1111/j.1440-1746.2007.04937.x. [DOI] [PubMed] [Google Scholar]
- 39.Marotta F., Chui D.H., Jain S., et al. Effect of a fermented nutraceutical on thioredoxin level and TNF-alpha signalling in cirrhotic patients. J. Biol. Regul. Homeost. Agents. 2011;25(1):37–45. [PubMed] [Google Scholar]
- 40.Basu A., Wilkinson M., Penugonda K., Simmons B., Betts N.M., Lyons T.J. Freeze-dried strawberry powder improves lipid profile and lipid peroxidation in women with metabolic syndrome: baseline and post intervention effects. Nutr. J. 2009;8:43. doi: 10.1186/1475-2891-8-43. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Basu A., Betts N.M., Nguyen A., Newman E.D., Fu D., Lyons T.J. Freeze-dried strawberries lower serum cholesterol and lipid peroxidation in adults with abdominal adiposity and elevated serum lipids. J. Nutr. 2014;144(6):830–837. doi: 10.3945/jn.113.188169. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Moazen S., Amani R., Homayouni Rad A., et al. Effects of freeze-dried strawberry supplementation on metabolic biomarkers of atherosclerosis in subjects with type 2 diabetes: a randomized double-blind controlled trial. Ann. Nutr. Metab. 2013;63(3):256–264. doi: 10.1159/000356053. [DOI] [PubMed] [Google Scholar]
- 43.Barona J., Blesso C.N., Andersen C.J., Park Y., Lee J., Fernandez M.L. Grape consumption increases anti-inflammatory markers and upregulates peripheral nitric oxide synthase in the absence of dyslipidemias in men with metabolic syndrome. Nutrients. 2012;4(12):1945–1957. doi: 10.3390/nu4121945. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Shishehbor F., Mohammad Shahi M., Zarei M., et al. Effects of concentrated pomegranate juice on subclinical inflammation and cardiometabolic risk factors for type 2 diabetes: a quasi-experimental study. Int. J. Endocrinol. Metab. 2016;14(1):e33835. doi: 10.5812/ijem.33835. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 45.Basu A, Newman ED, Bryant AL, Lyons TJ, Betts NM. Pomegranate polyphenols lower lipid peroxidation in adults with type 2 diabetes but have no effects in healthy volunteers: a pilot study. . J Nutr Metab . 2013. [DOI] [PMC free article] [PubMed]
- 46.Wu P.T., Fitschen P.J., Kistler B.M., et al. Effects of pomegranate extract supplementation on cardiovascular risk factors and physical function in hemodialysis patients. J. Med. Food. 2015;18(9):941–949. doi: 10.1089/jmf.2014.0103. [DOI] [PubMed] [Google Scholar]
- 47.Ghavipour M., Sotoudeh G., Tavakoli E., Mowla K., Hasanzadeh J., Mazloom Z. Pomegranate extract alleviates disease activity and some blood biomarkers of inflammation and oxidative stress in Rheumatoid Arthritis patients. Eur. J. Clin. Nutr. 2016 doi: 10.1038/ejcn.2016.151. [DOI] [PubMed] [Google Scholar]
- 48.Hosseini B., Saedisomeolia A., Wood L.G., Yaseri M., Tavasoli S. Effects of pomegranate extract supplementation on inflammation in overweight and obese individuals: A randomized controlled clinical trial. Complement. Ther. Clin. Pract. 2016;22:44–50. doi: 10.1016/j.ctcp.2015.12.003. [DOI] [PubMed] [Google Scholar]
- 49.Rivara M.B., Mehrotra R., Linke L., Ruzinski J., Ikizler T.A., Himmelfarb J. A pilot randomized crossover trial assessing the safety and short-term effects of pomegranate supplementation in hemodialysis patients. J. Ren. Nutr. 2015;25(1):40–49. doi: 10.1053/j.jrn.2014.07.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 50.Shema-Didi L., Kristal B., Ore L., Shapiro G., Geron R., Sela S. Pomegranate juice intake attenuates the increase in oxidative stress induced by intravenous iron during hemodialysis. Nutr. Res. 2013;33(6):442–446. doi: 10.1016/j.nutres.2013.04.004. [DOI] [PubMed] [Google Scholar]
- 51.Shema-Didi L., Sela S., Ore L., et al. One year of pomegranate juice intake decreases oxidative stress, inflammation, and incidence of infections in hemodialysis patients: a randomized placebo-controlled trial. Free Radic. Biol. Med. 2012;53(2):297–304. doi: 10.1016/j.freeradbiomed.2012.05.013. [DOI] [PubMed] [Google Scholar]
- 52.Castilla P., Echarri R., Dávalos A., et al. Concentrated red grape juice exerts antioxidant, hypolipidemic, and antiinflammatory effects in both hemodialysis patients and healthy subjects. Am. J. Clin. Nutr. 2006;84(1):252–262. doi: 10.1093/ajcn/84.1.252. [DOI] [PubMed] [Google Scholar]
- 53.Castilla P., Dávalos A., Teruel J.L., et al. Comparative effects of dietary supplementation with red grape juice and vitamin E on production of superoxide by circulating neutrophil NADPH oxidase in hemodialysis patients. Am. J. Clin. Nutr. 2008;87(4):1053–1061. doi: 10.1093/ajcn/87.4.1053. [DOI] [PubMed] [Google Scholar]
- 54.Dow C.A., Wertheim B.C., Patil B.S., Thomson C.A. Daily consumption of grapefruit for 6 weeks reduces urine F2-isoprostanes in overweight adults with high baseline values but has no effect on plasma high-sensitivity C-reactive protein or soluble vascular cellular adhesion molecule 1. J. Nutr. 2013;143(10):1586–1592. doi: 10.3945/jn.113.175166. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 55.Mellen P.B., Daniel K.R., Brosnihan K.B., Hansen K.J., Herrington D.M. Effect of muscadine grape seed supplementation on vascular function in subjects with or at risk for cardiovascular disease: a randomized crossover trial. J. Am. Coll. Nutr. 2010;29(5):469–475. doi: 10.1080/07315724.2010.10719883. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 56.Clifton P.M. Effect of grape seed extract and quercetin on cardiovascular and endothelial parameters in high-risk subjects. J. Biomed. Biotechnol. 2004;(5):272–278. doi: 10.1155/S1110724304403088. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 57.Hokayem M., Blond E., Vidal H., et al. Grape polyphenols prevent fructose-induced oxidative stress and insulin resistance in first-degree relatives of type 2 diabetic patients. Diabetes Care. 2013;36(6):1454–1461. doi: 10.2337/dc12-1652. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 58.Kar P., Laight D., Rooprai H.K., Shaw K.M., Cummings M. Effects of grape seed extract in Type 2 diabetic subjects at high cardiovascular risk: a double blind randomized placebo controlled trial examining metabolic markers, vascular tone, inflammation, oxidative stress and insulin sensitivity. Diabet. Med. 2009;26(5):526–531. doi: 10.1111/j.1464-5491.2009.02727.x. [DOI] [PubMed] [Google Scholar]
- 59.Weseler A.R., Ruijters E.J., Drittij-Reijnders M.J., Reesink K.D., Haenen G.R., Bast A. Pleiotropic benefit of monomeric and oligomeric flavanols on vascular health--a randomized controlled clinical pilot study. PLoS One. 2011;6(12):e28460. doi: 10.1371/journal.pone.0028460. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 60.Hou C.W., Lee S.D., Kao C.L., et al. Improved inflammatory balance of human skeletal muscle during exercise after supplementations of the ginseng-based steroid Rg1. PLoS One. 2015;10(1):e0116387. doi: 10.1371/journal.pone.0116387. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 61.Delui M.H., Fatehi H., Manavifar M., et al. The effects of panax ginseng on lipid profile, pro-oxidant: antioxidant status and high-sensitivity C reactive protein levels in hyperlipidemic patients in iran. Int. J. Prev. Med. 2013;4(9):1045–1051. [PMC free article] [PubMed] [Google Scholar]
- 62.Xia Z.Y., Liu X.Y., Zhan L.Y., He Y.H., Luo T., Xia Z. Ginsenosides compound (shen-fu) attenuates gastrointestinal injury and inhibits inflammatory response after cardiopulmonary bypass in patients with congenital heart disease. J. Thorac. Cardiovasc. Surg. 2005;130(2):258–264. doi: 10.1016/j.jtcvs.2005.02.046. [DOI] [PubMed] [Google Scholar]
- 63.Ebrahimpour Koujan S., Gargari B.P., Mobasseri M., Valizadeh H., Asghari-Jafarabadi M. Effects of Silybum marianum (L.) Gaertn. (silymarin) extract supplementation on antioxidant status and hs-CRP in patients with type 2 diabetes mellitus: a randomized, triple-blind, placebo-controlled clinical trial. Phytomedicine. 2015;22(2):290–296. doi: 10.1016/j.phymed.2014.12.010. [DOI] [PubMed] [Google Scholar]
- 64.Namazi N., Tarighat A., Bahrami A. The effect of hydro alcoholic nettle (Urtica dioica) extract on oxidative stress in patients with type 2 diabetes: a randomized double-blind clinical trial. Pak. J. Biol. Sci. 2012;15(2):98–102. doi: 10.3923/pjbs.2012.98.102. [DOI] [PubMed] [Google Scholar]
- 65.Namazi N., Esfanjani A.T., Heshmati J., Bahrami A. The effect of hydro alcoholic Nettle (Urtica dioica) extracts on insulin sensitivity and some inflammatory indicators in patients with type 2 diabetes: a randomized double-blind control trial. Pak. J. Biol. Sci. 2011;14(15):775–779. doi: 10.3923/pjbs.2011.775.779. [DOI] [PubMed] [Google Scholar]
- 66.Stote K.S., Clevidence B.A., Novotny J.A., Henderson T., Radecki S.V., Baer D.J. Effect of cocoa and green tea on biomarkers of glucose regulation, oxidative stress, inflammation and hemostasis in obese adults at risk for insulin resistance. Eur. J. Clin. Nutr. 2012;66(10):1153–1159. doi: 10.1038/ejcn.2012.101. [DOI] [PubMed] [Google Scholar]
- 67.Eichenberger P., Mettler S., Arnold M., Colombani P.C. No effects of three-week consumption of a green tea extract on time trial performance in endurance-trained men. Int. J. Vitam. Nutr. Res. 2010;80(1):54–64. doi: 10.1024/0300-9831/a000006. [DOI] [PubMed] [Google Scholar]
- 68.Bogdanski P., Suliburska J., Szulinska M., Stepien M., Pupek-Musialik D., Jablecka A. Green tea extract reduces blood pressure, inflammatory biomarkers, and oxidative stress and improves parameters associated with insulin resistance in obese, hypertensive patients. Nutr. Res. 2012;32(6):421–427. doi: 10.1016/j.nutres.2012.05.007. [DOI] [PubMed] [Google Scholar]
- 69.Calo L.A., Vertolli U., Davis P.A., et al. Molecular biology based assessment of green tea effects on oxidative stress and cardiac remodelling in dialysis patients. Clin. Nutr. 2014;33(3):437–442. doi: 10.1016/j.clnu.2013.06.010. [DOI] [PubMed] [Google Scholar]
- 70.Hsu S.P., Wu M.S., Yang C.C., et al. Chronic green tea extract supplementation reduces hemodialysis-enhanced production of hydrogen peroxide and hypochlorous acid, atherosclerotic factors, and proinflammatory cytokines. Am. J. Clin. Nutr. 2007;86(5):1539–1547. doi: 10.1093/ajcn/86.5.1539. [DOI] [PubMed] [Google Scholar]
- 71.Drobnic F., Riera J., Appendino G., et al. Reduction of delayed onset muscle soreness by a novel curcumin delivery system (Meriva®): a randomised, placebo-controlled trial. J. Int. Soc. Sports Nutr. 2014;11:31. doi: 10.1186/1550-2783-11-31. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 72.Di Silvestro R.A., Joseph E., Zhao S., Bomser J. Diverse effects of a low dose supplement of lipidated curcumin in healthy middle aged people. Nutr. J. 2012;11:79. doi: 10.1186/1475-2891-11-79. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 73.Wongcharoen W., Jai-Aue S., Phrommintikul A., et al. Effects of curcuminoids on frequency of acute myocardial infarction after coronary artery bypass grafting. Am. J. Cardiol. 2012;110(1):40–44. doi: 10.1016/j.amjcard.2012.02.043. [DOI] [PubMed] [Google Scholar]
- 74.Maithili Karpaga Selvi N., Sridhar M.G., Swaminathan R.P., Sripradha R. Efficacy of turmeric as adjuvant therapy in type 2 diabetic patients. Indian J. Clin. Biochem. 2015;30(2):180–186. doi: 10.1007/s12291-014-0436-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 75.Nieman D.C., Cialdella-Kam L., Knab A.M., Shanely R.A. Influence of red pepper spice and turmeric on inflammation and oxidative stress biomarkers in overweight females: a metabolomics approach. Plant Foods Hum. Nutr. 2012;67(4):415–421. doi: 10.1007/s11130-012-0325-x. [DOI] [PubMed] [Google Scholar]
- 76.Imani H., Tabibi H., Najafi I., Atabak S., Hedayati M., Rahmani L. Effects of ginger on serum glucose, advanced glycation end products, and inflammation in peritoneal dialysis patients. Nutrition. 2015;31(5):703–707. doi: 10.1016/j.nut.2014.11.020. [DOI] [PubMed] [Google Scholar]
- 77.Shidfar F., Rajab A., Rahideh T., Khandouzi N., Hosseini S., Shidfar S. The effect of ginger (Zingiber officinale) on glycemic markers in patients with type 2 diabetes. J. Complement. Integr. Med. 2015;12(2):165–170. doi: 10.1515/jcim-2014-0021. [DOI] [PubMed] [Google Scholar]
- 78.Vahdat Shariatpanahi Z., Mokhtari M., Taleban F.A., et al. Effect of enteral feeding with ginger extract in acute respiratory distress syndrome. J. Crit. Care. 2013;28(2):217.e1–217.e6. doi: 10.1016/j.jcrc.2012.04.017. [DOI] [PubMed] [Google Scholar]
- 79.Jensen G.S., Ager D.M., Redman K.A., Mitzner M.A., Benson K.F., Schauss A.G. Pain reduction and improvement in range of motion after daily consumption of an açai (Euterpe oleracea Mart.) pulp-fortified polyphenolic-rich fruit and berry juice blend. J. Med. Food. 2011;14(7-8):702–711. doi: 10.1089/jmf.2010.0150. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 80.Mulero J., Bernabé J., Cerdá B., et al. Variations on cardiovascular risk factors in metabolic syndrome after consume of a citrus-based juice. Clin. Nutr. 2012;31(3):372–377. doi: 10.1016/j.clnu.2011.11.014. [DOI] [PubMed] [Google Scholar]
- 81.Nemzer B.V., Rodriguez L.C., Hammond L., Disilvestro R., Hunter J.M., Pietrzkowski Z. Acute reduction of serum 8-iso-PGF2-alpha and advanced oxidation protein products in vivo by a polyphenol-rich beverage; a pilot clinical study with phytochemical and in vitro antioxidant characterization. Nutr. J. 2011;10:67. doi: 10.1186/1475-2891-10-67. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 82.Miglio C., Peluso I., Raguzzini A., et al. Fruit juice drinks prevent endogenous antioxidant response to high-fat meal ingestion. Br. J. Nutr. 2014;111(2):294–300. doi: 10.1017/S0007114513002407. [DOI] [PubMed] [Google Scholar]
- 83.Bakker G.C., van Erk M.J., Pellis L., et al. An antiinflammatory dietary mix modulates inflammation and oxidative and metabolic stress in overweight men: a nutrigenomics approach. Am. J. Clin. Nutr. 2010;91(4):1044–1059. doi: 10.3945/ajcn.2009.28822. [DOI] [PubMed] [Google Scholar]
- 84.Gupta H., Pawar D., Riva A., Bombardelli E., Morazzoni P. A randomized, double-blind, placebo-controlled trial to evaluate efficacy and tolerability of an optimized botanical combination in the management of patients with primary hypercholesterolemia and mixed dyslipidemia. Phytother. Res. 2012;26(2):265–272. doi: 10.1002/ptr.3542. [DOI] [PubMed] [Google Scholar]
- 85.Jin Y., Cui X., Singh U.P., et al. Systemic inflammatory load in humans is suppressed by consumption of two formulations of dried, encapsulated juice concentrate. Mol. Nutr. Food Res. 2010;54(10):1506–1514. doi: 10.1002/mnfr.200900579. [DOI] [PubMed] [Google Scholar]
- 86.Kim HJ, Yoon KH, Kang MJ, et al. A six-month supplementation of mulberry, korean red ginseng, and banaba decreases biomarkers of systemic low-grade inflammation in subjects with impaired glucose tolerance and type 2 diabetes. 2012. [DOI] [PMC free article] [PubMed]
- 87.Lamprecht M., Obermayer G., Steinbauer K., et al. Supplementation with a juice powder concentrate and exercise decrease oxidation and inflammation, and improve the microcirculation in obese women: randomised controlled trial data. Br. J. Nutr. 2013;110(9):1685–1695. doi: 10.1017/S0007114513001001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 88.Lerman R.H., Desai A., Lamb J.J., Chang J.L., Darland G., Konda V.R. A phytochemical-rich multivitamin-multimineral supplement is bioavailable and reduces serum oxidized low-density lipoprotein, myeloperoxidase, and plasminogen activator inhibitor-1 in a four-week pilot trial of healthy individuals. Glob. Adv. Health Med. 2014;3(2):34–39. doi: 10.7453/gahmj.2013.098. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 89.Mahmoodpoor A., Eslami K., Mojtahedzadeh M., et al. Examination of Setarud (IMOD™) in the management of patients with severe sepsis. Daru. 2010;18(1):23–28. [PMC free article] [PubMed] [Google Scholar]
- 90.Nieman D.C., Gillitt N.D., Knab A.M., et al. Influence of a polyphenol-enriched protein powder on exercise-induced inflammation and oxidative stress in athletes: a randomized trial using a metabolomics approach. PLoS One. 2013;8(8):e72215. doi: 10.1371/journal.pone.0072215. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 91.Panahi Y., Hosseini M.S., Khalili N., Naimi E., Majeed M., Sahebkar A. Antioxidant and anti-inflammatory effects of curcuminoid-piperine combination in subjects with metabolic syndrome: A randomized controlled trial and an updated meta-analysis. Clin. Nutr. 2015;34(6):1101–1108. doi: 10.1016/j.clnu.2014.12.019. [DOI] [PubMed] [Google Scholar]
- 92.Soare A., Weiss E.P., Holloszy J.O., Fontana L. Multiple dietary supplements do not affect metabolic and cardiovascular health. Aging (Albany, N.Y.) 2013 doi: 10.18632/aging.100597. [Epub ahead of print]. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 93.Braga M., Bissolati M., Rocchetti S., Beneduce A., Pecorelli N., Di Carlo V. Oral preoperative antioxidants in pancreatic surgery: a double-blind, randomized, clinical trial. Nutrition. 2012;28(2):160–164. doi: 10.1016/j.nut.2011.05.014. [DOI] [PubMed] [Google Scholar]
- 94.Mathur S., Devaraj S., Grundy S.M., Jialal I. Cocoa products decrease low density lipoprotein oxidative susceptibility but do not affect biomarkers of inflammation in humans. J. Nutr. 2002;132(12):3663–3667. doi: 10.1093/jn/132.12.3663. [DOI] [PubMed] [Google Scholar]
- 95.Solà R., Valls R.M., Godàs G., et al. Cocoa, hazelnuts, sterols and soluble fiber cream reduces lipids and inflammation biomarkers in hypertensive patients: a randomized controlled trial. PLoS One. 2012;7(2):e31103. doi: 10.1371/journal.pone.0031103. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 96.Martínez-López S., Sarriá B., Sierra-Cinos J.L., Goya L., Mateos R., Bravo L. Realistic intake of a flavanol-rich soluble cocoa product increases HDL-cholesterol without inducing anthropometric changes in healthy and moderately hypercholesterolemic subjects. Food Funct. 2014;5(2):364–374. doi: 10.1039/c3fo60352k. [DOI] [PubMed] [Google Scholar]
- 97.Sarriá B., Martínez-López S., Sierra-Cinos J.L., García-Diz L., Mateos R., Bravo L. Regular consumption of a cocoa product improves the cardiometabolic profile in healthy and moderately hypercholesterolaemic adults. Br. J. Nutr. 2014;111(1):122–134. doi: 10.1017/S000711451300202X. [DOI] [PubMed] [Google Scholar]
- 98.Lettieri-Barbato D., Tomei F., Sancini A., Morabito G., Serafini M. Effect of plant foods and beverages on plasma non-enzymatic antioxidant capacity in human subjects: a meta-analysis. Br. J. Nutr. 2013;109(9):1544–1556. doi: 10.1017/S0007114513000263. [DOI] [PubMed] [Google Scholar]
- 99.Serafini M., Miglio C., Peluso I., Petrosino T. Modulation of plasma non enzimatic antioxidant capacity (NEAC) by plant foods: the role of polyphenols. Curr. Top. Med. Chem. 2011;11(14):1821–1846. doi: 10.2174/156802611796235125. [DOI] [PubMed] [Google Scholar]
- 100.Pellegrini N., Serafini M., Salvatore S., Del Rio D., Bianchi M., Brighenti F. Total antioxidant capacity of spices, dried fruits, nuts, pulses, cereals and sweets consumed in Italy assessed by three different in vitro assays. Mol. Nutr. Food Res. 2006;50(11):1030–1038. doi: 10.1002/mnfr.200600067. [DOI] [PubMed] [Google Scholar]
- 101.Song F.L., Gan R.Y., Zhang Y., Xiao Q., Kuang L., Li H.B. Total phenolic contents and antioxidant capacities of selected chinese medicinal plants. Int. J. Mol. Sci. 2010;11(6):2362–2372. doi: 10.3390/ijms11062362. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 102.Pellegrini N., Serafini M., Colombi B., et al. Total antioxidant capacity of plant foods, beverages and oils consumed in Italy assessed by three different in vitro assays. J. Nutr. 2003;133(9):2812–2819. doi: 10.1093/jn/133.9.2812. [DOI] [PubMed] [Google Scholar]
- 103.Peluso I., Miglio C., Morabito G., Ioannone F., Serafini M. Flavonoids and immune function in human: a systematic review. Crit. Rev. Food Sci. Nutr. 2015;55(3):383–395. doi: 10.1080/10408398.2012.656770. [DOI] [PubMed] [Google Scholar]
- 104.Serafini M., Peluso I., Raguzzini A. Flavonoids as anti-inflammatory agents. Proc. Nutr. Soc. 2010;69(3):273–278. doi: 10.1017/S002966511000162X. [DOI] [PubMed] [Google Scholar]
- 105.Su Z.Y., Shu L., Khor T.O., Lee J.H., Fuentes F., Kong A.N. A perspective on dietary phytochemicals and cancer chemoprevention: oxidative stress, nrf2, and epigenomics. Top. Curr. Chem. 2013;329:133–162. doi: 10.1007/128_2012_340. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 106.Upadhyay S, Dixit M. Role of polyphenols and other phytochemicals on molecular signaling. 2015. [DOI] [PMC free article] [PubMed]
- 107.Shukla S.D., Bhatnagar M., Khurana S. Critical evaluation of ayurvedic plants for stimulating intrinsic antioxidant response. Front. Neurosci. 2012;6:112. doi: 10.3389/fnins.2012.00112. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 108.Jantan I., Ahmad W., Bukhari S.N. Plant-derived immunomodulators: an insight on their preclinical evaluation and clinical trials. Front. Plant Sci. 2015;6:655. doi: 10.3389/fpls.2015.00655. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 109.Yadav V.R., Prasad S., Sung B., Kannappan R., Aggarwal B.B. Targeting inflammatory pathways by triterpenoids for prevention and treatment of cancer. Toxins (Basel) 2010;2(10):2428–2466. doi: 10.3390/toxins2102428. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 110.Han K.H., Hashimoto N., Fukushima M. Relationships among alcoholic liver disease, antioxidants, and antioxidant enzymes. World J. Gastroenterol. 2016;22(1):37–49. doi: 10.3748/wjg.v22.i1.37. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 111.Wang L., Gao S., Jiang W., et al. Antioxidative dietary compounds modulate gene expression associated with apoptosis, DNA repair, inhibition of cell proliferation and migration. Int. J. Mol. Sci. 2014;15(9):16226–16245. doi: 10.3390/ijms150916226. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 112.Copple I.M., Shelton L.M., Walsh J., et al. Chemical tuning enhances both potency toward nrf2 and in vitro therapeutic index of triterpenoids. Toxicol. Sci. 2014;140(2):462–469. doi: 10.1093/toxsci/kfu080. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 113.Sirota R., Gibson D., Kohen R. The role of the catecholic and the electrophilic moieties of caffeic acid in Nrf2/Keap1 pathway activation in ovarian carcinoma cell lines. Redox Biol. 2015;4:48–59. doi: 10.1016/j.redox.2014.11.012. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 114.Son P.S., Park S.A., Na H.K., Jue D.M., Kim S., Surh Y.J. Piceatannol, a catechol-type polyphenol, inhibits phorbol ester-induced NF-{kappa}B activation and cyclooxygenase-2 expression in human breast epithelial cells: cysteine 179 of IKK{beta} as a potential target. Carcinogenesis. 2010;31(8):1442–1449. doi: 10.1093/carcin/bgq099. [DOI] [PubMed] [Google Scholar]
- 115.Wu R.P., Hayashi T., Cottam H.B., et al. Nrf2 responses and the therapeutic selectivity of electrophilic compounds in chronic lymphocytic leukemia. Proc. Natl. Acad. Sci. USA. 2010;107(16):7479–7484. doi: 10.1073/pnas.1002890107. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 116.Cichocki M., Blumczyńska J., Baer-Dubowska W. Naturally occurring phenolic acids inhibit 12-O-tetradecanoylphorbol-13-acetate induced NF-kappaB, iNOS and COX-2 activation in mouse epidermis. Toxicology. 2010;268(1-2):118–124. doi: 10.1016/j.tox.2009.12.013. [DOI] [PubMed] [Google Scholar]
- 117.Ishii T., Ishikawa M., Miyoshi N., et al. Catechol type polyphenol is a potential modifier of protein sulfhydryls: development and application of a new probe for understanding the dietary polyphenol actions. Chem. Res. Toxicol. 2009;22(10):1689–1698. doi: 10.1021/tx900148k. [DOI] [PubMed] [Google Scholar]
- 118.Nair S., Li W., Kong A.N. Natural dietary anti-cancer chemopreventive compounds: redox-mediated differential signaling mechanisms in cytoprotection of normal cells versus cytotoxicity in tumor cells. Acta Pharmacol. Sin. 2007;28(4):459–472. doi: 10.1111/j.1745-7254.2007.00549.x. [DOI] [PubMed] [Google Scholar]
- 119.Balogun E., Hoque M., Gong P., et al. Curcumin activates the haem oxygenase-1 gene via regulation of Nrf2 and the antioxidant-responsive element. Biochem. J. 2003;371(Pt 3):887–895. doi: 10.1042/BJ20021619. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 120.Petrosino T., Serafini M. Antioxidant modulation of F2-isoprostanes in humans: a systematic review. Crit. Rev. Food Sci. Nutr. 2014;54(9):1202–1221. doi: 10.1080/10408398.2011.630153. [DOI] [PubMed] [Google Scholar]