Interleukin-10 in the Vasculature: Pathophysiological Implications

2021 ◽  
Vol 20 ◽  
Author(s):  
Raiany Alves de Freitas ◽  
Victor Vitorino Lima ◽  
Gisele Facholi Bomfim ◽  
Fernanda Regina Casagrande Giachini
Keyword(s):  
Intracellular Signaling ◽  
Vascular Function ◽  
Vascular Tone ◽  
Vascular Tissue ◽  
Interleukin 10 ◽  
Vital Role ◽  
Inflammatory Processes ◽  
Anti Inflammatory ◽  
Intracellular Pathway ◽  
Potential Use

Abstract: Interleukin-10 (IL-10) is an important immunomodulatory cytokine, initially characterized as an anti-inflammatory agent released by immune cells during infectious and inflammatory processes. IL-10 exhibits biological functions that extend to the regulation of different intracellular signaling pathways directly associated with vascular function. This cytokine plays a vital role in vascular tone regulation through the change of important proteins involved in vasoconstriction and vasodilation. Numerous investigations covered here have shown that therapeutic strategies inducing IL-10 result in anti-inflammatory, anti-hypertrophic, antihyperplastic, anti-apoptotic and antihypertensive effects. This non-systematic review summarizes the modulating effects mediated by IL-10 in vascular tissue, particularly on vascular tone, and the intracellular pathway induced by this cytokine. We also highlight the advances in IL-10 manipulation as a therapeutic target in different cardiovascular pathophysiologies, including the physiological implications in animals and humans. Finally, the review illustrates current and potential future perspectives of the potential use of IL-10 in clinical trials, based on the clinical evidence.

scholarly journals Sex differences in vascular function: implication of endothelium-derived hyperpolarizing factor

2008 ◽  
Vol 197 (3) ◽  
pp. 447-462 ◽  
Author(s):  
Inmaculada C Villar ◽  
Adrian J Hobbs ◽  
Amrita Ahluwalia
Keyword(s):  
Sex Differences ◽  
Sex Hormones ◽  
Vascular Function ◽  
Vascular Tone ◽  
Inflammatory Responses ◽  
Vascular Inflammation ◽  
Critical Role ◽  
Premenopausal Women ◽  
Circulating Cells ◽  
Inflammatory Processes

The vascular endothelium plays a crucial role in the regulation of vascular homeostasis by controlling vascular tone, coagulation, and inflammatory responses. These actions are exerted by endothelial factors including nitric oxide, prostacyclin, and endothelium-derived hyperpolarizing factor (EDHF). The greater incidence of cardiovascular disease (CVD) in men and postmenopausal women compared with premenopausal women implies a vasoprotective phenotype of females, which may be influenced by sex hormones. These hormones, particularly estrogen, have modulatory effects on the endothelium and circulating cells that have been implicated in vascular inflammation and in the development of CVD. EDHF seems to be the predominant endothelial factor in the resistance vasculature of females and this mediator could afford the beneficial cardiovascular risk profile observed in premenopausal woman. In this review, we discuss sex differences in EDHF biology and how sex hormones can modulate EDHF responses. We also review the implication of sex hormone-dependent regulation of EDHF in inflammatory processes, platelet function, and repair after vascular damage, each of which have a critical role in several aspects of the pathogenesis of CVD.

scholarly journals EVALUATION OF INTERLEUKIN-10 LEVELS IN THE PLASMA OF PATIENTS WITH VARIOUS STAGES OF TUBERCULOSIS

2015 ◽  
Vol 88 (2) ◽  
pp. 164-167 ◽  
Author(s):  
Pacifique Ndishimye ◽  
Fouad Seghrouchni ◽  
Bianka Domokos ◽  
Olga Soritau ◽  
Abderrahim Sadak ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Interleukin 10 ◽  
Vital Role ◽  
Control Group ◽  
Clear Understanding ◽  
X Rays ◽  
Abnormal Chest ◽  
Anti Inflammatory ◽  
Tuberculosis Therapy ◽  
And Control

Mycobacterium tuberculosis (Mtb) infection remains one of the world’s major causes of illness and mortality. A clear understanding of the host defense against Mtb is imperatively needed for the control of this epidemic. When tuberculosis (TB) infection occurs, a variety of pro and anti-inflammatory cytokines play a vital role in the pathogenesis of this disease. Interleukin-10 (IL-10) is one of the most important anti-inflammatory cytokines reported to suppress the protective immune response against tuberculosis.The aim of the present study was to evaluate the association of plasma IL-10 levels with various disease stages of TB and the possible effects of treatment on these levels. A group of 30 patients with active pulmonary TB and a control group of 21 healthy individuals were enrolled in this study. The levels of IL-10 were measured before, during, and after treatment using commercially available enzyme-linked immune-sorbent assay (ELISA). Data were analyzed using GraphPad Prism version 5.0.The results showed that the levels of IL-10 had significant differences between the TB and control groups (p<0.05). The patients with abnormal chest X-Ray findings had higher IL-10 levels when compared to patients with normal X-Rays (p=0.03). A subgroup of 18 patients were followed during the treatment and the mean plasma concentration of IL-10 in patients before therapy was higher than in patients at 3 months of therapy and in patients after 6 months of therapy (p=0.01). However, the IL-10 level remained significantly higher in patients at the end of treatment compared with controls.These findings could be used in follow-up as clinical biomarker of the success of tuberculosis therapy.

Transcriptional mechanisms of acute lung injury

2001 ◽  
Vol 281 (5) ◽  
pp. L1037-L1050 ◽  
Author(s):  
Jie Fan ◽  
Richard D. Ye ◽  
Asrar B. Malik
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Nuclear Factor Κb ◽  
Interleukin 10 ◽  
Proinflammatory Mediators ◽  
Cellular Events ◽  
Inflammatory Stimuli ◽  
Inflammatory Processes ◽  
Anti Inflammatory ◽  
Inflammatory Molecules

Acute lung injury occurs as a result of a cascade of cellular events initiated by either infectious or noninfectious inflammatory stimuli. An elevated level of proinflammatory mediators combined with a decreased expression of anti-inflammatory molecules is a critical component of lung inflammation. Expression of proinflammatory genes is regulated by transcriptional mechanisms. Nuclear factor-κB (NF-κB) is one critical transcription factor required for maximal expression of many cytokines involved in the pathogenesis of acute lung injury. Activation and regulation of NF-κB are tightly controlled by a complicated signaling cascade. In acute lung injury caused by infection of bacteria, Toll-like receptors play a central role in initiating the innate immune system and activating NF-κB. Anti-inflammatory cytokines such as interleukin-10 and interleukin-13 have been shown to suppress inflammatory processes through inhibiting NF-κB activation. NF-κB can interact with other transcription factors, and these interactions thereby lead to greater transcriptional selectivity. Modification of transcription is likely to be a logical therapeutic target for acute lung injury.

Red wine extract, resveratrol, on maintenance of organ function following trauma-hemorrhage

2012 ◽  
Vol 2 (10) ◽  
pp. 351
Author(s):  
Fu-Chao Liu ◽  
Huang-Ping Yu
Keyword(s):  
Intracellular Signaling ◽  
Red Wine ◽  
Antioxidant Properties ◽  
Neutrophil Function ◽  
Protective Effects ◽  
Organ Function ◽  
Mitogen Activated Protein ◽  
Ros Formation ◽  
Anti Inflammatory ◽  
And Control

Resveratrol, is a polyphenol that can be extracted from grapes and red wine, possess potential anti-inflammatory effects, which would result in the reduction of cytokine production, the alteration of the expression of adhesion molecule molecules, and the inhibition of neutrophil function. Resveratrol might also act as an antioxidant, anti-aging, and control of cell cycle and apoptosis. Resveratrol has been shown to have protective effects for patients in shock-like states. Such protective phenomenon is reported to be implicated in a variety of intracellular signaling pathways including the regulation of the mitogen-activated protein kinases (MAPK)/ hemeoxygenase-1 (HO-1) pathway, activates estrogen receptor (ER), and the mediation of pro-inflammatory cytokines, reactive oxygen species (ROS) formation and reactive. Moreover, through anti-inflammatory effects and antioxidant properties, the resveratrol is believed to maintain organ function following trauma-hemorrhage.Key words: resveratrol, anti-inflammatory, trauma-hemorrhage.

ROS Inhibitory Activity and Cytotoxicity Evaluation of Benzoyl, Acetyl, Alkyl Ester, and Sulfonate Ester Substituted Coumarin Derivatives

2020 ◽  
Vol 16 (8) ◽  
pp. 1099-1111
Author(s):  
Uzma Salar ◽  
Khalid M. Khan ◽  
Almas Jabeen ◽  
Aisha Faheem ◽  
Farwa Naqvi ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Antiinflammatory Drug ◽  
Vital Role ◽  
Alkyl Ester ◽  
Flufenamic Acid ◽  
Coumarin Derivatives ◽  
Inflammatory Disorders ◽  
Enhanced Chemiluminescence ◽  
Anti Inflammatory ◽  
Sulfonate Ester

Background: A number of non-steroidal anti-inflammatory drugs (NSAIDs) including aspirin, indomethacin, ibuprofen, flufenamic acid, and phenylbutazone are being clinically used to treat inflammatory disorders. These NSAIDs are associated with serious side effects such as gastric ulceration, nephrotoxicity, and bleeding. Therefore, the identification of potent and safe therapy for inflammatory disorders is still of great interest to the medicinal chemist. Methods: A series of varyingly substituted benzoyl, acetyl, alkyl ester, and sulfonate ester substituted coumarins 1-64 were screened for the inhibition of ROS, generated from zymosan activated whole blood phagocytes, using luminol-enhanced chemiluminescence technique. Results: Among all tested compounds, 8 (IC50 = 65.0 ± 3.1 μM), 24 (IC50 = 41.8 ± 1.5 μM), 26 (IC50 = 10.6 ± 2.8 μM), 28 (IC50 = 20.9 ± 1.5 μM), and 41 (IC50 = 4.6 ± 0.3 μM) showed good anti- inflammatory potential as compared to standard antiinflammatory drug ibuprofen (IC50 = 54.3 ± 1.9 μM). Specifically, compounds 24, 26, 28, and 41 showed superior activity than standard antiinflammatory drug. Furthermore, compounds 12 (IC50 = 219.0 ± 1.4 μM), 14 (IC50 = 216.5 ± 6.2 μM), 16 (IC50 = 187.4 ± 2.2 μM), and 20 (IC50 = 196.2 ± 2.0 μM) showed moderate ROS inhibitory activity. Limited SAR study revealed that the hydroxy-substituted compound showed better ROS inhibition potential in case of 3-benzoyl and 3-ethylester coumarin derivatives. Whereas, chloro substitution was found to be important in case of 3-acetyl coumarin derivatives. Similarly, in case of sulfonate ester, chloro, and nitro groups especially at positions -4 and -3 of ring “R” played vital role in ROS inhibition. Furthermore, cytotoxicity of all active compounds was also checked on NIH-3T3 cell line. Compounds 12, 14, and 20 were found to be non-cytotoxic. Whereas, 8, 16, 24, 26, 28, and 41 were found to be very weak cytotoxic as compared to standard cycloheximide (IC50 = 0.13 ± 0.02 μM). Conclusion: Identified ROS inhibitors offer the possibility of additional modifications that could give rise to lead structures for further research in order to obtain more potent, and safer antiinflammatory agent.

HG-9-91-01 Attenuates Murine Experimental Colitis by Promoting Interleukin-10 Production in Colonic Macrophages Through the SIK/CRTC3 Pathway

2021 ◽  
Author(s):  
Yong Fu ◽  
Gailing Ma ◽  
Yuqian Zhang ◽  
Wenli Wang ◽  
Tongguo Shi ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Experimental Colitis ◽  
Underlying Mechanism ◽  
Interleukin 10 ◽  
Camp Response Element Binding ◽  
Cellular Level ◽  
Trinitrobenzene Sulfonic Acid ◽  
Murine Colitis ◽  
Anti Inflammatory

Abstract Background Interleukin-10 (IL-10) is a potent immunoregulatory cytokine that plays a pivotal role in maintaining mucosal immune homeostasis. As a novel synthetic inhibitor of salt-inducible kinases (SIKs), HG-9-91-01 can effectively enhance IL-10 secretion at the cellular level, but its in vivo immunoregulatory effects remain unclear. In this study, we investigated the effects and underlying mechanism of HG-9-91-01 in murine colitis models. Methods The anti-inflammatory effects of HG-9-91-01 were evaluated on 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)-, dextran sulfate sodium–induced colitis mice, and IL-10 knockout chronic colitis mice. The in vivo effector cell of HG-9-91-01 was identified by fluorescence-activated cell sorting and quantitative real-time polymerase chain reaction. The underlying mechanism of HG-9-91-01 was investigated via overexpressing SIKs in ANA-1 macrophages and TNBS colitis mice. Results Treatment with HG-9-91-01 showed favorable anticolitis effects in both TNBS- and DSS-treated mice through significantly promoting IL-10 expression in colonic macrophages but failed to protect against IL-10 KO murine colitis. Further study indicated that HG-9-91-01 markedly enhanced the nuclear level of cAMP response element-binding protein (CREB)-regulated transcription coactivator 3 (CRTC3), whereas treatment with lentiviruses encoding SIK protein markedly decreased the nuclear CRTC3 level in HG-9-91-01–treated ANA-1 macrophages. In addition, intracolonic administration with lentiviruses encoding SIK protein significantly decreased the nuclear CRTC3 level in the lamina propria mononuclear cells and ended the anti-inflammatory activities of HG-9-91-01. Conclusions We found that HG-9-91-01 promoted the IL-10 expression of colonic macrophages and exhibited its anticolitis activity through the SIK/CRTC3 axis, and thus it may represent a promising strategy for inflammatory bowel disease therapy.

scholarly journals SAT0315 INHIBITION OF MICROSOMAL PROSTAGLANDIN E SYNTHASE-1 (MPGES-1) BY GS-248 REDUCES PROSTAGLANDIN E2 BIOSYNTHESIS WHILE INCREASING PROSTACYCLIN IN HUMAN SUBJECTS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1103.2-1103
Author(s):  
C. Edenius ◽  
G. Ekström ◽  
J. Kolmert ◽  
R. Morgenstern ◽  
P. Stenberg ◽  
...  
Keyword(s):  
Whole Blood ◽  
Vascular Tone ◽  
Ex Vivo ◽  
Prostaglandin E ◽  
Maximum Plasma ◽  
Prostaglandin E Synthase ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Oral Doses ◽  
Microsomal Prostaglandin E Synthase

Background:Microsomal prostaglandin E synthase-1 (mPGES-1) catalyzes the formation prostaglandin (PG) E2from cyclooxygenase derived PGH2(1, 2). Inhibition of mPGES-1 leads to reduction of pro-inflammatory PGE2, while in vessels there is a concomitant increase of vasoprotective prostacyclin (PGI2) via shunting of PGH2(3,4). Apart from relieving symptoms in experimental animal models of inflammation, inhibitors of mPGES-1 cause relaxation of human medium sized arteries(4)and resistance arteries(5). The prostaglandin profile following mPGES-1 inhibition, explains the anti-inflammatory effects and also opens for the possibility of treating inflammatory diseases with concomitant vasculopathies. GS-248 is a potent and selective inhibitor of mPGES-1 exhibiting sub-nanomolar IC50in human whole bloodex vivo.Objectives:To evaluate safety, tolerability, pharmacokinetics and pharmacodynamics of GS-248.Methods:Healthy males and females (age 18–73 years) were included in the study. Six cohorts were administrated single oral doses of 1-300mg GS-248 (n=36) or placebo (n=12), three cohorts were administered once daily doses of 20-180mg GS-248 (n=18) or placebo (n=12) over ten days. In addition, 8 subjects were treated in a separate cohort with 200mg celecoxib bid for ten days. Blood samples were drawn for measurement of GS-248 exposure and production of PGE2after LPS incubationex vivo. The content of PGE2and PGI2metabolites was measured in urine. All analyses were performed by LC-MS/MS.Results:GS-248 was safe and well tolerated at all tested dose levels. Maximum plasma concentration was achieved 1 - 2.5 hours after dosing, and half-life was about 10 hours. Induced PGE2formationex vivo,catalyzed by mPGES-1, was completely inhibited for 24 hours after a single low dose (40mg) of GS-248. In urine, GS-248 dose-dependently reduced the excretion of PGE2metabolite by more than 50% whereas the excretion of PGI2metabolite increased more than twice the baseline levels. In the celecoxib cohort urinary metabolites of both PGE2and PGI2were reduced with approx 50%.Conclusion:GS-248 at investigated oral doses was safe and well tolerated. There was a sustained inhibition of LPS induced PGE2formation in whole blood. In urine, there was a metabolite shift showing reduced PGE2and increased PGI2, while celecoxib reduced both PGE2and PGI2metabolites. This suggests that selective inhibition of mPGES-1 results in systemic shunting of PGH2to PGI2formation, leading to anti-inflammatory and vasodilatory effects, while preventing platelet activation. The results warrant further evaluation of GS-248 in inflammatory conditions with vasculopathies such as Digital Ulcers and Raynaud’s Phenomenon in Systemic Sclerosis.References:[1]Korotkova M, Jakobsson PJ. Persisting eicosanoid pathways in rheumatic diseases. Nat Rev Rheumatol. 2014;10:229-41[2]Bergqvist F, Morgenstern R, Jakobsson PJ. A review on mPGES-1 inhibitors: From preclinical studies to clinical applications. Prostaglandins Other Lipid Mediat. 2019;147:106383[3]Kirkby NS, et al. Mechanistic definition of the cardiovascular mPGES-1/COX-2/ADMA axis. Cardiovasc Res. 2020[4]Ozen G, et al. Inhibition of microsomal PGE synthase-1 reduces human vascular tone by increasing PGI2: a safer alternative to COX-2 inhibition. Br J Pharmacol. 2017;174:4087-98[5]Larsson K, et al. Biological characterization of new inhibitors of microsomal PGE synthase-1 in preclinical models of inflammation and vascular tone. Br J Pharmacol. 2019;176:4625-38Disclosure of Interests:Charlotte Edenius Shareholder of: Gesynta Pharma, Consultant of: Gesynta Pharma,, Gunilla Ekström Shareholder of: Gesynta Pharma, Consultant of: Gesynta Pharma,, Johan Kolmert Consultant of: Gesynta Pharma,, Ralf Morgenstern Shareholder of: Gesynta Pharma, Employee of: Gesynta Pharma, Patric Stenberg Shareholder of: Gesynta Pharma, Employee of: Gesynta Pharma, Per-Johan Jakobsson Shareholder of: Gesynta Pharma, Grant/research support from: Gesynta Pharma, AstraZeneca,, Göran Tornling Shareholder of: Gesynta Pharma, Vicore Pharma,, Consultant of: Gesynta Pharma, Vicore Pharma, AnaMar

scholarly journals GLP-1 Analog Liraglutide Improves Vascular Function in Polymicrobial Sepsis by Reduction of Oxidative Stress and Inflammation

Antioxidants ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1175
Author(s):  
Johanna Helmstädter ◽  
Karin Keppeler ◽  
Franziska Aust ◽  
Leonie Küster ◽  
Katie Frenis ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Vascular Function ◽  
Vascular Inflammation ◽  
Cecal Ligation ◽  
Isometric Tension ◽  
Polymicrobial Sepsis ◽  
Dot Blot ◽  
Markers Of Inflammation ◽  
Anti Inflammatory ◽  
And Oxidative Stress

Sepsis causes high mortality in the setting of septic shock. LEADER and other trials revealed cardioprotective and anti-inflammatory properties of glucagon-like peptide-1 (GLP-1) analogs like liraglutide (Lira). We previously demonstrated improved survival in lipopolysaccharide (LPS)-induced endotoxemia by inhibition of GLP-1 degradation. Here we investigate the effects of Lira in the polymicrobial sepsis model of cecal ligation and puncture (CLP). C57BL/6J mice were intraperitoneally injected with Lira (200 µg/kg/d; 3 days) and sepsis induced by CLP after one day of GLP-1 analog treatment. Survival and body temperature were monitored. Aortic vascular function (isometric tension recording), protein expression (immunohistochemistry and dot blot) and gene expression (qRT-PCR) were determined. Endothelium-dependent relaxation in the aorta was impaired by CLP and correlated with markers of inflammation (e.g., interleukin 6 and inducible nitric oxide synthase) and oxidative stress (e.g., 3-nitrotyrosine) was higher in septic mice, all of which was almost completely normalized by Lira therapy. We demonstrate that the GLP-1 analog Lira ameliorates sepsis-induced endothelial dysfunction by the reduction of vascular inflammation and oxidative stress. Accordingly, the findings suggest that the antioxidant and anti-inflammatory effects of GLP-1 analogs may be a valuable tool to protect the cardiovascular system from dysbalanced inflammation in polymicrobial sepsis.

scholarly journals Dual Role of Interleukin-10 in Murine NZB/W F1 Lupus

2021 ◽  
Vol 22 (3) ◽  
pp. 1347
Author(s):  
Anaïs Amend ◽  
Natalie Wickli ◽  
Anna-Lena Schäfer ◽  
Dalina T. L. Sprenger ◽  
Rudolf A. Manz ◽  
...  
Keyword(s):  
B Cell ◽  
Disease Model ◽  
Interleukin 10 ◽  
Immune Functions ◽  
Murine Lupus ◽  
Anti Inflammatory ◽  
In Vivo Effects

As a key anti-inflammatory cytokine, IL-10 is crucial in preventing inflammatory and autoimmune diseases. However, in human and murine lupus, its role remains controversial. Our aim was to understand regulation and immunologic effects of IL-10 on different immune functions in the setting of lupus. This was explored in lupus-prone NZB/W F1 mice in vitro and vivo to understand IL-10 effects on individual immune cells as well as in the complex in vivo setting. We found pleiotropic IL-10 expression that largely increased with progressing lupus, while IL-10 receptor (IL-10R) levels remained relatively stable. In vitro experiments revealed pro- and anti-inflammatory IL-10 effects. Particularly, IL-10 decreased pro-inflammatory cytokines and slowed B cell proliferation, thereby triggering plasma cell differentiation. The frequent co-expression of ICOS, IL-21 and cMAF suggests that IL-10-producing CD4 T cells are important B cell helpers in this context. In vitro and in vivo effects of IL-10 were not fully concordant. In vivo IL-10R blockade slightly accelerated clinical lupus manifestations and immune dysregulation. Altogether, our side-by-side in vitro and in vivo comparison of the influence of IL-10 on different aspects of immunity shows that IL-10 has dual effects. Our results further reveal that the overall outcome may depend on the interplay of different factors such as target cell, inflammatory and stimulatory microenvironment, disease model and state. A comprehensive understanding of such influences is important to exploit IL-10 as a therapeutic target.

Anti-inflammatory Effects of Plant-based Foods and of their Constituents

2008 ◽  
Vol 78 (6) ◽  
pp. 293-298 ◽  
Author(s):  
Bernhard Watzl
Keyword(s):  
Cardiovascular Diseases ◽  
Bioactive Compounds ◽  
Pathological Condition ◽  
Wide Spectrum ◽  
Bioactive Constituents ◽  
Plant Foods ◽  
Whole Wheat ◽  
Markers Of Inflammation ◽  
Inflammatory Processes ◽  
Anti Inflammatory

Inflammation is a pathological condition underlying a number of diseases including cardiovascular diseases, cancer, and chronic inflammatory diseases. In addition, healthy, obese subjects also express markers of inflammation in their blood. Diet provides a variety of nutrients as well as non-nutritive bioactive constituents which modulate immunomodulatory and inflammatory processes. Epidemiological data suggest that dietary patterns strongly affect inflammatory processes. Primarily the intake of fruit and vegetables as well as of whole wheat is inversely associated with the risk of inflammation. In addition to observational studies there are also data from human intervention studies suggesting an anti-inflammatory potential of these plant foods. At the level of bioactive compounds occurring in plant foods, primarily carotenoids and flavonoids seem to modulate inflammatory as well as immunological processes. In conclusion, there is convincing evidence that plant foods and non-nutritive constituents associated with these foods modulate immunological and inflammatory processes. By means of anti-inflammatory activities a plant-based diet may contribute to the lower risk of cardiovascular diseases and cancer. A high intake of vegetables, fruit, and whole wheat as recommended by all international nutrition authorities provides a wide spectrum of bioactive compounds at health-promoting concentrations.

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