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Oxidative Medicine and Cellular Longevity
Volume 2018, Article ID 6015351, 17 pages
https://doi.org/10.1155/2018/6015351
Review Article

Biological Activities, Health Benefits, and Therapeutic Properties of Avenanthramides: From Skin Protection to Prevention and Treatment of Cerebrovascular Diseases

1Department of Clinical and Biological Sciences, University of Torino, Orbassano, Torino, Italy
2CCM Italia, Torino, Italy
3Proteomics & Mass Spectrometry Laboratory, ISPAAM, National Research Council, Napoli, Italy
4Plant Genetics and Breeding, Department of Agriculture, Forest and Food Sciences, University of Torino, Grugliasco, Torino, Italy

Correspondence should be addressed to Saverio Francesco Retta; ti.otinu@atter.ocsecnarf

Received 27 April 2018; Accepted 24 July 2018; Published 23 August 2018

Academic Editor: Daria M. Monti

Copyright © 2018 Andrea Perrelli et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Oat (Avena sativa) is a cereal known since antiquity as a useful grain with abundant nutritional and health benefits. It contains distinct molecular components with high antioxidant activity, such as tocopherols, tocotrienols, and flavanoids. In addition, it is a unique source of avenanthramides, phenolic amides containing anthranilic acid and hydroxycinnamic acid moieties, and endowed with major beneficial health properties because of their antioxidant, anti-inflammatory, and antiproliferative effects. In this review, we report on the biological activities of avenanthramides and their derivatives, including analogs produced in recombinant yeast, with a major focus on the therapeutic potential of these secondary metabolites in the treatment of aging-related human diseases. Moreover, we also present recent advances pointing to avenanthramides as interesting therapeutic candidates for the treatment of cerebral cavernous malformation (CCM) disease, a major cerebrovascular disorder affecting up to 0.5% of the human population. Finally, we highlight the potential of foodomics and redox proteomics approaches in outlining distinctive molecular pathways and redox protein modifications associated with avenanthramide bioactivities in promoting human health and contrasting the onset and progression of various pathologies.

The paper is dedicated to the memory of Adelia Frison

1. Introduction

Oats are cereal grain crops belonging to the family of Poaceae (or Gramineae) [1]. Two main species of oat grow naturally, namely, Avena sativa and Avena nuda. The former, known as common oat, is the most widely cultivated, especially in the cool and moist regions of Northern Europe and North America [2]. Among the common cereal grains, oats are consumed at lower rates than wheat and rice all over the world. However, dietary fiber content, nutritional value, and health benefits of oats are high. Indeed, the increasing interest of consumers towards whole grain oats is mainly driven by its advantageous composition in macronutrients: (i) lipids with a high degree of unsaturation, including oleic and linoleic acids (about 40% and 36% of total fatty acids, resp.), (ii) proteins with a favorable composition of essential amino acids, and (iii) dietary fibers with a high content of β-glucan (2–8.5% w/w of oat seed). In particular, the high levels of β-glucan present in oats have been shown to contribute in reducing total plasma concentration of cholesterol and low-density lipoprotein (LDL) cholesterol, the main risk factors for coronary heart disease (CHD).

A growing body of evidence suggests that oats contain other important bioactive compounds, such as phenolic compounds, which exert protective effects against the development of various pathologies, including cardiovascular diseases (CVDs), diabetes, inflammatory bowel disease (IBD), cancer, obesity, and celiac disease, acting synergistically with dietary fibers [3]. Phenolic compounds are major secondary products of plant metabolism, consisting of at least one aromatic ring bearing one or more hydroxyl groups (phenolic unit). Their chemical structure may range from that of a simple phenolic molecule (phenolic acids) to that of a complex high molecular weight polymer (polyphenols). Depending on the number and type of phenolic units, they can be divided into at least 10 different molecular classes, including simple phenols (phenolic acids), and intermediate (e.g., flavonoids and anthocyanins) and high (e.g., stilbenes, coumarins, and tannins) molecular weight polyphenols. From the biological point of view, phenolic compounds have been show to possess numerous activities, the most important being the antioxidant activity, which prevents lipid peroxidation and cellular oxidative damage mediated by harmful free radicals [4, 5]. This property is related to the ability of phenolic compounds to scavenge free radicals, donate hydrogen atoms or electron, or chelate metal cations, which is dictated mainly by the number and position of the hydroxyl groups and the nature of substitutions on the aromatic rings, as demonstrated by structure-activity relationship analyses. More in general, phenolic compounds have been involved in cellular defense against various stressful events [2, 6, 7] and shown to possess several health-promoting properties [8], including prophylactic activity against arteriosclerosis, CVDs, inflammatory processes, and certain forms of cancer [9, 10].

The type and concentration of phenolic compounds in whole-grain cereals are influenced by the plant variety and grain nature. In particular, besides containing high levels of phenolic acids, tocopherols, and alk(en)ylresorcinol derivatives, oats are a unique source of avenanthramides (Avns; also known as N-cinnamoylanthranilate alkaloids or anthranilic acid amides), which are not present in other cereals [11]. Avns are low molecular weight phenolic amides consisting of an anthranilic acid linked to a hydroxycinnamic acid with an amide bond (Figure 1). They were originally identified as phytoalexins produced by the plant in response to exposure to pathogens, such as fungi [12, 13]. Oats contain a unique group of approximately 40 different types of Avns, which are present in both oat grains and leaves [1416]. The most abundant are Avn-A (N-(4-hydroxycinnamoyl)-5-hydroxyanthranilic acid), Avn-B (N-(4-hydroxy-3-methoxycinnamoyl)-5-hydroxyanthranilic acid), and Avn-C (N-(3-4-dihydroxycinnamoyl)-5-hydroxyanthranilic acid) (Figure 1), which are amides of 5-hydroxyanthranilic acid with p-coumaric, ferulic, and caffeic hydroxycinnamic acids, respectively [13, 17, 18]. These Avns are constitutively expressed in the kernel, reaching the highest concentration in the bran, and appear in almost all milling fractions [17]. A number of studies demonstrate that these natural products have strong antioxidant activity both in vitro and in vivo, as well as anti-inflammatory, anti-itching, anti-irritant, antiatherogenic, and antiproliferative activities, which may prevent or limit cellular oxidative dysfunctions and the development of oxidative stress-related diseases, such as neurodegenerative and cardiovascular diseases, and provide additional protection against skin irritation, aging, CHD, and cancer [16, 17, 1932].

Figure 1: Chemical structure and names of some natural (Avn), synthetic (Tranilast), and recombinant (YAvn) avenanthramides. Avns are low molecular weight phenolic compounds consisting of an anthranilic acid linked to a hydroxycinnamic acid with an amide bond. Different forms of Avns have been either extracted from oats, produced by chemical synthesis, or generated by recombinant DNA techniques in yeast cells.

Apart from natural compounds isolated from oats, avenanthramide analogs endowed with important biological properties have been artificially produced by organic synthesis methodologies, including the pharmaceutical drug Tranilast™ (N-[3,4-dimethoxycinnamoyl]-anthranilic acid; Rizaban, Kissei Pharmaceutical Co., Japan), which is currently used in Japan and South Korea as an antihistamine to treat bronchial asthma, atopic dermatitis, keloids and hypertrophic scars, allergic conjunctivitis, allergic rhinitis, and other allergic disorders [3335]. Notably, whereas several years of clinical use have established that Tranilast has very low adverse effects and good toleration by patients, the beneficial effects of this drug have also been seen in a variety of other pathologies, such as scleroderma and other skin diseases related to excessive fibrosis, cancer, diabetes, and autoimmune, cardiovascular, and renal diseases [36]. Tranilast efficacy has been mainly attributed to its capacity to inhibit the release of proinflammatory factors from leukocytes, including mast cells and macrophages, and suppress collagen deposition, and has been associated mainly with the inhibition of the TGF-β pathway, although this drug affects other pathways as well [37, 38].

Besides natural and synthetic Avns, novel Avn analogs have been produced in recombinant yeast, including N-(4-hydroxycinnamoyl)-3-hydroxyanthranilic acid (YAvn I) and N-(3-4-dihydroxycinnamoyl)-3-hydroxyanthranilic acid (YAvn II), which were generated by engineering a Saccharomyces cerevisiae strain with two plant genes (4cl-2 from tobacco and hct from globe artichoke) encoding key proteins involved in the biosynthesis of phenolic esters [39]. Remarkably, YAvn I and YAvn II share structural similarity with Avn-A and Avn-C, respectively (Figure 1), and were shown to possess bioactive properties relevant to biomedical applications, including potent antioxidant, anti-inflammatory, and antiproliferative properties. Indeed, they were effective in rescuing major pathological phenotypes in both cellular and animal models of Cerebral Cavernous Malformation (CCM) disease, a human cerebrovascular disorder of genetic origin implicating oxidative stress and inflammation as main pathogenetic events [40, 41].

2. Radical-Scavenging and Antioxidant Activity of Avenanthramides

The antioxidant activity of oat components was initially suggested by the evidence that oat flour could be used as a food preservative from oxidative deterioration due to its ability in retarding the initial peroxide formation and rancidity [42, 43]. Subsequently, Lingnert and coworkers originally determined the antioxidative capacity of N-(4-hydroxy-3-methoxy-(E)-cynnamoil)-5-hydroxyanthranilic acid and N-(4-hydroxy-3-methoxy-(E)-cynnamoil)-5-hydroxy-4-methoxyanthranilic acid in oxygen consumption experiments with a linoleic acid-based system [44]. The antioxidant properties of oat extracts and their components, including avenanthramides, were eventually demonstrated directly by assaying purified compounds from different oat cultivars [45, 46]. In particular, Emmons and colleagues examined oat milling fractions to determine their potential as dietary antioxidants, showing that three avenanthramide isoforms (Avn-A, Avn-C, and Avn-K) were among the most important oat metabolites endowed with antioxidant activity [46]. Then, Peterson and coworkers synthesized the three major oat avenanthramides (Avn-A, Avn-B, and Avn-C) and tested their antioxidant activities using two in vitro assays, such as the inhibition of beta-carotene bleaching and the reaction with the free radical 2,2-diphenyl-1-picrylhy-drazyl (DPPH), demonstrating that Avn-C has greater antioxidant activity than Avn-B and Avn-A [47].

The antioxidant properties of Avns were also investigated in in vivo models. In particular, Avn-C supplementation in the diet of rats at a concentration of 0.1 g/kg was effective in reducing reactive oxygen species (ROS) levels in the soleus muscle. Moreover, Avn-C-fed rats had higher superoxide dismutase activity in the vastus lateralis muscle (DVL), liver, and kidney, and higher glutathione peroxidase activity in the heart and DVL, compared to control rats. In addition, Avn-C supplementation attenuated the increased ROS production in the soleus and lipid peroxidation in the heart induced by exercise [19].

The bioavailability of Avns was examined by Chen and coworkers in hamsters [22], where it was observed that plasma concentration of Avns and phenolic acids peak at 40 min after the animals were gavage with saline containing 0.25 g oat bran phenol-rich powder. While p-coumaric acid was the most bioavailable among oat phenolics, Avn bioavailability appeared very low, probably due to metabolite distribution in other tissues and the corresponding biotransformation rate. The same authors also investigated the bioavailability and antioxidant action of major Avns, including Avn-A, Avn-B, and Avn-C, in humans [21]. At doses of 0.5 and 1.0 g of an Avn-enriched mixture (AEM), Avns reached the maximum peak in plasma at 1.5 and 2.3 h, respectively. Avn-A and Avn-B bioavailability was 18- and 5-fold higher in humans than in hamsters, respectively. Interestingly, consumption of Avn-enriched oat extracts significantly increased the plasma concentration of reduced glutathione (GSH), the body’s master antioxidant. Specifically, after consumption of 0.1 g of AEM, plasma GSH levels increased 21% from baseline at 15 min, without apparent adverse side effects [21]. Moreover, Avn-rich extract from oat was also reported to possess an effective antioxidant activity against D-galactose-induced oxidative stress [48]. Furthermore, it was demonstrated that Avns, including Avn-A, significantly increased heme oxygenase-1 (HO-1) expression in HK-2 cells in both dose- and time-dependent manners, showing that this effect involved ROS production and Nrf2 nuclear translocation [49, 50].

The Avn analog Tranilast was also reported to be effective in reducing the generation of ROS, including hydrogen peroxide (H2O2) and hydroxyl radical (OH), suggesting potential clinical applications [51]. However, the mechanisms of its antioxidant activity are yet to be clarified.

On the other hand, Avn analogs produced in recombinant yeast, including YAvn I and YAvn II, were originally shown to have strong antioxidant activity when tested in an ABTS•+ radical quenching assay, as well as the capacity to reduce intracellular ROS levels in a cellular model of CCM disease, as evaluated with a cellular antioxidant assay [39]. Subsequent in vitro studies demonstrated that YAvn I and YAvn II positively regulate cell antioxidant defense mechanisms through the upregulation of forkhead box protein O1 (FOXO1) and superoxide dismutase 2 (SOD2) expression levels [40]. In addition, recent studies in an animal model of CCM disease have extended these findings, demonstrating the effectiveness of YAvns in major oxidative stress-related disease phenotypes [41] (Table 1).

Table 1: Antioxidant activity of natural, synthetic, and recombinant avenanthramides.

3. Anti-Inflammatory Activity of Avenanthramides

The ancient literature already described the anti-inflammatory and anti-itching properties of oat extracts. In fact, Greek and Latin literatures report the use of oatmeal as topical therapy for a variety of dermatological conditions [29]. Since 1945, several studies showed the benefits of colloidal oatmeal bath as soothing treatment as well as nonirritating, cleansing formulation for inflamed, itchy skin associated with various xerotic dermatitis [16, 29]. Despite widespread use for skin irritation, the phytochemicals present in oat and responsible for the anti-inflammatory activity were not defined until 2004. Liu and colleagues first reported the potential anti-inflammatory and antiatherogenic properties of Avn-enriched extracts of oats, which inhibited the IL-1β-stimulated endothelial cell secretion of proinflammatory cytokines (IL-6) and chemokines (IL-8 and MCP-1), as well as expression of adhesion molecules (ICAM-1, VCAM-1, and E-selectin) and adhesion of monocytes to endothelial cell monolayer [29]. Similarly, CH3-Avn-C, a synthetically prepared methyl ester derivative of Avn-C, significantly and dose-dependently decreased mRNA expression and secretion of IL-6, IL-8, and MCP-1 in endothelial cells and inhibited IL-1β- and TNFα-stimulated NF-κB activation by preventing the phosphorylation of IκB kinase and IκB [26]. Moreover, Sur and colleagues found that keratinocites treated with Avns displayed a significant inhibition of TNF-induced NF-κB activity and subsequent reduction of IL-8 release, suggesting that oat Avns may have putative anti-itching activity [16]. Furthermore, dihydro-avenanthramide D (DH Avn-D), a synthetic analog of avenanthramide, was shown to inhibit mast cell degranulation and exhibit anti-inflammatory effects through the activation of the neurokinin-1 receptor [52]. In addition, avenanthramide supplementation was able to attenuate exercise-induced inflammation in postmenopausal women by reducing neutrophil respiratory burst activity, plasma C-reactive protein and IL-1β levels, and NF-κB activation in peripheral blood mononuclear cells [53]. Notably, differences in the ability to inhibit NF-κB among Avns have been ascribed to molecular structural variations [54].

On the other hand, the anti-inflammatory properties of the Avn analog Tranilast have been attributed mainly to its capacity to inhibit the release of chemical mediators from mast cells and basophils [34, 55], suppress COX-2 and iNOS expression [56], and limit TNFα-induced secretion of IL-6 and surface expression of vascular adhesion molecules, including VCAM-1, ICAM-1 and E-selectin, in endothelial cells by inhibiting NF-κB-dependent gene transcription [38]. Furthermore, Tranilast anti-inflammatory properties were shown to be triggered by the induction of HO-1 expression via ERK1/2 activation [55]. Finally, recombinant YAvns were demonstrated to downregulate NF-κB and rescue inflammatory phenotypes in cellular and animal models of CCM disease [41] (Table 2).

Table 2: Anti-inflammatory activity of natural, synthetic, and recombinant avenanthramides.

4. Antiproliferative Activity of Avenanthramides

Clear evidence demonstrates that Avns, including Avn-C and its methylated derivative (CH3-Avn-C), can significantly inhibit proliferation of distinct cell lines, such as human colon and breast cancer cells, and vascular smooth muscle cells (VSMC) [25, 31, 57]. Indeed, it has been reported that Avns induce cell cycle arrest at the G1 phase by upregulating the p53-p21cip1 pathway and inhibiting phosphorylation of the retinoblastoma protein (pRB) [25], and may activate apoptosis [57]. Moreover, methylated Avn-C was shown to inhibit proteasome activity and increase the levels of ubiquitin-conjugated proteins in endothelial cells, suggesting that inhibition of proteasome activity and consequent stabilization of the p53 protein are a plausible mechanism underlying the inhibitory effect of Avns on the cell cycle [25]. In particular, by testing the antiproliferative effect of Avns on distinct cancer cell lines, it was found that Avn-enriched oat extracts, Avn-C, and the methyl-ester derivative of Avn-C were more effective on colon cancer cell lines, including CaCo-2, HT29, LS174T, and HCT116 cells, than on prostate or breast cancer cell lines [25]. Furthermore, the synthetic DH Avn-D was shown to inhibit human breast cancer cell invasion through inhibition of MAPK/NF-κB and MAPK/AP-1 pathways and suppression of MMP-9 expression [32]. In addition, the Avn analog Tranilast was shown to exert inhibitory effects on proliferation, epithelial-mesenchymal transition (EMT), and invasion of cancer cells [58]. Moreover, it was reported to inhibit proliferation, chemotaxis, and tube formation of human microvascular endothelial cells in vitro and angiogenesis in vivo [59], as well as vascular endothelial growth factor (VEGF)-induced vascular permeability [60], suggesting that it might ameliorate angiogenesis-related diseases, such as tumor metaplasia, rheumatoid arthritis, diabetic retinopathy, and age-related macular degeneration, acting as a novel angiogenesis inhibitor [59, 61, 62]. Finally, recent evidence demonstrates that recombinant YAvn I and YAvn II are endowed with stronger antiproliferative properties than natural Avns, including Avn-B, due to their enhanced capacity of reducing intracellular ROS levels and cyclin D1 expression [40] (Table 3).

Table 3: Antiproliferative activity of natural, synthetic, and recombinant avenanthramides.

5. Therapeutic Benefits of Avenanthramides

There is compelling evidence that oxidative stress plays a major role in the pathogenesis and progression of major human diseases, including atherosclerosis, diabetes, inflammatory diseases, cardiovascular diseases, cancer, and neurological disorders, such as amyotrophic lateral sclerosis, Alzheimer’s (AD) and Parkinson’s (PD) diseases [63], and is also implicated in aging [64].

Oxidative stress occurs either when excess ROS are produced in cells, which could overwhelm the normal antioxidant capacity, or upon impairment of antioxidant defense mechanisms. ROS toxicity contributes to protein, lipid and DNA damage, inflammation, cell and tissue injury, and apoptosis. Nevertheless, ROS also play important physiological functions, whereas emerging evidence demonstrates that the biological impact of ROS depends not only on their intracellular levels and rate of formation and decay but also on their chemical nature and subcellular localization [65, 66]. Thus, inappropriate removal of ROS by antioxidants may cause paradoxical reductive stress and thereby induce or promote disease [63, 67, 68].

Due to their capacity to scavenge ROS and prevent oxidative stress, antioxidants (including natural and synthetic phenolic compounds) have long been credited with helping to live longer and stay healthier, and looked upon as effective therapeutic options for prevention and treatment of various oxidative stress-related diseases. Natural antioxidants are primarily phenolics that may occur in all parts of plants [69]. Specifically, beneficial effects on human health of phenolic compounds with high antioxidant properties obtained from oats have been reported in many studies and shown to protect cells against oxidative damage [23, 70]. Furthermore, several compositions containing oat Avns or derivatives have been described in pharmaceutical patents for use in cosmetic, nutraceutical, and therapeutic preparations due to their antioxidant, anti-inflammatory, anti-itching, antiallergic, antihistaminic, antiasthmatic, and antiaging activities. In particular, the synthetic drug Tranilast has been approved since 1982 in Japan and South Korea and, as mentioned above, is currently used as an antihistamine to treat bronchial asthma, atopic dermatitis, allergic conjunctivitis, allergic rhinitis, and other allergic disorders, with indications for keloids and hypertrophic scars, scleroderma, and other skin disease related to excessive fibrosis [36]. In addition, it was proposed for treatment of autoimmune diseases, such as arthritis and multiple sclerosis, and as an inhibitor of angiogenesis [37, 71]. Moreover, the high potential of Tranilast in inhibiting pathological cellular growth processes, such as tumor-related ones, was investigated with promising results [37, 58, 7281].

On the other hand, a randomized, placebo-controlled, double-blind pilot study, led to determine whether the Avn-enriched bran reduces biomarkers of inflammation, demonstrated that consuming Avns in a whole food form, that is, Avn-enriched oat bran, may affect specific biomarkers of inflammation in older, overweight, or obese adults [82]. Considering the anti-inflammatory properties of Avns and their capacity to inhibit smooth muscle cell proliferation and increase NO production, these compounds were proposed for prevention or therapy of atherosclerosis and associated cardiovascular diseases. Data also pointed to the potential benefit of including oats and oat bran in daily meals over the long term [26]. Interestingly, recent evidence highlighted the combined antioxidant, anti-inflammatory, and anticancer effects of individual synthetized Avns and a mixture of natural Avns on CaCo-2 and Hep3B cancer cells, showing that both natural and synthetic Avns activate caspases 2, 8, and 3 and downregulate hTERT, MDR1, and COX-2 genes, and suggesting that oat-based foods fortified with Avns could be an alternative to produce functional foods with major health benefits [83]. Furthermore and importantly, recent findings demonstrated that both Tranilast and YAvns were effective in rescuing prooxidant and proinflammatory phenotypes associated with CCM disease, a cerebrovascular disorder associated with altered redox homeostasis and signaling and enhanced susceptibility to oxidative stress and inflammatory insults, thus widening the therapeutic potential of these compounds [41].

6. Avenanthramides as Potential Therapeutics for Cerebral Cavernous Malformation Disease

CCM, also known as cavernous angioma or cavernoma, is a major cerebrovascular disease characterized by clusters of abnormally dilated and leaky capillaries occurring in brain, spinal cord, and retina, with a prevalence of 0.3–0.5% in the general population. These vascular anomalies, referred to as CCM lesions, can be single or multiple (up to hundreds), as detected by magnetic resonance imaging, and may result in severe clinical symptoms at any age, including recurrent headaches, focal neurological deficits, seizures, stroke, and intracerebral hemorrhage (ICH) [84]. CCM disease has proven genetic origin (OMIM 116860), being caused by loss-of-function mutations in three genes, KRIT1 (CCM1), CCM2, and PDCD10 (CCM3). It may arise sporadically or is inherited as autosomal dominant condition with incomplete penetrance and highly variable expressivity even among members of the same family, including wide differences in lesion number, size, and susceptibility to ICH [8486]. Despite significant recent advances in our understanding of the pathophysiology of CCM disease, no direct therapeutic approaches are available so far, besides the surgical removal of accessible lesions [84, 87].

Accumulated evidence demonstrates that loss-of-function mutations of CCM genes have pleiotropic effects on several redox-sensitive molecules and mechanisms that control cellular homeostasis and defenses against oxidative stress and inflammation, thereby sensitizing cells to local oxidative stress and inflammatory events [84, 86, 8895]. In particular, KRIT1 loss-of-function has been shown to affect major antioxidant pathways and mechanisms, including the FOXO1-SOD2 axis and the Nrf2 antioxidant pathway [89, 94], and the autophagic degradation of dysfunctional, ROS-generating mitochondria [89, 91]. On the other hand, there is emerging evidence that Avns, including YAvns, can enhance cellular defenses against oxidative stress by inhibiting the activity of prooxidant and proinflammatory proteins, such as NADPH oxidase and NF-κB [41], and stimulating the upregulation of antioxidant molecules, such as GSH and SOD2 [21, 40]. Indeed, treatment of KRIT1-knockout and KRIT1-silenced cellular models with YAvns was effective in reverting molecular phenotypes caused by KRIT1 loss-of-function, including the downregulation of FOXO1 and SOD2 and the upregulation of cyclin D1 [40]. Furthermore, both YAvns and Tranilast were able to induce a rescue of major phenotypic signatures in a mouse model of CCM disease, including altered redox homeostasis and signaling, destabilized endothelial cell-cell junctions and blood-brain barrier, enhanced vascular permeability, and reduced susceptibility to oxidative stress and inflammatory insults, suggesting potential therapeutic benefits for CCM disease [41]. Further studies aimed at a comprehensive characterization of the pleiotropic effects and mechanisms of action of natural and recombinant Avns will provide useful insights into these and other promising therapeutic benefits.

7. Avenanthramide and Aging Processes: A New Elixir of Youth?

Oatmeal has been used for centuries as a soothing agent to relieve itch and irritation associated with various xerotic dermatoses. Today, it is available in various dosage forms from powders for the bath to shampoos, shaving gels, and moisturizing creams, and has been approved as a skin protectant by the US Food and Drug Administration (FDA) [27].

Among oat constituents, Avns are known to suppress histamine release at very low doses, helping to plump up the skin, reduce wrinkles, and restore the skin natural barrier. Indeed, oat Avns have been shown to represent the main group of active polyphenolic antioxidants responsible for oatmeal anti-inflammatory, antierythema (antiredness), antipruritic (anti-itching), and antihistaminic properties. Consistently, several studies have demonstrated their benefits in reducing eczema and other inflammatory skin conditions [16]. Another health and antiaging benefit of oat Avns is their antigenotoxic activity, which can protect the DNA of epidermal cells against environmental insults, including UV irradiation [21]. In hair care, oat Avns have been shown to prevent lipid peroxidation in human hair follicles and alleviate scalp itchiness and tenderness, indicating Avns as an ideal active ingredient for scalp care formulations [25]. Furthermore, Avns have been shown to prevent oxidation of LDL cholesterol and inhibit the first stages of atherosclerosis, gaining the reputation of being able to protect the aging cardiovascular system. In addition, as also described in this review, several studies in the past few years have suggested that oat Avns may be beneficial in the treatment of various aging-related human diseases associated with chronic oxidative stress and inflammation [96]. Notably, Avns exert their strong antioxidant and anti-inflammatory properties even at very low doses.

Taken together, the established beneficial effects of Avns in skin protection and treatment of dermatological diseases, and their emerging potentiality to prevent and treat chronic oxidative stress and inflammation associated with onset, progression and severity of aging-related diseases, including metabolic, cardiovascular, cerebrovascular and neurodegenerative diseases, point to these compounds as promising new elixir of youth with both cosmetic and pharmaceutical applications.

8. Foodomics for Elucidating Molecular Pathways Underlying Biological Effects of Avenanthramides in Chronic Diseases

Nutrition research has traditionally explored the functional importance of diverse food categories through a careful evaluation of various physiological phenomena and molecular markers characterizing a group of individuals fed with a defined diet. Bioactive food constituents may have significant beneficial effects for health promotion and disease prevention, with various compounds active in reducing the sustained oxidative stress and inflammation accompanying chronic diseases, for example, CVDs and/or metabolic syndromes. Unfortunately, chronic disorders are often complex, multifactorial pathogenetic processes; they are the result of combined genomic variant peculiarities interacting with environmental/behavioral factors. Hence, not only genetic factors but also homeostatic alterations related to the environment may be crucial in disease onset, progression, and severity.

In the last few years, nutrition research has moved from classical physiology and epidemiology to chemical biology, molecular biology, and genetics [97]. It has evolved similarly to pharmacological research, where the topic effect of a specific drug is evaluated on a defined cellular/organism model subjected to controlled perturbative events (such as drug treatment at a specific concentration and for a defined time), which are then assayed according to a holistic perspective through combined molecular approaches [98, 99]. In this context, foodomics has emerged as a novel and multidisciplinary research field in nutrition science, which aims at elucidating how diet can influence organism health [100, 101]. It is well known that bioactive compounds present in foods, when assimilated, can affect gene expression profiles in organism tissues/organs, and corresponding protein levels and metabolite representations, thus contributing to modulating the incidence of several chronic diseases. The study of these complex interactions requires the integration of different analytical approaches generating various dataset, which then are interpreted according to a system biology perspective by dedicated bioinformatic methods [102]. Thus, in a foodomics experiment, (i) genomics takes advantage of DNA microarray technologies to detect mRNA expression changes in response to diet; (ii) proteomics uses quantitative LC and MS methods combined with isotopic labelling procedures (TMT, iTRAQ, or SILAC) to define protein profile variations in dietary interventions; (iii) metabolomics uses the same separation and measure techniques to define the bioavailability of bioactive molecules in food and their molecular changes after ingestion, as well as organism plasma/urine metabolite profiles in response to diet; (iv) genetics defines common genetic variants involved in the individual response to diet through whole genome sequencing techniques. Integration of all information according to a multiomic elaboration allows simultaneously deciphering gene expression pathways, protein levels, and metabolite concentrations that are affected in healthy individuals experiencing a certain diet; the same information can be obtained for subjects suffering a certain pathological condition. Thus, it is possible to formulate dietary recommendations based on a system biology perspective to ensure a healthy condition or to prevent and treat chronic diseases, such as CVDs, obesity, and cancer [103]. In this context, we particularly underline the importance of foodomics studies that over time have been performed on human, animals, and animal models of human diseases administered with (i) rosemary extracts rich in polyphenols [104106] and corresponding isolated metabolite carnosol and carnosic acid [107, 108]; (ii) red-to-blue fruit extracts rich in anthocyanins [109]; (iii) vegetable extracts rich in flavonoids [110] and isoflavones or isolated genistein, daidzein [111], and flavone [112]; (iv) green tea extracts rich in polyphenols [113]; (v) olive oil extracts rich in polyphenols [114]; (vi) fish oil extracts rich in polyunsaturated fatty acids [115]; (vii) resveratrol-containing foods [116]; (viii) inulin-containing prebiotics and isolated inulin; (ix) increased dietary protein [117, 118]; (x) nutrients lacking normal Zn supplement [119]; (xi) augmented folate [120] and multivitamin/mineral supplement [121]. Due to the complexity of these studies, their results were often published in different articles. In most cases, experiments were performed on individuals fed with a food matrix containing various bioactive compounds; this is similar to other “omic” investigations, where traditional pharmacological remedies were tested through holistic approaches [122124]. In the next future, it is desirable that advanced foodomics studies, analogous to those reported above for other foods, will also be performed on organisms or animal models of human diseases fed with oat compounds, including isolated Avns and their recombinant derivatives, to unveil the molecular mechanisms underlying the corresponding biological effects and therapeutic benefits reported above. To this regard, particular attention should be paid to the effects of Avns on the intestinal microbiome, as this has been recognized as a fundamental player in human health and disease, affecting a variety of conditions such as host energy balance and immune responses [125], and has been recently implicated also in the pathogenesis of CCM disease, suggesting that manipulation of the bacterial microbiome may indeed be an effective therapeutic approach [126]. It is therefore important that future foodomics investigations will also include information from gut-residing bacteria and consequent modulation of the gut-brain axis.

9. Redox Proteomics for Detailing Chemical Modifications Hampered by Avenanthramides in Chronic Diseases

Oxidative and nitrosative stresses, due to an imbalance between the generation of ROS and reactive nitrogen species (RNS), and the antioxidant defense capacity of the organism, are important pathophysiological events contributing to the onset and progression of several human pathologies, including cardiovascular diseases and metabolic syndromes [127, 128]. ROS include superoxide anion (O2•−), hydroxyl (OH) and peroxyl (RO2), and alkoxyl (RO) radicals, as well as nonradical compounds, such as hydrogen peroxide (H2O2), hypochlorous acid (HOCl) and organic peroxides, which can be produced from either endogenous (e.g., mitochondrial electron transport chain, cytochrome P450 monooxygenases, and NADPH oxidases) or exogenous sources (e.g., pollutants, drugs, xenobiotics, and radiation). On the other hand, RNS are reactive compounds derived from nitric oxide (NO) following the activity of inducible nitric oxide synthases, and include peroxynitrite (ONOO), alkyl peroxynitrite (ROONO), nitrogen dioxide (NO2), and other molecules [129].

ROS and RNS affect major cellular components, including lipids, DNA and proteins, modifying their structure. In particular, hundreds of adducts of distinct nature have been identified in proteins as a result of the reaction of ROS and RNS with chemical groups present in amino acid side chain [130]. Through modulation of protein structure/function, ROS and RNS can influence a number of enzymatic activities and protein functions, thus affecting intracellular signal transduction pathways and gene expression profiles. While several enzymatic and nonenzymatic markers of chronic oxidative and nitrosative stresses are well known in different organs and body tissues/fluids, early protein targets of oxidative and nitrosative injuries are now becoming to be defined. The identification of putative oxidative biomarkers takes advantage of redox proteomics [131], which is indeed a branch of proteomics specifically designed to identify oxidized and nitrosized proteins and determine nature, extent, and location of oxidative/nitrosative posttranslational modifications in the proteomes of interest. Gel-based and gel-free redox proteomics techniques often use liquid chromatography coupled to mass spectrometry as the major platform to achieve the goal of identifying and fully characterizing oxidized and nitrosized target proteomes. In this context, dedicated redox proteomics methods have been developed to quali-quantitatively investigate (i) Cys oxidation to sulfenic, sulfinic, and sulfonic acid; (ii) Cys conversion to intra- and intermolecular cystine derivatives; (iii) Cys conversion into S-nitrosyl-cysteine; (iv) Met sulfoxidation to sulfone/sulfoxide derivatives; (v) Trp oxidation and nitrosation to (di)hydroxytryptophan, N-formylkynurenine, hydroxykynurenine, kynurenine, and nitrotryptophan; (vi) His oxidation to oxindolylalanine, 2-oxo-histidine, and 5-hydroxy-2-oxo-histidine; (vii) Tyr oxidation, nitrosation, and halogenation to di- and tri-hydroxyphenylalanine, 3,3-dityrosine, 3-nitrotyrosine, and 3,(5)-(di)halotyrosine, respectively; (viii) Pro, Arg, Lys, and Thr direct oxidation to 2-pyrrolidone, glutamic acid semialdehyde, aminoadipic semialdehyde, and 2-amino-3-ketobutyric acid, respectively; (ix) Lys and Arg glyco-oxidation to generate more than fifty distinct derivatives; (x) Cys, His, and Lys reactions with α,β-unsaturated aldehydes deriving from lipid peroxidation to generate more than thirty distinct derivatives; (xi) Cys modification with electrophic prostaglandins and isoprostanes deriving from arachidonic acid oxidation. Once identified, oxidized and nitrosized proteins can be placed in specific molecular pathways to provide insights into affected molecular and cellular functions associated with human diseases.

Conventional and early detection of above-mentioned oxidized and nitrosized protein markers in various diseases and metabolic syndromes has thus enabled to hypothesize a relationship between pathological hallmarks of such disorders and protein structural/functional modifications. This is the case of distinctive identifications of (i) carbonylation, Tyr chlorination, and Met sulfoxidation of target proteins in plasma and atherosclerotic lesions from subjects affected by coronary artery diseases [132, 133]; (ii) glycated, carbonylated, Met-sulfoxidized, Tyr-nitrated, and S-nitrosylated proteins in biological fluids and tissues of diabetic patients, or tissues of related animal models [134144]; (iii) carbonylation, Tyr nitration, and S-glutathionylation of target proteins in brain tissues of AD and mild cognitive impairment patients, or animal models of AD, PD, HD, and ALS [145150]; (iv) oxidized, carbonylated, and Tyr-nitrated and chlorinated proteins in body tissues of patients and animal models experiencing various acute inflammatory syndromes [151, 152]; (v) carbonylated proteins in bronchoalveolar lavage of patients with sarcoidosis and pulmonary fibrosis [153]; (vi) carbonylated proteins in the diaphragm and muscle tissues of severe chronic obstructive pulmonary disease patients and related animal models [154, 155]; (vii) glycoxidized and carbonylated proteins in urine and the kidney of patients with dialysis-related amyloidosis [156158]; (viii) oxidized proteins in human liver tissues after ischemia/reperfusion [159]; (ix) redox modified proteins in various tissues as a result of aging [160168]; (x) carbonylated, Tyr-nitrated, and S-sulphenylated proteins in hypertensive kidney disease [169171]; (xi) oxidized proteins in the amniotic fluid of preeclamptic women [172]. Whenever inserted in perturbative experiment pipelines, redox proteomics approaches are now allowing a monitoring of the degree of corresponding body tissue damage and the response to pharmacological therapies.

At the same time, they will provide a rationale to the positive/negative effects of a diet on healthy individuals and/or on patients suffering pathological conditions. In this context, pioneering experiments have been performed to evaluate the impact of (i) excessive caloric intake on oxidized and carbonylated proteins from adipose tissues of healthy men [173]; (ii) fasting on Cys-oxidized proteins from healthy animals [174]; (iii) high-fat and high-sucrose diet on carbonylated proteins from tissues and body fluids of healthy animals [175]; (iv) the assumption of glutathione derivatives on Tyr-nitrated proteins from brain-injured animal models [176]; (v) antioxidant-fortified diet on carbonylated and Tyr-nitrated proteins from brain tissues of animal models of AD [177]; (vi) high-fat and alcohol diet on carbonylated and Cys-oxidized proteins from tissues and body fluids of fatty liver disease patients and related animal models [178184]. In the close future, it is hypothesized that redox proteomics studies will also be performed on organisms or animal models of human diseases fed with oat compounds and derivatives, including isolated natural and recombinant Avns, in order to evaluate the capacity of such nutraceuticals to modulate oxidized and nitrosized proteomes in target tissues and body fluids.

10. Concluding Remarks

It is generally accepted that antioxidants exert health-promoting effects by scavenging intracellular ROS; thus, their consumption as food additives and nutraceuticals has been greatly encouraged. Nonetheless, to date, there is little clinical evidence for the long-term benefits of most antioxidants, while there are even alarms of health risks consequent to supplementation of lipophilic antioxidants [68]. Accordingly, the existence of a physiological role of specific ROS concentrations can explain the negative results from clinical trials, where large doses of exogenously-administered antioxidants or hyperactivation of antioxidant pathways with electrophilic therapeutics failed to improve outcomes of oxidative stress-related diseases or resulted even deleterious [63, 67, 185, 186]. Indeed, it is now well established that redox reactions bear the Janus faceted feature of promoting both physiological signaling responses and pathological cues in all biological systems, as well as that endogenous antioxidant molecules and mechanisms participate in both scenarios [63, 67]. Consistently, emerging evidence demonstrates that only intermediate levels of major regulators of antioxidant responses are beneficial, although both the low and high concentration thresholds for physiological versus pathological effects may vary largely depending on genetic and environmental factors and the cellular context [185]. Thus, given that most of the emerging therapeutic compounds with antioxidant properties influence redox-sensitive mechanisms, both their low and high concentration thresholds for physiological versus pathological effects have to be carefully considered.

In this light, further studies are necessary to fully address the beneficial effects of Avns in human health, including antioxidant, antiproliferative, anti-inflammatory, antiaging, and anticancer activities (Figure 2). In particular, useful insights could be derived from foodomics and redox proteomics studies aimed at a comprehensive characterization of molecules and mechanisms that mediate the pleiotropic effects of Avns in cellular and animal models of human diseases, including oxidative posttranslational modifications of structural and regulatory proteins. Moreover, novel therapeutic approaches, including combinatorial therapy and nanotechnology-based targeted drug delivery, are encouraged in order to allow site-directed application, appropriate dosing regimens, pharmacological repair of oxidized biomolecules, and triggering of endogenous antioxidant response systems, which could also be guided by the identification of predictive biomarkers.

Figure 2: Bioactivities and potential health benefits of avenanthramides. Both natural, synthetic, and recombinant avenanthramides have been shown to exhibit strong antioxidant, anti-inflammatory, and antiproliferative activities, which may provide protection against various cellular dysfunctions and human pathologies, including aging-related diseases.

Abbreviations

Avn:Avenanthramide
CCM:Cerebral cavernous malformations
CHD:Coronary heart disease
COX-2:Cyclooxygenase-2
FOXO1:Forkhead box protein O1
HO-1:Heme oxygenase-1
ICAM-1:Intercellular adhesion molecule 1
IκB:Nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor
LDL:Low-density lipoprotein
MMP:Matrix metalloproteinase
NF-κB:Nuclear factor kappa-light-chain-enhancer of activated B cells
VCAM-1:Vascular cell adhesion molecule 1
ROS:Reactive oxygen species
SOD2:Superoxide dismutase 2
TGF-β:Transforming growth factor-β
TNFα:Tumor necrosis factor alpha
VSMC:Vascular smooth muscle cells
YAvn:Yeast avenanthramide.

Conflicts of Interest

The authors declare no conflicts of interest.

Authors’ Contributions

Andrea Perrelli and Luca Goitre contributed equally to this work.

Acknowledgments

The authors are grateful to Eliana Trapani, Valerio Benedetti, Giulia Costantino, Federica Geddo, Alessia Zotta, Giovanna Bratti, and Gaudenzio Inverso for critically reading the manuscript and suggesting improvements, and to Santina Barbaro for helpful discussion. They also acknowledge the Italian Research Network for Cerebral Cavernous Malformation (CCM Italia, http://www.ccmitalia.unito.it/) and the Associazione Italiana Angiomi Cavernosi (AIAC, http://www.ccmitalia.unito.it/aiac/) for fundamental collaboration and support. Figure 2 is an artwork of Federica Geddo. This work was supported by grants from Telethon (GGP15219/coordinator) and the University of Torino (Local Research Funding 2014-17) to Saverio Francesco Retta.

References

  1. N. B. Halima, R. B. Saad, B. Khemakhem, I. Fendri, and S. Abdelkafi, “Oat (Avena sativa L.): oil and nutriment compounds valorization for potential use in industrial applications,” Journal of Oleo Science, vol. 64, no. 9, pp. 915–932, 2015. View at Publisher · View at Google Scholar · View at Scopus
  2. C. S. Buer, N. Imin, and M. A. Djordjevic, “Flavonoids: new roles for old molecules,” Journal of Integrative Plant Biology, vol. 52, no. 1, pp. 98–111, 2010. View at Publisher · View at Google Scholar · View at Scopus
  3. C. I. Abuajah, A. C. Ogbonna, and C. M. Osuji, “Functional components and medicinal properties of food: a review,” Journal of Food Science and Technology, vol. 52, no. 5, pp. 2522–2529, 2015. View at Publisher · View at Google Scholar · View at Scopus
  4. C. Rice-Evans and N. Miller, “Measurement of the antioxidant status of dietary constituents, low density lipoproteins and plasma,” Prostaglandins, Leukotrienes, and Essential Fatty Acids, vol. 57, no. 4-5, pp. 499–505, 1997. View at Publisher · View at Google Scholar
  5. A. Kozubek and J. H. P. Tyman, “Resorcinolic lipids, the natural non-isoprenoid phenolic amphiphiles and their biological activity,” Chemical Reviews, vol. 99, no. 1, pp. 1–26, 1999. View at Publisher · View at Google Scholar
  6. R. A. Dixon and N. L. Paiva, “Stress-induced phenylpropanoid metabolism,” Plant Cell, vol. 7, no. 7, pp. 1085–1097, 1995. View at Publisher · View at Google Scholar · View at Scopus
  7. D. Treutter, “Significance of flavonoids in plant resistance and enhancement of their biosynthesis,” Plant Biology, vol. 7, no. 6, pp. 581–591, 2005. View at Publisher · View at Google Scholar · View at Scopus
  8. M. N. Clifford, “Chlorogenic acids and other cinnamates—nature, occurrence and dietary burden,” Journal of Science and Food Agriculture, vol. 79, no. 3, pp. 362–372, 1999. View at Publisher · View at Google Scholar
  9. A. W. Boots, G. R. M. M. Haenen, and A. Bast, “Health effects of quercetin: from antioxidant to nutraceutical,” European Journal of Pharmacology, vol. 585, no. 2-3, pp. 325–337, 2008. View at Publisher · View at Google Scholar · View at Scopus
  10. M. Jang, L. Cai, G. O. Udeani et al., “Cancer chemopreventive activity of resveratrol, a natural product derived from grapes,” Science, vol. 275, no. 5297, pp. 218–220, 1997. View at Publisher · View at Google Scholar
  11. P. Mattila, J. M. Pihlava, and J. Hellstrom, “Contents of phenolic acids, alkyl- and alkenylresorcinols, and avenanthramides in commercial grain products,” Journal of Agricultural and Food Chemistry, vol. 53, no. 21, pp. 8290–8295, 2005. View at Publisher · View at Google Scholar · View at Scopus
  12. F. W. Collins, “Oat phenolics—avenanthramides, novel substituted N-cinnamoylanthranilate alkaloids from oat groats and hulls,” Journal of Agricultural and Food Chemistry, vol. 37, no. 1, pp. 60–66, 1989. View at Publisher · View at Google Scholar · View at Scopus
  13. Y. Okazaki, T. Isobe, Y. Iwata et al., “Metabolism of avenanthramide phytoalexins in oats,” The Plant Journal, vol. 39, no. 4, pp. 560–572, 2004. View at Publisher · View at Google Scholar · View at Scopus
  14. F. W. Collins, “Oat Phenolics—avenanthramides, substituted N-cinnamoyl-anthranilate alkaloids from oat bran and oat hulls,” Cereal Foods World, vol. 31, no. 8, pp. 593–593, 1986. View at Google Scholar
  15. C. L. Emmons and D. M. Peterson, “Antioxidant activity and phenolic content of oat as affected by cultivar and location,” Crop Science, vol. 41, no. 6, 2001. View at Publisher · View at Google Scholar
  16. R. Sur, A. Nigam, D. Grote, F. Liebel, and M. D. Southall, “Avenanthramides, polyphenols from oats, exhibit anti-inflammatory and anti-itch activity,” Archives of Dermatological Research, vol. 300, no. 10, pp. 569–574, 2008. View at Publisher · View at Google Scholar · View at Scopus
  17. M. Meydani, “Potential health benefits of avenanthramides of oats,” Nutrition Reviews, vol. 67, no. 12, pp. 731–735, 2009. View at Publisher · View at Google Scholar · View at Scopus
  18. K. Miyazawa, S. Hamano, and A. Ujiie, “Antiproliferative and c-myc mRNA suppressive effect of Tranilast on newborn human vascular smooth muscle cells in culture,” British Journal of Pharmacology, vol. 118, no. 4, pp. 915–922, 1996. View at Publisher · View at Google Scholar · View at Scopus
  19. L. Li Ji, D. Lay, E. Chung, Y. Fu, and D. M. Peterson, “Effects of avenanthramides on oxidant generation and antioxidant enzyme activity in exercised rats,” Nutrition Research, vol. 23, no. 11, pp. 1579–1590, 2003. View at Publisher · View at Google Scholar · View at Scopus
  20. K. Bratt, K. Sunnerheim, S. Bryngelsson et al., “Avenanthramides in oats (Avena sativa L.) and structure-antioxidant activity relationships,” Journal of Agricultural and Food Chemistry, vol. 51, no. 3, pp. 594–600, 2003. View at Publisher · View at Google Scholar · View at Scopus
  21. C.-Y. Oliver Chen, P. E. Milbury, F. William Collins, and J. B. Blumberg, “Avenanthramides are bioavailable and have antioxidant activity in humans after acute consumption of an enriched mixture from oats,” The Journal of Nutrition, vol. 137, no. 6, pp. 1375–1382, 2007. View at Publisher · View at Google Scholar
  22. C. Y. Chen, P. E. Milbury, H. K. Kwak, F. W. Collins, P. Samuel, and J. B. Blumberg, “Avenanthramides and phenolic acids from oats are bioavailable and act synergistically with vitamin C to enhance hamster and human LDL resistance to oxidation,” The Journal of Nutrition, vol. 134, no. 6, pp. 1459–1466, 2004. View at Publisher · View at Google Scholar
  23. Y. F. Chu, M. L. Wise, A. A. Gulvady et al., “In vitro antioxidant capacity and anti-inflammatory activity of seven common oats,” Food Chemistry, vol. 139, no. 1–4, pp. 426–431, 2013. View at Publisher · View at Google Scholar · View at Scopus
  24. A. Fagerlund, K. Sunnerheim, and L. H. Dimberg, “Radical-scavenging and antioxidant activity of avenanthramides,” Food Chemistry, vol. 113, no. 2, pp. 550–556, 2009. View at Publisher · View at Google Scholar · View at Scopus
  25. W. Guo, L. Nie, D. Wu et al., “Avenanthramides inhibit proliferation of human colon cancer cell lines in vitro,” Nutrition and Cancer, vol. 62, no. 8, pp. 1007–1016, 2010. View at Publisher · View at Google Scholar · View at Scopus
  26. W. Guo, M. L. Wise, F. W. Collins, and M. Meydani, “Avenanthramides, polyphenols from oats, inhibit IL-1β-induced NF-κB activation in endothelial cells,” Free Radical Biology & Medicine, vol. 44, no. 3, pp. 415–429, 2008. View at Publisher · View at Google Scholar · View at Scopus
  27. E. S. Kurtz and W. Wallo, “Colloidal oatmeal: history, chemistry and clinical properties,” Journal of Drugs in Dermatology, vol. 6, no. 2, pp. 167–170, 2007. View at Google Scholar
  28. A. M. Lee-Manion, R. K. Price, J. J. Strain, L. H. Dimberg, K. Sunnerheim, and R. W. Welch, “In vitro antioxidant activity and antigenotoxic effects of avenanthramides and related compounds,” Journal of Agricultural and Food Chemistry, vol. 57, no. 22, pp. 10619–10624, 2009. View at Publisher · View at Google Scholar · View at Scopus
  29. L. Liu, L. Zubik, F. W. Collins, M. Marko, and M. Meydani, “The antiatherogenic potential of oat phenolic compounds,” Atherosclerosis, vol. 175, no. 1, pp. 39–49, 2004. View at Publisher · View at Google Scholar · View at Scopus
  30. L. Nie, M. Wise, D. Peterson, and M. Meydani, “Mechanism by which avenanthramide-c, a polyphenol of oats, blocks cell cycle progression in vascular smooth muscle cells,” Free Radical Biology & Medicine, vol. 41, no. 5, pp. 702–708, 2006. View at Publisher · View at Google Scholar · View at Scopus
  31. L. Nie, M. L. Wise, D. M. Peterson, and M. Meydani, “Avenanthramide, a polyphenol from oats, inhibits vascular smooth muscle cell proliferation and enhances nitric oxide production,” Atherosclerosis, vol. 186, no. 2, pp. 260–266, 2006. View at Publisher · View at Google Scholar · View at Scopus
  32. Y. R. Lee, E. M. Noh, H. J. Oh et al., “Dihydroavenanthramide D inhibits human breast cancer cell invasion through suppression of MMP-9 expression,” Biochemical and Biophysical Research Communications, vol. 405, no. 4, pp. 552–557, 2011. View at Publisher · View at Google Scholar · View at Scopus
  33. H. Azuma, K. Banno, and T. Yoshimura, “Pharmacological properties of N-(3,4-dimethoxycinnamoyl) anthranilic acid (N-5), a new anti-atopic agent,” British Journal of Pharmacology, vol. 58, no. 4, pp. 483–488, 1976. View at Publisher · View at Google Scholar · View at Scopus
  34. H. Komatsu, M. Kojima, N. Tsutsumi et al., “Study of the mechanism of inhibitory-action of Tranilast on chemical mediator release,” The Japanese Journal of Pharmacology, vol. 46, no. 1, pp. 43–51, 1988. View at Publisher · View at Google Scholar · View at Scopus
  35. M. Okuda, T. Ishikawa, Y. Saito, T. Shimizu, and S. Baba, “A clinical evaluation of N-5 with perennial-type allergic rhinitis—a test by the multi-clinic, intergroup, double-blind comparative method,” Annals of Allergy, vol. 53, no. 2, pp. 178–185, 1984. View at Google Scholar
  36. A. Eudes, E. E. K. Baidoo, F. Yang et al., “Production of Tranilast [N-(3,4-dimethoxycinnamoyl)-anthranilic acid] and its analogs in yeast Saccharomyces cerevisiae,” Applied Microbiology and Biotechnology, vol. 89, no. 4, pp. 989–1000, 2011. View at Publisher · View at Google Scholar · View at Scopus
  37. S. Darakhshan and A. B. Pour, “Tranilast: a review of its therapeutic applications,” Pharmacological Research, vol. 91, pp. 15–28, 2015. View at Publisher · View at Google Scholar · View at Scopus
  38. M. Spiecker, I. Lorenz, N. Marx, and H. Darius, “Tranilast inhibits cytokine-induced nuclear factor kappaB activation in vascular endothelial cells,” Molecular Pharmacology, vol. 62, no. 4, pp. 856–863, 2002. View at Publisher · View at Google Scholar · View at Scopus
  39. A. Moglia, C. Comino, S. Lanteri et al., “Production of novel antioxidative phenolic amides through heterologous expression of the plant's chlorogenic acid biosynthesis genes in yeast,” Metabolic Engineering, vol. 12, no. 3, pp. 223–232, 2010. View at Publisher · View at Google Scholar · View at Scopus
  40. A. Moglia, L. Goitre, S. Gianoglio et al., “Evaluation of the bioactive properties of avenanthramide analogs produced in recombinant yeast,” BioFactors, vol. 41, no. 1, pp. 15–27, 2015. View at Publisher · View at Google Scholar · View at Scopus
  41. L. Goitre, P. V. DiStefano, A. Moglia et al., “Up-regulation of NADPH oxidase-mediated redox signaling contributes to the loss of barrier function in KRIT1 deficient endothelium,” Scientific Reports, vol. 7, no. 1, p. 8296, 2017. View at Publisher · View at Google Scholar · View at Scopus
  42. L. Lowen, L. Anderson, and R. W. Harrison, “Cereal flours as antioxidants for fishery products,” Industrial & Engineering Chemistry, vol. 29, no. 2, pp. 151–156, 1937. View at Publisher · View at Google Scholar · View at Scopus
  43. F. N. Peters, “Oat flour as an antioxidant,” Industrial & Engineering Chemistry, vol. 29, no. 2, pp. 146–151, 1937. View at Publisher · View at Google Scholar · View at Scopus
  44. H. Lingnert, K. Vallentin, and C. E. Eriksson, “Measurement of antioxidative effect in model system,” Journal of Food Processing and Preservation, vol. 3, no. 2, pp. 87–103, 1979. View at Publisher · View at Google Scholar · View at Scopus
  45. L. H. Dimberg, O. Theander, and H. Lingnert, “Avenanthramides—a group of phenolic antioxidants in oats,” Cereal Chemistry, vol. 70, no. 6, pp. 637–641, 1993. View at Google Scholar
  46. C. L. Emmons, D. M. Peterson, and G. L. Paul, “Antioxidant capacity of oat (Avena sativa L.) extracts. 2. In vitro antioxidant activity and contents of phenolic and tocol antioxidants,” Journal of Agricultural and Food Chemistry, vol. 47, no. 12, pp. 4894–4898, 1999. View at Publisher · View at Google Scholar · View at Scopus
  47. D. M. Peterson, M. J. Hahn, and C. L. Emmons, “Oat avenanthramides exhibit antioxidant activities in vitro,” Food Chemistry, vol. 79, no. 4, pp. 473–478, 2002. View at Publisher · View at Google Scholar · View at Scopus
  48. Y. Ren, X. Yang, X. Niu, S. Liu, and G. Ren, “Chemical characterization of the avenanthramide-rich extract from oat and its effect on D-galactose-induced oxidative stress in mice,” Journal of Agricultural and Food Chemistry, vol. 59, no. 1, pp. 206–211, 2011. View at Publisher · View at Google Scholar · View at Scopus
  49. H. Mori, H. Tanaka, K. Kawada, H. Nagai, and A. Koda, “Suppressive effects of Tranilast on pulmonary fibrosis and activation of alveolar macrophages in mice treated with bleomycin—role of alveolar macrophages in the fibrosis,” The Japanese Journal of Pharmacology, vol. 67, no. 4, pp. 279–289, 1995. View at Publisher · View at Google Scholar · View at Scopus
  50. J. Fu, Y. Zhu, A. Yerke et al., “Oat avenanthramides induce heme oxygenase-1 expression via Nrf2-mediated signaling in HK-2 cells,” Molecular Nutrition & Food Research, vol. 59, no. 12, pp. 2471–2479, 2015. View at Publisher · View at Google Scholar · View at Scopus
  51. Y. Miyachi, S. Imamura, and Y. Niwa, “The effect of Tranilast of the generation of reactive oxygen species,” Journal of Pharmacobio-Dynamics, vol. 10, no. 6, pp. 255–259, 1987. View at Publisher · View at Google Scholar · View at Scopus
  52. T. Lotts, K. Agelopoulos, N. Q. Phan et al., “Dihydroavenanthramide D inhibits mast cell degranulation and exhibits anti-inflammatory effects through the activation of neurokinin-1 receptor,” Experimental Dermatology, vol. 26, no. 8, pp. 739–742, 2017. View at Publisher · View at Google Scholar · View at Scopus
  53. R. Koenig, J. R. Dickman, C. Kang, T. Zhang, Y. F. Chu, and L. L. Ji, “Avenanthramide supplementation attenuates exercise-induced inflammation in postmenopausal women,” Nutrition Journal, vol. 13, no. 1, p. 21, 2014. View at Publisher · View at Google Scholar · View at Scopus
  54. J. Yang, B. Ou, M. L. Wise, and Y. F. Chu, “In vitro total antioxidant capacity and anti-inflammatory activity of three common oat-derived avenanthramides,” Food Chemistry, vol. 160, pp. 338–345, 2014. View at Publisher · View at Google Scholar · View at Scopus
  55. H. O. Pae, S. O. Jeong, B. S. Koo, H. Y. Ha, K. M. Lee, and H. T. Chung, “Tranilast, an orally active anti-allergic drug, up-regulates the anti-inflammatory heme oxygenase-1 expression but down-regulates the pro-inflammatory cyclooxygenase-2 and inducible nitric oxide synthase expression in RAW264.7 macrophages,” Biochemical and Biophysical Research Communications, vol. 371, no. 3, pp. 361–365, 2008. View at Publisher · View at Google Scholar · View at Scopus
  56. H. Inone, H. Ohshima, H. Kono et al., “Suppressive effects of Tranilast on the expression of inducible cyclooxygenase (COX2) in interleukin-1β-stimulated fibroblasts,” Biochemical Pharmacology, vol. 53, no. 12, pp. 1941–1944, 1997. View at Publisher · View at Google Scholar · View at Scopus
  57. J. Hastings and J. Kenealey, “Avenanthramide-C reduces the viability of MDA-MB-231 breast cancer cells through an apoptotic mechanism,” Cancer Cell International, vol. 17, no. 1, p. 93, 2017. View at Publisher · View at Google Scholar · View at Scopus
  58. M. Hiroi, M. Onda, E. Uchida, and T. Aimoto, “Anti-tumor effect of N-[3,4-dimethoxycinnamoyl]-anthranilic acid (Tranilast) on experimental pancreatic cancer,” Journal of Nippon Medical School, vol. 69, no. 3, pp. 224–234, 2002. View at Publisher · View at Google Scholar · View at Scopus
  59. M. Isaji, H. Miyata, Y. Ajisawa, Y. Takehana, and N. Yoshimura, “Tranilast inhibits the proliferation, chemotaxis and tube formation of human microvascular endothelial cells in vitro and angiogenesis in vivo,” British Journal of Pharmacology, vol. 122, no. 6, pp. 1061–6, 1997. View at Publisher · View at Google Scholar · View at Scopus
  60. M. Isaji, H. Miyata, Y. Ajisawa, and N. Yoshimura, “Inhibition by Tranilast of vascular endothelial growth factor (VEGF)/vascular permeability factor (VPF)-induced increase in vascular permeability in rats,” Life Sciences, vol. 63, no. 4, pp. PL71–PL74, 1998. View at Publisher · View at Google Scholar · View at Scopus
  61. M. Isaji, H. Miyata, and Y. Ajisawa, “Tranilast: a new application in the cardiovascular field as an antiproliferative drug,” Cardiovascular Drug Reviews, vol. 16, no. 3, pp. 288–299, 1998. View at Publisher · View at Google Scholar
  62. M. Isaji, N. Aruga, J. Naito, and H. Miyata, “Inhibition by Tranilast of collagen accumulation in hypersensitive granulomatous inflammation in vivo and of morphological changes and functions of fibroblasts in vitro,” Life Sciences, vol. 55, no. 15, pp. PL287–PL292, 1994. View at Publisher · View at Google Scholar · View at Scopus
  63. K. M. Holmstrom and T. Finkel, “Cellular mechanisms and physiological consequences of redox-dependent signalling,” Nature Reviews Molecular Cell Biology, vol. 15, no. 6, pp. 411–421, 2014. View at Publisher · View at Google Scholar · View at Scopus
  64. S. Miwa, Oxidative Stress in Aging: from Model Systems to Human Diseases, S. Miwa, Ed., Human Press, 2008.
  65. S. F. Retta, P. Chiarugi, L. Trabalzini, P. Pinton, and A. M. Belkin, “Reactive oxygen species: friends and foes of signal transduction,” Journal of Signal Transduction, vol. 2012, Article ID 534029, 1 page, 2012. View at Publisher · View at Google Scholar
  66. L. Goitre, B. Pergolizzi, E. Ferro, L. Trabalzini, and S. F. Retta, “Molecular crosstalk between integrins and cadherins: do reactive oxygen species set the talk?” Journal of Signal Transduction, vol. 2012, Article ID 807682, 12 pages, 2012. View at Publisher · View at Google Scholar
  67. C. Espinosa-Diez, V. Miguel, D. Mennerich et al., “Antioxidant responses and cellular adjustments to oxidative stress,” Redox Biology, vol. 6, pp. 183–197, 2015. View at Publisher · View at Google Scholar · View at Scopus
  68. H. H. H. W. Schmidt, R. Stocker, C. Vollbracht et al., “Antioxidants in translational medicine,” Antioxidants & Redox Signaling, vol. 23, no. 14, pp. 1130–1143, 2015. View at Publisher · View at Google Scholar · View at Scopus
  69. V. Lobo, A. Patil, A. Phatak, and N. Chandra, “Free radicals, antioxidants and functional foods: impact on human health,” Pharmacognosy Reviews, vol. 4, no. 8, pp. 118–126, 2010. View at Publisher · View at Google Scholar · View at Scopus
  70. N. Okarter and R. H. Liu, “Health benefits of whole grain phytochemicals,” Critical Reviews in Food Science and Nutrition, vol. 50, no. 3, pp. 193–208, 2010. View at Publisher · View at Google Scholar · View at Scopus
  71. M. Rogosnitzky, R. Danks, and E. Kardash, “Therapeutic potential of Tranilast, an anti-allergy drug, in proliferative disorders,” Anticancer Research, vol. 32, no. 7, pp. 2471–2478, 2012. View at Google Scholar
  72. J. Fan, J. Stanfield, Y. Guo et al., “Effect of trans-2,3-dimethoxycinnamoyl azide on enhancing antitumor activity of romidepsin on human bladder cancer,” Clinical Cancer Research, vol. 14, no. 4, pp. 1200–1207, 2008. View at Publisher · View at Google Scholar · View at Scopus
  73. T. Goto, T. Nemoto, K. Ogura, T. Hozumi, and N. Funata, “Successful treatment of desmoid tumor of the chest wall with Tranilast: a case report,” Journal of Medical Case Reports, vol. 4, no. 1, p. 384, 2010. View at Publisher · View at Google Scholar
  74. K. Izumi, A. Mizokami, Y. Q. Li et al., “Tranilast inhibits hormone refractory prostate cancer cell proliferation and suppresses transforming growth factor beta1-associated osteoblastic changes,” Prostate, vol. 69, no. 11, pp. 1222–1234, 2009. View at Publisher · View at Google Scholar · View at Scopus
  75. K. Nakajima, Y. Okita, and S. Matsuda, “Sensitivity of scirrhous gastric cancer to 5-fluorouracil and the role of cancer cell-stromal fibroblast interaction,” Oncology Reports, vol. 12, no. 1, pp. 85–90, 2004. View at Publisher · View at Google Scholar
  76. N. Noguchi, S. Kawashiri, A. Tanaka, K. Kato, and H. Nakaya, “Effects of fibroblast growth inhibitor on proliferation and metastasis of oral squamous cell carcinoma,” Oral Oncology, vol. 39, no. 3, pp. 240–247, 2003. View at Publisher · View at Google Scholar · View at Scopus
  77. M. Platten, C. Wild-Bode, W. Wick, J. Leitlein, J. Dichgans, and M. Weller, “N-[3,4-dimethoxycinnamoyl]-anthranilic acid (Tranilast) inhibits transforming growth factor-β release and reduces migration and invasiveness of human malignant glioma cells,” International Journal of Cancer, vol. 93, no. 1, pp. 53–61, 2001. View at Publisher · View at Google Scholar · View at Scopus
  78. H. Shime, M. Kariya, A. Orii et al., “Tranilast inhibits the proliferation of uterine leiomyoma cells in vitro through G1 arrest associated with the induction of p21(waf1) and p53,” The Journal of Clinical Endocrinology & Metabolism, vol. 87, no. 12, pp. 5610–5617, 2002. View at Publisher · View at Google Scholar · View at Scopus
  79. V. Subramaniam, O. Ace, G. J. Prud'homme, and S. Jothy, “Tranilast treatment decreases cell growth, migration and inhibits colony formation of human breast cancer cells,” Experimental and Molecular Pathology, vol. 90, no. 1, pp. 116–122, 2011. View at Publisher · View at Google Scholar · View at Scopus
  80. V. Subramaniam, R. Chakrabarti, G. J. Prud’homme, and S. Jothy, “Tranilast inhibits cell proliferation and migration and promotes apoptosis in murine breast cancer,” Anti-Cancer Drugs, vol. 21, no. 4, pp. 351–361, 2010. View at Publisher · View at Google Scholar · View at Scopus
  81. M. Yamamoto, T. Yamauchi, K. Okano, M. Takahashi, S. Watabe, and Y. Yamamoto, “Tranilast, an anti-allergic drug, down-regulates the growth of cultured neurofibroma cells derived from neurofibromatosis type 1,” The Tohoku Journal of Experimental Medicine, vol. 217, no. 3, pp. 193–201, 2009. View at Publisher · View at Google Scholar · View at Scopus
  82. D. McKay, C. O. Chen, F. W. Collins, and J. Blumberg, “Avenanthramide-enriched oats have an anti-inflammatory action: a pilot clinical trial,” The FASEB Journal, vol. 29, 2015. View at Google Scholar
  83. E. S. Scarpa, M. Mari, E. Antonini, F. Palma, and P. Ninfali, “Natural and synthetic avenanthramides activate caspases 2, 8, 3 and downregulate hTERT, MDR1 and COX-2 genes in CaCo-2 and Hep3B cancer cells,” Food & Function, vol. 9, no. 5, pp. 2913–2921, 2018. View at Publisher · View at Google Scholar
  84. S. F. Retta and A. J. Glading, “Oxidative stress and inflammation in cerebral cavernous malformation disease pathogenesis: two sides of the same coin,” The International Journal of Biochemistry & Cell Biology, vol. 81, Part B, pp. 254–270, 2016. View at Publisher · View at Google Scholar · View at Scopus
  85. H. Choquet, L. Pawlikowska, M. T. Lawton, and H. Kim, “Genetics of cerebral cavernous malformations: current status and future prospects,” Journal of Neurosurgical Sciences, vol. 59, no. 3, pp. 211–220, 2015. View at Google Scholar
  86. E. Trapani and S. F. Retta, “Cerebral cavernous malformation (CCM) disease: from monogenic forms to genetic susceptibility factors,” Journal of Neurosurgical Sciences, vol. 59, no. 3, pp. 201–209, 2015. View at Google Scholar
  87. K. D. Flemming, “Clinical management of cavernous malformations,” Current Cardiology Reports, vol. 19, no. 12, p. 122, 2017. View at Publisher · View at Google Scholar · View at Scopus
  88. L. Goitre, E. de Luca, S. Braggion et al., “KRIT1 loss of function causes a ROS-dependent upregulation of c-Jun,” Free Radical Biology & Medicine, vol. 68, pp. 134–147, 2014. View at Publisher · View at Google Scholar · View at Scopus
  89. L. Goitre, F. Balzac, S. Degani et al., “KRIT1 regulates the homeostasis of intracellular reactive oxygen species,” PLoS One, vol. 5, no. 7, article e11786, 2010. View at Publisher · View at Google Scholar · View at Scopus
  90. C. C. Gibson, W. Zhu, C. T. Davis et al., “Strategy for identifying repurposed drugs for the treatment of cerebral cavernous malformation,” Circulation, vol. 131, no. 3, pp. 289–299, 2015. View at Publisher · View at Google Scholar · View at Scopus
  91. S. Marchi, M. Corricelli, E. Trapani et al., “Defective autophagy is a key feature of cerebral cavernous malformations,” EMBO Molecular Medicine, vol. 7, no. 11, pp. 1403–1417, 2015. View at Publisher · View at Google Scholar · View at Scopus
  92. S. Marchi, E. Trapani, M. Corricelli, L. Goitre, P. Pinton, and S. F. Retta, “Beyond multiple mechanisms and a unique drug: defective autophagy as pivotal player in cerebral cavernous malformation pathogenesis and implications for targeted therapies,” Rare Diseases, vol. 4, no. 1, article e1142640, 2016. View at Publisher · View at Google Scholar · View at Scopus
  93. H. Choquet, E. Trapani, L. Goitre et al., “Cytochrome P450 and matrix metalloproteinase genetic modifiers of disease severity in cerebral cavernous malformation type 1,” Free Radical Biology & Medicine, vol. 92, pp. 100–109, 2016. View at Publisher · View at Google Scholar · View at Scopus
  94. C. Antognelli, E. Trapani, S. Delle Monache et al., “KRIT1 loss-of-function induces a chronic Nrf2-mediated adaptive homeostasis that sensitizes cells to oxidative stress: implication for cerebral cavernous malformation disease,” Free Radical Biology & Medicine, vol. 115, pp. 202–218, 2018. View at Publisher · View at Google Scholar · View at Scopus
  95. C. Antognelli, E. Trapani, S. Delle Monache et al., “Data in support of sustained upregulation of adaptive redox homeostasis mechanisms caused by KRIT1 loss-of-function,” Data in Brief, vol. 16, pp. 929–938, 2018. View at Publisher · View at Google Scholar · View at Scopus
  96. S. Sang and Y. Chu, “Whole grain oats, more than just a fiber: role of unique phytochemicals,” Molecular Nutrition & Food Research, vol. 61, no. 7, 2017. View at Publisher · View at Google Scholar · View at Scopus
  97. V. García-Cañas, C. Simó, C. León, and A. Cifuentes, “Advances in nutrigenomics research: novel and future analytical approaches to investigate the biological activity of natural compounds and food functions,” Journal of Pharmaceutical and Biomedical Analysis, vol. 51, no. 2, pp. 290–304, 2010. View at Publisher · View at Google Scholar · View at Scopus
  98. A. Wilmes, A. Limonciel, L. Aschauer et al., “Application of integrated transcriptomic, proteomic and metabolomic profiling for the delineation of mechanisms of drug induced cell stress,” Journal of Proteomics, vol. 79, pp. 180–194, 2013. View at Publisher · View at Google Scholar · View at Scopus
  99. B. Titz, A. Elamin, F. Martin et al., “Proteomics for systems toxicology,” Computational and Structural Biotechnology Journal, vol. 11, no. 18, pp. 73–90, 2014. View at Publisher · View at Google Scholar · View at Scopus
  100. V. García-Cañas, C. Simó, M. Herrero, E. Ibáñez, and A. Cifuentes, “Present and future challenges in food analysis: foodomics,” Analytical Chemistry, vol. 84, no. 23, pp. 10150–10159, 2012. View at Publisher · View at Google Scholar · View at Scopus
  101. M. Kussmann, M. Affolter, K. Nagy, B. Holst, and L. B. Fay, “Mass spectrometry in nutrition: understanding dietary health effects at the molecular level,” Mass Spectrometry Reviews, vol. 26, no. 6, pp. 727–750, 2007. View at Publisher · View at Google Scholar · View at Scopus
  102. L. Badimon, G. Vilahur, and T. Padro, “Systems biology approaches to understand the effects of nutrition and promote health,” British Journal of Clinical Pharmacology, vol. 83, no. 1, pp. 38–45, 2017. View at Publisher · View at Google Scholar · View at Scopus
  103. T. Zheng, Y. Ni, J. Li, B. K. C. Chow, and G. Panagiotou, “Designing dietary recommendations using system level interactomics analysis and network-based inference,” Frontiers in Physiology, vol. 8, p. 753, 2017. View at Publisher · View at Google Scholar · View at Scopus
  104. A. Valdés, K. A. Artemenko, J. Bergquist, V. García-Cañas, and A. Cifuentes, “Comprehensive proteomic study of the antiproliferative activity of a polyphenol-enriched rosemary extract on colon cancer cells using nanoliquid chromatography-orbitrap MS/MS,” Journal of Proteome Research, vol. 15, no. 6, pp. 1971–1985, 2016. View at Publisher · View at Google Scholar · View at Scopus
  105. A. Valdés, V. García-Cañas, L. Rocamora-Reverte, Á. Gómez-Martínez, J. A. Ferragut, and A. Cifuentes, “Effect of rosemary polyphenols on human colon cancer cells: transcriptomic profiling and functional enrichment analysis,” Genes & Nutrition, vol. 8, no. 1, pp. 43–60, 2013. View at Publisher · View at Google Scholar · View at Scopus
  106. A. Valdés, V. García-Cañas, A. Pérez-Sánchez et al., “Shotgun proteomic analysis to study the decrease of xenograft tumor growth after rosemary extract treatment,” Journal of Chromatography A, vol. 1499, pp. 90–100, 2017. View at Publisher · View at Google Scholar · View at Scopus
  107. A. Valdés, V. García-Cañas, C. Simó et al., “Comprehensive foodomics study on the mechanisms operating at various molecular levels in cancer cells in response to individual rosemary polyphenols,” Analytical Chemistry, vol. 86, no. 19, pp. 9807–9815, 2014. View at Publisher · View at Google Scholar · View at Scopus
  108. A. Valdés, V. García-Cañas, K. A. Artemenko, C. Simó, J. Bergquist, and A. Cifuentes, “Nano-liquid chromatography-orbitrap MS-based quantitative proteomics reveals differences between the mechanisms of action of carnosic acid and carnosol in colon cancer cells,” Molecular & Cellular Proteomics, vol. 16, no. 1, pp. 8–22, 2017. View at Publisher · View at Google Scholar · View at Scopus
  109. F. Olivas-Aguirre, J. Rodrigo-García, N. Martínez-Ruiz et al., “Cyanidin-3-O-glucoside: physical-chemistry, foodomics and health effects,” Molecules, vol. 21, no. 9, 2016. View at Publisher · View at Google Scholar · View at Scopus
  110. G. Breikers, S. G. J. van Breda, F. G. Bouwman et al., “Potential protein markers for nutritional health effects on colorectal cancer in the mouse as revealed by proteomics analysis,” Proteomics, vol. 6, no. 9, pp. 2844–2852, 2006. View at Publisher · View at Google Scholar · View at Scopus
  111. D. Fuchs, R. Piller, J. Linseisen, H. Daniel, and U. Wenzel, “The human peripheral blood mononuclear cell proteome responds to a dietary flaxseed-intervention and proteins identified suggest a protective effect in atherosclerosis,” Proteomics, vol. 7, no. 18, pp. 3278–3288, 2007. View at Publisher · View at Google Scholar · View at Scopus
  112. A. Herzog, B. Kindermann, F. Döring, H. Daniel, and U. Wenzel, “Pleiotropic molecular effects of the pro-apoptotic dietary constituent flavone in human colon cancer cells identified by protein and mRNA expression profiling,” Proteomics, vol. 4, no. 8, pp. 2455–2464, 2004. View at Publisher · View at Google Scholar · View at Scopus
  113. M. P. G. Barnett, J. M. Cooney, Y. E. M. Dommels et al., “Modulation of colonic inflammation in mdr1a−/− mice by green tea polyphenols and their effects on the colon transcriptome and proteome,” Journal of Nutritional Biochemistry, vol. 24, no. 10, pp. 1678–1690, 2013. View at Publisher · View at Google Scholar · View at Scopus
  114. B. de Roos, X. Zhang, G. Rodriguez Gutierrez et al., “Anti-platelet effects of olive oil extract: in vitro functional and proteomic studies,” European Journal of Nutrition, vol. 50, no. 7, pp. 553–562, 2011. View at Publisher · View at Google Scholar · View at Scopus
  115. B. de Roos, A. Geelen, K. Ross et al., “Identification of potential serum biomarkers of inflammation and lipid modulation that are altered by fish oil supplementation in healthy volunteers,” Proteomics, vol. 8, no. 10, pp. 1965–1974, 2008. View at Publisher · View at Google Scholar · View at Scopus
  116. B. Khakimov and S. B. Engelsen, “Resveratrol in the foodomics era: 1 : 25,000,” Annals of the New York Academy of Sciences, vol. 1403, no. 1, pp. 48–58, 2017. View at Publisher · View at Google Scholar · View at Scopus
  117. D. S. Rowlands, J. S. Thomson, B. W. Timmons et al., “Transcriptome and translational signaling following endurance exercise in trained skeletal muscle: impact of dietary protein,” Physiological Genomics, vol. 43, no. 17, pp. 1004–1020, 2011. View at Publisher · View at Google Scholar · View at Scopus
  118. F. Raymond, L. Wang, M. Moser et al., “Consequences of exchanging carbohydrates for proteins in the cholesterol metabolism of mice fed a high-fat diet,” PLoS One, vol. 7, no. 11, article e49058, 2012. View at Publisher · View at Google Scholar
  119. H. T. Dieck, F. Doring, D. Fuchs, H.-P. Roth, and H. Daniel, “Transcriptome and proteome analysis identifies the pathways that increase hepatic lipid accumulation in zinc-deficient rats,” The Journal of Nutrition, vol. 135, no. 2, pp. 199–205, 2005. View at Publisher · View at Google Scholar
  120. S. J. Duthie, G. Horgan, B. de Roos et al., “Blood folate status and expression of proteins involved in immune function, inflammation, and coagulation: biochemical and proteomic changes in the plasma of humans in response to long-term synthetic folic acid supplementation,” Journal of Proteome Research, vol. 9, no. 4, pp. 1941–1950, 2010. View at Publisher · View at Google Scholar · View at Scopus
  121. M. G. Mathias, C. A. Coelho-Landell, M. P. Scott-Boyer et al., “Clinical and vitamin response to a short-term multi-micronutrient intervention in Brazilian children and teens: from population data to interindividual responses,” Molecular Nutrition & Food Research, vol. 62, no. 6, article e1700613, 2018. View at Publisher · View at Google Scholar · View at Scopus
  122. X. Z. Li, S. N. Zhang, K. X. Wang, S. M. Liu, and F. Lu, “iTRAQ-based quantitative proteomics study on the neuroprotective effects of extract of Acanthopanax senticosus harm on SH-SY5Y cells overexpressing A53T mutant α-synuclein,” Neurochemistry International, vol. 72, pp. 37–47, 2014. View at Publisher · View at Google Scholar · View at Scopus
  123. A. Manavalan, L. Feng, S. K. Sze, J. M. Hu, and K. Heese, “New insights into the brain protein metabolism of Gastrodia elata-treated rats by quantitative proteomics,” Journal of Proteomics, vol. 75, no. 8, pp. 2468–2479, 2012. View at Publisher · View at Google Scholar · View at Scopus
  124. U. Ramachandran, A. Manavalan, H. Sundaramurthi et al., “Tianma modulates proteins with various neuro-regenerative modalities in differentiated human neuronal SH-SY5Y cells,” Neurochemistry International, vol. 60, no. 8, pp. 827–836, 2012. View at Publisher · View at Google Scholar · View at Scopus
  125. J. L. Sonnenburg and F. Backhed, “Diet-microbiota interactions as moderators of human metabolism,” Nature, vol. 535, no. 7610, pp. 56–64, 2016. View at Publisher · View at Google Scholar · View at Scopus
  126. A. T. Tang, J. P. Choi, J. J. Kotzin et al., “Endothelial TLR4 and the microbiome drive cerebral cavernous malformations,” Nature, vol. 545, no. 7654, pp. 305–310, 2017. View at Publisher · View at Google Scholar · View at Scopus
  127. I. Dalle-Donne, A. Scaloni, D. Giustarini et al., “Proteins as biomarkers of oxidative/nitrosative stress in diseases: the contribution of redox proteomics,” Mass Spectrometry Reviews, vol. 24, no. 1, pp. 55–99, 2005. View at Publisher · View at Google Scholar · View at Scopus
  128. A. Scaloni, E. Codarin, V. di Maso et al., “Modern strategies to identify new molecular targets for the treatment of liver diseases: the promising role of proteomics and redox proteomics investigations,” Proteomics Clinical Applications, vol. 3, no. 2, pp. 242–262, 2009. View at Publisher · View at Google Scholar · View at Scopus
  129. H. Y. Yang and T. H. Lee, “Antioxidant enzymes as redox-based biomarkers: a brief review,” BMB Reports, vol. 48, no. 4, pp. 200–208, 2015. View at Publisher · View at Google Scholar · View at Scopus
  130. A. Bachi, I. Dalle-Donne, and A. Scaloni, “Redox proteomics: chemical principles, methodological approaches and biological/biomedical promises,” Chemical Reviews, vol. 113, no. 1, pp. 596–698, 2013. View at Publisher · View at Google Scholar · View at Scopus
  131. D. A. Butterfield and M. Perluigi, “Redox proteomics: a key tool for new insights into protein modification with relevance to disease,” Antioxidants & Redox Signaling, vol. 26, no. 7, pp. 277–279, 2017. View at Publisher · View at Google Scholar · View at Scopus
  132. T. Vaisar, P. Mayer, E. Nilsson, X. Q. Zhao, R. Knopp, and B. J. Prazen, “HDL in humans with cardiovascular disease exhibits a proteomic signature,” Clinica Chimica Acta, vol. 411, no. 13-14, pp. 972–979, 2010. View at Publisher · View at Google Scholar · View at Scopus
  133. X. Fu, Y. Wang, J. Kao et al., “Specific sequence motifs direct the oxygenation and chlorination of tryptophan by myeloperoxidase,” Biochemistry, vol. 45, no. 12, pp. 3961–3971, 2006. View at Publisher · View at Google Scholar · View at Scopus
  134. A. S. Shah, L. Tan, J. L. Long, and W. S. Davidson, “Proteomic diversity of high density lipoproteins: our emerging understanding of its importance in lipid transport and beyond,” Journal of Lipid Research, vol. 54, no. 10, pp. 2575–2585, 2013. View at Publisher · View at Google Scholar · View at Scopus
  135. T. Koeck, J. A. Corbett, J. W. Crabb, D. J. Stuehr, and K. S. Aulak, “Glucose-modulated tyrosine nitration in beta cells: targets and consequences,” Archives of Biochemistry and Biophysics, vol. 484, no. 2, pp. 221–231, 2009. View at Publisher · View at Google Scholar · View at Scopus
  136. T. Koeck, B. Willard, J. W. Crabb, M. Kinter, D. J. Stuehr, and K. S. Aulak, “Glucose-mediated tyrosine nitration in adipocytes: targets and consequences,” Free Radical Biology & Medicine, vol. 46, no. 7, pp. 884–892, 2009. View at Publisher · View at Google Scholar · View at Scopus
  137. N. Ranjan Singh, P. Rondeau, L. Hoareau, and E. Bourdon, “Identification of preferential protein targets for carbonylation in human mature adipocytes treated with native or glycated albumin,” Free Radical Research, vol. 41, no. 10, pp. 1078–1088, 2009. View at Publisher · View at Google Scholar · View at Scopus
  138. A. Jaleel, G. C. Henderson, B. J. Madden et al., “Identification of de novo synthesized and relatively older proteins accelerated oxidative damage to de novo synthesized apolipoprotein A-1 in type 1 diabetes,” Diabetes, vol. 59, no. 10, pp. 2366–2374, 2010. View at Publisher · View at Google Scholar · View at Scopus
  139. C. H. Shao, G. J. Rozanski, R. Nagai et al., “Carbonylation of myosin heavy chains in rat heart during diabetes,” Biochemical Pharmacology, vol. 80, no. 2, pp. 205–217, 2010. View at Publisher · View at Google Scholar · View at Scopus
  140. Z. Hashim and S. Zarina, “Advanced glycation end products in diabetic and non-diabetic human subjects suffering from cataract,” Age, vol. 33, no. 3, pp. 377–384, 2011. View at Publisher · View at Google Scholar · View at Scopus
  141. K. Horie, T. Miyata, K. Maeda et al., “Immunohistochemical colocalization of glycoxidation products and lipid peroxidation products in diabetic renal glomerular lesions. Implication for glycoxidative stress in the pathogenesis of diabetic nephropathy,” Journal of Clinical Investigation, vol. 100, no. 12, pp. 2995–3004, 1997. View at Publisher · View at Google Scholar · View at Scopus
  142. M. G. Rosca, T. G. Mustata, M. T. Kinter et al., “Glycation of mitochondrial proteins from diabetic rat kidney is associated with excess superoxide formation,” American Journal of Physiology-Renal Physiology, vol. 289, no. 2, pp. F420–F430, 2005. View at Publisher · View at Google Scholar · View at Scopus
  143. C. H. Shao, H. L. Capek, K. P. Patel et al., “Carbonylation contributes to SERCA2a activity loss and diastolic dysfunction in a rat model of type 1 diabetes,” Diabetes, vol. 60, no. 3, pp. 947–959, 2011. View at Publisher · View at Google Scholar · View at Scopus
  144. K. R. Bidasee, Y. Zhang, C. H. Shao et al., “Diabetes increases formation of advanced glycation end products on sarco(endo)plasmic reticulum Ca2+-ATPase,” Diabetes, vol. 53, no. 2, pp. 463–473, 2004. View at Publisher · View at Google Scholar · View at Scopus
  145. R. Sultana, H. F. Poon, J. Cai et al., “Identification of nitrated proteins in Alzheimer's disease brain using a redox proteomics approach,” Neurobiology of Disease, vol. 22, no. 1, pp. 76–87, 2006. View at Publisher · View at Google Scholar · View at Scopus
  146. J. Choi, M. C. Sullards, J. A. Olzmann et al., “Oxidative damage of DJ-1 is linked to sporadic Parkinson and Alzheimer diseases,” Journal of Biological Chemistry, vol. 281, no. 16, pp. 10816–10824, 2006. View at Publisher · View at Google Scholar · View at Scopus
  147. A. Castegna, M. Aksenov, M. Aksenova et al., “Proteomic identification of oxidatively modified proteins in Alzheimer's disease brain. Part I: creatine kinase BB, glutamine synthase, and ubiquitin carboxy-terminal hydrolase L-1,” Free Radical Biology & Medicine, vol. 33, no. 4, pp. 562–571, 2002. View at Publisher · View at Google Scholar · View at Scopus
  148. F. Di Domenico, R. Sultana, A. Ferree et al., “Redox proteomics analyses of the influence of co-expression of wild-type or mutated LRRK2 and Tau on C. elegans protein expression and oxidative modification: relevance to Parkinson disease,” Antioxidants & Redox Signaling, vol. 17, no. 11, pp. 1490–1506, 2012. View at Publisher · View at Google Scholar · View at Scopus
  149. M. Perluigi, R. Sultana, G. Cenini et al., “Redox proteomics identification of 4-hydroxynonenal-modified brain proteins in Alzheimer's disease: role of lipid peroxidation in Alzheimer's disease pathogenesis,” Proteomics - Clinical Applications, vol. 3, no. 6, pp. 682–693, 2009. View at Publisher · View at Google Scholar · View at Scopus
  150. D. A. Butterfield, M. Perluigi, T. Reed et al., “Redox proteomics in selected neurodegenerative disorders: from its infancy to future applications,” Antioxidants & Redox Signaling, vol. 17, no. 11, pp. 1610–1655, 2012. View at Publisher · View at Google Scholar · View at Scopus
  151. D. Perez-Sala, E. Cernuda-Morollon, and F. J. Canada, “Molecular basis for the direct inhibition of AP-1 DNA binding by 15-deoxy-Δ12,14-prostaglandin J2,” Journal of Biological Chemistry, vol. 278, no. 51, pp. 51251–51260, 2003. View at Publisher · View at Google Scholar · View at Scopus
  152. K. S. Aulak, M. Miyagi, L. Yan et al., “Proteomic method identifies proteins nitrated in vivo during inflammatory challenge,” Proceedings of the National Academy of Sciences, vol. 98, no. 21, pp. 12056–12061, 2001. View at Publisher · View at Google Scholar · View at Scopus
  153. E. Barreiro, J. Gea, G. Matar, and S. N. A. Hussain, “Expression and carbonylation of creatine kinase in the quadriceps femoris muscles of patients with chronic obstructive pulmonary disease,” American Journal of Respiratory Cell and Molecular Biology, vol. 33, no. 6, pp. 636–642, 2005. View at Publisher · View at Google Scholar · View at Scopus
  154. E. Barreiro, J. Gea, M. di Falco, L. Kriazhev, S. James, and S. N. A. Hussain, “Protein carbonyl formation in the diaphragm,” American Journal of Respiratory Cell and Molecular Biology, vol. 32, no. 1, pp. 9–17, 2005. View at Publisher · View at Google Scholar · View at Scopus
  155. J. Marin-Corral, J. Minguella, A. L. Ramirez-Sarmiento, S. N. A. Hussain, J. Gea, and E. Barreiro, “Oxidised proteins and superoxide anion production in the diaphragm of severe COPD patients,” European Respiratory Journal, vol. 33, no. 6, pp. 1309–1319, 2009. View at Publisher · View at Google Scholar · View at Scopus
  156. R. R. Cocklin, Y. Zhang, K. D. O’Neill et al., “Identity and localization of advanced glycation end products on human beta2-microglobulin using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry,” Analytical Biochemistry, vol. 314, no. 2, pp. 322–325, 2003. View at Publisher · View at Google Scholar · View at Scopus
  157. T. Miyata, S. Taneda, R. Kawai et al., “Identification of pentosidine as a native structure for advanced glycation end products in beta-2-microglobulin-containing amyloid fibrils in patients with dialysis-related amyloidosis,” Proceedings of the National Academy of Sciences, vol. 93, no. 6, pp. 2353–2358, 1996. View at Publisher · View at Google Scholar · View at Scopus
  158. A. K. Padival, J. W. Crabb, and R. H. Nagaraj, “Methylglyoxal modifies heat shock protein 27 in glomerular mesangial cells,” FEBS Letters, vol. 551, no. 1–3, pp. 113–118, 2003. View at Publisher · View at Google Scholar · View at Scopus
  159. L. Cesaratto, C. Vascotto, C. D'Ambrosio et al., “Overoxidation of peroxiredoxins as an immediate and sensitive marker of oxidative stress in HepG2 cells and its application to the redox effects induced by ischemia/reperfusion in human liver,” Free Radical Research, vol. 39, no. 3, pp. 255–268, 2009. View at Publisher · View at Google Scholar · View at Scopus
  160. E. K. Ahmed, A. Rogowska-Wrzesinska, P. Roepstorff, A. L. Bulteau, and B. Friguet, “Protein modification and replicative senescence of WI-38 human embryonic fibroblasts,” Aging Cell, vol. 9, no. 2, pp. 252–272, 2010. View at Publisher · View at Google Scholar · View at Scopus
  161. M. B. Feeney and C. Schoneich, “Tyrosine modifications in aging,” Antioxidants & Redox Signaling, vol. 17, no. 11, pp. 1571–1579, 2012. View at Publisher · View at Google Scholar · View at Scopus
  162. C. Bregere, I. Rebrin, and R. S. Sohal, “Detection and characterization of in vivo nitration and oxidation of tryptophan residues in proteins,” Methods in Enzymology, vol. 441, pp. 339–349, 2008. View at Publisher · View at Google Scholar · View at Scopus
  163. J. P. Rabek, W. H. Boylston III, and J. Papaconstantinou, “Carbonylation of ER chaperone proteins in aged mouse liver,” Biochemical and Biophysical Research Communications, vol. 305, no. 3, pp. 566–572, 2003. View at Publisher · View at Google Scholar · View at Scopus
  164. R. A. Vaishnav, M. L. Getchell, H. F. Poon et al., “Oxidative stress in the aging murine olfactory bulb: redox proteomics and cellular localization,” Journal of Neuroscience Research, vol. 85, no. 2, pp. 373–385, 2007. View at Publisher · View at Google Scholar · View at Scopus
  165. L. Prokai, L. J. Yan, J. L. Vera-Serrano, S. M. Stevens, and M. J. Forster, “Mass spectrometry-based survey of age-associated protein carbonylation in rat brain mitochondria,” Journal of Mass Spectrometry, vol. 42, no. 12, pp. 1583–1589, 2007. View at Publisher · View at Google Scholar · View at Scopus
  166. S. Poggioli, H. Bakala, and B. Friguet, “Age-related increase of protein glycation in peripheral blood lymphocytes is restricted to preferential target proteins,” Experimental Gerontology, vol. 37, no. 10-11, pp. 1207–1215, 2002. View at Publisher · View at Google Scholar · View at Scopus
  167. M. Hamelin, J. Mary, M. Vostry, B. Friguet, and H. Bakala, “Glycation damage targets glutamate dehydrogenase in the rat liver mitochondrial matrix during aging,” FEBS Journal, vol. 274, no. 22, pp. 5949–5961, 2007. View at Publisher · View at Google Scholar · View at Scopus
  168. S. J. Hong, G. Gokulrangan, and C. Schoneich, “Proteomic analysis of age dependent nitration of rat cardiac proteins by solution isoelectric focusing coupled to nanoHPLC tandem mass spectrometry,” Experimental Gerontology, vol. 42, no. 7, pp. 639–651, 2007. View at Publisher · View at Google Scholar · View at Scopus
  169. R. Tyther, B. McDonagh, and D. Sheehan, “Proteomics in investigation of protein nitration in kidney disease: technical challenges and perspectives from the spontaneously hypertensive rat,” Mass Spectrometry Reviews, vol. 30, no. 1, pp. 121–141, 2011. View at Publisher · View at Google Scholar · View at Scopus
  170. R. Tyther, A. Ahmeda, E. Johns, and D. Sheehan, “Proteomic identification of tyrosine nitration targets in kidney of spontaneously hypertensive rats,” Proteomics, vol. 7, no. 24, pp. 4555–4564, 2007. View at Publisher · View at Google Scholar · View at Scopus
  171. R. Tyther, A. Ahmeda, E. Johns, and D. Sheehan, “Protein carbonylation in kidney medulla of the spontaneously hypertensive rat,” Proteomics - Clinical Applications, vol. 3, no. 3, pp. 338–346, 2009. View at Publisher · View at Google Scholar · View at Scopus
  172. C. Vascotto, A. M. Salzano, C. D'Ambrosio et al., “Oxidized transthyretin in amniotic fluid as an early marker of preeclampsia,” Journal of Proteome Research, vol. 6, no. 1, pp. 160–170, 2007. View at Publisher · View at Google Scholar · View at Scopus
  173. G. Boden, C. Homko, C. A. Barrero et al., “Excessive caloric intake acutely causes oxidative stress, GLUT4 carbonylation, and insulin resistance in healthy men,” Science Translational Medicine, vol. 7, no. 304, article 304re7, 2015. View at Publisher · View at Google Scholar · View at Scopus
  174. K. E. Menger, A. M. James, H. M. Cochemé et al., “Fasting, but not aging, dramatically alters the redox status of cysteine residues on proteins in Drosophila melanogaster,” Cell Reports, vol. 13, no. 6, p. 1285, 2015. View at Publisher · View at Google Scholar · View at Scopus
  175. L. Méndez, M. Pazos, E. Molinar-Toribio et al., “Protein carbonylation associated to high-fat, high-sucrose diet and its metabolic effects,” The Journal of Nutritional Biochemistry, vol. 25, no. 12, pp. 1243–1253, 2014. View at Publisher · View at Google Scholar · View at Scopus
  176. N. Morales-Prieto, J. Ruiz-Laguna, and N. Abril, “Dietary Se supplementation partially restores the REDOX proteomic map of M. spretus liver exposed to p,p'-DDE,” Food and Chemical Toxicology, vol. 114, pp. 292–301, 2018. View at Publisher · View at Google Scholar · View at Scopus
  177. W. O. Opii, G. Joshi, E. Head et al., “Proteomic identification of brain proteins in the canine model of human aging following a long-term treatment with antioxidants and a program of behavioral enrichment: relevance to Alzheimer's disease,” Neurobiology of Aging, vol. 29, no. 1, pp. 51–70, 2008. View at Publisher · View at Google Scholar · View at Scopus
  178. S. K. Suh, B. L. Hood, B. J. Kim, T. P. Conrads, T. D. Veenstra, and B. J. Song, “Identification of oxidized mitochondrial proteins in alcohol-exposed human hepatoma cells and mouse liver,” Proteomics, vol. 4, no. 11, pp. 3401–3412, 2004. View at Publisher · View at Google Scholar · View at Scopus
  179. V. B. Patel, C. H. Spencer, T. A. Young, M. O. Lively, and C. C. Cunningham, “Effects of 4-hydroxynonenal on mitochondrial 3-hydroxy-3-methylglutaryl (HMG-CoA) synthase,” Free Radical Biology & Medicine, vol. 43, no. 11, pp. 1499–1507, 2007. View at Publisher · View at Google Scholar · View at Scopus
  180. A. Venkatraman, A. Landar, A. J. Davis et al., “Oxidative modification of hepatic mitochondria protein thiols: effect of chronic alcohol consumption,” American Journal of Physiology-Gastrointestinal and Liver Physiology, vol. 286, no. 4, pp. G521–G527, 2004. View at Publisher · View at Google Scholar
  181. Y. Li, Z. Luo, X. Wu et al., “Proteomic analyses of cysteine redox in high-fat-fed and fasted mouse livers: implications for liver metabolic homeostasis,” Journal of Proteome Research, vol. 17, no. 1, pp. 129–140, 2018. View at Publisher · View at Google Scholar · View at Scopus
  182. D. L. Carbone, J. A. Doorn, Z. Kiebler, and D. R. Petersen, “Cysteine modification by lipid peroxidation products inhibits protein disulfide isomerase,” Chemical Research in Toxicology, vol. 18, no. 8, pp. 1324–1331, 2005. View at Publisher · View at Google Scholar · View at Scopus
  183. B. J. Song, K. H. Moon, N. U. Olsson, and N. Salem Jr., “Prevention of alcoholic fatty liver and mitochondrial dysfunction in the rat by long-chain polyunsaturated fatty acids,” Journal of Hepatology, vol. 49, no. 2, pp. 262–273, 2008. View at Publisher · View at Google Scholar · View at Scopus
  184. K. H. Moon, B. L. Hood, B. J. Kim et al., “Inactivation of oxidized and S-nitrosylated mitochondrial proteins in alcoholic fatty liver of rats,” Hepatology, vol. 44, no. 5, pp. 1218–1230, 2006. View at Publisher · View at Google Scholar · View at Scopus
  185. M. Dodson, M. Redmann, N. S. Rajasekaran, V. Darley-Usmar, and J. Zhang, “KEAP1-NRF2 signalling and autophagy in protection against oxidative and reductive proteotoxicity,” Biochemical Journal, vol. 469, no. 3, pp. 347–355, 2015. View at Publisher · View at Google Scholar · View at Scopus
  186. J. Johansen, A. K. Harris, D. J. Rychly, and A. Ergul, “Oxidative stress and the use of antioxidants in diabetes: linking basic science to clinical practice,” Cardiovascular Diabetology, vol. 4, no. 1, p. 5, 2005. View at Publisher · View at Google Scholar · View at Scopus