Food Regimes on Oxidative Stress: Comparison
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Please note this is a comparison between Version 2 by Rita Xu and Version 1 by Angela Alibrandi.

The existence of significant differences between two dietary regimes (omnivorous vs. semi-vegetarian) with reference to some oxidative stress markers (SOD, GPx, TRxR, GR, AGEs, and AOPPs) using non-parametric combination methodology based on a permutation test.

  • oxidative stress
  • food regimes
  • non-parametric combination test

1. Introduction

Oxidative stress is a detrimental process that occurs when excess free radicals accumulate in tissues and cells due to the loss of balance between oxidant production and antioxidant defense mechanisms [1]. Free radicals (mainly reactive oxygen species (ROS)) are normal products of cell metabolism and are necessary for several cell processes when present at low levels. On the contrary, excess free radicals, due to their overproduction and/or inadequate removal, cause the oxidation of all macromolecules (proteins, lipids, and DNA), altering their structure and inhibiting their normal functions. These oxidative changes result in cell injury, apoptosis, and death and promote tissue inflammation, damage, and dysfunction [2,3][2][3].

2. Oxidative Stress: Generality and Relationship with the Modern Lifestyle

Free radicals are highly unstable and reactive molecules with one or more unpaired electrons on the external atomic orbital, which rapidly react with other molecules to catch the missing electron, generating new free radicals in a chain reaction. They are normally produced in cells during numerous enzymatic and metabolic processes, for which they are often necessary [1]. Under physiological conditions, there is an equilibrium between the production and removal of free radicals called redox homeostasis. Multiple enzymatic and nonenzymatic defense systems and antioxidants operate to prevent ROS accumulation and counteract oxidative damage. Enzymatic antioxidants include the glutathione peroxidase (GPx)/glutathione reductase (GR) system and glutathione-S-transferases (GSTs), which represent the first-line defense against oxidants in almost every cell type with a tissue-specific distribution. The thioredoxin (TRx)/thioredoxin reductase (TRxR) system represents another important system for ROS detoxification. At the highest levels of oxidants, catalases (CAT) and superoxide dismutase (SOD) also contribute to the enzymatic degradation of free radicals. Nonenzymatic antioxidant defenses include endogenous molecules, such as mitochondrial uncoupling proteins, reduced glutathione (GSH), and transport proteins synthesized in the liver (ceruloplasmin, transferrin, albumin, etc.), as well as exogenous products, such as uric acid and vitamins E and C, which are mainly derived from one’s diet [1,2,3][1][2][3]. Among the exogenous compounds, selenium (Se) is also relevant for antioxidant defense since both GPx and TRx are selenoproteins, which contain a Se atom in their catalytic domain in the form of selenocysteine [4]. Inadequate Se supplementation may impair both the expression and enzymatic activity of the antioxidant enzymes GPx and TRx [3], whereas Se supplementation may help prevent the oxidative damage of thyroid cells, as demonstrated in in vitro models [5]. When free radicals are produced in excess, are not adequately removed, or both, a condition of oxidative stress (OS) occurs and causes cell damage, apoptosis, and death, and tissue inflammation [2,6][2][6]. Almost all cell types and tissues are susceptible to oxidative damage, although with tissue-specific differences [1,2,7][1][2][7]. A condition of OS may be the consequence of physiological processes (aging and cell senescence), lifestyle changes (reduced physical activity, alcohol abuse, smoking, etc.), exposure to environmental triggers (pollutants, radiations, drugs, chemicals from any sources, etc.), or dysmetabolic or dietary factors (overweight/obesity, impaired glucose tolerance, dysbiosis, reduced intake of antioxidants, excess food additives, etc.) [3,5,7][3][5][7]. The modern lifestyle, which is associated with unhealthy changes in dietary habits, reduced physical activity, psychological stress overload, and increased exposure to chemicals from different sources (pesticides, heavy metals, food additives, environmental pollutants, smoking, etc.), may favor the occurrence of a condition of OS, which in turn can contribute to the increasing burden of chronic diseases in industrialized societies [3,7][3][7]. In particular, changes in dietary habits have emerged as a driver of or a main contributor to many pathological conditions and are related to increased OS at the tissue and cellular levels. In previous decades, diets rich in salt, refined sugars, and calories, fats, and proteins from animal sources, and low in fiber have become more common in the general population than plant-based dietary regimens rich in whole grains, fruits, and vegetables. Additionally, the consumption of processed and fast food has increased, along with the consequent exposure to food additives and preservatives, contaminants, and food-contacting (packaging) materials. This dietary regimen, the so-called Western-type diet (WTD), has harmful effects on health and may enhance the risk of chronic inflammatory disorders, both indirectly, through increasing fat mass and obesity, and directly, by altering the intestinal microbiota composition, dysregulating immune responses, and enhancing OS [3,7,8,9,10,11,12][3][7][8][9][10][11][12].

3. Scientific Background

OS has been involved in the pathogenesis of several inflammatory and immune-mediated disorders [1[1][2][3][7],2,3,7], such as cardiovascular diseases, diabetes, neurodegenerative diseases, cancer [7], and autoimmune diseases (AIDs), including thyroid AID [3,13,14,15][3][13][14][15]. In autoimmune thyroid disorders (AITD), excess ROS could induce the modification of tissue proteins, which become neo-antigens or may dysregulate the immune system, promoting the onset of an AITD in genetically predisposed individuals [16,17][16][17]. Moreover, excess ROS increases the proinflammatory state by enhancing the synthesis and release of cytokines, further contributing to tissue damage and disease progression [3,13][3][13]. The most common AITD at any age is represented by autoimmune thyroiditis, also referred to as Hashimoto’s thyroiditis (HT), which is the main cause of hypothyroidism in iodine-sufficient areas. HT prevalence in the general population is estimated at around 5%, and its incidence has increased significantly over the last few decades, mostly in industrialized countries, maybe as a consequence of changing environmental factors, as reported above [18]. A close and bidirectional relationship exists between thyroid autoimmunity and OS, as it has emerged from experimental and clinical studies [3]. On the one hand, excess ROS causes the oxidation of proteins (for instance, thyroglobulin), which become highly immunogenic and may promote autoimmune reactions in genetically predisposed individuals. On the other hand, once autoimmunity has been triggered, the infiltrating T and B lymphocytes develop a chronic inflammatory milieu in which ROS accumulate and exert a toxic effect on the surrounding cells, contributing to parenchymal destruction and disease progression [3,18][3][18]. Moreover, antioxidant defenses are often reduced/impaired in HT, even in euthyroidism, and do not counteract ROS overproduction [3,18][3][18]. Overall, human studies described increased OS in TH, even in euthyroidism [3]. Ates et al. reported a negative correlation between serum total antioxidant activity and anti-thyroperoxidase antibodies (TPO-Ab) [15], while Baser et al. reported a positive correlation between serum oxidants and anti-thyroglobulin (Tg-Ab) antibodies [19], and Ruggeri et al. confirmed that the TPO-Ab were independent predictors of the oxidative status in euthyroid HT patients [14]. As the role of OS in thyroid autoimmunity has emerged, interest has grown in peripheral/circulating biomarkers of oxidative stress, and many of these parameters have been measured to evaluate the impact and clinical relevance of oxidative stress in ATD, with sometimes conflicting results [3]. They include the following:
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Antioxidant markers, such as antioxidant enzymes SOD, GR, GPx, TRxR, and paraoxonase 1 (PON-1) activity; total plasma antioxidant activity (TEAA); and biological antioxidant potential (BAP) [3,14,15,19,20,21,22][3][14][15][19][20][21][22].
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Markers of oxidative stress, such as advanced glycation end products (AGEs) and their receptor (RAGE), advanced oxidation protein products (AOPPs), derived reactive oxygen (d-ROMS), malondialdehyde (MDA), oxidized-low density lipoprotein (ox-LDL), total oxidant status (TOS), and oxidative stress index (OSI), to mention a few [3,14,15,19,20,21,22,23,24,25,26][3][14][15][19][20][21][22][23][24][25][26].
In particular, ourthe study group has provided strong evidence of the role of AGEs as a reliable marker of oxidative stress in HT [12,14,22,23][12][14][22][23]. AGEs are a family of compounds formed by nonenzymatic glycation of macromolecules (proteins, lipids, or nucleic acids). By binding their receptors (RAGEs) expressed on various cells, AGEs promote inflammation by regulating different signal transduction cascades and related transcription factors, such as nuclear factor kappa B (NF-kB). Two C-truncated isoforms of RAGE—the soluble RAGE and the esRAGE—bind to AGEs but fail to initiate an intracellular signal transduction cascade and, therefore, exert protective anti-inflammatory effects, acting as antagonists to the actions of AGEs [23]. The total body of AGEs’ burden is the sum of AGEs from dietary sources and endogenous synthesis. Methylglyoxal (MG) is the most common endogenous mediator of AGE synthesis, which is present ubiquitously in all cells as a product of normal metabolism, and its formation is markedly increased in hyperglycemia, accounting for the role of AGE accumulation in the pathogenesis of diabetic complications [27]. All other AGEs are exogenous, mainly derived from food. In particular, animal fat and proteins (mainly red meat and fatty cheese, followed by poultry, fish, and eggs) have higher levels of AGEs than carbohydrate foods, vegetables, and fruits [27]. Additionally, cooking techniques are important since roasting, broiling, and frying foods at high temperature increases their AGE content [27]. As a consequence, the WTD is high in AGEs. There is increasing evidence that AGEs play a role in the pathogenesis of several chronic diseases involving oxidative stress and inflammation, including cardiovascular, metabolic, and neurocognitive diseases, so reducing glycation load is certainly of health benefit [27]. WResearchers first reported higher serum levels of AGEs in HT patients than in healthy controls [14]. In the same studies, wresearchers assessed the oxidant/antioxidant status and found that oxidants (d-ROMs and AGEs) were increased and antioxidants (BAP) decreased in HT patients compared to controls [14]. Moreover, AGE serum levels were inversely correlated with serum antioxidant potential, indicating an imbalance between ROS production and antioxidant defenses in HT patients, i.e., a condition of OS [14]. WResearchers confirmed the finding of increased levels of AGEs in subsequent studies [12,22[12][22][23],23], correlating such an increase to reduced serum levels of the protective soluble receptor sRAGE [23] and reduced activity of the antioxidant paraoxonase (PON-1) [22]. Noteworthy, these changes in oxidative balance occurred irrespective of thyroid function alterations, autoimmunity per se being responsible for them. The parameters mentioned above could be used as biochemical markers of oxidative stress and chronic inflammation to better predict disease onset and progression, allowing finer patient monitoring. Moreover, greater knowledge of the oxidative stress imbalance in chronic inflammatory disorders could open new perspectives in developing tailored therapeutic approaches to thyroid autoimmune disorders that significantly impair patients’ quality of life. Moreover, wresearchers correlated changes in oxidative balance to the dietary habits of our HT patients. WeResearchers reported that serum AGEs were significantly higher in HT patients than in controls, while the activity of GPx and TRxR, as well as total plasma antioxidant activity (TEAA), were lower, confirming a condition of oxidative stress in HT patients. When evaluating the dietary habits of ourthe cohort of patients and controls, it emerged that nutritional patterns, mainly the consumption of animal foods, influenced the oxidative stress parameters in HT patients [12]. The results of this study suggested that a low intake of animal food (mainly meat) has a potentially protective effect on thyroid autoimmunity due to the positive influence of this dietary habit on redox balance.

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