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The role of antioxidant supplement in immune system

The trifecta of powerhouse antioxidants (tart cherry, blueberries and acai fruit) are featured in Javita’s ActiveBlendz Defend.Read on for more on the healthy benefits of these powerful nutrients… 


This review will discuss some issues related to the risk/benefit profile of the use of dietary antioxidants. Thus, recent progress regarding the potential benefit of dietary antioxidants in the treatment of chronic diseases with a special focus on immune system and neurodegenerative disorders will be discussed here. It is well established that reactive oxygen species (ROS) play an important role in the etiology of numerous diseases, such as atherosclerosis, diabetes and cancer. Among the physiological defense system of the cell, the relevance of antioxidant molecules, such as glutathione and vitamins is quite well established. Recently, the interest of researchers has, for example, been conveyed on antioxidant enzyme systems, such as the heme oxygenase/biliverdin reductase system, which appears modulated by dietary antioxidant molecules, including polyphenols and beta-carotene. These systems possibly counteract oxidative damage very efficiently and finally modulate the activity of oxidative phenomena occurring, for instance, during pathophysiological processes. Although evidence shows that antioxidant treatment results in cytoprotection, the potential clinical benefit deriving from both nutritional and supplemental antioxidants is still under wide debate. In this line, the inappropriate assumption of some lipophylic vitamins has been associated with increased incidence of cancer rather than with beneficial effects.IntroductionThe term “free radicals” designates a family of compounds characterized by great reactivity due to the impaired electron in the outer orbital. To this group belong reactive oxygen species (ROS), such as superoxide anion, hydroxyl radical and hydrogen peroxide, as well as reactive nitrogen species (RNS) which include nitric oxide and peroxynitrite. Although structurally different, free radicals share similar mechanisms to harm body’s cells and tissues through damage on proteins, DNA and lipids [1]. The alterations of membrane functions occurring as a consequence of phospholipid modifications represent a relevant, radical species-dependent injury, either when considering the organism as a whole, or a specific integrated function, such as the immune response [2]. The potential therapeutic applications of antioxidants in free radical-related diseases led to the hypothesis of their use to slow down or reverse, for example, symptoms associated with with neurodegenerative disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), or spongiform encephalopathies. Such effect could occur through a block of proinflammatory cytokines action and the resulting oxidative damage [34567]. However, several clinical studies demonstrated that not only malnutrition, but also the excess of certain nutrients (e.g. iron, alpha-tocopherol, beta-carotene, ascorbic acid) may set into motion oxidation phenomena and, therefore, cell injury [89]. Thus, it is of relevance that prior to considering introducing antioxidant therapy into mainstream medicine, significant advances in basic cell biology, pharmacology and clinical bioanalysis will be required.

Oxidative Stress
The body is normally under a dynamic equilibrium between free radical generation and quenching. The physiological defense systems to counteract free radicals encompass endogenous enzyme systems, such as catalase, glutathione reductase and superoxide dismutase, as well as glutathione, urate and coenzyme Q, or exogenous factors (β-carotene, vitamin C, vitamin E and selenium) [10]. All these molecules have an antioxidant effect due to their ability to transform ROS into stable and harmless compounds or by scavenging both ROS and RNS with a redox-based mechanism [10]. Very recently, a main role in the fight against oxidative stress has been assumed by enzymes such as heme oxygenase (HO) and biliverdin reductase (BVR). Heme oxygenase is a microsomal enzyme which metabolizes heme into ferrous iron, carbon monoxide and biliverdin (BV); the latter is then reduced by BVR into bilirubin (BR), a molecule endowed with strong antioxidant and antinitrosative activities [11121314]. Interestingly, all these protective factors act in a concerted way, enhancing the antioxidant defense system of the cell. When the balance between ROS/RNS and antioxidants turns in favor of the former, oxidative/nitrosative stress occurs. Although oxidative stress is associated with most diseases, routine assay methods are not nowadays available in the clinical practice. A strategy widely used to determine oxidative stress is measurement of malonyldialdehyde, F2-isoprostanes, or 8-hydroxydesoxyguanosine. Actually, these molecules are regarded as the most reliable markers available [15]. A classic example of an oxidation product apparently leading to disease, is oxidized cholesterol in low-density lipoprotein (LDL), which displays a higher atherogenic potential than native LDL, and mainly involved in the pathogenesis of atherosclerosis and coronary heart disease (CHD) [16].At the cellular level, a large body of data clearly demonstrated that ROS, when produced in low amounts and in a controlled manner, are physiological components of the signalling generated by cytokines, growth factors and neurotrophic peptides [171819202122], although they may also activate apoptotic cell death [23]. Extracellularly generated ROS can diffuse through anion channels into the cytoplasm; the resulting variation in the cell redox state leads to modulation of an array of transcription factors (eg. NF-kB, AP-1), protein kinases (e.g. AKT, JNK, p38), and receptor activated MAP kinases involved in apoptosis [17242526]. Moreover, the proapoptotic molecules Fas and Fas ligand (FasL) undergo positive transcriptional regulation after exposure to oxidants [27]. Interestingly, Krammer and Colleagues demonstrated that in vitro administration of vitamin E suppresses FasL mRNA expression and protects T cells of HIV-1 infected individuals from Fas mediated apoptosis [28]. Moreover, it was demonstrated that administration of combinations of vitamin E and C to cultures of human umbilical vein endothelial cells (HUVEC) treated with lipopolysaccharide could prevent apoptosis by upregulation of Bcl-2 [29].


Antioxidants, The Immune System And Related Disorders

The protective function against external pathogens carried out by the immune system is by itself a source of ROS, since activated neutrophils, produce free radicals to a significant extent [30]. Moreover, during the inflammatory process, activation of phagocytes through the interaction of proinflammatory mediators, or bacterial products with specific receptors results in the assembly of the multicomponent flavoprotein NADPH oxidase which catalyzes the production of large quantities of the superoxide anion radical (O2 -) [31]. In addition to classical reactive oxygen metabolites, activated neutrophils and monocytes release the hemoprotein myeloperoxidase (MPO) into the extracellular space, where it catalyzes the oxidation of Cl- by H2O2 to yield hypochlorous acid (HClO) [32]. HClO is a non-specific oxidizing and chlorinating agent that reacts rapidly with a variety of biological compounds, such as sulphydryls, polyunsatured fatty acids, DNA, pyridine nucleotides, aliphatic and aromatic aminoacids and nitrogen-containing compounds [333435]. Moreover, apart from their direct toxic effects, neutrophil-derived oxidants may promote tissue injury indirectly by altering the protease/antiprotease equilibrium that normally exists within the intestinal interstitium. The oxidative inactivation of important protease inhibitors, coupled to the oxidant-mediated activation of latent proteases, creates a favorable environment for neutrophils that allows degradation of the interstitial matrix through elastases, collagenases and gelatinases, as well as injury to epithelial cells [3637]. However, not only immune cell produce ROS necessary for the microbicidal activity, but they are also sensitive to external ROS, due to their high polyunsaturated fatty acids (PUFA) content. Immune cells are atypical, as compared with other somatic cells, in that they contain high levels of antioxidant vitamins, presumably providing protection against lipid peroxidation and immunosuppression, both of which are well known risks posed by high PUFA content [38]. The reactivity of immune cells to exogenous ROS has been shown to be age-dependent. In fact, lymphocytes from elderly individuals appear to be more sensitive to exposure to hydrogen peroxide than those from young adults [39]. Moreover, it has been demonstrated that a micronutrient deficiency can be the cause of suppression of immune function affecting both innate T-cell-mediated immune response and adaptive antibody response, thus altering the balanced host response. Therefore, an adequate intake of vitamins and antioxidant elements seems to be essential for an efficient function of the immune system. Micronutrient deficiency occurs in various conditions, such as eating disorders, tobacco smokers, chronic diseases, aging. During aging, changes in the immune system are frequent and associated with increased susceptibility to infections. Antioxidant vitamins and trace elements contribute to maintain an effective immune response [40]. For example, administration of vitamin E supplement to healthy elderly patients produced an increased antibody titer to both hepatitis B and tetanus vaccine [41], thus enhancing T-cell mediated functions. In conclusion, maintaining adequate antioxidant status may provide a useful approach in attenuating cell injury and dysfunction observed in some inflammatory/autoimmune disorders [4243].

Autoimmunity has been for decades considered the result of a breakdown in self-tolerance. At the present, it is known that autoimmunity is a physiological process [44]. This phenomenon becomes pathological when the number of autoreactive cells, and particularly the avidity of their receptors for autoantigens, increases [44]. Triggering of the disease usually depends both on the increase in immunogenicity of the target cell, which may be secondary to a viral infection (Chediak-Higashi syndrome and Griscelli syndrome by EBV), and on the individual’s own capacity to recognize the autoantigens (HLA, or T cell repertoire in Familial hemophagocytic lymphohistiocytosis [FHL]) [45]. Moreover, apart from the genetic defects that may predispose to autoimmune diseases, one must take into account the environmental factors that are implicated in the development of such pathologies. Among them, an important role is played by xenobiotics such as chemicals, drugs and metals [46]. Iron, aluminum, and manganese readily cross the blood brain barrier via specific or non-specific carriers, and contribute to the nervous tissue damage [4748]. The toxic effects of metals are mediated through free radical formation, or enzyme inhibition [4950515253]. In addition, metals may act as immunosuppressants (cytostatically), or as immunoadjuvants (through non-specific activation of the immune response) [5455]. Several mechanisms are proposed on how metals may act within the immune system to induce autoimmunity. Patients suffering from scleroderma develop autoantigens with metal-binding sites. After metal binding, free radical species are generated which fragment auto-antigens thereby exposing cryptic epitopes, which may then trigger autoimmunity [5657]. Taken together, these findings underlie the importance of exogenous factors in the pathogenesis of autoimmunity. Nevertheless, all these elements do not appear sufficient to provoke chronic autoimmune diseases such as Multiple Slerosis (MS), myasthenia gravis, Insulin Dependent Diabetes Mellitus (IDDM) or Hashimoto’s thyroiditis, and the passage to chronic disease is usually secondary to a defect in immunoregulation.

Click here to read more from this 2008 article in Nutrition Journal.


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