Oxidative stress PUFAs

Such imbalanced antioxidant systems in schizophrenia could lead to oxidative stress- and ROS-mediated injury as supported by increased lipid peroxidation products and reduced membrane polyunsaturated fatty acids (PUFAs). Decrease in membrane phospholipids in blood cells of psychotic patients (Keshavan et al., 1993 Reddy et al., 2004) and fibroblasts from drug-naive patients (Mahadik et al., 1994) as well as in postmortem brains (Horrobin et al., 1991) have indeed been reported. It has also been suggested that peripheral membrane anomalies correlate with abnormal central phospholipid metabolism in first-episode and chronic schizophrenia patients (Pettegrewet al., 1991 Yao et al., 2002). Recently, a microarray and proteomic study on postmortem brain showed anomalies of mitochondrial function and oxidative stress pathways in schizophrenia (Prabakaran et al., 2004). Mitochondrial dysfunction in schizophrenia has also been observed by Ben-Shachar (2002) and Altar et al. (2005). As main ROS producers, mitochondria are particularly susceptible to oxidative damage. Thus, a deficit in glutathione (GSH) or immobilization stress induce greater increase in lipid peroxidation and protein oxidation in mitochondrial rather than in cytosolic fractions of cerebral cortex (Liu et al., 1996). 

Reactive aldehydes generated from hpid peroxidation are involved in CVD (266). Another example lies with the role of oxidative stress in the pathophysiology of asthma (267). Lipid peroxidation, as determined by plasma iso-prostanes, is related to disease severity in mild asthma. Tumor cell lines are sensitive to PUFA and to associated oxidation products (268). This sensitivity depends on the antioxidant defense mechanism, as well as on culture conditions. Hydroperoxy docosahexaenoic acid is a major metabolite, responsible for the cytotoxicity of DHA. 

The high degree of unsaturation of n-3 and n-6 FA, especially long-chain PUFA such as AA, DPA, EPA and DHA, makes them highly susceptible to oxidation and to generate potential pro-oxidants leading to induce an oxidative stress. 

LDL consist of a lipid core of cholesteryl esters and triglycerides surrounded by a coat of cholesterol and phospholipids. The coat contains several molecules of vitamin E and apolipoprotein. Under oxidant stress, both lipids and protein are oxidized. The breakdown of the PUFA yields aldehydes and ketones of small molecular weight, which go on to react further. These structural changes ensure that oxidized LDL ceases to be a substrate for the LDL receptor instead it becomes a substrate for the scavenger receptor. 

The cardioprotective role of n-3 PUFA as suggested by epidemiologic and clinical findings seems not to be in line with the prooxidant nature and the oxidant stress hypothesis of atherosclerosis formation. How can this paradox be reconciled ... 

Overlooked or largely ignored have been studies demonstrating an antioxidant effect of n-3 PUFA in vitro, in various animal oxidant stress models, and in humans. Table 1 lists the many reports describing effects of n-3 LC-PUFA on ROS-mediated events, ROS biomarkers, and antioxidative defense systems, which can be interpreted in terms of an antioxidant activity of n-3 LC-PUFA. 

Fig. 2. Interplay among superoxide anion, nitric oxide, and eicosanoids in high oxidative stress. The biological function of nitric oxide in target cells is influenced by the cellular redox state. In increased oxidative stress, which results in an oxidizing environment, NO readily form free radicals, including the highly reactive peroxynitrite (OONO ). Peroxynitrite can influence eicosanoid synthesis by interfering with different enzyme systems of the arachidonic acid cascade. Increased free radicals may also catalyze nonenzymic peroxidation of membrane PUFA (e.g., arachidonic acid), resulting in increased production of isoprostanes that possess potent vasoconstrictor activity. PLA, phospholipase NO, nitric oxide NOS, nitric oxide synthase NADPH oxidase, vascular NAD(P)H oxidase 02 , superoxide anion PUFA, polyunsaturated fatty acids EPA, eicosapentaenoic acid DHA, docosahexaenoic acid COX, cyclooxygenase PGI2 synthase, prostacyclin synthase.

Although the COX reaction requires catalytic levels of peroxide, the enzyme activity is not directly affected by ROS production (Smith 2008). However, ROS-mediated increase of the inducible enzymes involved in the arachidonic acid cascade, including phospholipases that provide free AA and other PUFA substrates for COX-mediated reactions, COX-2 and prostaglandin synthases (see Section 3.1), makes the formation of eicosanoids sensitive to the cellular redox status, and this can impact on disease states characterized by oxidative stress (Korbecki et al. 2013). 

Although cholesterol is about 10-fold less reactive in autoxidation than PUFA there is still interest in the products that have been associated with oxidant stress. Cholesterol, free and bound to ester, is measured after separation into free and ester cholesterol by selective extraction and hydrolysis using gas chromatography-tandem mass spectrometry (GC/MS/MS) [61]. Oxidized cholesterol, oxysterols, can be analyzed using LC-MS/MS with a minimum of manipulation or by using GC/MS/MS after derivatization [62-66]. 

It is important to note that the modifications generated by those lipid oxidation products contribute nearly to the same extent to DNA damage than the direct oxidized bases (Winczura et al. 2012). These lipid peroxidation aldehydes-DNA adducts have been reported in vivo in rodent and human DNA, in a wide variety of organs and tissue. For most of them, they can be found at a basal state (Marnett 1999 Nair et al. 1999, 2007), but their concentration is increased in the case of oxidative stress due, for instance, to inflammatory processes (Nair et al. 2007), but also in the case of PUFA-rich diet (Fang et al. 2007). For etheno-adducts, most of the studies report the presence of unsubstituted adducts, making the identification of the reactant enal impossible. However, a substituted etheno-adduct specific to the lipid oxidation product 4-oxo-nonenal has been found in greater amounts in the small intestine of mice prone to intestinal cancer (Min mice) and overexpressing the enzyme COX-2 involved in inflammatory processes than in the small intestine of control mice (Williams et al. 2006). 

Amino acid residues are potential targets of free radical oxidation and nitration. Carbonyl derivatives of proteins may be formed by the interaction of protein amino acid side chains, mainly cysteine, histidine, and lysine residues with reactive aldehydes, such as HNE and ONE generated by peroxidation of PUFAs (polyunsaturated fatty acids). Amino acid and peptide biomarkers of oxidative stress are typically focused on specific proteins related to disease pathology. For instance, the oxidation of histidine and methionine are typically discussed in (3-amyloid plaque formation and HNE-derived histidine adducts are the main focus of modifications on low-density lipoprotein (LDL) (An-nangudi et al., 2008). However, there are several specific examples of general biomarkers of oxidative stress that include endogenous histidine containing dipeptides such as carnosine and anserine as well as the very stable o,o -dityrosine. These will be discussed below. 

Paradoxically, linoleic acid, although an n-6 PUFA, has an athero-genetic role through oxidative stress and cytokine mediated inflammatory response on the endothelium (reviewed in ref. 103). Com oil (an n-6 PUFA source) increased oxidative stress and induced endothelial damage (104) On the other side, the incorporation of palm olein oil containing 38% palmitic acid, a saturated fatty acid, into a moderate fat, moderate cholesterol diet of nonhuman primate has antiatherogenic activity independent of cholesterolemic effects (105). 

SDG directly lowers serum cholesterol. Because lignans modulate the enzymes 7-hydroxylase and acyl CoA cholesterol transferase, they may be able to decrease serum cholesterol, as both of these enzymes are involved in cholesterol metabolism. Lignans may also lower oxidative stress. Enterodiol, enterolactone, and SDG act as antioxidants by inhibiting the peroxidation of PUFA in vitro at levels that may be achievable in vivo. Inhibiting peroxidation of PUFA may decrease oxidation of low-density lipoprotein, a key player in atherogenesis. Finally, SDG has been reported to act as an antagonist of platelet-activating factor (PAF) [58]. 

Rukkumani, R., Aruna, K., Varma, P.S., Rajasekaran, K.N., and Menon, V.P. 2004. Comparative effects of curcumin and an analog of curcumin on alcohol and PUFA induced oxidative stress. J. Pharm. Pharm. Sci., 7 274-283. 

Although canola oil contains a high level of OA, it also contains a relatively high level of LNA and thus the potential to increase oxidative stress in vivo. Oxidized LDL (ox-LDL) plays a fundamental role in the development of atherosclerosis. High PUFA intakes were found to promote the formation of ox-LDL whereas LPT, enriched with OA were stabler to oxidation. In vitro-conjugated diene formation (a measure of lipid oxidation) of the LDL fraction of snbjects fed diets, where canola oil or high... 

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