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Antioxidant status and lipid peroxidation in small intestinal mucosa of children with celiac disease

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Abstract

To explain the role of oxidative stress in the pathology of celiac disease. The activities of antioxidant enzymes and the levels of glutathione and lipid hydroperoxides were measured in the samples of small intestinal biopsies from 39 children with different forms of the disease and in 19 control subjects. The activities of analyzed enzymes varied significantly between the examined groups. An increase in the activities of superoxide dismutase was observed in patients with active and silent celiac disease, while the activities of glutathione peroxidase and glutathione reductase and the glutathione content were significantly reduced. The level of lipid hydroperoxides was significantly elevated in these groups. Oxidative stress is an important factor in the pathogenesis of celiac disease. The antioxidant capacity of celiac patients is significantly reduced, mostly by a depletion of glutathione. Natural antioxidants and appropriate dietary supplements could be important complements to the classic therapy of celiac disease.

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... 4 Gliadins are transformed into immunogenic and toxic peptides in the intestine through proteolysis that damage the prooxidant-antioxidant balance via free radical overproduction in the intestinal mucosa. [5][6][7] The toxic peptides cause changes in enterocyte morphology, disorders related to the tight junctions, and oxidative stress resulting in apoptosis. 7 Thiols are organic compounds that have carbon-bonded sulfhydryl groups. ...
... Studies in patients with celiac disease have shown decreased plasma glutathione levels and glutathione peroxidase and reductase activities in these patients through small bowel biopsies. 5,22 Stojiljkovic et al., 5,23 in two studies, reported a decrease in glutathione peroxidase levels in both small bowel biopsies and the serum of patients with celiac disease. ...
... Studies in patients with celiac disease have shown decreased plasma glutathione levels and glutathione peroxidase and reductase activities in these patients through small bowel biopsies. 5,22 Stojiljkovic et al., 5,23 in two studies, reported a decrease in glutathione peroxidase levels in both small bowel biopsies and the serum of patients with celiac disease. ...
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Background Toxic gliadin peptide damages enterocytes in celiac disease by causing oxidative stress. Thiols are organic compounds that defend against oxidative stress. This study aimed to investigate the changes in thiol–disulfide homeostasis in children with celiac disease. Methods The study included patients with celiac disease, children diagnosed with functional gastrointestinal disorders, and healthy children. Patients’ serum native and total thiol–disulfide amounts, disulfide/total thiol percent ratios, disulfide/native thiol percent ratios, and native thiol/total thiol percent ratios were measured. Results The study involved 172 children, of whom 90 (52.3%) were girls. The mean participant age was 8.6 ± 4.2 years. A total of 59 (34.3%) children had celiac disease, 56 (32.6%) had functional gastrointestinal disorders, and 57 (33.1%) were healthy. The total thiol and disulfide levels of patients with celiac disease (305 ± 87 μmol/L and 25 ± 15 μmol/L, respectively) were significantly lower than those of healthy children (349 ± 82 μmol/L and 40 ± 15 μmol/L, respectively) (P = 0.006 and P < 0.001, respectively). Native and total thiol levels (226 ± 85 μmol/L and 279 ± 99 μmol/L, respectively) in patients with celiac disease who consumed a gluten‐containing diet were significantly lower than those of patients who consumed a gluten‐free diet (278 ± 64 μmol/L and 327 ± 69 μmol/L, respectively) (P = 0.017 and P = 0.041, respectively). Conclusions Thiol–disulfide homeostasis, an important antioxidant defense component of the gastrointestinal system, is disrupted in children with celiac disease. A gluten‐free diet helped partially ameliorate this decline.
... Gluten-free products are deficient in nutritional and especially pro-health constituents, resulting in the occurrence of many disorders, such as osteoporosis, esophageal cancer, and infertility [5,6]. It should be noted that many authors [7][8][9][10] have indicated oxidative stress and cellular redox status as potential factors in the pathogenesis of celiac disease. People with CD usually exhibit significant oxidative stress and impaired performance of antioxidant enzymes (glutathione peroxidase, glutathione reductase, superoxide dismutase (SOD), and catalase), which form an important antioxidant barrier in the body, and are therefore prone to oxidant-antioxidant imbalance and DNA damage. ...
... Additionally, in vitro studies have shown redox imbalance and increased free radical levels after exposure of cells to gliadin [50]. Stojiljković et al., [7] showed that oxidative stress is strongly associated with CD, and that antioxidant capacity in celiac patients is impaired by glutathione (GSH) depletion and reduced activity of glutathione peroxidase and glutathione reductase (GPx and GR), as well the activity of other enzymes, including CuZn SOD and Mn SOD. It has also been shown that the greater the oxidative stress in people with celiac disease, the more advanced the mucosal damage is. ...
... It has also been shown that the greater the oxidative stress in people with celiac disease, the more advanced the mucosal damage is. Therefore, a diet rich in natural antioxidants may be beneficial for complete mucosal healing in celiac patients [7]. ...
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Gluten-free products based on starch and hydrocolloids are deficient in nutrients and do not contain pro-health substances. Therefore, they should be enriched in raw materials naturally rich in antioxidants, especially if they are intended for celiac patients, prone to high oxidative stress. Apart from the traditionally used pseudo-cereals, seeds, vegetables and fruits, innovative substrates such as the by-product (especially in Poland) dry apple pomace could be applied. The study material consisted of gluten-free bread enriched with apple pomace. The content of individual polyphenols, the content of total polyphenol and flavonoids, and also the antioxidant potential of the bread were determined by the UPLC-PDA-MS/MS methods. It was observed that apple pomace was a natural concentrate of bioactive substances from the group of polyphenols. In summary, gluten-free bread with 5% content of apple pomace showed the highest organoleptic scores and contained high levels of phenolic compounds. The values of total phenolic content, and the amounts of flavonoids, phenolic acids and phloridzin in this bread were 2.5, 8, 4 and 21 times higher in comparison to control.
... 7 As for CD, gluten might affect the pro-oxidant-antioxidant balance in intestinal mucosa, inducing an overproduction of free radicals. 8,9 The activities of antioxidant enzymes have been investigated in various kinds of biological samples from patients with CD. [10][11][12] A role in inflammatory intestinal diseases has been hypothesized for members of the Paraoxonase family, whose expression appeared reduced in intestinal biopsies. 13 As concerns paraoxonase-1 (PON1) involvement in CD, reports are scarce. ...
... Actually, the presence of an oxidative stress associated with gluten toxicity has already been reported. 8,[10][11][12] In this framework, the serum patients' increased activities of PON1 arylesterase, total SOD and MnSOD can be explained as an attempt to counteract the raised amounts of circulating oxidants. ...
... To the best of our knowledge, this is the first report describing serum total SOD and MnSOD activities in adult patients with active CD, although circulating levels of CuZnSOD 10 and both MnSOD and CuZnSOD intestinal mucosa activities have been reported to be increased in paediatric patients. 11 In these patients, a decrease in activities dealing with glutathione, as well as in the total amount of reduced glutathione (GSH), was also demonstrated even after several years of GFD. [10][11][12] Such pro-oxidant prevalence deeply involves a mitochondrial detoxifying enzyme as MnSOD, whose expression has been reported to increase depending on both the redox-sensitive NF-kB factor 35 and the oxidative stress. ...
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Background: Celiac disease (CD) is a gluten-sensitive autoimmune disorder. Gluten toxicity encompasses a wide spectrum of target organ functions and pathologies, including the activation of the immune response and triggering of oxidative stress. The aim of this study was to investigate inflammation and the redox balance in patients with active CD, and to evaluate whether alteration of mitochondrial function is involved in the disease status. Design: In this prospective case-control study, blood samples from sixteen adult CD patients and sixteen healthy controls (HC) were investigated for IL-1β, IL-6, and IL-8 plasma concentrations, for serum PON1 arylesterase, total and MnSOD antioxidant enzymes activities, induced TBARs levels, and for lymphocyte mtDNA content. Results: Patients showed IL-8 and IL-1β concentrations significantly higher than HC counterparts. Patients had a significantly higher content of induced TBARS compared to HC value, indicating a shift in their serum redox balance towards pro-oxidant species. The assay of antioxidant enzymes activities showed a significant 25% increase in PON1, a higher total SOD, and a significant 21% higher MnSOD in patients compared to HC. Lymphocytes mtDNA content in patients was significantly two-fold higher than in HC, supporting the induction of mitochondrial biogenesis. The patients' mitochondrial compensatory response may explain the correlation between MnSOD activity and mtDNA content. The patients' mitochondrial oxidative stress, cooperating to cytokines secretion, may justify the correlation between IL-1β concentration and mtDNA content. Conclusions: These results highlight the mitochondrial involvement in CD and suggest the evaluation of the mtDNA content as a potential diagnostic and follow-up parameter. This article is protected by copyright. All rights reserved.
... It cannot be excluded that they predispose patients with CD to other autoimmune diseases [6,[12][13][14]. This seems to be particularly true of undiagnosed or diagnosed but untreated/ inappropriately treated disease [15,16]. ...
... Antioxidant enzymes include, for example, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione S-transferase (GST), and glucose-6-phosphate dehydrogenase (G6PDH). Nonenzymatic mechanisms include, among others, glutathione (GSH), vitamin C (ascorbic acid), vitamin E (α-tocopherol), β-carotene, vitamin A (retinol), flavonoids, and binding proteins-transferrin, ceruloplasmin, and albumin [16]. Some nonenzymatic antioxidants are essential diet components and are found in many food products. ...
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Aims Oxidative stress is a factor involved in the pathogenesis of celiac disease (CD), possibly affecting the course of the disease and celiac-related complications. We assessed the intensity of oxidative processes and the efficiency of antioxidant defense in children with celiac disease. Methods. Group I (n = 32) consisted of children with CD treated with a gluten-free diet, and group II (n = 24) consisted of healthy children on a traditional diet. Antioxidative and oxidative status was assessed by measurement of serum total antioxidant capacity (TAC), total oxidant capacity (TOC), and oxidized low-density lipoprotein (ox-LDL) and on the basis of oxidative stress index (OSI). Results There were no significant differences in serum TAC, TOC, ox-LDL, and OSI between children with CD and healthy children. Cluster analysis showed that the group of children with CD is not homogeneous in terms of serum TAC and TOC levels. About 50% of these children had TAC levels < 1.3 mmol/L and TOC levels > 0.35 mmol/L. Conclusions Strict adherence to a gluten-free diet by children with CD seems to be important for maintaining oxidative-antioxidant balance. However, further research is needed to identify factors potentially responsible for increased oxidative stress in some children with celiac disease despite adherence to a gluten-free diet.
... Therefore, considering the pattern of MICA/B expression in different cell lineages observed, signals for induction of MICA/B may be part of a more general mechanism associated to the ongoing inflammatory process in the small intestine in untreated CD patients. Several studies on intestinal tissue, isolated cells from intestinal mucosa or epithelial cell lines support a link between cellular (heat, oxidative and ER) stress and mucosal damage [14,[26][27][28][29]. Particularly, the occurrence of oxidative stress was observed in intestinal biopsies from untreated CD patients, which was evidenced as increased level of prostaglandins E2 while the levels of the antioxidants enzyme glutathione peroxidase and reductase, and consequently reduced glutathione (GSH), were decreased [30]. In addition, induciblenitric oxide synthase (iNOS), which is constitutively expressed in duodenal enterocytes, showed increased activity in untreated CD [31]. ...
... Remarkably, we observed a higher expression of BiP in the epithelia of untreated CD duodenal samples but not in healthy tissue. Therefore, and in accordance with previous studies, our results suggest that an oxidative and an ER stress are present in CD enteropathy [14,27,30,32]. Furthermore, the observation of TIA-1 + granules in lamina propria mononuclear cells from untreated CD patients further supports this idea. ...
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The MICA/B genes (MHC class I chain related genes A and B) encode for non conventional class I HLA molecules which have no role in antigen presentation. MICA/B are up-regulated by different stress conditions such as heat-shock, oxidative stress, neoplasic transformation and viral infection. Particularly, MICA/B are expressed in enterocytes where they can mediate enterocyte apoptosis when recognised by the activating NKG2D receptor present on intraepithelial lymphocytes. This mechanism was suggested to play a major pathogenic role in active celiac disease (CD). Due to the importance of MICA/B in CD pathogenesis we studied their expression in duodenal tissue from CD patients. By immunofluorescence confocal microscopy and flow cytometry we established that MICA/B was mainly intracellularly located in enterocytes. In addition, we identified MICA/B(+) T cells in both the intraepithelial and lamina propria compartments. We also found MICA/B(+) B cells, plasma cells and some macrophages in the lamina propria. The pattern of MICA/B staining in mucosal tissue in severe enteropathy was similar to that found in in vitro models of cellular stress. In such models, MICA/B were located in stress granules that are associated to the oxidative and ER stress response observed in active CD enteropathy. Our results suggest that expression of MICA/B in the intestinal mucosa of CD patients is linked to disregulation of mucosa homeostasis in which the stress response plays an active role.
... In one study from Sweden, rectal NO production increased after gluten challenge in patients with celiac disease and correlated with mucosal myeloperoxidase [11]. An increase of markers of oxidative damage of lipids (thiobarbituric acid-reactive substances and lipid hydroperoxides) and proteins (carbonyl groups) have been demonstrated in plasma, in circulating cells and in intestinal cells of patients with CD [12][13][14]. The rational of this study is to look for the role of age on the clinical presentation including the subclinical cardiac involvement, and the status of the free radicals. ...
... Previous studies did not measure or assess the peroxynitrite free radical as this study and our findings document the role of nitrative stress syndrome in this disease. Significant higher level of MDA reported in this study is in agreement with other studies which, carried out in CD children, confirmed that CD is associated with oxidative damage [12,13,27]. There is evidence that gluten ingestion induced an increased oxidative stress due to overproduction of free radicals: reactive oxygen and nitrogen species [30]. ...
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Abstract Background and objectives: The clinical presentations of celiac disease (CD) are remarkably various age dependent. Free radicals overproduction may implicate in pathogenesis of CD or its complications. This study aimed to assess newly diagnosed CD from the following points of view: clinical presentation, cardiac involvement and free radicals overproduction taking in consideration the age of diagnosis. Methods: This study designed as a cross sectional in cohort patients with newly diagnosed celiac disease. Patients presented with diarrhea responded to the gluten free diet and positive serological tests of CD were admitted in the study. Left ventricular function was assessed by measuring the ejection fraction (%) and the free radicals were assessed by measuring the serum NO and peroxynitrite (ONOO) as well as malondialdehyde (MDA), a biomarker of lipid peroxidation. Results: One hundred eighty two newly diagnosed CD patients (73males and 109 females) were studied. There were no significant differences in intestinal and extra intestinal clinical manifestations at any age ranged between 4 and 65 years. Ejection fraction of patients at any age of clinical presentation was within normal range of corresponding healthy subjects. Also the hematological indices and biochemical tests did not show significant variation regarding the age. Significant high serum MDA, NO and ONOO levels compared with healthy subjects' levels were observed. Interpretations and conclusions: There are no significant differences between child and adult CD regarding the clinical presentations, biochemical findings, cardiac assessment and overproduction of reactive oxygen and nitrogen. Nitrosative stress syndrome is associated with celiac disease at any age.
... In a related study on the blood of CD patients, Stojiljkovic et al. (2007) found a marked increase in SOD activity, while GPx was significantly decreased. When measured in samples harvested from the small intestinal biopsies from CD children, SOD activity was also elevated, while the activities of GPx and GSR, as well as GSH levels were significantly decreased, thus showing an impairment of GSHdependent enzymes (Stojiljkovic et al., 2009). High levels of lipid oxidation (measured as TBARS levels) were found in the blood as well as in the small intestine mucosa of CD children in other related studies (Odetti et al., 1998;Stojiljkovic et al., 2009) respectively). ...
... When measured in samples harvested from the small intestinal biopsies from CD children, SOD activity was also elevated, while the activities of GPx and GSR, as well as GSH levels were significantly decreased, thus showing an impairment of GSHdependent enzymes (Stojiljkovic et al., 2009). High levels of lipid oxidation (measured as TBARS levels) were found in the blood as well as in the small intestine mucosa of CD children in other related studies (Odetti et al., 1998;Stojiljkovic et al., 2009) respectively). All these results clearly indicate that the oxidative stress detected in the intestine mucosa is reflected in the blood of CD patients. ...
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The objective of this study was to evaluate the level of genomic instability in patients with celiac disease and to establish a relationship between inflammation, oxidative stress, and DNA damage in these patients. Myeloperoxidase (MPO) activity, adenosine deaminase, nitric oxide (NOx), thiobarbituric acid, catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), and DNA damage were evaluated in peripheral blood samples from 47 celiac disease patients and 31 controls. Patients with celiac disease presented higher levels of DNA damage in comparison to controls (p=0.023). This difference was also observed for markers of oxidative stress, such as CAT (p=0.011) and SOD (p=0.013), and inflammatory markers such as MPO (p < 0.001) and NOx (p=0.009). Positive correlations were found between DNA damage levels and the values of CAT (r=0.405; p=0.009) and SOD (r=0.516; p < 0.001). Positive correlations were also found between GPx and NOx (r=0.349; p=0.030) and MPO and NOx (r=0.239; p=0.039). CAT and NOx showed a negative correlation (r= −0.315; p=0.042). In conclusion, intestinal inflammation can have systemic effects, causing an imbalance between oxidant and antioxidant markers, which may promote increased levels of DNA damage.
... In one study from Sweden, rectal NO production increased after gluten challenge in patients with celiac disease and correlated with mucosal myeloperoxidase [11]. An increase of markers of oxidative damage of lipids (thiobarbituric acid-reactive substances and lipid hydroperoxides) and proteins (carbonyl groups) have been demonstrated in plasma, in circulating cells and in intestinal cells of patients with CD [12][13][14]. The rational of this study is to look for the role of age on the clinical presentation including the subclinical cardiac involvement, and the status of the free radicals. ...
... Previous studies did not measure or assess the peroxynitrite free radical as this study and our findings document the role of nitrative stress syndrome in this disease. Significant higher level of MDA reported in this study is in agreement with other studies which, carried out in CD children, confirmed that CD is associated with oxidative damage [12,13,27]. There is evidence that gluten ingestion induced an increased oxidative stress due to overproduction of free radicals: reactive oxygen and nitrogen species [30]. ...
Article
Full-text available
Background and objectives: The clinical presentations of celiac disease (CD) are remarkably various age dependent. Free radicals overproduction may implicate in pathogenesis of CD or its complications. This study aimed to assess newly diagnosed CD from the following points of view: clinical presentation, cardiac involvement and free radicals overproduction taking in consideration the age of diagnosis.Methods: This study designed as a cross sectional in cohort patients with newly diagnosed celiac disease.Patients presented with diarrhea responded to the gluten free diet and positive serological tests of CD were admitted in the study. Left ventricular function was assessed by measuring the ejection fraction (%) and the free radicals were assessed by measuring the serum NO and peroxynitrite (ONOO) as well as malondialdehyde (MDA), a biomarker of lipid peroxidation.Results: One hundred eighty two newly diagnosed CD patients (73males and 109 females) were studied. There were no significant differences in intestinal and extra intestinal clinical manifestations at any age ranged between 4 and 65 years. Ejection fraction of patients at any age of clinical presentation was within normal range of corresponding healthy subjects. Also the hematological indices and biochemical tests did not show significant variation regarding the age. Significant high serum MDA, NO and ONOO levels compared with healthy subjects' levels were observed.Interpretations and conclusions: There are no significant differences between child and adult CD regarding the clinical presentations, biochemical findings, cardiac assessment and overproduction of reactive oxygen and nitrogen. Nitrosative stress syndrome is associated with celiac disease at any age.
... Gliadin exposure induces an oxidative imbalance, and some markers of oxidative stress, such as 4-hydroxy-2-nonenal and an increase in the oxidation (GSSG)/reduced (GSH) glutathione ratio have been demonstrated in vitro 23 . Duodenal biopsies of CD patients also demonstrated markers of oxidative damage, as shown here demonstrated [24][25] . Differently from what we found, in children SOD activity seems to be increased in the gut of CD patients, CAT did not change and there was a decrease in the glutathione-related antioxidant defenses 25 . ...
... Duodenal biopsies of CD patients also demonstrated markers of oxidative damage, as shown here demonstrated [24][25] . Differently from what we found, in children SOD activity seems to be increased in the gut of CD patients, CAT did not change and there was a decrease in the glutathione-related antioxidant defenses 25 . SOD is an enzyme with antioxidant properties. ...
Article
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Celiac disease is a chronic systemic inflammatory condition caused by an inappropriate immune response to gluten of wheat, rye and barley, with a prevalence of about 1: 100 in the Caucasian population when occurs inflammatory response and seems to involve high levels of interleukins. Objective: Determine the presence of oxidative stress and inflammation in the gut CD patients Methods: Transversal study including patients undergoing upper gastrointestinal (GI) endoscopy was performed. The study population consisted 24 cases and 26 controls. The duodenal levels of protein carbonyls, thiobarbituric acid reactive species (TBARS), as well as catalase (CAT), superoxide dismutase (SOD) activities were measured. Gut levels of interleukin (IL) 6, 8 and 10 were also determined. The Marsh classification was recorded and used as a parameter of severity. Results: Both IL-6 and IL-10, but not IL8, were increased in CD patients when compared to healthy individuals. Oxidative damage parameters were increased while antioxidant defenses were decreased in our sample. Both IL6 levels and SOD activity were related to Marsh score. Conclusions: Different markers of inflammation and oxidative stress are altered in the gut of CD patients, and some of them are related severity.
... peripheral blood of celiac children [26]. In subsequent papers , the same authors reported that GPx activity in the small intestine was also significantly lower in children with untreated and silent CD than in controls, and they showed a positive correlation between GPx activity and both GR and GSH concentrations [13,27]. ...
... The pattern of the observed GPx3 activity in serum seems to be very similar to that reported by other authors in intestinal mucosa, suggesting that these changes may be systemic. The activity of GPx depends on the availability of GSH and selenium, which depletion reported in celiac patients [13,26,27]. It appears, that the GSH and selenium reduction is followed by a decrease of the GPx activities. ...
Article
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INTRODUCTION Oxidative stress is considered as one of the mechanisms responsible for gluten toxicity, but its role in celiac disease (CD) remains unclear. OBJECTIVES To evaluate oxidative imbalance in the pathomechanism of CD by determining the concentrations of nitric oxide (NO) and selected antioxidant parameters. PATIENTS AND METHODS The study involved 197 adult patients: 53 patients with untreated active CD, 92 celiac patients on gluten-free diet (GFD), and 52 controls. Serum concentrations of antioxidants (uric acid, bilirubin, ferritin, albumin) and serum levels of celiac antibodies, NO, glutathione peroxidase (GPx3) and vitamin E were measured. A histopathological study of duodenal biopsy was performed. RESULTS Celiac patients had higher uric acid concentrations than controls (P<0.001). NO levels were higher in patients with active CD than in controls (P<0.01) and were significantly correlated with the degree of mucosal damage (r2=0.04; P=0.01). Vitamin E levels were decreased in celiac patients (P<0.01) and GPx3 activity was reduced in patients with active CD compared with controls (P<0.001). CONCLUSIONS Oxidative imbalance may be involved in the pathomechanism of CD in adults. GFD only partially reduces oxidative stress. Serum NO levels seem to be a marker of the effectiveness of treatment. Uric acid may act as an antioxidant in CD.
... There is an increasing body of evidence suggesting a relationship between oxidative stress and CD. Studies have revealed a reduced activity of peroxidase and glutathione reductase, as well as decreased glutathione levels, in the small intestine of patients with CD, while an increased activity of copper-and zinc-containing superoxide dismutase has been shown in patients with active CD [5,6]. Reduced glutathione peroxidase activity may be partially explained by glutathione defi ciency due to chronic inflammation of the small intestine [7]. ...
... Our results also indicate that in patients with CD it is enzymatic antioxidants that play the major role in oxidative imbalance. Th e reduced activity of these antioxidants in this population has been reported before [5,6,9]. ...
Article
Introduction: Oxidative stress with an excessive free radical production and a reduction in the activity of protective antioxidants is considered as one of the mechanisms responsible for gluten toxicity. However, its role in celiac disease (CD) is unclear. Objectives: Evaluation of plasma nonenzymatic antioxidant capacity in patients with CD (both untreated patients and those receiving gluten-free diet [GFD]) by measuring the ferric reducing ability of plasma (FRAP) as well as assessing selected plasma antioxidants. Patients and methods: The study included 169 adult patients: 48 patients with untreated active CD, 72 patients with CD on a GFD, and 49 healthy controls. In each group, we measured the serum levels of selected antioxidants (uric acid, bilirubin, albumin, and vitamin E) and used the FRAP assay to assess the total antioxidant capacity (TAC) of plasma. In each patient, serological and histopathological activity of CD was also evaluated. Results: There were no significant differences in the TAC of plasma measured with the FRAP assay between the study groups. Patients with CD had higher uric acid levels compared with controls (p <0.001), while bilirubin levels were lower in patients with active disease than in controls (p <0.05). Serum vitamin E levels were lower in all patients with CD compared with controls (p <0.01). Conclusions: The FRAP assay is not the method of choice for assessing the TAC of plasma in patients with CD. Owing to high serum uric acid levels, the FRAP assay results in these patients may be overestimated despite the reduced levels of other plasma antioxidants.
... In spite of everything above mentioned, HNE was never directly associated with increased intestinal permeability. In favor of this assumption are studies showing that patients with celiac disease, liver cirrhosis or chronic inflammatory bowel disease, such as ulcerative colitis and Crohn's disease, all characterized by chronic inflammation, have increased intestinal permeability, but also increased levels of lipid hydroperoxides (Aw, 2005;Ramachandran and Balasubramanian, 2001;Stojiljkovic et al., 2009). These permeability changes occur probably due to processes affecting lipids, as they are known to play important role in maintaining proper functioning of the intestine. ...
... Antioxidant enzyme activities SOD, CAT, GPx, and GR activity was determined using previously described methods by STOJILJKOVIAE et al. (2009). ...
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This study examined the effects of chronic restraint stress (CRS) on gene expression of tyrosine hydroxylase (TH), dopamine-β-hydroxylase (DBH), dopamine transporter (DAT), noradrenaline transporter (NET), vesicular monoamine transporter 2 (VMAT2), catechol-O-methyltransferase (COMT) and antioxidant enzymes such as superoxide dismutase (SOD1 and SOD2), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR), as well as concentrations of dopamine (DA) and noradrenaline (NA), activities of monoamine oxidase (MAO A and MAO B) and activities of antioxidant enzymes (SOD1, SOD2, CAT, GPx and GR) in the rat prefrontal cortex (PFC). We found that CRS decreases gene expression of TH and DBH and concentrations of DA, which probably confirms the decrease of de novo synthesis of catecholamine. CRS increased protein levels of NET and VMAT2, which was followed by increased NA concentration. The increased activity of MAO A and MAO B, as well as increased protein levels of COMT probably indicate increased catecholamine degradation, which was followed by increased activity of SOD1, SOD2 and CAT, as well as decreased activity of GPx under stress conditions. Our findings confirm the increased prefrontal noradrenergic turnover in animals exposedto CRS. The molecular mechanisms by which CRS changes catecholaminergic turnover and the antioxidant defense system in the PFC may be very important for research on numerous psychiatric diseases caused by chronic stress.
... The activities of glutathione peroxidase and reductase as well as GSH levels were decreased in small intestine from celiac disease patients, although Cu/ZnSOD activity was increased in patients with active disease [266,267]. The decrease in glutathione peroxidase activity may be explained, at least in part, by the selenium deficiency associated with chronic inflammatory damage of the small intestine [268]. ...
Article
Redox signaling regulates physiological self-renewal, proliferation, migration and differentiation in gastrointestinal epithelium by modulating Wnt/β-catenin and Notch signaling pathways mainly through NADPH oxidases (NOXs). In the intestine, intracellular and extracellular thiol redox status modulates the proliferative potential of epithelial cells. Furthermore, commensal bacteria contribute to intestine epithelial homeostasis through NOX1- and dual oxidase 2-derived reactive oxygen species (ROS). The loss of redox homeostasis is involved in the pathogenesis and development of a wide diversity of gastrointestinal disorders, such as Barrett's esophagus, esophageal adenocarcinoma, peptic ulcer, gastric cancer, ischemic intestinal injury, celiac disease, inflammatory bowel disease and colorectal cancer. The overproduction of superoxide anion together with inactivation of superoxide dismutase are involved in the pathogenesis of Barrett's esophagus and its transformation to adenocarcinoma. In Helicobacter pylori-induced peptic ulcer, oxidative stress derived from the leukocyte infiltrate and NOX1 aggravates mucosal damage, especially in HspB+ strains that downregulate Nrf2. In celiac disease, oxidative stress mediates most of the cytotoxic effects induced by gluten peptides and increases transglutaminase levels, whereas nitrosative stress contributes to the impairment of tight junctions. Progression of inflammatory bowel disease relies on the balance between pro-inflammatory redox-sensitive pathways, such as NLRP3 inflammasome and NF-κB, and the adaptive up-regulation of Mn superoxide dismutase and glutathione peroxidase 2. In colorectal cancer, redox signaling exhibits two Janus faces: On the one hand, NOX1 up-regulation and derived hydrogen peroxide enhance Wnt/β-catenin and Notch proliferating pathways; on the other hand, ROS may disrupt tumor progression through different pro-apoptotic mechanisms. In conclusion, redox signaling plays a critical role in the physiology and pathophysiology of gastrointestinal tract.
... Because arylesterase is a serum enzyme which protects low density lipoprotein against oxidative damage and is firmly bound to high density lipoprotein, we would expect the arylesterase enzyme level to be lower due to high consumption in case of oxidative stress. When similar studies in the literature are examined, it can be seen that oxidant parameters (lipid hydro peroxides, thiobarbituric acid-reactive substances, 8-hydroxyguanosine) increase (12)(13)(14) and antioxidant parameters (glutathione, PON1, PON3...) decrease (15,16) in gluten-sensitive enteropathy disease. When we partitioned gluten-sensitive enteropathy patients into two as the patients agreeable with a gluten free eating routine and the patients resistant to a gluten free eating regimen, it was found that OSI rate was higher and PON1 level was lower in the patients agreeable with a gluten free eating routine. ...
... However, there are studies conducted with low molecular weight thiol compounds. Stojiljković et al [25] have shown that in intestinal tissues of celiac patients in the pediatric age group, GSH level that constitutes a big part of intra cellular thiol content decreases and lipid hydroperoxide level which is an oxidant substance that plays a role in cell membrane damage increases. These results have indicated that GDH redox cycle is disrupted in celiac patients. ...
... Oxidative stress was evaluated in CD children. The activities of glutathione peroxidase and glutathione were much reduced and the level of lipid hydro peroxides was much higher in the samples of small intestinal biopsies [51]. Regenerating islet-derived 1 alpha (REGIα), an 18 kDa soluble glycoprotein, was significantly increase in the of CD patients sera [52]. ...
Article
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Celiac disease is still under diagnosed, although many diagnostic tests are available. Serological tests revealed many clinical aspects of celiac disease. We will discuss in this review the most important findings in terms of diagnosis of celiac disease.
... To reduce the negative impact of free radicals 73 children with acute diarrhea Completed the study (n=29) Selenium group (n=36) and to protect tissues from oxidants, the body needs antioxidants. 6,7 One such antioxidant is seleniumcontaining gastrointestinal glutathione peroxidase, an enzyme commonly found in the mucosal epithelium of the gastrointestinal tract. 8 Selenium deficiency concurrent with diarrhea can increase oxidative stress and decrease the differentiation and proliferation of T cells as well as the increase toxicity of T lymphocytes. ...
Article
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Background Acute watery diarrhea remains a major health problem affecting infants and children in developing countries. Selenium deficiency may be a risk factor for diarrhea and vice versa. Few studies have been conducted on the effectiveness of selenium for the treatment of diarrhea in children. Objective To determine the effectiveness of selenium in reducing the severity of acute watery diarrhea in children. Methods A single-blind, randomized clinical trial was done in children with acute watery diarrhea, aged six months to two years, and who visited the community health center in Simalungun from May to August 2012. Children were randomized into either the selenium or placebo (maltodextrin) group. We monitored diarrheal frequency, stool consistency, and duration of diarrhea. Mann-Whitney, Fisher’s, and Kolmogorov-Smirnov tests were used to compare the two groups. Results Sixty-five children were recruited into the study, of whom 36 children received selenium and 29 children received a placebo. The selenium group had significantly lower frequency of diarrhea (bouts per day) than the placebo group on days 2, 3, and 4 after treatment onset [day 2: 3.5 vs. 4.1, respectively (P=0.016); day 3: 2.7 vs. 3.4, respectively (P=0.002); day 4: 2.1 vs. 2.8, respectively (P
... 111 Selenium deficiency has already been reported in coeliac patients with regard to low GPx activity. 112 ...
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Crohn's disease and ulcerative colitis, known together as inflammatory bowel diseases (IBDs), and celiac disease are the most common disorders affecting not only adults but also children. Both IBDs and celiac disease are associated with oxidative stress, which may play a significant role in their etiologies. Reactive oxygen species (ROS) such as superoxide radicals (O2·−), hydroxyl radicals (·−OH), hydrogen peroxide (H2O2), and singlet oxygen (1O2) are responsible for cell death via oxidation of DNA, proteins, lipids, and almost any other cellular constituent. To protect biological systems from free radical toxicity, several cellular antioxidant defense mechanisms exist to regulate the production of ROS, including enzymatic and nonenzymatic pathways. Superoxide dismutase catalyzes the dismutation of O2·− to H2O2 and oxygen. The glutathione redox cycle involves two enzymes: glutathione peroxidase, which uses glutathione to reduce organic peroxides and H2O2; and glutathione reductase, which reduces the oxidized form of glutathione with concomitant oxidation of nicotinamide adenine dinucleotide phosphate. In addition to this cycle, GSH can react directly with free radicals. Studies into the effects of free radicals and antioxidant status in patients with IBDs and celiac disease are scarce, especially in pediatric patients. It is therefore very necessary to conduct additional research studies to confirm previous data about ROS status and antioxidant activities in patients with IBDs and celiac disease, especially in children.
... Alcohol extraction of gluten produces a soluble fraction, the prolamins (gliadin in wheat, secalin in rye, and hordein in barley), and an insoluble fraction, the glutenins, which are both toxic for patients with celiac disease and consist the environmental stimuli responsible for the development of the intestinal damage (Ciclitira et al. 1984). The disease is characterized by histopathological damage mainly located in the proximal small intestine, including villus atrophy, crypt hyperplasia, flattened mucosa, and increased epithelial lymphocytic infiltration (Stojiljkovic et al. 2009;Ferretti et al. 2012). It affects approximately 0.5-1% of the worldwide population; however, more than half of the patients remain undetected. ...
... The reduced nutritional value of many GF foods may lead to low micronutrient intake (Table 24.1 ) and poor vitamin and mineral status in coeliac patients [ 5 ] . Even antioxidant status is much lower in celiac patients [ 23,24 ] , which may be partially caused by low content of antioxidants in GF foods based on starches and re fi ned fl ours [ 25 ] . Therefore, the development of more nutrient-rich GF products is of great importance. ...
... The reduced nutritional value of many GF foods may lead to low micronutrient intake (Table 24.1 ) and poor vitamin and mineral status in coeliac patients [ 5 ] . Even antioxidant status is much lower in celiac patients [ 23,24 ] , which may be partially caused by low content of antioxidants in GF foods based on starches and re fi ned fl ours [ 25 ] . Therefore, the development of more nutrient-rich GF products is of great importance. ...
Chapter
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Gluten is the major storage protein in cereals such as wheat, rye and barley, or their crossbreds. In the wheat flour the gluten proteins contribute 80–85 % of the total protein content. These proteins contain peptides with high glutamine/proline content which are resistant to digestion by human proteases and may trigger damage to the small intestines. Gluten intolerance is a lifelong intolerance to gluten proteins [1]. A couple of decades ago, gluten intolerance was considered an uncommon disorder in the world, with prevalence rates of 1 in 1,000 or lower [2]. However, the development of novel sensitive and specific screening methods for gluten intolerance improved considerably diagnosis rates and resulted in an epidemiologic shift. Recent population studies have reported a much higher prevalence of gluten intolerance and it is now estimated to be 1:100–1:200 [1, 3].
... In addition, LPO generate more ROS, causing exacerbation of oxidative stress. Combined effects of LPO deleterious mechanisms in the GIT results in intestinal inflammation (Stojiljkovic et al., 2009), and consequently diarrhoea unless efficient inhibition mechanisms of the processes are in place. The good LPO inhibitory activity of the phenolic-enriched extracts of the Ozoroa and Searsia species tested in this work indicate that the plant have potential as supportive therapy in diarrhoea episodes. ...
Article
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The safety and effectiveness of many of the medicinal plants used in traditional medicine by rural people with little or no access to allopathic drugs is yet to be evaluated. With this in mind, Ozoroa and Searsia (previously known as Rhus) species traditionally used in South Africa to treat microbial infections and gastrointestinal disorders were selected for in vitro evaluation of biological activities and cytotoxicity. Phenolic-enriched leaf extracts were prepared using mixture of 1% HCl acidified 70% acetone and n-hexane. The crude extract was further fractionated with solvent of different polarities. Crude extracts and fractions were tested against Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Enterococcus faecalis, Aspergillus fumigatus, Candida albicans and Cryptococcus neoformans. In addition, the antioxidant potentials were determined by DPPH, ABTS, hydroxyl radical scavenging and linoleic acid peroxidation inhibition. The cytotoxic activity of the crude extracts was assayed against Vero cells. The crude extract and the various fractions had good biological activities. The most noteworthy activity is the growth inhibition of the hexane and dichloromethane fractions with MIC values as low as 19 μg/ml. The ethyl acetate and butanol fractions had moderate to low antimicrobial activities with MICs ranging from 39 to 2500 μg/ml. The polar fractions were more active against the fungal pathogens compared with the non-polar fraction. In the DPPH antioxidant assays, the active compounds were concentrated in the polar fractions (IC50 of the crude extract ranged between 0.90 and 15.82 μg/ml). The ethyl acetate fraction was the most active (IC50 ranging between 0.84 and 7.92 μg/ml). Although the water fraction was the most polar, the antioxidant activities were low due to the transfer of the active components into the ethyl acetate and butanol fractions. The crude extracts also had good linoleic acid peroxidation inhibition (LC50 ranging between 13.99 and 40.45 μg/ml). Crude extracts and fractions of the Ozoroa mucronata, O. paniculosa, Searsia leptodictya, S. pendulina, and S. pentheri species tested in this study had good activities relating to diarrhoea mechanisms of pharmacological relevance. However, use of phenolic-enriched crude extracts from these plants for diarrhoeal treatment or any other diseases need to be applied with caution as most of the plant extracts were reasonably toxic against Vero cell line. A next step in the possible application of these extracts to treat diarrhoea would be to identify the bioactive and toxic compounds.
... However, there are studies conducted with low molecular weight thiol compounds. Stojiljković et al [25] have shown that in intestinal tissues of celiac patients in the pediatric age group, GSH level that constitutes a big part of intra cellular thiol content decreases and lipid hydroperoxide level which is an oxidant substance that plays a role in cell membrane damage increases. These results have indicated that GDH redox cycle is disrupted in celiac patients. ...
Article
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AIM To determine dynamic thiol/disulphide homeostasis in celiac disease and to examine the associate with celiac autoantibodies and gluten-free diet. METHODS Seventy three patients with celiac disease and 73 healthy volunteers were enrolled in the study. In both groups, thiol/disulphide homeostasis was examined with a new colorimetric method recently developed by Erel and Neselioglu. RESULTS In patients with celiac disease, native thiol (P = 0.027) and total thiol (P = 0.031) levels were lower, while disulphide (P < 0.001) level, disulphide/native thiol (P < 0.001) and disulphide/total thiol (P < 0.001) ratios were higher compared to the control group. In patients who do not comply with a gluten-free diet, disulphide/native thiol ratio was found higher compared to the patients who comply with the diet (P < 0.001). In patients with any autoantibody-positive, disulphide/native thiol ratio was observed higher compared to the patients with autoantibody-negative (P < 0.05). It is found that there is a negative correlation between celiac autoantibodies, and native thiol, total thiol levels and native thiol/total thiol ratio, while a positive correlation is observed between disulphide, disulphide/native thiol and disulphide/total thiol levels. CONCLUSION This study is first in the literature which found that the patients with celiac disease the dynamic thiol/disulphide balance shifts through disulphide form compared to the control group.
... Because arylesterase is a serum enzyme which protects low density lipoprotein against oxidative damage and is firmly bound to high density lipoprotein, we would expect the arylesterase enzyme level to be lower due to high consumption in case of oxidative stress. When similar studies in the literature are examined, it can be seen that oxidant parameters (lipid hydro peroxides, thiobarbituric acid-reactive substances, 8-hydroxyguanosine) increase (12)(13)(14) and antioxidant parameters (glutathione, PON1, PON3...) decrease (15,16) in gluten-sensitive enteropathy disease. When we partitioned gluten-sensitive enteropathy patients into two as the patients agreeable with a gluten free eating routine and the patients resistant to a gluten free eating regimen, it was found that OSI rate was higher and PON1 level was lower in the patients agreeable with a gluten free eating routine. ...
Article
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Background: The objective here is to examine the role of overall oxidative stress in the etiopathogenesis of glutensensitive enteropathy disease and its relationship with gluten free diet and autoantibodies. Methods: Eighty gluten-sensitive enteropathy patients and 80 control group participants were included in the study. As oxidative stress parameters, we researched total antioxidant status (TAS), total oxidant status (TOS), oxidative stress index (OSI), paraoxonase-1 and arylesterase parameters in the serum samples of gluten-sensitive enteropathy patients. Results: In comparison to the control group, gluten-sensitive enteropathy patients had lower TAS, paraoxonase-1 and arylesterase levels and gluten-sensitive enteropathy patients had considerable TOS and OSI levels. In contrast, patients who agreed to the gluten free eating routine had a higher OSI proportion and patients who did not conform to the gluten free eating regimen had a lower paraoxonase- 1 level. An affirming reciprocation was de tected amidst TOS and OSI proportion and gluten-sensitive enteropathy autoantibodies and C-reactive protein levels and a negative correlation was found between arylesterase level and glu - ten-sensitive enteropathy autoantibodies. Conclusions: We observed oxidative stress levels to be higher in gluten-sensitive enteropathy patients contrasted with the control group. Oxidative stress level showed differences in gluten-sensitive enteropathy patients depending on gluten diet content and autoantibody positivity. In point
... Antioxidant Enzyme Activities. SOD, GPx, and GR activities were determined using assays for enzyme activities, as we previously described [31]. ...
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This study examined the effects of lithium on gene expression and activity of the antioxidant enzymes copper-zinc superoxide dismutase (SOD1), manganese superoxide dismutase (SOD2), catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR) in the hippocampus of chronically stressed rats. In addition, we examined the effects of lithium on anxiety behaviors, hippocampal concentrations of dopamine (DA) and malondialdehyde (MDA), protein levels of brain-derived neurotrophic factor (BDNF), tyrosine hydroxylase (TH), dopamine transporter (DAT), and catechol-O-methyltransferase (COMT), as well as activity of monoamine oxidase (MAO) in chronically stressed rats. The investigated parameters were quantified by real-time RT-PCR, Western blot analyses, and assays of enzyme activities. We found that lithium did not change gene expression of SOD1, CAT, GPx, and GR but decreased gene expression of SOD2 in chronically stressed rats. A very important result in this study was that lithium treatment decreased the enzyme activities of SOD1 and SOD2 but increased the enzyme activities of GPx and GR in stress condition, which indicates the control of redox balance. The reduced concentration of MDA confirms this. In addition, we found that lithium treatment decreased high protein levels of BDNF and DAT in chronically stressed rats to the level found in unstressed animals. Also, lithium treatment increased the expression of TH but decreased the enzyme activity of MAO B, which contributed to the increase of the hippocampal concentration of DA in chronically stressed rats to the level of unstressed animals. Finally, lithium treatment in animals exposed to chronic stress increased the time spent in open arms. Lithium-induced modulation of hippocampal antioxidant status and attenuation of oxidative stress stabilized behavior in animals with high anxiety index. In addition, reduced oxidative stress was followed by the changes of both turnover of DA and levels of BDNF protein in chronically stressed rats treated with lithium. These findings may be important in preclinical research of the effects of lithium on oxidative stress level in pathological conditions.
... Previous data [3,4] revealed that oxidative stress and ROS play an important role in the pathogenesis of CD. Our former investigations demonstrated that the antioxidant defense system is notably disturbed in the blood and intestinal mucosa of patients with CD [5,6]. The aim of this study was to investigate alterations in SOD activity and protein levels, as well as the level of lipid peroxidation in blood and intestinal mucosa of pediatric CD patients. ...
... However, malabsorption alone does not explain the pathophysiology and clinical course of numerous extraintestinal manifestations as well as non classic symptoms that predominate in adult patients with CD. Other mechanisms have been proposed including gluten toxicity with oxidative imbalance and autoimmunity [23,24] . In this study, we have examined less extensively studied, factors implicated in CD, such as HSP70, HIF1α, and the proapoptotic factor BAX. We found these 3 factors to be overexpressed in active CD, with varying degrees of activity in patients on GFD. ...
Article
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AIM To evaluate selected intestinal parameters of oxidative stress, and antioxidant capacity in adult celiac disease patients with extraintestinal manifestations. METHODS The study involved 85 adult patients divided into the following subgroups: (1) patients with newly diagnosed celiac disease (CD) (n = 7); (2) celiac patients not adhering to a gluten-free diet (GFD) (n = 22); (3) patients with CD on the GFD (n = 31); and (4) patients with functional disorders of the gastrointestinal tract, serving as controls (n = 25). Celiac patients presented with non-classic symptoms or extraintestinal manifestations. Standard blood tests including serum antioxidant levels (uric acid, bilirubin, and vitamin D), celiac antibody levels, and histopathological status of duodenal biopsy specimens have been determined. The expression of mRNA for tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), interleukin 10 (IL-10), superoxide dismutase (SOD), heat-shock protein 70 (HSP-70), hypoxia-inducible factor 1 (HIF-1α), and BAX in the duodenal mucosa of patients was analyzed by reverse transcriptase-polymerase chain reaction. RESULTS The mean plasma uric acid level in patients with active CD (newly diagnosed and nonadherent patients) and treated celiac patients was significantly higher than in controls (260.17 ± 53.65 vs 190.8 ± 22.98, P < 0.001, and 261.7 ± 51.79 vs 190.8 ± 22.98, P < 0.001, respectively). The mean bilirubin concentration in active and treated celiac patients was significantly lower than in controls (8.23 ± 5.04 vs 10.48 ± 4.08, P < 0.05 and 8.06 ± 3.31 vs 10.48 ± 4.08, P < 0.05, respectively). The mean plasma vitamin D level was significantly lower in active celiac patients than in treated celiac patients and controls (19.37 ± 9.03 vs 25.15 ± 11.2, P < 0.05 and 19.37 ± 9.03 vs 29.67 ± 5.12, P < 0.001, respectively). The expression of TNF-α, IL-10, and HSP-70 mRNAs was significantly elevated in the celiac groups regardless of the diet when compared with controls. Patients on the GFD presented a significantly lower mRNA expression of TNF-α and IL-10 than in newly diagnosed and nonadherent patients (P < 0.05). The expression of SOD mRNA was significantly elevated in celiac patients compared with controls (P < 0.05), with a significant difference between treated and untreated patients (P < 0.05). The expression of HIF-1α mRNA and BAX mRNA was significantly higher in patients with active CD compared with controls and patients on GFD, while no difference was observed between the latter two groups. CONCLUSION Increased intestinal expression of HSP-70 despite GFD indicates that GFD only partially reduced oxidative stress. CD patients exhibited an oxidative imbalance and inflammatory response despite GFD. Uric acid may act as an important antioxidant in CD.
... The result was expressed in arbitrary units normalized in relation to β actin. Antioxidant enzyme activities SOD 1, SOD 2 and CAT activity was determined using previously described methods by Stojiljković et al. [18]. ...
Article
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This study examined the effects of chronic restraint stress (CRS: 2 hours × 14 days) on gene expression of three antioxidant enzymes, copper, zinc superoxide dismutase (SOD 1), manganese superoxide dismutase (SOD 2) and catalase (CAT) in the rat hippocampus. Also, we examined changes in the activities of SOD 1, SOD 2 and CAT in the hippocampus of chronically stressed rats. Investigated parameters were quantifi ed by using real-time RT-PCR, Western blot analysis and assay of enzymatic activity. We found that CRS did not change mRNA and protein levels of SOD 1 and CAT, but increased mRNA and protein levels of SOD 2. However, CRS treatment increased the enzyme activities of SOD 1, SOD 2 and CAT. Our fi ndings indicate that the increased activity of antioxidant enzymes (SOD 1, SOD 2 and CAT) in the hippocampus may be an important adaptive phenomenon of the antioxidant defense system in chronically stressed rats.
... The antioxidant capacity during wheat intolerance disease such as CD has been reported to be significantly reduced mainly due to depletion of glutathione (Stojiljkovic et al., 2009). In this context, an adjunct of natural antioxidants and appropriate dietary supplements is often recommended as a standard therapy for a CD patient. ...
Article
Wheat protein contributes a significant part in human diet, apart from its well-known nutritional values, wheat gluten/gliadin proteins are also responsible for the many allergic/inflammatory diseases and chronic inflammation in the small intestine may cause diarrhea and malabsorption, in a specific population of individuals. In the present study, the antigenic characteristics of twelve wheat varieties of diverse origin namely C273, C281, C286, C306, C518, C591, Agra Local, 9D, 8A, Raj4229, HD3027, NP824 released during 1920–2012 were evaluated. Gliadin proteins from these varieties were tested on human colon cancer cell line HCT116 to assess their effect on inflammation, oxidative and nitrosative stress, pro-inflammatory cytokines. The results show that these wheat varieties induced high levels of ROS/RNS and MPO activity which was further supported by the increase in the mRNA levels of a cytokine such as IL-1β and IL-15. It can be concluded that gliadin from these wheat varieties is suggested to act as a potential antigen by enhancing the level of inflammation irrespective of their year of release and origin which if not controlled may lead to the initiation of celiac disease in genetically susceptible individuals or may be responsible for other wheat protein intolerance associated diseases.
... SOD, CAT, GPx, and GR activities were determined using methods previously described by Stojiljković et al. [64]. Determination of total SOD activity was performed using Oxis Bioxytech SOD-525 Assay (Oxis International, Inc., Portland, OR, USA). ...
... These patients have an intolerance to gluten and recent studies have suggested that patients with CD have reduced antioxidant capacity. 65,66 Given that oxidative stress likely plays a role in cataract formation, it was hypothesized that patients with CD are at an increased risk of cataract development. 65,67 Mollazadegan and colleagues performed a population-based cohort study to determine the risk of cataract among persons with biopsy proven CD. ...
Article
We review the current literature regarding the risk factors for cataract and the association between cataract and systemic disease. Numerous epidemiologic studies have found that the risk factors for age‐related cataract formation include age, sex, race and myopia. Modifiable risk factors include smoking, socioeconomic status and ultra‐violet light exposure. Alcohol intake and nutritional status may play a role in cataract formation. Cataract has been associated with many systemic diseases mainly diabetes mellitus, hypertension, obesity, chronic kidney disease and autoimmune disease. Cataract is also a hallmark of many metabolic disorders and syndromes. These findings are important to help implement risk factor and lifestyle‐modification strategies that can hopefully decrease the burden of global cataract blindness.
... It is possible that the oxidative stress induced by gliadin is responsible for free radical damage of important cellular structures, adversely affecting their functions [57][58][59]. It has been reported that gluten consumption by celiac disease patients induces the overproduction of ROS, triggering a cascade of reactions causing oxidative stress throughout the body [60]. It has also been suggested that gliadin disturbs the balance between cellular oxidants and antioxidants through the overproduction of ROS in the small intestinal mucosa of celiac patients [61]. ...
Article
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Gliadin is a major protein component of gluten and causes gluten toxicity through intestinal stress. We previously showed that gliadin intake induces oxidative stress in the intestine and reduces fertility in a Caenorhabditis elegans model. To elucidate the possible link between intestinal stress and reproduction, changes in the intestine and germ cells of C. elegans after gliadin intake were examined at the molecular level. Gliadin intake increased reactive oxygen species (ROS) production in the intestine, decreased intestinal F-actin levels, and increased germ cell apoptosis. These gliadin-triggered effects were suppressed by antioxidant treatment. These results suggest that ROS production in the intestine induced by gliadin intake causes disruption of intestinal integrity and increases germ cell apoptosis. Gliadin-induced germ cell apoptosis (GIGA) was suppressed by depletion of cep-1, ced-13, egl-1, or mpk-1. However, HUS-1 was not activated, suggesting that GIGA is activated through the mitogen-activated protein kinase (MAPK) pathway and is CEP-1-dependent but is a separate pathway from that controlling the DNA damage response. Taken together, our results suggest that gliadin causes intestinal barrier disruption through ROS production and interacts with the germ cells to reduce fertility through GIGA.
Article
Background: This study aimed to investigate the effects of lithium treatment on gene expression and activity of the prefrontal antioxidant enzymes: copper, zinc superoxide dismutase (SOD1), manganes superoxide dismutase (SOD2), catalase (CAT), and glutathione peroxidase (GPx) in animals exposed to chronic restraint stress (CRS). Methods: The investigated parameters were quantified using real-time RT-PCR, Western blot analyses, and assays of enzyme activities. Results: We found that lithium treatment decreased gene expression of SOD2, as well as the activities of SOD1 and SOD2 in chronically stressed rats to the levels found in unstressed animals. However, lithium treatment in animals exposed to CRS increased prefrontal GPx activity to the levels found in unstressed animals. Conclusions: These findings confirm that treatment with lithium induced the modulation of prefrontal antioxidant status in chronically stressed rats. Our results may be very important in biomedical research for understanding the role of lithium in maintaining the stability of prefrontal antioxidant defense system in neuropsychiatric disorders caused by chronic stress.
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The celiac disease is an autoimmune gastrointestinal disorder caused by gluten from wheat, rye or barley. In genetically predisposed persons, gluten induces the immune-mediated inflammation of small intestinal mucosa. Histological lesions include intraepithelial lymphocytosis, crypt hypertrophy and villous atrophy, resulting in malabsorption of micro- and macronutrients. The only treatment for celiac patients is a permanent gluten-free diet (GFD). Reactive oxygen species (ROS) and oxidative stress are strongly associated with the celiac disease. Glutathione (GSH) is a main detoxifier of endogenous and exogenous ROS in the intestine. In order to explain the role of glutathione redox cycle in celiac patients, we examined the activities of GSH-related antioxidant (AO) enzymes glutathione peroxidase (GPx) and glutathione reductase (GR), as well as the concentration of GSH in small intestinal biopsies and peripheral blood of children affected by the celiac disease. The concentration of lipid hydroperoxides (LOOH) as markers of oxidative damage was measured in the same samples. The results clearly demonstrate a significant malfunction of GSH redox cycle with a concomitant decrease in the capacity to regenerate GSH and detoxify LOOH in celiac patients, even after several years of GFD. The oral administration of GSH and a diet rich in natural antioxidants, as well as appropriate dietary supplements, could be of great benefit to the patients.
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An imbalance between the production of oxygen and nitrogen free radicals and their degradation by the antioxidant system are the major causative factors for the wheat intolerance diseases. In the present study, we have examined the wheat gliadin protein-induced oxidative and nitrosative stress and downstream responses in the human intestinal cell lines viz. HCT-116 and HT-29. The role of phytochemical curcumin was investigated to alleviate the gliadin associated cellular damages. The focus of the study was to identify the role of key DNA repair enzyme apurinic/apyrimidinic endonuclease 1 (APE1) in gliadin protein-induced toxicity in the intestine, which may be crucial for establishing the gut-associated diseases. Reactive oxygen species (ROS); reactive nitrogen species (RNS); mitochondrial ROS; mitochondrial trans-membrane potential; protein carbonylation; lipid peroxidation; and the oxidized DNA base damage was estimated in HCT-116 and HT-29 cells after 24 h treatment of 160 µg/ml of gliadin, 10 µM of curcumin and its combination. In addition, the transcriptional expression and enzymatic activities of antioxidants (SOD; Catalase; and GSH) were measured in the in these cells. Furthermore, the cross-talk between the nuclear factor erythroid 2-related factor-2 (Nrf-2) and the multifunctional enzyme APE1 was analyzed by the immunofluorescent based imaging and co-immunoprecipitation assays. The endonuclease activity of APE1 and the DNA-protein interaction of NRF-2 with ARE was analyzed by using electrophoretic mobility shift assay (EMSA) with the nuclear lysates of HCT-116 and HT-29 cells. Results suggest that 3 h pre-treatment of curcumin followed by the treatment of gliadin protein for 24 h time protect the HCT-116 and HT-29 cells via (1) decreasing the ROS, RNS, oxidative stress, mitochondrial ROS, recuperate mitochondrial trans-membrane potential; (2) reestablishing the cellular antioxidant defence systems; (3) enhancing the DNA-repair via APE1 and which further activates the ARE elements via activation of Nrf-2. In conclusion, wheat gliadin induces the oxidative/nitrosative stress, mitochondrial damage and damages the cellular biomolecules; hence is associated with the disease pathogenesis and tissue damage in wheat intolerance diseases. The gliadin induced stress and its consequences are significantly reduced by the pre-treatment of curcumin via DNA repair pathways and oxidative stress which is evident through the interaction between two essential proteins of these pathways APE1 and Nrf-2 hence suggesting the role of curcumin based management of wheat intolerance diseases like celiac disease.
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The black chokeberry, Aronia melanocarpa (Family Rosaceae), is native to North America and was introduced into Europe in the XIX century. Aronia melanocarpa contain particularly high amounts of procyanidins, anthocyanins, and phenolic acids. These antioxidants reduce the oxidative damage of human cells that can lead to cancer, heart disease, diabetes, hypertension, hypercholesterolemia. The black chokeberry may be used in the treatment and prevention of numerous civilization diseases.
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The aim of the study was to evaluate and compare oxidase and ferroxidase ceruloplasmin activities (U L -1) and their specific activities (U g -1) in sera of celiac patients with different histopathological severity. This study included 75 celiac patients with different mean age (18.68±11.13) year, who had positive screen for celiac antibodies and who had gastrointestinal symptoms. In order to simplify the comparison with the healthy control group, celiac patients were divided into two groups according to their histopathological severity: Severe (marsh III a, b, c) and less severe (marsh 0,1). All these patients have been evaluating for S.CB. ferroxidase and S.CB. oxidase activities as well as its specific activities. Furthermore, the concentrations of total protein, albumin, copper and iron, were measured too. Non-significant increase (p>0.05) in serum ferroxidase activity of ceruloplasmin was found in all above mentioned patients groups in comparison to that of the control group, while its specific activity showed a significant increase for more severe mucosal histopathological damage (marsh III a, b, c) patients and (p>0.05) for less severe mucosal histopathological damage (marsh 0,1) patients in comparison to that of control group. As far as serum oxidase ceruloplasmin activities is concerned, a significant increase (p<0.05) was observed in all patients groups, while its specific activity showed non-significant increase (p>0.05) in sera of more severe mucosal histopathological damage (marsh III a, b, c) patients and a significant increase (p<0.05) for less severe mucosal histopathological damage (marsh 0,1) patients. Among the patients groups, serum copper levels showed non-significant increased (p = 0.1) and serum iron level was found to decrease significantly in patients with more severe mucosal histopathological damage (marsh III a, b, c) in comparison to that of control group. Meanwhile the mean values of patients total protein and their albumin were found to show non-significant increase (p>0.05) in comparison to that of the control groups.
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Celiac disease (CD) is an autoimmune condition that occurs in genetically predisposed people where the ingestion of gluten produces damage in the small intestine. The treatment accepted until now is a strict gluten free diet. This implies the need for novel or adjuvant treatments, in addition to the standard of care. The present study aimed to assess the effect of gold nanoparticles phytosynthesized with Cornus mas extract (AuCM) compared to Cornus mas extract (CM) and luteolin (LT) on Caco-2 cells, exposed or not to gliadin. Ultraviolet-visible spectroscopy and transmission electron microscopy were used for the characterization of AuCM. Measured cellular outcomes included oxidative stress markers (malondialdehyde level, catalase and superoxide dismutase activities), inflammatory response and cellular signaling and transcription factors involved in apoptosis (NFκB, pNFκB, NOS2, TNF-α, TRAIL, Bax, Bcl-2, p53). The internalization of gold nanoparticles in cells was evidenced by transmission electron microscopy (TEM). The gliadin administration induced oxidative stress, improved the activity of antioxidants enzymes, increased NOS2 and NFκB expressions and reduced pNFκB/NFκB ratio. In addition, gliadin enhanced TRAIL and Bcl-2 levels and reduced p53 expression in Caco-2 cells. The pretreatment with AuCM, CM extract and LT diminished oxidative stress and reduced NOS2 activity. AuCM and CM treatment amplified the expression of p53 and pNFκB/NFκB ratio and diminished Bcl-2, NFκB and pNFκB, especially AuCM. The results obtained confirmed that AuCM mitigate some of gliadin effects on Caco-2 cells through modulation of oxidative stress and inflammation.
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Celiac disease (CeD) is an autoimmune enteropathy caused by gluten intake in genetically predisposed individuals. We investigated the metabolism of CeD by metabolic profiling of intestinal mucosa, blood plasma and urine using NMR spectroscopy and multivariate analysis. The metabolic profile of the small intestinal mucosa was compared between patients with CeD (n = 64) and disease controls (DCs, n = 30). The blood plasma and urinary metabolomes of CeD patients were compared with healthy controls (HCs, n = 39). Twelve metabolites (proline (Pro), arginine (Arg), glycine (Gly), histidine (His), glutamate (Glu), aspartate, tryptophan (Trp), fumarate, formate, succinate (Succ), glycerophosphocholine (GPC) and allantoin (Alln)) of intestinal mucosa differentiated CeD from controls. The metabolome of blood plasma with 18 metabolites (Pro, Arg, Gly, alanine, Glu, glutamine, glucose (Glc), lactate (Lac), acetate (Ace), acetoacetate (AcAc), β‐hydroxybutyrate (β‐OHB), pyruvate (Pyr), Succ, citrate (Cit), choline (Cho), creatine (Cr), phosphocreatine (PCr) and creatinine) and 9 metabolites of urine (Pro, Trp, β‐OHB, Pyr, Succ, N‐methylnicotinamide (NMN), aminohippurate (AHA), indoxyl sulfate (IS) and Alln) distinguished CeD from HCs. Our data demonstrated changes in nine metabolic pathways. The altered metabolites were associated with increased oxidative stress (Alln), impaired healing and repair mechanisms (Pro, Arg), compromised anti‐inflammatory and cytoprotective processes (Gly, His, NMN), altered energy metabolism (Glc, Lac, β‐OHB, Ace, AcAc, Pyr, Succ, Cit, Cho, Cr and PCr), impaired membrane metabolism (GPC and Cho) and intestinal dysbiosis (AHA and IS). An orthogonal partial least square discriminant analysis model provided clear differentiation between patients with CeD and controls in all three specimens. A classification model built by combining the distinguishing metabolites of blood plasma and urine samples gave an AUC of 0.99 with 97.7% sensitivity, 93.3% specificity and a predictive accuracy of 95.1%, which was higher than for the models built separately using small intestinal mucosa, blood plasma and urine. In conclusion, a panel of metabolic biomarkers in intestinal biopsies, plasma and urine samples has potential to differentiate CeD from controls and may complement traditional tests to improve the diagnosis of CeD.
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Diseases of the gastrointestinal (GI) tract include infection at the mucosal surface, cancers, and chronic inflammatory conditions such as Crohn's disease and ulcerative colitis. These conditions involve reactive free radical species and oxidative damage during their progression and perhaps in their origin. The term oxidative stress has traditionally referred to the imbalance between the generation of reactive oxygen species and the activity of antioxidant defenses. While short-term oxidative responses are beneficial, such as during invasion by a pathogen, long-term oxidative stress can cause tissue destruction due to the production of peroxides and free radicals that damage proteins, lipids, and DNA in the cell. Endogenous and exogenous antioxidants can counteract reactive species in the GI tract, and thus, a balance between oxidative and antioxidant responses is critical for maintaining intestinal health. This chapter will discuss redox biology of the GI tract and how an intricate balance between oxidative and antioxidant responses must be regulated to maintain good GI health. Evidence for the role of oxidative and antioxidant responses associated with GI diseases and syndromes will be reviewed, as well as, an overview of therapeutics to combat oxidative damage associated with GI disease. © Springer-Verlag Berlin Heidelberg 2014. All rights are reserved.
Article
The effects of chronic restraint stress (CRS, 2 h during 14 days) on gene expression of tyrosine hydroxylase (TH), catechol-O-methyltransferase (COMT), and glutathione peroxidase (GPx) were studied in the rat hippocampus. Changes in the dopamine (DA) concentration and activities of monoamine oxidases (MAO A and MAO B) and GPx in this cerebral structure of chronically stressed rats were also examined. The investigated parameters were quantified using real-time RT-PCR, Western blot analyses, and assay of enzymatic activity. We found that CRS decreased the TH protein level and DA concentration, which probably confirms the statement that de novo synthesis of DA is suppressed under stress conditions. The increased activities of MAO B, as well as the increased level of COMT protein, are believed to be related to intensified DA catabolism conditions. Also, a decreased activity of GPx in the hippocampus of chronically stressed animals was found. The increased enzymatic activity of MAO B negatively correlated with the reduced activity of GPx under the above-mentioned stress conditions. These events in the hippocampus of chronically stressed animals could synergistically cause oxidative damage to the mitochondria.
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A large body of circumstantial evidence emphasizes the critical role of reactive oxygen species (ROS), including superoxide anion and nitric oxide (NO), in acute and chronic pediatric diseases. About 15 years ago, measurement of oxidative damage affecting tissues and organs using specific biomarkers was introduced into the field of pediatric medicine. This chapter is intended to describe recent progress in clinical application of oxidative stress biomarkers in pediatric medicine. First, this chapter briefly presents the biochemistry and pathophysiology of ROS and antioxidative defense systems. Second, it discusses the interrelationship of endothelial dysfunction, NO system blockade, and oxidative stress. Third, it presents a list of clinically applicable biomarkers, along with pediatric diseases in which enhanced oxidative stress might be involved. The discussion emphasizes that many good biomarkers are readily measurable using enzyme-linked immunosorbent assay. Fourth, this chapter presents age-related reference normal ranges of oxidative stress biomarkers, including urinary acrolein-lysine, 8-hydroxy-2′-deoxyguanosine, nitrite/nitrate, and pentosidine. Furthermore, our new and interesting data related to oxidative stress and antioxidative defenses in congenital metabolic disorders, such as Wilson disease, urea cycle defects, citrin deficiency, and phenylketonuria, are presented. Rapid diagnostic tests for measuring blood levels of total hydroperoxides and biological antioxidative potential and urinary levels of 8-hydroxy-2′-deoxyguanosine are also explained. Finally, this chapter describes recent clinical studies that have evaluated the efficacy of antioxidative intervention for oxidative-stress-related diseases. Repeated measurement of multiple appropriate parameters will enable us to discern the pathophysiological patterns of pediatric diseases and guide our therapies appropriately. © Springer-Verlag Berlin Heidelberg 2014. All rights are reserved.
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The celiac disease is an autoimmune gastrointestinal disorder caused by gluten from wheat, rye or barley. In genetically predisposed persons, gluten induces the immune-mediated inflammation of small intestinal mucosa. Histological lesions include intraepithelial lymphocytosis, crypt hypertrophy and villous atrophy, resulting in malabsorption of micro- and macronutrients. The only treatment for celiac patients is a permanent gluten-free diet (GFD). Reactive oxygen species (ROS) and oxidative stress are strongly associated with the celiac disease. Glutathione (GSH) is a main detoxifier of endogenous and exogenous ROS in the intestine. In order to explain the role of glutathione redox cycle in celiac patients, we examined the activities of GSH-related antioxidant (AO) enzymes glutathione peroxidase (GPx) and glutathione reductase (GR), as well as the concentration of GSH in small intestinal biopsies and peripheral blood of children affected by the celiac disease. The concentration of lipid hydroperoxides (LOOH) as markers of oxidative damage was measured in the same samples. The results clearly demonstrate a significant malfunction of GSH redox cycle with a concomitant decrease in the capacity to regenerate GSH and detoxify LOOH in celiac patients, even after several years of GFD. The oral administration of GSH and a diet rich in natural antioxidants, as well as appropriate dietary supplements, could be of great benefit to the patients.
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Objective: This article tries to answer the question whether or not there is evidence for a relationship between celiac disease (CD) and ADHD. A review of the current literature on this topic is provided. Method: PUBMED/MEDLINE, Web of Science, and Google scholar were searched to include all published trials on ADHD and CD (no date limitation, both noncontrolled and controlled trials). In addition, the reference list of included studies was screened to find other relevant articles. Results: Eight studies report a possible association between CD and ADHD; however, the results are inconsistent. Only three out of eight studies report a positive correlation between ADHD and CD. Conclusion: Up till now, there is no conclusive evidence for a relationship between ADHD and CD. Therefore, it is not advised to perform routine screening of CD when assessing ADHD (and vice versa) or to implement gluten-free diet as a standard treatment in ADHD.
Chapter
It is becoming increasingly apparent that reactive oxygen species (ROS), including superoxide anion and nitric oxide (NO), exert multiple biological effects over a wide spectrum, from physiological regulatory functions to damaging alterations contributing to the pathogenesis of diverse diseases. This chapter presents an overview of recent progress in the clinical application of oxidative stress biomarkers in pediatric medicine. First, the review briefly presents important physiological and pathophysiological aspects of ROS and antioxidative defense systems. Second, the interrelationship of NO system blockade, endothelial dysfunction, and oxidative stress is discussed. Third, a list of clinically applicable biomarkers is presented, along with pediatric diseases in which enhanced oxidative stress might be involved. Many good biomarkers are readily measurable using enzyme-linked immunosorbent assay. Rapid diagnostic tests for measuring oxidative stress status have been introduced. Fourth, age-related reference normal ranges of oxidative stress biomarkers are presented, including those for urinary acrolein-lysine, 8-hydroxy-2′-deoxyguanosine, nitrite/nitrate, and pentosidine. Finally, recent clinical studies that have evaluated the efficacy of antioxidative intervention for oxidative stress-related diseases are explained. Although not comprehensive, this review provides a brief perspective of current pediatric research which highlights the adverse health effects of ROS actions and therapeutic strategies for ROS-associated diseases.
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The study was carried out to study expression of Toll like receptors 2 (TLR2), natural/inducible Treg and Interferon-γ alongside oxidative stress and understand their significance in pediatric samples. Influence of oxidative stress on Celiac Disease was analysed by evaluating lipid peroxidation, reduced glutathione, Glutathione peroxidase, etc. A comparison was performed among CD patients, CD patients on gluten free diet (GFD), and healthy controls. Peripheral nTregs exhibited a similar pattern of reduced numbers in CD and GFD cases when compared to healthy controls. On the other hand, inducible Tregs were much lower in GFD patients as compared to CD patients. Expression of TLR2 on iTregs was elevated in CD and GFD, however, expression on nTregs was unaltered in all the three groups. The inflammatory cytokine IFN-γ positive Treg cells were found to be elevated in CD as compared to control group. Oxidative stress was elevated in CD as compared to healthy controls while that in GFD samples was lower in comparison to CD. The levels of LPO, activities of enzymes SOD and Catalase were higher in CD and GFD samples when compared to controls. However, enzyme Glutathione peroxidase and reduced glutathione levels declined in both CD and GFD groups as compared to controls. This report highlights the effect of elevated oxidative stress in CD on reduced traffic of iTregs toward periphery. A strong correlation was observed between the cytokine IFN-γ and TLR2 expression in movement of iTregs in CD patients.
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The present study examined the wheat protein gliadin‐induced oxidative and nitrosative stress and its downstream responses in human intestinal HCT‐116 and HT‐29 cells. The beneficial role of dietary phytochemical curcumin and role of multifunctional enzyme Apurinic/aprymidinic endonuclease 1 (APE1) a major player involved in the base excision repair (BER)‐pathway in gliadin intolerant intestinal HCT‐116 and HT‐29 cell lines were evaluated as an in vitro model study. The cultured cells were exposed to gliadin protein, H2O2, and curcumin followed by the assessment of oxidative stress and the consequences were measured using spectrophotometric, PCR, flow cytometer, Western blotting, confocal microscopy, and other methods. Results demonstrate that a 3 h pretreatment of curcumin, followed by the treatment of gliadin protein for 24 h time period protected both the HCT‐116 and HT‐29 cells via: (i) decreasing the ROS/RNS, restoring the mitochondrial transmembrane potential; (ii) re‐establishing the cellular antioxidant defense system (superoxide dismutase, catalase, and GSH); (iii) enhancing the functions of APE1 viz. endonuclease activity and redox activation of transcription factor Nrf‐2, the later binds with the antioxidant response elements (ARE) and activates downstream targets involved in cell survival. The cross‐talk between APE1 and Nrf‐2 was also established using immunofluorescence imaging and co‐immunoprecipitation assays. In conclusion, gliadin protein induces oxidative/nitrosative stress, mitochondrial dysfunction and it damages cellular biomolecules in the intestinal cells. Hence it can be attributed to the tissue damage and disease pathogenesis in wheat intolerance‐associated intestinal diseases. The gliadin‐induced stress and its consequences are significantly reduced by the pretreatment of curcumin via BER‐pathway and ARE‐pathway; which is evident through the interaction between these two essential proteins. Hence suggesting for the intervention of curcumin and other natural dietary phytochemicals‐based disease management and treatment of gliadin intolerance associated intestinal diseases like celiac disease.
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We previously found that exogenous GSH enhances mucosal GSH and promotes lipid hydroperoxide metabolism by rat small intestine (AW, T. Y., and M. W. WIlliams, 1992. Am. J. Physiol. 263:G665-G672). In this study, we have developed an in vivo bile and lymph fistula rat model to test the hypothesis that biliary GSH is an important luminal source of GSH. Peroxidized fish oil was infused into the proximal intestine, and hydroperoxide accumulation in lumen, mucosa, and lymph was determined. Diversion of bile decreased mucosal GSH and increased hydroperoxide accumulation in all fractions. Supplementation with GSH, but not with GSSG, increased tissue GSH and attenuated hydroperoxide accumulation (50-60%), consistent with enhancement of hydroperoxide removal by exogenous GSH. Addition of native bile deficient in GSH, but not cysteine, cystine, or GSSG, decreased luminal and lymph hydroperoxide levels by 20-30%. Amino acid supplementation concurrently attenuated hydroperoxide recoveries in these fractions by 30-40% and increased mucosal GSH by 40%, indicating a role for biliary amino acids in hydroperoxide elimination. The effect of amino acids was abolished by buthionine sulfoximine, confirming their role in GSH biosynthesis. Collectively, the results demonstrate that bile is a rich source of reductant for maintaining mucosal GSH to promote intestinal metabolism of luminal peroxidized lipids.
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Reactive oxygen species contribute to tissue injury in inflammatory bowel disease (IBD). The tripeptide glutathione (GSH) is the most important intracellular antioxidant. To investigate constituent amino acid plasma levels and the GSH redox status in different compartments in IBD with emphasis on intestinal GSH synthesis in Crohn's disease. Precursor amino acid levels were analysed in plasma and intestinal mucosa. Reduced (rGSH) and oxidised glutathione (GSSG) were determined enzymatically in peripheral blood mononuclear cells (PBMC), red blood cells (RBC), muscle, and in non-inflamed and inflamed ileum mucosa. Mucosal enzyme activity of gamma-glutamylcysteine synthetase (gamma GCS) and gamma-glutamyl transferase (gamma GT) was analysed. Blood of healthy subjects and normal mucosa from a bowel segment resected for tumor growth were used as controls. Abnormally low plasma cysteine and cystine levels were associated with inflammation in IBD (p < 10(-4)). Decreased rGSH levels were demonstrated in non-inflamed mucosa (p < 0.01) and inflamed mucosa (p = 10(-6)) in patients with IBD, while GSSG increased with inflammation (p = 0.007) compared with controls. Enzyme activity of gamma GCS was reduced in non-inflamed mucosa (p < 0.01) and, along with gamma GT, in inflamed mucosa (p < 10(-4)). The GSH content was unchanged in PBMC, RBC, and muscle. Decreased activity of key enzymes involved in GSH synthesis accompanied by a decreased availability of cyst(e)ine for GSH synthesis contribute to mucosal GSH deficiency in IBD. As the impaired mucosal antioxidative capacity may further promote oxidative damage, GSH deficiency might be a target for therapeutic intervention in IBD.
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Recently, it has become increasingly apparent that oxidants, in addition to being agents of cytotoxicity, can play an important role in mediating specific cell responses and expression of genes involved in degenerative pathophysiologic states, such as inflammation and cancer. In particular, nuclear transcription factor kappaB (NF-kappaB), a multisubunit transcription factor, has been implicated in the transcriptional up-regulation of inflammatory genes in response to oxidants or changes in cellular oxidation-reduction status. This paper provides an overview of the cellular responses to oxidative stress and oxidation-reduction imbalance and the role of NF-kappaB in these responses and summarizes the current strategies used to study NF-kappaB activation and nuclear translocation, particularly in relation to dietary oxidant-mediated pathophysiology of the intestine.
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Celiac disease is a gluten-sensitive enteropathy, characterized by villous atrophy, which is reversed by gluten withdrawal. A minority of patients with celiac-like enteropathy are resistant to gluten-free diet, so-called refractory sprue, or unclassified sprue. Refractory sprue is a diagnosis of exclusion; all other causes of a celiac-like enteropathy must be eliminated before a diagnosis of refractory sprue can be made. Recent evidence suggests that refractory sprue comprises a heterogenous group of patients with diverse underlying causes. A small proportion of these patients seem to have an adult form of autoimmune enteropathy, characterized by the presence of antienterocyte antibodies. However, a larger group of patients with refractory sprue now seem to have a cryptic intestinal T-cell lymphoma, characterized by the presence of phenotypically abnormal, monoclonal intraepithelial lymphocytes, despite benign cytology. Current therapeutic options include nutritional support and immunosuppressive therapy, but response is variable. The prognosis of refractory sprue may be poor; patients may die of severe malabsorption, or through synchronous or metachronous development of an enteropathy-associated T-cell lymphoma. Based on this recent evidence, patients with refractory sprue should be screened for antienterocyte antibodies and have T-cell receptor and monoclonal antibody studies performed; this could facilitate identification of cases of adult-onset autoimmune enteropathy and those of cryptic T-cell lymphoma. Moreover, early recognition of the malignant nature of the intestinal infiltrate in some cases of refractory sprue could permit the development of novel chemotherapeutic regimens for this condition.
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Celiac disease, induced by dietary gluten, is characterized by mucosal atrophy and local inflammation associated with cell infiltration and activation. Unlike other food proteins, gluten and its proteolytic fragments, besides inducing a specific immune response, were shown to activate components of innate immunity and cause, e.g., direct stimulation of TNF-alpha and IL-10 and a significant rise in NO production by peritoneal macrophages. The identity of the active fragments was established by separating the peptic digest of gliadin by RP-HPLC chromatography. The purest fraction with the highest activity was analyzed by mass spectrometry, and the gliadin peptide sequence was identified as VSFQQPQQQYPSSQ. This peptide (T) and its N- and C-terminally shortened forms (A, B, C and D, E, F) were synthesized. Peptide B (FQQPQQQYPSSQ) elicited the highest TNF-alpha, IL-10, and RANTES secretion and increase in IFN-gamma-primed NO production by mouse macrophages. In contrast, C-terminally shortened peptides had a lower ability to stimulate macrophages than the native form.
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Despite the progress made in understanding the immunological aspects of the pathogenesis of coeliac disease (CD), the early steps that allow gliadin to cross the intestinal barrier are still largely unknown. The aim of this study was to establish whether gliadin activates a zonulin dependent enterocyte intracellular signalling pathway(s) leading to increased intestinal permeability. The effect of gliadin on the enterocyte actin cytoskeleton was studied on rat intestinal epithelial (IEC-6) cell cultures by fluorescence microscopy and spectrofluorimetry. Zonulin concentration was measured on cell culture supernatants by enzyme linked immunosorbent assay. Transepithelial intestinal resistance (Rt) was measured on ex vivo intestinal tissues mounted in Ussing chambers. Incubation of cells with gliadin led to a reversible protein kinase C (PKC) mediated actin polymerisation temporarily coincident with zonulin release. A significant reduction in Rt was observed after gliadin addition on rabbit intestinal mucosa mounted in Ussing chambers. Pretreatment with the zonulin inhibitor FZI/0 abolished the gliadin induced actin polymerisation and Rt reduction but not zonulin release. Gliadin induces zonulin release in intestinal epithelial cells in vitro. Activation of the zonulin pathway by PKC mediated cytoskeleton reorganisation and tight junction opening leads to a rapid increase in intestinal permeability.
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To evaluate the effects of gliadin on the oxidative environment in the "in vivo-like" model of a three-dimensional cell culture system. LoVo cell line (intestinal adenocarcinoma) multicellular spheroids were treated with digested gliadin (with albumin used as a control). Spheroid volumes, cell viability and morphology, lactate dehydrogenase (LDH) release, content of reduced glutathione (GSH) and activity of GSH-related enzymes were examined. The data were statistically analyzed using the Student's t-test. was considered statistically significant. Gliadin reduced cell viability (from 20% to 60%) and led to morphological alterations characterized by apoptotic findings and cytoskeletal injuries. LDH activity increased. The content of GSH reduced (-20% vs controls), and activity of GSH-related enzymes was significantly inhibited. Gliadin treatment induces an imbalance in the antioxidative mechanism of cells cultured by the three-dimensional technique. This alteration may explain the cell damage directly caused by gliadin and the subsequent morphological abnormalities.
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Celiac disease is an autoimmune disease that occurs in genetically predisposed individuals as the result of an immune response to gluten. This immune response occurs in both the lamina propria and the epithelium of the small intestine. There is a close link to HLA DQ2 and DQ8, although these HLA genes account for only 40% of the genetic influence. Environmental factors, such as the amount and timing of gluten administration in infancy, as well as breastfeeding, influence the disease. Serologic screening studies that use sensitive and specific antibody tests have revealed the disease to be common, occurring in approximately 1% of the population. Clinical presentations are diverse and atypical; the majority of patients lack diarrhea. Therapy is a gluten-free diet that requires avoidance of wheat, rye, and barley, although there is potential for other therapies based on our understanding of the pathophysiology of the disease.
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To evaluate the interplay between gliadin and LoVo cells and the direct effect of gliadin on cytoskeletal patterns. We treated LoVo multicellular spheroids with digested bread wheat gliadin in order to investigate their morphology and ultrastructure (by means of light microscopy and scanning electron microscopy), and the effect of gliadin on actin (phalloidin fluorescence) and the tight-junction protein occludin and zonula occluden-1. The treated spheroids had deep holes and surface blebs, whereas the controls were smoothly surfaced ovoids. The incubation of LoVo spheroids with gliadin decreased the number of intracellular actin filaments, impaired and disassembled the integrity of the tight-junction system. Our data obtained from an "in vivo-like" polarized culture system confirm the direct noxious effect of gliadin on the cytoskeleton and tight junctions of epithelial cells. Unlike two-dimensional cell culture systems, the use of multicellular spheroids seems to provide a suitable model for studying cell-cell interactions.
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Oxidative stress has been implicated in the pathogenesis of coeliac disease. The aim of this study was to examine the modulation of the biochemical response to oxidative stress in untreated and treated coeliac disease. The study involved peripheral blood samples from 39 paediatric patients (18 with active, 11 with silent form of the disease, 10 on gluten-free diet [GFD]) and 30 control subjects. The activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR), as well as the concentrations of total glutathione (GSH) and lipid hydroperoxides (LOOH) were determined in patients and controls. In comparison to the controls, a significant increase in SOD activity was found in the active group (P<0.05), while CAT activity was elevated in GFD group (P<0.05). GPx activity was lower in patients than in controls (active and silent, P<0.001; GFD, P<0.01). GSH contents were significantly reduced in all patient groups (P<0.001) as well, while the concentration of LOOH was elevated in active and silent group (P<0.001). The concentration of LOOH correlated negatively with the activity of GPx (r = -0.32, P<0.01) and the concentration of GSH (r = -0.70, P<0.001). A significant positive correlation was found between the concentration of GSH and the activity of GPx (r = 0.57, P<0.001). The results show evidence of increased oxidative stress in untreated coeliac disease. Although LOOH were not significantly elevated in the GFD group, changes in antioxidant enzyme activities and GSH content demonstrate that oxidative stress persists even in treated patients.
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Chapter
The intestine is unique among all fully differentiated organs in that it sits at the interface between the organism and its lumenal environment. In this regard, the intestine is a primary site of nutrient absorption and a critical defense barrier against dietary-derived mutagens, carcinogens, and oxidants. An important class of oxidants present in the human diet is lipid hydroperoxides, which are toxic products of oxidized polyunsaturated fats. Accumulation of peroxidized lipids in the gut lumen can contribute to impairment of mucosal metabolic pathways, enterocyte dysfunction independent of cell injury, and development of gut pathologies, such as cancer. Despite this recognition, and the implication of dietary peroxidized lipids in gut pathologies, we know little of the underlying mechanisms of the genesis of the disease processes or of the pathways of intestinal metabolism and lumenal disposition of dietary lipid hydroperoxides in vivo. This chapter summarizes our current understanding of the determinants of the intestinal absorption and metabolism of peroxidized lipids. In particular, we review the evidence supporting the pivotal role that GSH and NADPH play in the overall mucosal metabolism of toxic lipid hydroperoxides, and how reductant availability can be compromised under certain pathophysiological conditions, such as chronic hypoxia. The discussion is pertinent to understanding dietary lipid peroxides and GSH redox balance in intestinal physiology and pathophysiology and the significance of lumenal GSH in preserving the metabolic integrity of the intestinal epithelium.
Article
Patients with villous atrophy due to coeliac disease have an increased risk of developing small intestinal malignancies. Intestinal glutathione (GSH) and glutathione S-transferases (GST) are involved in the protection against carcinogenesis. The aim of this study was to evaluate GSH content and GST enzyme activity in small intestinal mucosa of untreated coeliacs compared to controls. We evaluated GSH content and GST enzyme activity, including the levels of GST classes α, μ, π, θ in small intestinal biopsies of untreated coeliacs (flat mucosa, Marsh IHC, n=12) compared to normal subjects (n=23). Next, we evaluated GSH and GST's in coeliacs in remission (Marsh 0-1, n=11), coeliacs with persisting villous atrophy while on a gluten-free diet (partial villous atrophy, Marsh IIIA (n=5); subtotal villous atrophy, Marsh IIIB (n=6) and patients with infiltrative/crypt-hyperplastic Marsh II lesions (n=4). Total GST enzyme activity and content of GSTa are markedly suppressed in Marsh IIIC lesions compared to controls (resp. 220±79 vs. 4641189 nmol/mg protein-min (P<0.001) and 2.79±2.46 vs. 6.47±2.29 μg/mg protein (P<0.001). In coeliacs in remission these levels normalized. Total GST enzyme activity and GSTα levels are proportionately lowered according to the degree of mucosal pathology in Marsh II, IIIA and IIIB. (Spearman's σ correlation coefficient for total GST, -0.596, P<0.001; GSTα, -0.620, P<0.001). GSTμ, π and θ and GSH levels are not significantly different in the selected study groups of mucosal pathology compared to controls. Total GST enzyme activity and content of GSTα in small intestinal mucosa are significantly lower in untreated coeliac disease compared to controls. In Marsh II, IIIA and IIIB, GST enzyme activity and GSTα content are proportionally lower according to the degree of mucosal pathology. Normal values are seen in coeliacs in remission. This correlation between coeliac disease and a suppressed GSH/GST detoxification system may explain in part the carcinogenic risk in untreated coeliac disease.
Article
The cytotoxic effects of various prolamin-derived peptides on Caco-2 cells were investigated by measuring the alterations of several parameters at different stages of cell differentiation. The PT digest of bread wheat was active in inhibiting cell proliferation (by about 50%), whereas the other digests from durum wheat, maize and bovine serum albumin (BSA) did not affect the proliferating activity of cells. Compared with the control, colony-forming ability was inhibited by 20% by treatment with cereals that are toxic in coeliac disease (bread wheat, rye, oats and barley). BSA and maize peptides are devoid of this in vitro effect. However, the decrease in alkaline phosphatase activity during Caco-2 cell differentiation was observed in the presence of bread wheat. This could be due to slowing down of the enterocytic differentiation of cells that are susceptible to interaction with toxic peptides. Therefore, long-term cultures of Caco-2 cells constitute a useful in vitro model to assess the ability of cereal proteins to damage the coeliac small intestine.
Article
The influence of dietary peroxides, vitamin E and selenium on glutathione peroxidase (GSH-Px) activity in the gastrointestinal tract of the rat was investigated. Feeding 7% oxidized stripped corn oid (peroxide value 1,000) in a diet adequate in selenium and vitamin E increased the specific activity of GSH-Px in the stomach mucosa. Feeding oxidized oil produced an increase in the wet weight of the intestinal mucosa which was associated with a decrease in the specific activity of the enzyme. Total GSH-Px activity in the intestinal mucosa was unchanged or moderately increased. These changes were unaffected by the presence of vitamin E in the diet. Dietary peroxides had no effect on GSH-Px activity in the plasma or in the perirenal and paraepididymal adipose tissues. Subacute vitamin E deficiency had no consistent effect on the activity of the enzyme in several tissues examined. In rats fed a Se deficient diet glutathione peroxidase activity decreased markedly in most tissues but only slightly in the intestinal mucosa. The moderate decrease in the intestine may be explained by the accessibility of residual dietary Se to the mucosal cells. The role of Se in the detoxification of peroxides in foods and the response of gastrointestinal GSH-Px to dietary peroxides are discussed.
Article
The absorption and lymphatic transport of peroxidized MaxEPA fish oil was studied using the lymph fistula rat to determine the role of mucosal glutathione (GSH) in intestinal metabolism of luminal lipid hydroperoxides. Decreasing intestinal GSH concentrations with buthionine sulfoximine (BSO, 1.15 +/- 0.20 nmol/g), diethyl maleate (DEM, 0.93 +/- 0.26 nmol/g), phorone (1.46 +/- 0.14 nmol/g), or 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU, 1.54 +/- 0.18 nmol/g) compared with control (2.60 +/- 0.38 nmol/g) resulted in higher luminal recovery of the infused lipid hydroperoxide (% of infused dose): BSO (87.8 +/- 4.8%), DEM (86.1 +/- 1.3%), phorone (78.1 +/- 2.1%), and BCNU (71.7 +/- 4.8%) compared with control (52.8 +/- 4.3%). These results suggest that decreased elimination of luminal peroxidized lipids is associated with decreased tissue GSH. Treatment of rats with BSO, DEM, phorone, or BCNU resulted in dramatic increases in appearance of peroxidized lipids in lymph over 6-h lipid infusion (54.7 +/- 3.7, 57.7 +/- 4.6, 46.4 +/- 2.7, and 42.1 +/- 3.9 nmol, respectively) compared with control (20.5 +/- 3.4 nmol). The results are consistent with decreased intracellular metabolism of absorbed hydroperoxides and enhanced transport into lymph under GSH-deficient conditions. The current findings suggest that the function of the mucosal GSH peroxidase/oxidized glutathione (GSSG) reductase system may play an important role in intestinal handling of luminal lipid hydroperoxides. A compromised function of this detoxication mechanism in GSH-deficient states can significantly alter the metabolic fate of dietary peroxidized lipids.
Article
Oxidative biotransformation of xenobiotics and endogenous substances involves glutathione in reduced form as an integral component through two mechanisms: glutathione peroxidase catalysing the reduction of hydrogen peroxide and organic hydroperoxides, and glutathione-S-transferases catalysing the conjugation of oxygenated derivatives with glutathione. We studied glutathione and glutathione-related enzyme activities in haemolysed venous blood samples from 49 healthy children and from 11 children with diabetes mellitus, 10 children with rheumatoid arthritis, seven children with active coeliac disease, and seven children with acute lymphoblastic leukaemia. Among the healthy children glutathione content and the activities of glutathione reductase, glutathione peroxidase, and glutathione-S-transferase were unrelated to sex; age-dependent differences were also minor. The patients with diabetes mellitus had decreased activity of glutathione reductase. The patients with acute lymphoblastic leukaemia had increased activity of both glutathione peroxidase and glutathione-S-transferase, possibly reflecting an adaptive response to free-radicals. The patients with active coeliac disease had control levels of all measured parameters of glutathione-related reactions indicating, since we earlier found decreased activities of glutathione peroxidase in intestinal mucosa of celiacs, that blood may not always reflect tissue-specific changes.
Article
Glutathione (GSH) deficiency produced in mice by giving buthionine sulfoximine leads to severe degeneration of the epithelial cells of the jejunum and colon. This is prevented by giving GSH monoester (orally or i.p.) and also by giving GSH (orally, but not i.p.). The i.p. administration leads to high plasma levels of GSH but does not appreciably increase GSH levels in intestinal mucosa or pancreas. These and previous studies on lens, lung, lymphocytes, liver, heart, and skeletal muscle indicate that there is very little, if any, transport of intact GSH from plasma to these tissues. Cells can use extracellular GSH by a pathway involving its cleavage, uptake of products and intracellular GSH synthesis. Epithelial cells of the gastrointestinal tract may use this pathway and can also take up lumenal GSH (which arises partly from the bile) by a mechanism(s) that may involve transport of dipeptides or of GSH. It is suggested that biliary GSH normally functions in the protection of intestinal mucosa. Administration of GSH may be protective of the gastrointestinal epithelium and may also serve as a good source of cysteine moieties for intracellular GSH synthesis in the gastrointestinal tract and in other tissues. Administration of GSH delivery agents such as GSH esters is more effective than administration of GSH in increasing cellular and mitochondrial levels of GSH.
Article
Oxygen-derived free radical generating capacity of polymorphonuclear cells in 27 patients with ulcerative colitis, 10 with acute bacterial diarrhea and 20 healthy volunteers, was measured by the luminol-dependent chemiluminescence method by stimulation of formyl-methionyl-leucyl-phenylalanine. Oxidative free radical generating capacity of polymorphonuclear cells in patients with active ulcerative colitis was markedly enhanced as compared with control (p less than 0.01), while this enhanced free radical production by the cells was not detected at remission stage. Serial analyses revealed that oxidative free radical production by the cells in patients with ulcerative colitis was markedly enhanced with clinical deterioration of the disease, but it returned to normal level with an improvement of clinical features. These results suggest that the increased oxidative free radical production by polymorphonuclear cells could be related to the pathogenesis or aggravation of ulcerative colitis.
Article
It has been suggested that the molar ratio of octadeca 9,11 dienoic acid to linoleic acid in biological material provides an index of activity along the non-peroxide pathway of a free radical attack on polyunsaturated fatty acids. In 17 adults with cystic fibrosis the 'molar ratio' in nasal epithelial cells--a recognised target of the disease--exceeded that in 20 controls (median 2.09%, range 1.70-3.01% versus 1.56, 0.92-2.23%, p = 0.0002). The difference was also apparent, although less stark, upon analysis of serum in a further 22 CF patients (2.48%, 1.60-5.24%) and 25 controls (1.96%, 0.81-3.90%, p = 0.0348). There was no correlation between the 'molar ratio' and blood white cell count or erythrocyte sedimentation rate, severity of lung or liver disease, indicating that the raised values are a primary feature, rather than reflecting disease severity. Aberrant free radical activity may underlie cellular dysfunction in cystic fibrosis.
Article
Biotransformation of ingested xenobiotics is known to take place in the gastrointestinal mucosa of laboratory animals and adult humans as well as in the liver. We studied the activities of aryl hydrocarbon hydroxylase, epoxide hydrolase, and glutathione peroxidase in 242 peroral small intestinal biopsy samples of children aged eight months to 18 years: 201 with normal histology, 21 with partial villous atrophy, and 20 with severe villous atrophy. All these enzymes were detectable even in the youngest children. The aryl hydrocarbon hydroxylase activity was age dependent, while the other measured enzyme activities were not related to the age of the patients. The aryl hydrocarbon hydroxylase activity was not related to the mucosal histology, but the epoxide hydrolase and glutathione peroxidase activities were diminished in samples with severe villous atrophy as compared with normal mucosa. This suggests that small intestinal mucosa with villous atrophy may produce oxidated, reactive metabolites, but further metabolism into detoxication products is decreased. This may expose persons with mucosal atrophy to possible harmful effects of environmental xenobiotics entering the body even at low doses.
Article
The effect of dietary selenium on the detoxification of dietary peroxides via the glutathione peroxidase system was studied. Rats were fed Torula yeast-based selenium-deficient diets with either 15% fresh tocopherol-stripped corn oil or 15% autoxidized corn oil with a peroxide value of 692 mEq/kg. Rats fed these two diets were further divided into groups that were fed either 0 or 2 ppm selenium as selenomethi- onine. Body weight gain of the two groups of rats fed the autoxidized oil was significantly lower than that of the two groups fed fresh corn oil. The specific activity of glutathione peroxidase in various regions of the gastrointestinal tract, liver, blood, and adipose from selenium-supplemented rats was significantly higher than in these tissues from the non- supplemented rats. In the rats not supplemented with selenium, glutathione peroxidase activity was significantly increased in the group fed autoxidized corn oil; increased activity was not observed in tissues of selenium-supplemented rats fed peroxides. With few exceptions, glutathione reducíaseactivity was the same in tissues from each of the four dietary groups. Significantly more peroxide accumulated in the adipose of the peroxide-fed rats not supplemented with selenium than in the adipose of the other three groups. J. Nutr. 104: 1069-1078, 1974.
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The human diet contains a great variety of natural mutagens and carcinogens, as well as many natural antimutagens and anticarcinogens. Many of these mutagens and carcinogens may act through the generation of oxygen radicals. Oxygen radicals may also play a major role as endogenous initiators of degenerative processes, such as DNA damage and mutation (and promotion), that may be related to cancer, heart disease, and aging. Dietary intake of natural antioxidants could be an important aspect of the body's defense mechanism against these agents. Many antioxidants are being identified as anticarcinogens. Characterizing and optimizing such defense systems may be an important part of a strategy of minimizing cancer and other age-related diseases.
Neoplasms constitute the major complication of coeliac disease, and highgrade T-cell lymphoma of the small intestine (enteropathy-associated T-cell lymphoma) is the most common neoplasm in this category. HLA genotyping indicates that in patients with enteropathy-associated T-cell lymphoma have the coeliac disease associated DQA1∗0501, DQB1∗0201 phenotype, although additional HLA-DR/DQ alleles may represent risk factors for lymphoma development. Molecular biological and immunohistochemical studies have shown that the intestinal mucosa distant from the tumour contains clonal populations of small T cells, often of the same clone as the high-grade T-cell lymphoma. These findings suggest that enteropathyassociated T-cell lymphoma arises in the setting of coeliac disease and evolves from reactive intraepithelial lymphocytes through a low-grade lymphocytic neoplasm to a high-grade tumour, which is usually the cause of the presenting symptoms. Most cases of chronic ulcerative enteropathy (ulcerative jejunitis) are probably part of the same disease process. If the ulceration occurs at a time when the neoplastic T-cells are of a low grade, morphological recognition of tumour cells in the ulcers may be impossible.
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To determine antioxidant vitamin concentrations, lipid peroxidation, and an index of nitric oxide production in patients in the intensive care unit (ICU) with septic shock and relate the findings to the presence of secondary organ failure. A prospective, observational study. A nine-bed ICU in a University teaching hospital. Sixteen consecutive patients with septic shock, defined as: a) clinical evidence of acute infection; b) hypo- or hyperthermia (< 35.6 degrees C or > 38.3 degrees C); c) tachypnea (> 20 breaths/min or being mechanically ventilated); d) tachycardia (> 90 beats/min); e) shock (systolic pressure < 90 mm Hg) or receiving inotropes. Fourteen patients also had secondary organ dysfunction. None. Antioxidant vitamin concentrations were significantly lower in the patients than the reference range obtained from a comparable group of healthy controls. The mean plasma retinol (vitamin A) concentration was 26.5 +/- 19.3 micrograms/dL compared with 73.5 +/- 18.3 micrograms/dL in healthy subjects (p < .01). Additionally, 13 (81%) patients had retinol values below the lower limit of our reference range (< 37.0 micrograms/dL). Tocopherol (vitamin E) plasma concentrations were below the reference range in all patients (< 9.0 mg/L), with a mean value of 3.6 +/- 2.0 mg/L compared with 11.5 +/- 1.3 mg/L in healthy subjects (p < .001). Plasma beta carotene and lycopene concentrations were undetectable (< 15 micrograms/L) in eight (50%) patients, and below our reference range (< 101 micrograms/L and < 154 micrograms/L, respectively) in the remaining patients. In the five patients with three or more dysfunctional secondary organs, plasma thiobarbituric acid-reactive substances were significantly increased (p < .05), suggesting increased lipid peroxidation. Concentrations of thiobarbituric acid-reactive substances correlated negatively with both plasma retinol and plasma tocopherol (r2 = .42, p < .01 and r2 = .48, p < .005, respectively). In the five patients from whom we were able to collect urine, nitrite excretion was increased approximately 400-fold (p < .001). These data indicate decreased antioxidant status in the face of enhanced free radical activity, and suggest potential therapeutic strategies involving antioxidant repletion.
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Free radicals and antioxidants are widely discussed in the clinical and nutritional literature. Antioxidants are needed to prevent the formation and oppose the actions of reactive oxygen and nitrogen species, which are generated in vivo and cause damage to DNA, lipids, proteins, and other biomolecules. Endogenous antioxidant defenses (superoxide dismutases, H2O2-removing enzymes, metal binding proteins) are inadequate to prevent damage completely, so diet-derived antioxidants are important in maintaining health. Many dietary compounds have been suggested to be important antioxidants: The evidence for a key role of vitamins E and C is strong, but that for carotenoids and related plant pigments is weaker. Interest is also growing in the role of plant phenolics, especially flavonoids. Some antioxidants can exert prooxidant effects in vitro, but their physiological relevance is uncertain. Experimental approaches to the optimization of antioxidant nutrient intake are proposed.
Coeliac disease is the life-long intolerance to dietary gluten, usually characterized by severe damage to the small-intestinal mucosa. The widespread use of sensitive diagnostic tools, such as the serum anti-gliadin and the anti-endomysial antibodies, has shown not only that coeliac disease is one of the commonest disorders in Western countries but also that this condition is characterized by a higher degree of clinical variability than previously thought (typical, atypical and silent forms). The existence of a latent-potential coeliac disease and even a gluten-sensitive disease with immunological activation of an otherwise normal small-intestinal mucosa has recently been postulated. An increased prevalence of coeliac disease in a number of other disorders has also been reported in both children and adults. The reasons for such a wide clinical heterogeneity are still poorly understood but are likely to depend on both genetic and environmental factors. Further investigations are required to evaluate the impact of undiagnosed, clinically milder forms of coeliac disease on the well-being of the population.
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In order to study the role of oxidative stress in celiac disease, protein carbonyl groups, thiobarbituric acid-reactive substance and pentosidine were evaluated in the plasma of nine patients with asymptomatic celiac disease and in a control group (n = 25). Plasma alpha-tocopherol, retinol and lipids were determined in the same samples. The levels of markers of oxidative stress derived from both protein (carbonyl groups) and lipids (thiobarbituric acid-reactive substances) were significantly higher in celiac disease patients, whereas lipoproteins and alpha-tocopherol were significantly lower. These data indicate that in celiac disease, even when asymptomatic, a redox imbalance persists; this is probably caused by an absorption deficiency, even if slight. Dietary supplementation with antioxidant molecules may offer some benefit and deserves further investigation.
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It has long been recognized that hydroperoxides are agents of cytotoxicity. However, in recent years, it is increasingly apparent that lipid hydroperoxide may play an important role in mediating cellular and molecular events in degenerative pathophysiological processes that lead to intestinal disorders, such as cancer. Yet, surprisingly, little is known of the intestinal disposition of peroxidized lipids and of the metabolic factors that determine mucosal peroxide elimination. The present paper summarizes the evidence for the pivotal role of reductant (GSH and NADPH) availability in intestinal peroxide detoxication. This information will provide important insights into the relationship between luminal lipid hydroperoxides and intestinal GSH redox homeostasis, and is pertinent to understanding how dietary oxidants like lipid peroxides, can impact intestinal integrity with implications for genesis of gut pathology.