Homocysteine in Schizophrenia: Independent Pathogenetic Factor with Prooxidant Activity or Integral Marker of Other Biochemical Disturbances?

A wide range of studies have demonstrated that hyperhomocysteinemia is associated with the risk of schizophrenia, but currently available assumptions about the direct involvement of homocysteine (Hcy) in the pathogenesis of schizophrenia are hypothetical. It is possible that in vivo Hcy is only a marker of folate metabolism disturbances (which are involved in methylation processes) and is not a pathogenetic factor per se. Only one study has been conducted in which associations of hyperhomocysteinemia with oxidative stress in schizophrenia (oxidative damage to protein and lipids) have been found, and it has been suggested that the oxidative stress may be induced by the elevated Hcy in schizophrenic patients. But the authors did not study the level of reduced glutathione (GSH), as well as possible causes of hyperhomocysteinemia—disturbances of folate metabolism. The aim of this work is to analyze the association of Hcy levels with the following: (1) redox markers in schizophrenia GSH, markers of oxidative damage of proteins and lipids, and the activity of antioxidant enzymes in blood serum; (2) with the level of folate and cobalamin (В12); and (3) with clinical features of schizophrenia measured using the Positive and Negative Syndrome Scale (PANSS). 50 patients with schizophrenia and 36 healthy volunteers, matched by sex and age, were examined. Hcy in patients is higher than in healthy subjects ( p = 0.0041 ), and this may be due to the lower folate level in patients ( p = 0.0072 ). In patients, negative correlation was found between the level of Hcy both with the level of folate ( ρ = − 0.38 , p = 0.0063 ) and with the level of B12 ( ρ = − 0.36 , p = 0.0082 ). At the same time, patients showed higher levels of oxidative modification of serum proteins ( p = 0.00046 ) and lower catalase (CAT) activity ( p = 0.014 ). However, Hcy is not associated with the studied markers of oxidative stress in patients. In the group of patients with an increased level of Hcy (>10 μmol/l, n = 42 ) compared with other patients ( n = 8 ), some negative symptoms (PANSS) were statistically significantly more pronounced: difficulty in abstract thinking (N5, p = 0.019 ), lack of spontaneity and flow in conversation (N6, p = 0.022 ), stereotyped thinking (N7, p = 0.013 ), and motor retardation (G7, p = 0.050 ). Thus, in patients with schizophrenia, hyperhomocysteinemia caused by deficiency of folate and B12 is confirmed and can be considered a marker of disturbances of vitamin metabolism. The redox imbalance is probably not directly related to hyperhomocysteinemia and is hypothetically caused by other pathological processes or by an indirect effect of Hcy, for example, on the enzymatic antioxidant defence system (CAT activity), which requires further exploration. Further study of the role of Hcy in the pathogenesis of schizophrenia is relevant, since the proportion of patients with hyperhomocysteinemia is high and correlations of its level with negative symptoms of schizophrenia are noted.

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Glial cytotoxicity of low doses of cadmium as a model of heavy metal pollution influence on vertebrates

Ecology and Noospherology ◽

10.15421/032001 ◽

2020 ◽

Vol 31 (1) ◽

pp. 3-10

Author(s):

V. S. Nedzvetsky ◽

V. Ya. Gasso ◽

A. M. Hahut ◽

I. A. Hasso

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Programmed Cell Death ◽

Oxidative Damage ◽

Cadmium Chloride ◽

Glioma Cells ◽

Low Doses ◽

Genotoxic Effects ◽

Cadmium Ions

Cadmium is a common transition metal that entails an extremely wide range of toxic effects in humans and animals. The cytotoxicity of cadmium ions and its compounds is due to various genotoxic effects, including both DNA damage and chromosomal aberrations. Some bone diseases, kidney and digestive system diseases are determined as pathologies that are closely associated with cadmium intoxication. In addition, cadmium is included in the list of carcinogens because of its ability to initiate the development of tumors of several forms of cancer under conditions of chronic or acute intoxication. Despite many studies of the effects of cadmium in animal models and cohorts of patients, in which cadmium effects has occurred, its molecular mechanisms of action are not fully understood. The genotoxic effects of cadmium and the induction of programmed cell death have attracted the attention of researchers in the last decade. In recent years, the results obtained for in vivo and in vitro experimental models have shown extremely high cytotoxicity of sublethal concentrations of cadmium and its compounds in various tissues. One of the most studied causes of cadmium cytotoxicity is the development of oxidative stress and associated oxidative damage to macromolecules of lipids, proteins and nucleic acids. Brain cells are most sensitive to oxidative damage and can be a critical target of cadmium cytotoxicity. Thus, oxidative damage caused by cadmium can initiate genotoxicity, programmed cell death and inhibit their viability in the human and animal brains. To test our hypothesis, cadmium cytotoxicity was assessed in vivo in U251 glioma cells through viability determinants and markers of oxidative stress and apoptosis. The result of the cell viability analysis showed the dose-dependent action of cadmium chloride in glioma cells, as well as the generation of oxidative stress (p <0.05). Calculated for 48 hours of exposure, the LD50 was 3.1 μg×ml-1. The rates of apoptotic death of glioma cells also progressively increased depending on the dose of cadmium ions. A high correlation between cadmium concentration and apoptotic response (p <0.01) was found for cells exposed to 3–4 μg×ml-1 cadmium chloride. Moreover, a significant correlation was found between oxidative stress (lipid peroxidation) and induction of apoptosis. The results indicate a strong relationship between the generation of oxidative damage by macromolecules and the initiation of programmed cell death in glial cells under conditions of low doses of cadmium chloride. The presented results show that cadmium ions can induce oxidative damage in brain cells and inhibit their viability through the induction of programmed death. Such effects of cadmium intoxication can be considered as a model of the impact of heavy metal pollution on vertebrates.

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Mn Inhibits GSH Synthesis via Downregulation of Neuronal EAAC1 and Astrocytic xCT to Cause Oxidative Damage in the Striatum of Mice

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/4235695 ◽

2018 ◽

Vol 2018 ◽

pp. 1-15 ◽

Cited By ~ 7

Author(s):

Xinxin Yang ◽

Haibo Yang ◽

Fengdi Wu ◽

Zhipeng Qi ◽

Jiashuo Li ◽

...

Keyword(s):

Oxidative Stress ◽

Oxidative Damage ◽

Dependent Manner ◽

Protein Levels ◽

Key Factor ◽

Protein Sulfhydryl ◽

Mrna And Protein Expression ◽

The Brain

Excessive manganese (Mn) can accumulate in the striatum of the brain following overexposure. Oxidative stress is a well-recognized mechanism in Mn-induced neurotoxicity. It has been proven that glutathione (GSH) depletion is a key factor in oxidative damage during Mn exposure. However, no study has focused on the dysfunction of GSH synthesis-induced oxidative stress in the brain during Mn exposure. The objective of the present study was to explore the mechanism of Mn disruption of GSH synthesis via EAAC1 and xCT in vitro and in vivo. Primary neurons and astrocytes were cultured and treated with different doses of Mn to observe the state of cells and levels of GSH and reactive oxygen species (ROS) and measure mRNA and protein expression of EAAC1 and xCT. Mice were randomly divided into seven groups, which received saline, 12.5, 25, and 50 mg/kg MnCl2, 500 mg/kg AAH (EAAC1 inhibitor) + 50 mg/kg MnCl2, 75 mg/kg SSZ (xCT inhibitor) + 50 mg/kg MnCl2, and 100 mg/kg NAC (GSH rescuer) + 50 mg/kg MnCl2 once daily for two weeks. Then, levels of EAAC1, xCT, ROS, GSH, malondialdehyde (MDA), protein sulfhydryl, carbonyl, 8-hydroxy-2-deoxyguanosine (8-OHdG), and morphological and ultrastructural features in the striatum of mice were measured. Mn reduced protein levels, mRNA expression, and immunofluorescence intensity of EAAC1 and xCT. Mn also decreased the level of GSH, sulfhydryl, and increased ROS, MDA, 8-OHdG, and carbonyl in a dose-dependent manner. Injury-related pathological and ultrastructure changes in the striatum of mice were significantly present. In conclusion, excessive exposure to Mn disrupts GSH synthesis through inhibition of EAAC1 and xCT to trigger oxidative damage in the striatum.

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Oxidative stress and lipid peroxidation with exposure of emerging disinfection byproduct 2,6-dichlorobenzoquinone in mice

10.21203/rs.3.rs-672041/v1 ◽

2021 ◽

Author(s):

Shi-Wei Li ◽

Ming-Hui Chang ◽

Wen-Jun Zhao ◽

He-Lian Li ◽

Hong-Jie Sun ◽

...

Keyword(s):

Oxidative Stress ◽

Lipid Peroxidation ◽

Oxidative Damage ◽

Heme Oxygenase 1 ◽

Quinone Oxidoreductase ◽

Disinfection Byproduct ◽

Adult Mice ◽

Stress Damage ◽

The Impact

Abstract 2,6-dichlorobenzoquinone (2,6-DCBQ) is an emerging disinfection byproduct frequently detected in drinking water. Previous studies have indicated that 2,6-DCBQ causes oxidative stress damage in some live systems, but this has yet to be tested in vivo in mammals. In the present study, adult mice were exposed to 2,6-DCBQ for 30 d via gavage at 0 ~ 100 mg kg− 1 with the responses of antioxidant enzymes (superoxide dismutase [SOD] and catalase [CAT]), key oxidative stress response genes (Heme oxygenase-1 [HO-1], NADPH quinone oxidoreductase 1 [NQO1] and glutamate-L-cysteine ligase catalytic subunit [GCLC]) in the Nrf2-keap1 pathway, and lipid peroxidation (malonaldehyde, MDA) as an indicator of oxidative damage being measured. Our results indicated that 2,6-DCBQ decreased the activities of SOD and CAT, repressed transcription of key genes in the Nrf2-keap1 pathway, and caused measurable oxidative damage. These results reveal the impact of 2,6-DCBQ in a model mammalian system and are key to understanding the potential impacts of 2,6-DCBQ in humans.

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Protein-L-isoaspartate O-methyltransferase is required for in vivo control of oxidative damage in red blood cells

Haematologica ◽

10.3324/haematol.2020.266676 ◽

2020 ◽

pp. 0-0

Author(s):

Angelo D’Alessandro ◽

Ariel Hay ◽

Monika Dzieciatkowska ◽

Benjamin C. Brown ◽

Evan J Morrison ◽

...

Keyword(s):

Oxidative Stress ◽

Reactive Oxygen Species ◽

Oxidative Damage ◽

Red Blood Cells ◽

Blood Cells ◽

Reactive Oxygen ◽

Metabolic Reprogramming ◽

Oxygen Species ◽

Common Amino Acid

Red blood cells have the special challenge of a large amount of reactive oxygen species (from their substantial iron load and Fenton reactions) combined with the inability to synthesize new gene products. Considerable progress has been made in elucidating the multiple pathways by which red blood cells neutralize reactive oxygen species via NADPH driven redox reactions. However, far less is known about how red blood cells repair the inevitable damage that does occur when reactive oxygen species break through anti-oxidant defenses. When structural and functional proteins become oxidized, the only remedy available to red blood cells is direct repair of the damaged molecules, as red blood cells cannot synthesize new proteins. Amongst the most common amino acid targets of oxidative damage is the conversion of asparagine and aspartate side chains into a succinimidyl group through deamidation or dehydration, respectively. Red blood cells express an L-Isoaspartyl methyltransferase (PIMT, gene name PCMT1) that can convert succinimidyl groups back to an aspartate. Herein, we report that deletion of PCMT1 significantly alters red blood cell metabolism in a healthy state, but does not impair the circulatory lifespan of red blood cells. Through a combination of genetic ablation, bone marrow transplantation and oxidant stimulation with phenylhydrazine in vivo or blood storage ex vivo, we use omics approaches to show that, when animals are exposed to oxidative stress, red blood cells from PCMT1 knockout undergo significant metabolic reprogramming and increased hemolysis. This is the first report of an essential role of PCMT1 for normal RBC circulation during oxidative stress.

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Nrf2 mediated ER-phagy protects against oxidative damage in intervertebral disc degeneration

10.1101/2021.11.21.469451 ◽

2021 ◽

Author(s):

zhen lin ◽

libin ni ◽

cheng teng ◽

zhao zhang ◽

xinlei lu ◽

...

Keyword(s):

Oxidative Stress ◽

Intervertebral Disc ◽

Oxidative Damage ◽

Er Stress ◽

Disc Degeneration ◽

Intervertebral Disc Degeneration ◽

Cellular Damage ◽

Nucleus Pulposus Cells

Intervertebral disc degeneration (IDD) increases the risk of low back pain (LBP). Oxidative stress may induce cellular damage and contribute to various diseases including IDD. Endoplasmic reticulum autophagy (ER-phagy) is a specific type of autophagy, its role in oxidative stress induced damage as well as in IDD is unknown. This study explores the role of ER-phagy in oxidative damage in intervertebral disc nucleus pulposus cells (NPCs), as well as the Nrf2/FAM134B axis in ER-phagy regulation and IDD therapy. We found ER-phagy was decreased in NPCs during oxidative stress; while FAM134B may promote ER-phagy and alleviate oxidative stress induced ER-stress and apoptosis. In addition, the nuclear transcription factor Nrf2 may promote the expression of FAM134B as well as ER-phagy, and suppress ER-stress and apoptosis in NPCs. Furthermore, overexpression of FAM134B and Nrf2 could effectively attenuate the progression of IDD in rats in vivo. These results suggest Nrf2/FAM134B mediated ER-phagy may combat oxidative damage in cells; meanwhile, ER-phagy as well as Nrf2 could be potential therapeutic targets for IDD.

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Restoration of Autophagic Flux Rescues Oxidative Damage and Mitochondrial Dysfunction to Protect against Intervertebral Disc Degeneration

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/7810320 ◽

2019 ◽

Vol 2019 ◽

pp. 1-27 ◽

Cited By ~ 5

Author(s):

Liang Kang ◽

Qian Xiang ◽

Shengfeng Zhan ◽

Yu Song ◽

Kun Wang ◽

...

Keyword(s):

Oxidative Stress ◽

Intervertebral Disc ◽

Oxidative Damage ◽

Mitochondrial Dysfunction ◽

Disc Degeneration ◽

Cell Apoptosis ◽

Intervertebral Disc Degeneration ◽

Autophagic Flux ◽

Ecm Degradation

Oxidative stress-induced mitochondrial dysfunction and nucleus pulposus (NP) cell apoptosis play crucial roles in the development of intervertebral disc degeneration (IDD). Increasing studies have shown that interventions targeting impaired autophagic flux can maintain cellular homeostasis by relieving oxidative damage. Here, we investigated the effect of curcumin (CUR), a known autophagy activator, on IDD in vitro and in vivo. CUR suppressed tert-butyl hydroperoxide- (TBHP-) induced oxidative stress and mitochondrial dysfunction and thereby inhibited human NP cell apoptosis, senescence, and ECM degradation. CUR treatment induced autophagy and enhanced autophagic flux in an AMPK/mTOR/ULK1-dependent manner. Notably, CUR alleviated TBHP-induced interruption of autophagosome-lysosome fusion and impairment of lysosomal function and thus contributed to the restoration of blocked autophagic clearance. These protective effects of CUR in TBHP-stimulated human NP cells resembled the effects produced by the autophagy inducer rapamycin, but the effects were partially eliminated by 3-methyladenine- and compound C-mediated inhibition of autophagy initiation or chloroquine-mediated obstruction of autophagic flux. Lastly, CUR also exerted a protective effect against puncture-induced IDD progression in vivo. Our results showed that suppression of excessive ROS production and mitochondrial dysfunction through enhancement of autophagy coupled with restoration of autophagic flux ameliorated TBHP-induced human NP cell apoptosis, senescence, and ECM degradation. Thus, maintenance of the proper functioning of autophagy represents a promising therapeutic strategy for IDD, and CUR might serve as an effective therapeutic agent for IDD.

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Antioxidant Activity In vivo and Ex Vivo of Tautomeric Pair of Polyprenylated Benzophenone - Garcinielliptone FC (Platonia insignis Mart Seeds)

Current Bioactive Compounds ◽

10.2174/1573407214666180914120726 ◽

2020 ◽

Vol 16 (3) ◽

pp. 284-293

Author(s):

George Laylson da Silva Oliveira ◽

Maria das Dores Alves de Oliveira ◽

Maria da Conceição Oliveira Prado ◽

Alexandre de Barros Falcão Ferraz ◽

José Carlos Correia Lima da Silva ◽

...

Keyword(s):

Oxidative Stress ◽

Lipid Peroxidation ◽

Antioxidant Activity ◽

Oxidative Damage ◽

Ex Vivo ◽

Redox Balance ◽

Oxidative Stress Biomarkers ◽

Iron Citrate

Background: Garcinielliptone FC corresponds to a polyprenylated acylphloroglucinol having a benzophenonic core (diphenylmethanone) substituted with isoprenyl(s) group(s) (3-methyl-2-butenyl) and 2-isopropenyl-hex-5-enyl. Objective: The present work evaluated the antioxidant activity of garcinielliptone FC (GFC) in vitro against non-biological radicals [2,2-diphenyl-1-picrylhydrazyl (DPPH•) and 2,2'-azinobis-3- ethylbenzothiazoline-6-sulfonic acid (ABTS•+)] and ex vivo against oxidative damage induced by AAPH (2,2'-azobis-2-methylpropionamidine dihydrochloride) and iron/citrate ion in erythrocytes and mitochondria, respectively. Methods: In addition to the protective effect, the main biochemical indexes of oxidative stress, such as lipid peroxidation through the formation of Thiobarbituric Acid Reactive Substances (TBARS), Superoxide Dismutase (SOD), Catalase (CAT) activity and reduced glutathione (GSH) levels. Results: According to the results obtained in erythrocytes, the antioxidant results at concentrations of 0.1, 0.3, 0.7, 1.5 and 3.0 mM were 26.34 ± 0.68, 43.39 ± 2.17, 62.27 ± 2.17, 86.69 ± 0.47 and 92.89 ± 0.45%, respectively, where GFC reduced the rate of oxidative hemolysis when compared to AAPH (p<0.05). The antioxidant activity observed in erythrocytes was also seen in mitochondria in which GFC reduced mitochondrial swelling by increasing the absorbance when compared to iron/citrate ion complex (p<0.05). In both biological models, GFC had an antioxidant effect on erythrocyte and mitochondrial redox balance when analyzing oxidative stress biomarkers, such as reduction of lipid peroxidation and inhibition of depletion in the activity of SOD, CAT and GSH levels. Conclusion: In conclusion, GFC had in vitro and ex vivo antioxidant activity against oxidative damage induced in erythrocytes and mitochondria acting on the erythrocytic and mitochondrial redox balance.

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Experimental Guidelines for Studies Designed to Investigate the Impact of Antioxidant Supplementation on Exercise Performance

International Journal of Sport Nutrition and Exercise Metabolism ◽

10.1123/ijsnem.20.1.2 ◽

2010 ◽

Vol 20 (1) ◽

pp. 2-14 ◽

Cited By ~ 41

Author(s):

Scott K. Powers ◽

Ashley J. Smuder ◽

Andreas N. Kavazis ◽

Matthew B. Hudson

Keyword(s):

Oxidative Stress ◽

Oxidative Damage ◽

Antioxidant Capacity ◽

Exercise Performance ◽

Human Performance ◽

Experimental Situation ◽

Redox Balance ◽

Experimental Conditions ◽

Wide Range ◽

The Impact

Research interest in the effects of antioxidants on exercise-induced oxidative stress and human performance continues to grow as new scientists enter this field. Consequently, there is a need to establish an acceptable set of criteria for monitoring antioxidant capacity and oxidative damage in tissues. Numerous reports have described a wide range of assays to detect both antioxidant capacity and oxidative damage to biomolecules, but many techniques are not appropriate in all experimental conditions. Here, the authors present guidelines for selecting and interpreting methods that can be used by scientists to investigate the impact of antioxidants on both exercise performance and the redox status of tissues. Moreover, these guidelines will be useful for reviewers who are assigned the task of evaluating studies on this topic. The set of guidelines contained in this report is not designed to be a strict set of rules, because often the appropriate procedures depend on the question being addressed and the experimental model. Furthermore, because no individual assay is guaranteed to be the most appropriate in every experimental situation, the authors strongly recommend using multiple assays to verify a change in biomarkers of oxidative stress or redox balance.

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4-PHENYLBUTYRATE: MOLECULAR MECHANISMS AND AGING INTERVENTION POTENTIAL

Innovation in Aging ◽

10.1093/geroni/igz038.379 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

pp. S101-S101

Author(s):

Michael R Bene ◽

Kevin Thyne ◽

Jonathan Dorigatti ◽

Adam B Salmon

Keyword(s):

Oxidative Stress ◽

Stress Response ◽

Molecular Mechanisms ◽

Oxidative Stress Response ◽

Chemical Chaperone ◽

Mouse Muscle ◽

Age Related ◽

Primary Mouse ◽

Wide Range

Abstract 4-Phenylbutyrate (PBA) is a FDA approved drug for treating patients with urea cycle disorders. Additionally, PBA acts upon several pathways thought of as important modifiers of aging including: histone deacetylation, proteostasis as a chemical chaperone, and stress resistance by regulating expression of oxidative stress response proteins. PBA has also been shown to extend lifespan and improve markers of age-related health in Drosophila. Due to its wide range of effects PBA has been investigated for use in numerous age-related disorders including neurodegenerative and cardiovascular diseases. To better understand the effects of PBA on the molecular level, we used both in cellulo and in vivo studies. Treatment of primary mouse fibroblasts, C2C12 mouse muscle cells, and NCTC 1469 mouse liver cells with PBA demonstrated differential responses among cell lines to upregulation of oxidative stress response and histone acetylation. Specifically, upregulation of the oxidative stress response protein DJ-1 by PBA was found to have a corresponding dose response curve to histone H3 acetylation in primary fibroblasts. To study effects of PBA in vivo, four cohorts of HET3 mice were treated with PBA at different doses in drinking water for 4 weeks. PBA was well tolerated and led to different effects on body composition dependent on the sex of mice. We are currently investigating the molecular effects of PBA treatment in multiple tissues samples from these mice. The potential of PBA to alter many fundamental pathways, and specifically those related to stress responses, make it an attractive prospect for treatment of many age-related disorders.

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High levels of oxidative stress in rats infected with Blastocystis hominis

Parasitology ◽

10.1017/s0031182009991351 ◽

2009 ◽

Vol 137 (4) ◽

pp. 605-611 ◽

Cited By ~ 20

Author(s):

S. CHANDRAMATHI ◽

K. SURESH ◽

S. SHUBA ◽

A. MAHMOOD ◽

U. R. KUPPUSAMY

Keyword(s):

Oxidative Stress ◽

Oxidative Damage ◽

Intestinal Parasites ◽

Lipid Hydroperoxide ◽

Parasitic Infections ◽

Blastocystis Hominis ◽

Oxidative Stress Biomarkers ◽

Antioxidant Power ◽

Damage Level

SUMMARYObjective: Numerous studies have revealed the presence of oxidative stress in parasitic infections. However, such studies were lacking in the Malaysian population. Previously, we have provided evidence that oxidative stress is elevated in Malaysians infected with intestinal parasites. Stool examinations revealed that about 47·5% of them were infected with the polymorphic protozoa, Blastocystis hominis. However, they were found to have mixed infection with other intestinal parasites. Methodology: Therefore, in order to investigate the role of B. hominis alone in affecting oxidative stress status, here we compared the levels of oxidative stress biomarkers in urine and blood samples between uninfected and B. hominis-infected rats. Results: Infected rats exhibited elevated levels of oxidative indices namely advanced oxidative protein products (AOPP), hydrogen peroxide (H2O2) and lipid hydroperoxide (LHP) indicating that their overall oxidative damage level was higher. Ferric reducing antioxidant power (FRAP) was elevated at the initial stage of infection but decreased significantly during the last week of study duration suggesting that the antioxidant status of the host may be overwhelmed by oxidative damage. Conclusion: To date, this is the first comprehensive in vivo study to provide evidence for Blastocystis infection to correlate with significant oxidative burst leading to oxidative stress.

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