Publications by authors named "Robert Pazdro"

19 Publications

  • Page 1 of 1

The effects of different doses of curcumin compound on growth performance, antioxidant status, and gut health of broiler chickens challenged with Eimeria species.

Poult Sci 2020 Nov 3;99(11):5936-5945. Epub 2020 Sep 3.

Department of Poultry Science, University of Georgia, Athens, GA, USA. Electronic address:

Supplementation of broiler diets with feed additives such as chemotherapeutic drugs and antibiotics has side effects, meat residues, and antibiotics resistance complications. Plant-derived natural compounds could be safe and easy substitutes for chemical additives. One of the natural compounds is curcumin, the extract from herbal plant Curcuma longa, known for its antioxidant and antimicrobial properties which may be effective in reducing coccidia infection in poultry. The objective of this study was to evaluate the effects of curcumin on Eimeria challenged (C) and nonchallenged (NC) Cobb 500 broilers. A total of 360 12-day-old male chicks were housed in 36 cages in a completely randomized design with 6 replicates per treatment of 10 birds each cage. The six corn-soybean meal-based treatment diets were fed from day 12 to 20 to C and NC birds in 3-by-two factorial arrangement: nonchallenged control (NCC), NC + 100 mg/kg curcumin, NC + 200 mg/kg curcumin, challenged control (CC), C + 100 mg/kg curcumin, and C + 200 mg/kg curcumin. Broilers in C groups were inoculated orally with 50,000 oocysts of Eimeria maxima, 50,000 oocysts of Eimeria tenella, and 250,000 oocysts of Eimeria acervulina on day 14. The intestinal permeability (day 19), growth performance parameters, and intestinal lesion scoring were measured and recorded on day 20. The means were subjected to two-way ANOVA, and main factors effect and their interactions were considered. The growth performance and permeability were higher (P < 0.001) in the NC and C groups, respectively. However, no interaction was observed between curcumin dose and cocci challenge on both of these parameters. Results from lesion scores and oocyst shedding showed reduction (P < 0.050) in birds fed C + 200 mg/kg curcumin compared with those fed C + 100 mg/kg curcumin or CC. Curcumin treatment showed higher production of GSH (P = 0.002) and total glutathione (GSH+2GSSG) (P = 0.002) but lower GSH/GSSG ratio (P < 0.001) than the NCC group. Curcumin exhibited some positive responses on antioxidant capacity, lesion score, and oocyst shedding in the present study, suggesting that curcumin alone or a combination with other feed additives could be a dietary strategy to improve gut health in broilers.
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http://dx.doi.org/10.1016/j.psj.2020.08.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7647913PMC
November 2020

The effects of L-Arginine supplementation on growth performance and intestinal health of broiler chickens challenged with Eimeria spp.

Poult Sci 2020 Nov 26;99(11):5844-5857. Epub 2020 Aug 26.

Department of Poultry Science, University of Georgia, Athens, GA, 30602, USA. Electronic address:

This study evaluated the effects of varying levels of L-arginine (Arg) on performance and intestinal health of broilers challenged with Eimeria. Cobb 500 male chicks (n = 720) were randomly distributed in a 5 × 2 factorial arrangement (6 replicates/12 birds). The main factors were Arg levels (1.04, 1.14, 1.24, 1.34, 1.44%) and challenge or non-challenge with Eimeria. At day 12, in the challenge group, each bird received orally 12,500 Eimeria maxima, 12,500 Eimeria tenella, and 62,500 Eimeria acervulina sporulated oocysts. At 5 d postinfection (dpi), intestinal permeability was measured. At 6 and 14 dpi, performance, intestinal histomorphology, nutrient digestibility, tight junction protein (TJP) gene expression, and antioxidant markers were evaluated. Few interactions were found, and when significant, the supplementation of Arg did not counteract the negative effects of Eimeria challenge. Challenge, regardless of Arg level, increased intestinal permeability, although the expression of Claudin-1, a TJP, was upregulated. At 6 dpi, the antioxidant system was impaired by the challenge. Moreover, growth performance, intestinal histomorphology, and nutrient digestibility were negatively affected by challenge at 6 and 14 dpi. Regardless of challenge, from 0 to 14 dpi, birds fed 1.44% showed higher weight gain than 1.04% of Arg, and birds fed 1.34% showed lower feed conversion than 1.04% of Arg. At 5 dpi, intestinal permeability was improved in birds fed 1.34% than 1.04% of Arg. Moreover, 1.34% of Arg upregulated the expression of the TJP Zonula occludens-1 (ZO-1) as compared with 1.24 and 1.44% of Arg at 6 dpi. At 14 dpi, 1.44% of Arg upregulated the expression of ZO-1 and ZO-2 compared with 1.24 and 1.34% of Arg. The nutrient digestibility was quadratically influenced by Arg, whereas the antioxidant markers were unaffected. Thus, the challenge with Eimeria had a negative impact on growth and intestinal health. The dietary supplementation of levels ranging from 1.24 to 1.44% of Arg showed promising results, improving overall growth, intestinal integrity, and morphology in broilers subjected or not to Eimeria challenge.
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http://dx.doi.org/10.1016/j.psj.2020.08.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7647855PMC
November 2020

Form of Vitamin E Supplementation Affects Oxidative and Inflammatory Response in Exercising Horses.

J Equine Vet Sci 2020 08 29;91:103103. Epub 2020 Apr 29.

Department of Animal and Dairy Science, University of Georgia, Athens, GA.

Vitamin E is an essential antioxidant that may benefit athletes by reducing oxidative stress and influencing cytokine expression. Supplements can be derived from natural or manufactured synthetic sources. This study aimed to determine (1) if supplemental vitamin E is beneficial to exercising horses and (2) if there is a benefit of natural versus synthetic vitamin E. After 2 weeks on the control diet (vitamin E-deficient grain and hay), 18 horses were divided into three groups and fed the control diet plus (1) 1000 IU/d synthetic α-tocopherol (SYN-L), (2) 4000 IU/d synthetic α-tocopherol (SYN-H), or (3) 4000 IU/d RRR-α-tocopherol (natural source [NAT]). On day 7, horses began a 6-week training protocol, with standard exercise tests (SETs) performed before and after the 6-week protocol. Venous blood samples were collected on days 0, 7, 29, and 49. Horses fed NAT had higher α-tocopherol (P < .05) at post-SET1 through post-SET2. Plasma thiobarbituric acid-reactive substance levels were lower in NAT versus SYN-L horses after SET2 (P = .02). Serum aspartate aminotransferase was lower after exercise in NAT horses versus SYN-L and SYN-H (P = .02), and less reduction in stride duration was seen after exercise in NAT as compared with SYN-L and SYN-H (P = .02). Gene expression of tumor necrosis factor α was lower in NAT compared with SYN-H (P = .01) but not SYN-L. In conclusion, feeding higher levels of natural vitamin E source resulted in higher serum α-tocopherol levels as well as some improvement in oxidative and inflammatory response and improved functional outcomes in response to an exercise test.
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http://dx.doi.org/10.1016/j.jevs.2020.103103DOI Listing
August 2020

Effects of Inorganic Zn and Cu Supplementation on Gut Health in Broiler Chickens Challenged With spp.

Front Vet Sci 2020 28;7:230. Epub 2020 Apr 28.

Department of Poultry Science, University of Georgia (UGA), Athens, GA, United States.

An experiment was conducted to evaluate the effect of different levels of inorganic copper and zinc on growth performance, intestinal permeability, intestinal lesion scores, oocyst shedding, antioxidant properties and bone quality in broilers challenged with spp. A total of 360 d-old male Cobb broiler chickens were housed in floor cages for 12 days at the Poultry Research Center. At 12 days of age, birds were placed in grower Petersime batteries and distributed in a completely randomized design with 10 birds per cage, six replicates per treatment, and six treatments. There were six corn-soybean meal-based dietary treatments: non-challenged control (NC), challenged control (CC), 100 ppm Cu (100 Cu), 150 ppm Cu (150 Cu), 80 ppm Zn (80 Zn), and 100 ppm Zn (100 Zn). Broilers received the treatment diets for 9 days (12-20d). Birds, except NC, were challenged with (50,000 oocysts/bird), (50,000 oocysts/bird), and (250,000 oocysts/bird) on 14d. On 20d, the growth performance was recorded, and one bird/cage was used for analysis of intestinal permeability, antioxidant properties and bone quality. Lesion score was recorded at 20 days of age in eight birds/cage. The means were subjected to ANOVA and, when significant, compared by Duncan's test. Intestinal permeability was significantly improved when birds received the 100 Zn diet ( < 0.05). In addition, lesion scores on duodenum were reduced when broilers received diets 150 Cu as compared to CC diet ( < 0.05). However, growth performance was not positively influenced by inclusion of inorganic minerals as compared to the NC diet. Furthermore, activity of superoxide dismutase and bone quality were not affected, whereas glutathione status was improved with mineral supplementation in all groups. This study showed that Cu and Zn supplementation improves intestinal integrity during the spp. infection, suggesting that Cu and Zn supplementation would be a potential strategy to reduce detrimental effects of infection in broilers.
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http://dx.doi.org/10.3389/fvets.2020.00230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212353PMC
April 2020

Impact of Supplementary Amino Acids, Micronutrients, and Overall Diet on Glutathione Homeostasis.

Nutrients 2019 May 11;11(5). Epub 2019 May 11.

Department of Foods and Nutrition, University of Georgia, Athens, GA 30602, USA.

Glutathione (GSH) is a critical endogenous antioxidant found in all eukaryotic cells. Higher GSH concentrations protect against cellular damage, tissue degeneration, and disease progression in various models, so there is considerable interest in developing interventions that augment GSH biosynthesis. Oral GSH supplementation is not the most efficient option due to the enzymatic degradation of ingested GSH within the intestine by γ-glutamyltransferase, but supplementation of its component amino acids-cysteine, glycine, and glutamate-enhances tissue GSH synthesis. Furthermore, supplementation with some non-precursor amino acids and micronutrients appears to influence the redox status of GSH and related antioxidants, such as vitamins C and E, lowering systemic oxidative stress and slowing the rate of tissue deterioration. In this review, the effects of oral supplementation of amino acids and micronutrients on GSH metabolism are evaluated. And since specific dietary patterns and diets are being prescribed as first-line therapeutics for conditions such as hypertension and diabetes, the impact of overall diets on GSH homeostasis is also assessed.
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http://dx.doi.org/10.3390/nu11051056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6566166PMC
May 2019

Heritability of the aged glutathione phenotype is dependent on tissue of origin.

Mamm Genome 2018 10 14;29(9-10):619-631. Epub 2018 Jul 14.

Department of Foods and Nutrition, University of Georgia, 305 Sanford Drive, Athens, GA, 30602, USA.

Glutathione is a ubiquitous antioxidant that protects cells against reactive oxygen species and other chemical stressors. Despite its functional importance, the impact of genetics on the glutathione system has yet to be fully appreciated. Here, we investigated the heritability of glutathione levels and redox status in a disease-relevant condition: advanced age. We assembled a panel of 18-21-month-old mice representing 19 inbred strains and quantified the levels of reduced and oxidized glutathione, and their sums and ratios, in liver, kidney, heart, pancreas, cerebral cortex, and striatum. Heritability values were calculated for each phenotype and the results varied by tissue of origin. Cardiac glutathione phenotypes exhibited the highest heritabilities (G = 0.44-0.67), while striatal glutathione was least heritable (G = 0.11-0.29). Statistical relationships between tissues were evaluated, and the emergence of significant correlations suggested that despite tissue-specific heritabilities, at least some shared regulatory mechanisms may exist. Overall, these data highlight another mechanism by which genetic background determines antioxidant protection and stress resistance.
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http://dx.doi.org/10.1007/s00335-018-9759-2DOI Listing
October 2018

A high-fat diet differentially regulates glutathione phenotypes in the obesity-prone mouse strains DBA/2J, C57BL/6J, and AKR/J.

Nutr Res 2016 Dec 17;36(12):1316-1324. Epub 2016 Oct 17.

Department of Foods and Nutrition, University of Georgia, 305 Sanford Dr, Athens, GA 30602, USA. Electronic address:

The ubiquitous tripeptide glutathione (GSH) is a critical component of the endogenous antioxidant defense system. Tissue GSH concentrations and redox status (GSH/GSSG) are genetically controlled, but it is unclear whether interactions between genetic background and diet affect GSH homeostasis. The current study tested the hypothesis that a high-fat diet regulates GSH homeostasis in a manner dependent on genetic background. At 4 months of age, female mice representing 3 obesity-prone inbred strains-C57BL/6J (B6), DBA/2J (D2), and AKR/J (AKR)-were randomly assigned to consume a control (10% energy from fat) or high-fat (62% energy from fat) diet for 10 weeks (n=5/diet per strain). Tissue GSH levels, GSSG levels, and GSH/GSSG were quantified, and hepatic expression of GSH-related enzymes was evaluated by quantitative reverse transcription polymerase chain reaction. The high-fat diet caused a decrease in hepatic GSH/GSSG in D2 mice. In contrast, B6 mice exhibited a decrease in GSSG levels in the liver and kidney, as well as a resultant increase in renal GSH/GSSG. AKR mice also exhibited increased renal GSH/GSSG on a high-fat diet. Finally, the high-fat diet induced a unique gene expression response in D2 mice compared with B6 and AKR. The D2 response was characterized by up-regulation of glutamate-cysteine ligase modifier subunit and down-regulation of glutathione reductase, whereas the B6 and AKR responses were characterized by up-regulation of glutathione peroxidase 1. Two-way analysis of variance analyses confirmed several diet-strain interactions within the GSH system, and linear regression models highlighted relationships between body mass and GSH outcomes as well. Overall, our data indicate that dietary fat regulates the GSH system in a strain-dependent manner.
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http://dx.doi.org/10.1016/j.nutres.2016.10.004DOI Listing
December 2016

The anthocyanin cyanidin-3-O-β-glucoside modulates murine glutathione homeostasis in a manner dependent on genetic background.

Redox Biol 2016 10 25;9:254-263. Epub 2016 Aug 25.

Department of Foods and Nutrition, University of Georgia, Athens, GA 30602, USA. Electronic address:

Anthocyanins are a class of phytochemicals that have generated considerable interest due to their reported health benefits. It has been proposed that commonly consumed anthocyanins, such as cyandin-3-O-β-glucoside (C3G), confer cellular protection by stimulating biosynthesis of glutathione (GSH), an endogenous antioxidant. Currently, it is unknown whether the health effects of dietary anthocyanins are genetically determined. We therefore tested the hypothesis that anthocyanin-induced alterations in GSH homeostasis vary by genetic background. Mice representing five genetically diverse inbred strains (A/J, 129S1/SvImJ, CAST/EiJ, C57BL/6J, and NOD/ShiLtJ) were assigned to a control or 100mg/kg C3G diet (n=5/diet/strain) for six weeks. GSH and GSSG levels were quantified in liver, kidney, heart, pancreas, and brain samples using HPLC. The C3G diet promoted an increase in renal GSH concentrations, hepatic GSH/GSSG, and cardiac GSH/GSSG in CAST/EiJ mice. C3G treatment also induced an increase in pancreatic GSH/GSSG in C57BL/6J mice. In contrast, C3G did not affect GSH homeostasis in NOD/ShiLtJ mice. Surprisingly, the C3G-diet caused a decrease in hepatic GSH/GSSG in A/J and 129S1/SvImJ mice compared to controls; C3G-treated 129S1/SvImJ mice also exhibited lower total glutathione in the heart. Overall, we discovered that C3G modulates the GSH system in a strain- and tissue-specific manner. To our knowledge, this study is the first to show that the redox effects of anthocyanins are determined by genetic background.
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http://dx.doi.org/10.1016/j.redox.2016.08.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5021773PMC
October 2016

Heritability of in vitro phenotypes exhibited by murine adipose-derived stromal cells.

Mamm Genome 2016 10 8;27(9-10):460-8. Epub 2016 Jul 8.

Department of Foods and Nutrition, University of Georgia, 305 Sanford Drive, Athens, GA, 30602, USA.

Adipose-derived stromal cells (ADSCs) exhibit significant potential as therapeutic agents to promote tissue regeneration. Success of ADSC-based therapies is dependent upon efficient cell expansion in vitro as well as postinjection survival in the caustic milieu of damaged tissue. Genetic background regulates ADSC proliferative capacity and stress resistance, but the extent of the genetic effect size is not completely defined. The present study aimed to quantify phenotypic ranges and heritability of in vitro ADSC characteristics. ADSCs were isolated from mice representing 16 genetically diverse inbred mouse strains, including 12 classical inbred strains and four wild-derived strains. Cells were grown in vitro, and proliferative capacity and oxidative stress resistance were assessed. The fold change for ADSC growth ranged from 0.87 (BALB/cByJ) to 23.60 (POHN/DehJ), relative to original seeding density. The heritability of proliferative capacity was estimated to be 0.6462 (p = 9.967 × 10(-15)), and this phenotype was not associated with other ADSC traits. Cell viability following H2O2 treatment ranged from 39.81 % (CAST/EiJ) to 91.60 % (DBA/2 J), and the heritability of this phenotype was calculated as 0.6146 (p = 1.22 × 10(-12)). Relationships between cell viability and weight of the donor fat pad were also discovered. Donor genetic background is a major determinant of in vitro ADSC phenotypes. This study supports the development of forward genetics strategies to identify genes that underlie ADSC phenotypic diversity, which will inform efforts to improve cell-based therapies.
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http://dx.doi.org/10.1007/s00335-016-9655-6DOI Listing
October 2016

Circulating Concentrations of Growth Differentiation Factor 11 Are Heritable and Correlate With Life Span.

J Gerontol A Biol Sci Med Sci 2016 12 16;71(12):1560-1563. Epub 2016 Jan 16.

Department of Foods and Nutrition and

Growth differentiation factor 11 (GDF11) is member of the transforming growth factor β (TGF-β) superfamily of proteins. Circulating GDF11 concentrations appear to decline with age, and its depletion is associated with cardiac hypertrophy and other morbidities. Knowledge of GDF11 regulation is limited, and the effects of natural genetic variation on GDF11 levels are currently undefined. We tested whether genetic background determines serum GDF11 concentrations using two classical inbred mouse strains: C57BL/6J (B6) and BALB/cByJ (BALB). B6 mice exhibited significantly higher GDF11 levels than BALB mice, and these strain differences were consistent throughout the life span. Overall, interactions between age and genetic background determined GDF11 concentrations, which were unaffected by sex. We then surveyed a panel of 22 genetically diverse inbred mouse strains and discovered a sixfold range in GDF11 levels at middle age. We estimated that 74.52% of phenotypic variation in GDF11 levels was attributable to genetic background. We used the Mouse Phenome Database to screen for phenotypes that correlate with GDF11. Interestingly, GDF11 levels predicted median strain life spans. This study revealed high heritability of GDF11 levels. Furthermore, our correlative data suggest that GDF11 may serve as a novel predictor of mammalian life span.
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http://dx.doi.org/10.1093/gerona/glv308DOI Listing
December 2016

Genetic analysis of tissue glutathione concentrations and redox balance.

Free Radic Biol Med 2014 Jun 5;71:157-164. Epub 2014 Mar 5.

Department of Foods and Nutrition and University of Georgia, Athens, GA 30602, USA; The Jackson Laboratory, Bar Harbor, ME 04609, USA. Electronic address:

Glutathione redox balance-defined as the ratio GSH/GSSG-is a critical regulator of cellular redox state, and declines in this ratio are closely associated with oxidative stress and disease. However, little is known about the impact of genetic variation on this trait. Previous mouse studies suggest that tissue GSH/GSSG is regulated by genetic background and is therefore heritable. In this study, we measured glutathione concentrations and GSH/GSSG in liver and kidney of 30 genetically diverse inbred mouse strains. Genetic background caused an approximately threefold difference in hepatic and renal GSH/GSSG between the most disparate strains. Haplotype association mapping determined the loci associated with hepatic and renal glutathione phenotypes. We narrowed the number of significant loci by focusing on those located within protein-coding genes, which we now consider to be candidate genes for glutathione homeostasis. No candidate genes were associated with both hepatic and renal GSH/GSSG, suggesting that genetic regulation of GSH/GSSG occurs predominantly in a tissue-specific manner. This is the first quantitative trait locus study to examine the genetic regulation of glutathione concentrations and redox balance in mammals. We identified novel candidate genes that have the potential to redefine our knowledge of redox biochemistry and its regulation and inform future therapeutic applications.
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http://dx.doi.org/10.1016/j.freeradbiomed.2014.02.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4043295PMC
June 2014

Murine adipose tissue-derived stromal cell apoptosis and susceptibility to oxidative stress in vitro are regulated by genetic background.

PLoS One 2013 4;8(4):e61235. Epub 2013 Apr 4.

The Jackson Laboratory, Bar Harbor, Maine, United States of America.

Adipose tissue-derived stromal cells (ADSCs) are of interest for regenerative medicine as they are isolated easily and can differentiate into multiple cell lineages. Studies of their in vitro proliferation, survival, and differentiation are common; however, genetic effects on these phenotypes remain unknown. To test if these phenotypes are genetically regulated, ADSCs were isolated from three genetically diverse inbred mouse strains--C57BL/6J (B6), BALB/cByJ (BALB), and DBA/2J (D2)--in which genetic regulation of hematopoietic stem function is well known. ADSCs from all three strains differentiated into osteogenic and chondrogenic lineages in vitro. ADSCs from BALB grew least well in vitro, probably due to apoptotic cell death after several days in culture. BALB ADSCs were also the most susceptible to the free radical inducers menadione and H2O2. ADSCs from the three possible F1 hybrids were employed to further define genetic regulation of ADSC phenotypes. D2, but not B6, alleles stimulated ADSC expansion in BALB cells. In contrast, B6, but not D2, alleles rescued BALB H2O2 resistance. We conclude that low oxidative stress resistance does not limit BALB ADSC growth in vitro, as these phenotypes are genetically regulated independently. In addition, ADSCs from these strains are an appropriate model system to investigate genetic regulation of ADSC apoptosis and stress resistance in future studies. Such investigations are essential to optimize cell expansion and differentiation and thus, potential for regenerative medicine.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0061235PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3617166PMC
November 2013

The antioxidant 3H-1,2-dithiole-3-thione potentiates advanced glycation end-product-induced oxidative stress in SH-SY5Y cells.

Exp Diabetes Res 2012 17;2012:137607. Epub 2012 May 17.

Department of Nutrition Science, Purdue University, West Lafayette, IN 47907, USA.

Oxidative stress is implicated as a major factor in the development of diabetes complications and is caused in part by advanced glycation end products (AGEs). AGEs ligate to the receptor for AGEs (RAGE), promoting protein kinase C (PKC)-dependent activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and superoxide radical generation. While scavenging antioxidants are protective against AGEs, it is unknown if induction of endogenous antioxidant defenses has the same effect. In this study, we confirmed that the compound 3H-1,2-dithiole-3-thione (D3T) increases reduced-state glutathione (GSH) concentrations and NADPH:quinone oxidoreductase 1 (NQO1) activity in SH-SY5Y cells and provides protection against H(2)O(2). Surprisingly, D3T potentiated oxidative damage caused by AGEs. In comparison to vehicle controls, D3T caused greater AGE-induced cytotoxicity and depletion of intracellular GSH levels while offering no protection against neurite degeneration or protein carbonylation. D3T potentiated AGE-induced reactive oxygen species (ROS) formation, an effect abrogated by inhibitors of PKC and NADPH oxidase. This study suggests that chemical induction of endogenous antioxidant defenses requires further examination in models of diabetes.
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http://dx.doi.org/10.1155/2012/137607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3362848PMC
October 2012

Differential effects of α-tocopherol and N-acetyl-cysteine on advanced glycation end product-induced oxidative damage and neurite degeneration in SH-SY5Y cells.

Biochim Biophys Acta 2012 Apr 10;1822(4):550-6. Epub 2012 Jan 10.

Department ofNutrition Science, Purdue University, 700 West State Street, West Lafayette, IN 47907, USA.

Advanced glycation end products (AGEs) result from non-enzymatic glycation of proteins and cause cellular oxidative stress in a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-dependent manner. Due to these effects, AGEs are implicated as a causal factor in diabetic complications. Several antioxidants, including vitamin E, improve cell viability and diminish markers of oxidative damage in cells exposed to AGEs. However, vitamin E has been studied in cell culture systems with primary focus on apoptosis and lipid peroxidation, while its influences on AGE-induced protein and DNA oxidation, intracellular antioxidant status and cell morphology remain largely unknown. Here, we verify the suppression of AGE-induced cell death and lipid peroxidation by 200μM α-tocopherol in SH-SY5Y cells. We report the partial inhibition of DNA oxidation and a decrease in protein carbonyl formation by α-tocopherol with no effects on intracellular GSH concentrations. We observed that 2mM N-acetyl cysteine (NAC) also had a suppressive effect on DNA and protein oxidation, but unlike α-tocopherol, it caused a marked increase in intracellular GSH. Finally, we compared the ability of both antioxidants to maintain neurites in SH-SY5Y cells and found that α-tocopherol had no effect on neurite loss due to AGEs, while NAC fully maintained cell morphology. Thus, while α-tocopherol suppressed AGE-induced macromolecule damage, it was ineffective against neurite degeneration. These results may implicate thiol oxidation and maintenance as a major regulator of neurite degeneration in this model.
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http://dx.doi.org/10.1016/j.bbadis.2012.01.003DOI Listing
April 2012

The role of vitamin E and oxidative stress in diabetes complications.

Mech Ageing Dev 2010 Apr 20;131(4):276-86. Epub 2010 Mar 20.

Department of Foods and Nutrition, Purdue University, 700 West State Street, West Lafayette, IN 47907, USA.

Diabetes is a disease characterized by poor glycemic control for which risk of the type 2 form increases with age. A rise in blood glucose concentration causes increased oxidative stress which contributes to the development and progression of diabetes-associated complications. Studies have shown that primary antioxidants or genetic manipulation of antioxidant defenses can at least partially ameliorate this oxidative stress and consequentially, reduce severity of diabetic complications in animal models. Data from humans is less clear and will be summarized in this review. We highlight results from studies performed to investigate the role of vitamin E in preventing diabetes-induced oxidative damage in cell culture, animal models, and human participants, and summarize evidence testing whether this nutrient has an effect on outcomes related to the diabetic complications of nephropathy, retinopathy, and neuropathy. The most compelling evidence for an effect of vitamin E in diabetes is on protection against lipid peroxidation, whereas effects on protein and DNA oxidation are less pronounced. More studies are required to make definitive conclusions about the effect of vitamin E treatment on diabetes complications in human subjects.
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http://dx.doi.org/10.1016/j.mad.2010.03.005DOI Listing
April 2010

Omega-3 fatty acid status in attention-deficit/hyperactivity disorder.

Prostaglandins Leukot Essent Fatty Acids 2006 Oct-Nov;75(4-5):299-308. Epub 2006 Sep 8.

Department of Foods and Nutrition, West Lafayette IN 47909-2059, USA.

Lower levels of long-chain polyunsaturated fatty acids, particularly omega-3 fatty acids, in blood have repeatedly been associated with a variety of behavioral disorders including attention-deficit/hyperactivity disorder (ADHD). The exact nature of this relationship is not yet clear. We have studied children with ADHD who exhibited skin and thirst symptoms classically associated with essential fatty acid (EFA) deficiency, altered plasma and red blood cell fatty acid profiles, and dietary intake patterns that do not differ significantly from controls. This led us to focus on a potential metabolic insufficiency as the cause for the altered fatty acid phenotype. Here we review previous work and present new data expanding our observations into the young adult population. The frequency of thirst and skin symptoms was greater in newly diagnosed individuals with ADHD (n = 35) versus control individuals without behavioral problems (n = 112) drawn from the Purdue student population. A follow up case-control study with participants willing to provide a blood sample, a urine sample, a questionnaire about their general health, and dietary intake records was conducted with balancing based on gender, age, body mass index, smoking and ethnicity. A number of biochemical measures were analyzed including status markers for several nutrients and antioxidants, markers of oxidative stress, inflammation markers, and fatty acid profiles in the blood. The proportion of omega-3 fatty acids was found to be significantly lower in plasma phospholipids and erythrocytes in the ADHD group versus controls whereas saturated fatty acid proportions were higher. Intake of saturated fat was 30% higher in the ADHD group, but intake of all other nutrients was not different. Surprisingly, no evidence of elevated oxidative stress was found based on analysis of blood and urine samples. Indeed, serum ferritin, magnesium, and ascorbate concentrations were higher in the ADHD group, but iron, zinc, and vitamin B6 were not different. Our brief survey of biochemical and nutritional parameters did not give us any insight into the etiology of lower omega-3 fatty acids, but considering the consistency of the observation in multiple ADHD populations continued research in this field is encouraged.
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http://dx.doi.org/10.1016/j.plefa.2006.07.004DOI Listing
January 2007

Sugar radicals in DNA: isolation of neutral radicals in gamma-irradiated DNA by hole and electron scavenging.

Radiat Res 2005 May;163(5):591-602

Department of Chemistry, Oakland University, Rochester, Michigan 48309, USA.

In this investigation of the radical formation and the reaction of radicals in gamma-irradiated DNA, we report the isolation of putative neutral radicals by the scavenging of holes by Fe(CN)6(4-) and of electrons by Fe(CN)6(3-). Experiments are performed under conditions that emphasize direct and quasi-direct effects (collectively called direct-type effects.) Samples containing Fe(CN)6(4-) show effective scavenging of holes and the ESR spectra obtained arise principally from DNA anion radicals and neutral radicals. On the other hand, for samples containing Fe(CN)6(3-), electron scavenging is highly efficient, and the resulting spectra arise principally from guanine cation radicals and neutral radicals. When both Fe(CN)6(4-) and Fe(CN)6(3-) are present, a near complete scavenging of cation radicals and anion radicals is observed at 77 K, and the ESR spectra that result originate predominantly with neutral radicals which are assigned predominantly to radicals on the sugar phosphate backbone. A notable finding is the presence of spectral components that indicate the formation, through the rupture of the C3'-O bond, of a neutral deoxyribose radical; a concurrent strand break must accompany formation of this radical. This radical was previously reported in argon-ion-irradiated DNA and now, for the first time, is reported in DNA irradiated with low-LET radiation.
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http://dx.doi.org/10.1667/rr3347DOI Listing
May 2005

Formation of 8-oxo-7,8-dihydroguanine-radicals in gamma-irradiated DNA by multiple one-electron oxidations.

Nucleic Acids Res 2004 15;32(22):6565-74. Epub 2004 Dec 15.

Department of Chemistry, Oakland University, Rochester, MI 38309, USA.

Electron spin resonance (ESR) studies of radicals formed by radiation-induced multiple one-electron oxidations of guanine moieties in DNA are reported in this work. Annealing of gamma-irradiated DNA from 77 to 235 K results in the hydration of one electron oxidized guanine (G*+) to form the 8-hydroxy-7,8-dihydroguanin-7-yl-radical (*GOH) having one beta-proton coupling of 17-28 G and an anisotropic nitrogen coupling, A(parallel), of approximately 20 G, A(perpendicular) = 0 with g(parallel) = 2.0026 and g(perpendicular) = 2.0037. Further annealing to 258 K results in the formation of a sharp singlet at g = 2.0048 with line-width of 5.3 G that is identified as the 8-oxo-7,8-dihydroguanine one-electron-oxidized radical (8-oxo-G*+). This species is formed via two one-electron oxidations of *GOH. These two one-electron oxidation steps leading to the formation of 8-oxo-G*+ from *GOH in DNA, are in accordance with the expected ease of oxidation of *GOH and 8-oxo-G. The incorporation of oxygen from water in G*+ leading to *GOH and to 8-oxo-G*+ is verified by ESR studies employing 17O isotopically enriched water, which provide unambiguous evidence for the formation of both radicals. ESR analysis of irradiated-DNA in the presence of the electron scavenger, Tl3+, demonstrates that the cationic pathway leads to the formation of the 8-oxo-G*+. In irradiated DNA-Tl3+ samples, Tl3+ captures electrons. Tl2+ thus produced is a strong oxidant (2.2 V), which is metastable at 77 K and is observed to increase the formation of G*+ and subsequently of 8-oxo-G*+ upon annealing. We find that in the absence of the electron scavenger the yield of 8-oxo-G*+ is substantially reduced as a result of electron recombinations with G*+ and possible reaction with *GOH.
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http://dx.doi.org/10.1093/nar/gkh989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC545457PMC
January 2005

The formation of DNA sugar radicals from photoexcitation of guanine cation radicals.

Radiat Res 2004 May;161(5):582-90

Department of Chemistry, Oakland University, Rochester, Michigan 48309, USA.

In this investigation of radical formation and reaction in gamma- irradiated DNA and model compounds, we report the conversion of the guanine cation radical (one-electron oxidized guanine, G(.+)) to the C1' sugar radical and another sugar radical at the C3' or C4' position (designated C3'(.)/C4'(.)) by visible and UV photolysis. Electron spin resonance (ESR) spectroscopic investigations were performed on salmon testes DNA as well as 5'-dGMP, 3'-dGMP, 2'-deoxyguanosine and other nucleosides/nucleotides as model systems. DNA samples (25- 150 mg/ml D(2)O) were prepared with Tl(3+) or Fe(CN)(3-)(6) as electron scavengers. Upon gamma irradiation of such samples at 77 K, the electron-gain path in the DNA is strongly suppressed and predominantly G(.+) is found; after UV or visible photolysis, the fraction of the C1' sugar radical increases with a concomitant reduction in the fraction of G(.+). In model systems, 3'- dGMP(+.) and 5'-dGMP(+.) were produced by attack of Cl(.-)(2) on the parent nucleotide in 7 M LiCl glass. Subsequent visible photolysis of the 3'-dGMP(+.) (77 K) results predominantly in formation of C1'(.) whereas photolysis of 5'-dGMP(+.) results predominantly in formation of C3'(.)/C4'(.). We propose that sugar radical formation is a result of delocalization of the hole in the electronically excited base cation radical into the sugar ring, followed by deprotonation at specific sites on the sugar.
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http://dx.doi.org/10.1667/rr3167DOI Listing
May 2004