Zsolt Radak - Academia.edu (original) (raw)
Papers by Zsolt Radak
Cancer Letters, 2005
N-Glycosylases excise the damaged adducts from DNA. 7,8-Dihydro-8-oxoguanine in human cells is re... more N-Glycosylases excise the damaged adducts from DNA. 7,8-Dihydro-8-oxoguanine in human cells is repaired by OGG1 and hNTH1. The activities of hOGG1 and hNTH1 were measured, using modified and 32 P labelled oligonucleotides, in bronchial biopsy samples of smoking patients with non-small cell lung carcinoma. The activity of hOOG1 was significantly higher in biopsies from tumour tissues compared with intra-individual control samples. On the contrary, the activity of endonuclease III homologue, hNTH1, was lower in tumours compared to controls. These opposing alterations in DNA repair enzymes may affect cancer growth due to the increased formation of AP sites. q
Journal of Sport and Health Science, 2013
and sharing with colleagues.
Annals of The New York Academy of Sciences, 2004
Archives of Biochemistry and Biophysics, 2000
The oxygen flux into the mitochondria of skeletal muscle increases with exercise. However, the ex... more The oxygen flux into the mitochondria of skeletal muscle increases with exercise. However, the extent of oxidative damage to mitochondrial proteins of skeletal muscle has only been estimated. We studied the alteration of reactive carbonyl derivatives (RCD) in mitochondrial and cytosolic fractions of skeletal muscle following 9 weeks of swimming training in rats. The RCD content of mitochondria was significantly
Neurochemistry International, 2001
We were interested in the effects of immobilization (IM), a single bout of exercise (E) and immob... more We were interested in the effects of immobilization (IM), a single bout of exercise (E) and immobilization followed by exercise (EIM) on memory and oxidative damage of macromolecules in hippocampus of rat brain. Eight hours of IM resulted in impairment of passive avoidance test (memory retrieval deficit) and increased latency to start locomotion in an open-field test. Two hours of
Free Radical Biology and Medicine, 1999
Moderate daily exercise is known to be beneficial to health, reducing risks of a number of age-re... more Moderate daily exercise is known to be beneficial to health, reducing risks of a number of age-related disorders. Molecular mechanisms that bring about these effects are not clear. In contrast, it has been claimed that some types of prolonged physical exertion are detrimental to health because active oxygen species are generated excessively by enhanced oxygen consumption. Using two age groups
Neurochemistry International, 2001
The biochemical mechanisms by which regular exercise significantly benefits health and well being... more The biochemical mechanisms by which regular exercise significantly benefits health and well being, including improved cognitive function, are not well understood. Four-week-old (young) and 14-month-old (middle aged) Wistar rats were randomly assigned to young control and young exercised, middle-aged control and middle-aged exercised groups. Exercise groups were exposed to a swimming regime of 1 h a day, 5 days a
Oxidative Medicine and Cellular Longevity, 2015
Background. Regular exercise at moderate intensity reduces cardiovascular risks. Matrix metallopr... more Background. Regular exercise at moderate intensity reduces cardiovascular risks. Matrix metalloproteinases (MMPs) play a major role in cardiac remodeling, facilitating physiological adaptation to exercise. The aim of this study was to examine the influence of voluntary physical exercise on the MMP-2 enzyme activity and to investigate the cardiac performance by measurement of angina susceptibility of the heart, the basal blood pressure, the surviving aorta ring contraction, and the cardiac infarct size after I/Rinduced injury. Methods. Male Wistar rats were divided into control and exercising groups. After a 6-week period, the serum level of MMP-2, basal blood pressure, cardiac angina susceptibility (the ST segment depression provoked by epinephrine and 30 s later phentolamine), AVP-induced heart perfusion and aorta ring contraction, infarct size following 30 min ischemia and 120 min reperfusion, and coronary effluent MMP-2 activity were measured. Results. Voluntary wheel-running exercise decreased both the sera (64 kDa and 72 kDa) and the coronary effluent (64 kDa) MMP-2 level, reduced the development of ST depression, improved the isolated heart perfusion, and decreased the ratio of infarct size. Conclusion. 6 weeks of voluntary exercise training preserved the heart against cardiac injury. This protective mechanism might be associated with the decreased activity of MMP-2.
![Research paper thumbnail of [Correlation of the microbiota and intestinal mucosa in the pathophysiology and treatment of irritable bowel, irritable eye, and irritable mind syndrome]](https://attachments.academia-assets.com/44485715/thumbnails/1.jpg)
](Orvosi hetilap, Jan 14, 2014
Accumulating clinical evidence supports co-morbidity of irritable bowel, irritable eye and irrita... more Accumulating clinical evidence supports co-morbidity of irritable bowel, irritable eye and irritable mind symptoms. Furthermore, perturbation of the microbiota-host symbiosis (dysbiosis) is considered a common pathogenic mechanism connecting gastrointestinal, ocular and neuropsychiatric symptoms. Consequently, maintaining or restoring microbiota-host symbiosis represents a new approach to treat these symptoms or to prevent their relapses. Current treatment approach assigned a primary role to live probiotics alone or in combination with prebiotics to enhance colonization of beneficial bacteria and to strengthen the symbiosis. However, several papers showed major benefits of heat-killed probiotics as compared to their live counterparts on both intestinal and systemic symptoms. Recently, in addition to killing probiotics, in a proof of concept study lysates (fragments) of probiotics in combination with vitamins A, B, D and omega 3 fatty acids were successfully tested. These findings su...
Previous studies have demonstrated that brain-derived neurotrophic factor (BDNF) played a role in... more Previous studies have demonstrated that brain-derived neurotrophic factor (BDNF) played a role in the eating behavior and glucose and lipid metabolism. In this study we measured the serum BDNF levels in newly diagnosed female patients with type 2 diabetes mellitus (n = 24, aged 34-59 years) and female subjects with normal glucose tolerance (n = 7, aged 34-56 years). The
8-Oxo-7,8-dihydroguanine is one the most abundant base lesions in pro-and eukaryotic DNA. In mamm... more 8-Oxo-7,8-dihydroguanine is one the most abundant base lesions in pro-and eukaryotic DNA. In mammalian cells, it is excised by the 8-oxoguanine DNA glycosylases (OGG1) during DNA base excision repair, and the generated free 8-oxoG base (8-oxoG) is one of the DNA-derived biomarkers of oxidative stress in biological samples. The modification of 8-oxoG in the context of nucleoside and DNA has been the subject of many studies; however, the oxidative transformation of the free 8-oxoG base has not been described. By using biochemical and cell biological assays, we showed that in the presence of molecular oxygen, the free 8-oxoG base transformed to a highly reactive hydroperoxide (8-oxoG*). Specifically, 8-oxoG* oxidizes Amplex Red to resorufin, H 2 DCF to DCF, Fe 2+ to Fe 3+ , and GSH to GSSG. This property of 8-oxoG* was diminished by treatment with catalase, glutathione peroxidase, but not superoxide dismutase. 8-oxoG* formation was prevented by reducing agents or nitrogen atmosphere. Its addition to H 2 DCF-DA-loaded cells rapidly increased intracellular DCF fluorescence. There were no such properties observed for 8oxodeoxyguanosine, 2,6-diamino-4-hydroxy-5-formamidopyrimidine, 2'-deoxyguanosine, guanine, adenine, guanosine and 8-hydroxyadenine. These data imply that a free 8-oxoG base is more susceptible to oxidation than is its nucleoside form and, consequently, it stands as unique among intact and oxidatively modified purines.
Regular physical exercise retards a number of age-associated disorders, in spite of the paradox t... more Regular physical exercise retards a number of age-associated disorders, in spite of the paradox that free radical generation is significantly enhanced with exercise. Eight weeks of treadmill running resulted in nearly a 40% increase in maximal oxygen uptake in both middle-aged (20-month-old) and aged (30-month-old) rats. The ageassociated increase in 8-hydroxy-2'-deoxyguanosine (8-OHdG) content was significantly attenuated in gastrocnemius muscle by exercise. The 8-OHdG repair, as measured by the excision of 32 P-labeled damaged oligonucleotide, increased in muscle of exercising animals. The reactive carbonyl derivatives (RCD) of proteins did not increase with aging. However, when the muscle homogenate was exposed to a mixture of 1 mM iron sulfate and 50 mM ascorbic acid, the muscle of old control animals accumulated more RCD than that of the trained or adult groups. The chymotrypsin-like activity of proteasome complex increased in muscle of old trained rats. We suggest that regular exercise-induced adaptation attenuates the age-associated increase in 8-OHdG levels, and increases the activity of DNA repair and resistance against oxidative stress in proteins.
International Journal of Molecular Sciences, 2014
Many, if not all, environmental pollutants/chemicals and infectious agents increase intracellular... more Many, if not all, environmental pollutants/chemicals and infectious agents increase intracellular levels of reactive oxygen species (ROS) at the site of exposure. ROS not only function as intracellular signaling entities, but also induce damage to cellular molecules including DNA. Among the several dozen ROS-induced DNA base lesions generated in the genome, 8-oxo-7,8-dihydroguanine (8-oxoG) is one of the most abundant because of guanine's lowest redox potential among DNA bases. In mammalian cells, 8-oxoG is repaired by the 8-oxoguanine DNA glycosylase-1 (OGG1)-initiated DNA base excision repair pathway (OGG1-BER). Accumulation of 8-oxoG in DNA has traditionally been associated with mutagenesis, as well as various human diseases and aging processes, while the free 8-oxoG base in body fluids is one of the best biomarkers of ongoing pathophysiological processes. In this review, we discuss the biological significance of the 8-oxoG base and particularly the role of OGG1-BER in the activation of small GTPases and changes in gene expression, including those that regulate pro-inflammatory chemokines/cytokines and cause inflammation.
Innate Immunity, 2009
Lactoferrin is a non-heme iron-binding glycoprotein, produced by mucosal epithelial cells and gra... more Lactoferrin is a non-heme iron-binding glycoprotein, produced by mucosal epithelial cells and granulocytes in most mammalian species. It is involved in regulation of immune responses, possesses anti-oxidant, anti-carcinogenic, anti-inflammatory properties, and provides protection against various microbial infections. In addition, lactoferrin has been implicated in protection against the development of insult-induced systemic inflammatory response syndrome (SIRS) and its progression into septic conditions in vivo. Here we show a potential mechanism by which lactoferrin lessens oxidative insult at the cellular and tissue levels after lipopolysaccharide (LPS) exposure. Lactoferrin pretreatment of cells decreased LPS-mediated oxidative insults in a dosedependent manner. Lipopolysaccharide-induced oxidative burst was found to be of mitochondrial origin, and release of reactive oxygen species (ROS) was localized to the respiratory complex III. Importantly, lactoferrin nearly abolished LPS-induced increases in mitochondrial ROS generation and the accumulation of oxidative damage in the DNA. In vivo, pretreatment of experimental animals with lactoferrin significantly (P<0.05) lowered LPS-induced mitochondrial dysfunction as shown by both decreased release of H 2 O 2 and DNA damage in the mitochondria. In contrast, deferoxamine, an iron chelating compound, provided only partial protection in LPS-treated animals. Together, these data suggest that lactoferrin protects against oxidative insult at the mitochondrial level, and indicate a potential utility of lactoferrin in prevention and treatment of SIRS.
Dose-Response, 2013
ᮀ Low capacity runner (LCR) rats have been developed by divergent artificial selection for treadm... more ᮀ Low capacity runner (LCR) rats have been developed by divergent artificial selection for treadmill endurance capacity to explore an aerobic biology-disease connection. The beneficial effects of resveratrol supplementation have been demonstrated in endurance running. In this study it was examined whether 12 weeks of treadmill exercise training and/or resveratrol can retrieve the low running performance of the LCR and impact mitochondrial biogenesis and quality control. Resveratrol regressed running performance in trained LCR (p<0.05). Surprisingly, exercise and resveratrol treatments significantly decreased pAMPK/AMPK, SIRT1, SIRT4, forkhead transcription factor 1 (FOXO1) and mitochondrial transcription factor A (TFAM) levels in these animals (p<0.05). Mitochondrial fusion protein, HSP78 and polynucleotide phosphorylase were significantly induced in LCR-trained, LCR-resveratrol treated, LCR-trained and resveratol treated groups compared to LCR-controls. The data indicate that the AMPK-SIRT1-NAMPT-FOXO1 axis could be important to the limited aerobic endurance capacity of low running capacity rats. Resveratrol supplementation was not beneficial in terms of aerobic endurance performance, mitochondrial biogenesis, or quality control.
Journal of immunology (Baltimore, Md. : 1950), 2014
8-Oxoguanine-DNA glycosylase-1 (OGG1) is the primary enzyme for repairing 7,8-dihydro-8-oxoguanin... more 8-Oxoguanine-DNA glycosylase-1 (OGG1) is the primary enzyme for repairing 7,8-dihydro-8-oxoguanine (8-oxoG) via the DNA base excision repair pathway (OGG1-BER). Accumulation of 8-oxoG in the genomic DNA leads to genetic instability and carcinogenesis and is thought to contribute to the worsening of various inflammatory and disease processes. However, the disease mechanism is unknown. In this study, we proposed that the mechanistic link between OGG1-BER and proinflammatory gene expression is OGG1's guanine nucleotide exchange factor activity, acquired after interaction with the 8-oxoG base and consequent activation of the small GTPase RAS. To test this hypothesis, we used BALB/c mice expressing or deficient in OGG1 in their airway epithelium and various molecular biological approaches, including active RAS pulldown, reporter and Comet assays, small interfering RNA-mediated depletion of gene expression, quantitative RT-PCR, and immunoblotting. We report that the OGG1-initiated rep...
Free radical biology & medicine, Jan 19, 2015
Reactive oxygen species inflict oxidative modifications on various biological molecules, includin... more Reactive oxygen species inflict oxidative modifications on various biological molecules, including DNA. One of the most abundant DNA base lesions 8-oxo-7,8-dihydroguanine (8-oxoG) is repaired by 8-oxoguanine DNA glycosylase-1 (OGG1) during DNA base excision repair (OGG1-BER). 8-OxoG accumulation in DNA has been associated with various pathological and aging processes, while its role is unclear. The lack of OGG1-BER in Ogg1-/- mice resulted in decreased inflammatory responses, increased susceptibility to infections and metabolic disorders. Therefore, we proposed that OGG1 and/or 8-oxoG base may have a role in immune and homeostatic processes. To test our hypothesis, we challenged mouse lungs with OGG1-BER product 8-oxoG base and changes in gene expression were determined by RNA sequencing and data were analyzed by gene ontology and statistical tools. RNA-Seq analysis identified 1592 differentially expressed (≥ 3-fold change) transcripts. The upregulated mRNAs were related to biologic...
Respiratory Physiology & Neurobiology, 2007
Exposure to high altitude, which is associated with decreased oxygen pressure, could result in ox... more Exposure to high altitude, which is associated with decreased oxygen pressure, could result in oxidative/reductive stress, enhanced generation of reactive oxygen and nitrogen species (RONS), and related oxidative damage to lipids, proteins, and DNA. The severity of oxidative challenge is related to the degree of altitude. A wide range of RONS generating systems are activated during exposure to high altitude, including the mitochondrial electron transport chain, xanthine oxidase, and nitric oxide synthase. High altitude appears to weaken the enzymatic and non-enzymatic antioxidant systems, and increased nutritional uptake of antioxidant vitamins are beneficial to reduce the altitude-induced oxidative damage. The pattern of high altitude exposure-associated oxidative damage resembles ischemia/reperfusion injury. The adaptive process to this oxidative challenge requires a relatively long period of time. Physical exercise or an enhanced level of physical activity at high altitude, exacerbates the extent of the oxidative challenge. Therefore, special attention is necessary to curb the degree of oxidative stress.
Pfl�gers Archiv European Journal of Physiology, 2002
Regular physical exercise retards a number of age-associated disorders, in spite of the paradox t... more Regular physical exercise retards a number of age-associated disorders, in spite of the paradox that free radical generation is significantly enhanced with exercise. Eight weeks of treadmill running resulted in nearly a 40% increase in maximal oxygen uptake in both middle-aged (20-month-old) and aged (30-month-old) rats. The ageassociated increase in 8-hydroxy-2'-deoxyguanosine (8-OHdG) content was significantly attenuated in gastrocnemius muscle by exercise. The 8-OHdG repair, as measured by the excision of 32 P-labeled damaged oligonucleotide, increased in muscle of exercising animals. The reactive carbonyl derivatives (RCD) of proteins did not increase with aging. However, when the muscle homogenate was exposed to a mixture of 1 mM iron sulfate and 50 mM ascorbic acid, the muscle of old control animals accumulated more RCD than that of the trained or adult groups. The chymotrypsin-like activity of proteasome complex increased in muscle of old trained rats. We suggest that regular exercise-induced adaptation attenuates the age-associated increase in 8-OHdG levels, and increases the activity of DNA repair and resistance against oxidative stress in proteins.
Pfl�gers Archiv European Journal of Physiology, 1998
It is known that acute physical exercise may have diverse pathophysiological consequences in vari... more It is known that acute physical exercise may have diverse pathophysiological consequences in various organs due to free radical formation. We have investigated whether a period of anaerobic running to exhaustion in rats results in oxidative modification of proteins in the lungs. Six rats of an exercised group (E) ran for two periods of 5 min at a speed of 30 m·min -1 followed by a recovery period of 5 min, and then by a third period of running to exhaustion. Reactive carbonyl derivatives (RCD) were measured by the Western blot technique on lungs of E and control (C) rats. In addition, the activity of glutamine synthetase (GS) was also monitored as marker of oxidative damage to proteins. This investigation revealed significant exercise-induced increases in accumulation of RCD in the lungs of the E group compared with the C group. The RCD signals were visibly stronger in proteins with molecular weight of 55 kDa and 32 kDa. The activity of GS was higher by about 30% in E rats than in C rats. The present data suggest that anaerobic exercise induces protein oxidation in the lungs.
Cancer Letters, 2005
N-Glycosylases excise the damaged adducts from DNA. 7,8-Dihydro-8-oxoguanine in human cells is re... more N-Glycosylases excise the damaged adducts from DNA. 7,8-Dihydro-8-oxoguanine in human cells is repaired by OGG1 and hNTH1. The activities of hOGG1 and hNTH1 were measured, using modified and 32 P labelled oligonucleotides, in bronchial biopsy samples of smoking patients with non-small cell lung carcinoma. The activity of hOOG1 was significantly higher in biopsies from tumour tissues compared with intra-individual control samples. On the contrary, the activity of endonuclease III homologue, hNTH1, was lower in tumours compared to controls. These opposing alterations in DNA repair enzymes may affect cancer growth due to the increased formation of AP sites. q
Journal of Sport and Health Science, 2013
and sharing with colleagues.
Annals of The New York Academy of Sciences, 2004
Archives of Biochemistry and Biophysics, 2000
The oxygen flux into the mitochondria of skeletal muscle increases with exercise. However, the ex... more The oxygen flux into the mitochondria of skeletal muscle increases with exercise. However, the extent of oxidative damage to mitochondrial proteins of skeletal muscle has only been estimated. We studied the alteration of reactive carbonyl derivatives (RCD) in mitochondrial and cytosolic fractions of skeletal muscle following 9 weeks of swimming training in rats. The RCD content of mitochondria was significantly
Neurochemistry International, 2001
We were interested in the effects of immobilization (IM), a single bout of exercise (E) and immob... more We were interested in the effects of immobilization (IM), a single bout of exercise (E) and immobilization followed by exercise (EIM) on memory and oxidative damage of macromolecules in hippocampus of rat brain. Eight hours of IM resulted in impairment of passive avoidance test (memory retrieval deficit) and increased latency to start locomotion in an open-field test. Two hours of
Free Radical Biology and Medicine, 1999
Moderate daily exercise is known to be beneficial to health, reducing risks of a number of age-re... more Moderate daily exercise is known to be beneficial to health, reducing risks of a number of age-related disorders. Molecular mechanisms that bring about these effects are not clear. In contrast, it has been claimed that some types of prolonged physical exertion are detrimental to health because active oxygen species are generated excessively by enhanced oxygen consumption. Using two age groups
Neurochemistry International, 2001
The biochemical mechanisms by which regular exercise significantly benefits health and well being... more The biochemical mechanisms by which regular exercise significantly benefits health and well being, including improved cognitive function, are not well understood. Four-week-old (young) and 14-month-old (middle aged) Wistar rats were randomly assigned to young control and young exercised, middle-aged control and middle-aged exercised groups. Exercise groups were exposed to a swimming regime of 1 h a day, 5 days a
Oxidative Medicine and Cellular Longevity, 2015
Background. Regular exercise at moderate intensity reduces cardiovascular risks. Matrix metallopr... more Background. Regular exercise at moderate intensity reduces cardiovascular risks. Matrix metalloproteinases (MMPs) play a major role in cardiac remodeling, facilitating physiological adaptation to exercise. The aim of this study was to examine the influence of voluntary physical exercise on the MMP-2 enzyme activity and to investigate the cardiac performance by measurement of angina susceptibility of the heart, the basal blood pressure, the surviving aorta ring contraction, and the cardiac infarct size after I/Rinduced injury. Methods. Male Wistar rats were divided into control and exercising groups. After a 6-week period, the serum level of MMP-2, basal blood pressure, cardiac angina susceptibility (the ST segment depression provoked by epinephrine and 30 s later phentolamine), AVP-induced heart perfusion and aorta ring contraction, infarct size following 30 min ischemia and 120 min reperfusion, and coronary effluent MMP-2 activity were measured. Results. Voluntary wheel-running exercise decreased both the sera (64 kDa and 72 kDa) and the coronary effluent (64 kDa) MMP-2 level, reduced the development of ST depression, improved the isolated heart perfusion, and decreased the ratio of infarct size. Conclusion. 6 weeks of voluntary exercise training preserved the heart against cardiac injury. This protective mechanism might be associated with the decreased activity of MMP-2.
Orvosi hetilap, Jan 14, 2014
Accumulating clinical evidence supports co-morbidity of irritable bowel, irritable eye and irrita... more Accumulating clinical evidence supports co-morbidity of irritable bowel, irritable eye and irritable mind symptoms. Furthermore, perturbation of the microbiota-host symbiosis (dysbiosis) is considered a common pathogenic mechanism connecting gastrointestinal, ocular and neuropsychiatric symptoms. Consequently, maintaining or restoring microbiota-host symbiosis represents a new approach to treat these symptoms or to prevent their relapses. Current treatment approach assigned a primary role to live probiotics alone or in combination with prebiotics to enhance colonization of beneficial bacteria and to strengthen the symbiosis. However, several papers showed major benefits of heat-killed probiotics as compared to their live counterparts on both intestinal and systemic symptoms. Recently, in addition to killing probiotics, in a proof of concept study lysates (fragments) of probiotics in combination with vitamins A, B, D and omega 3 fatty acids were successfully tested. These findings su...
Previous studies have demonstrated that brain-derived neurotrophic factor (BDNF) played a role in... more Previous studies have demonstrated that brain-derived neurotrophic factor (BDNF) played a role in the eating behavior and glucose and lipid metabolism. In this study we measured the serum BDNF levels in newly diagnosed female patients with type 2 diabetes mellitus (n = 24, aged 34-59 years) and female subjects with normal glucose tolerance (n = 7, aged 34-56 years). The
8-Oxo-7,8-dihydroguanine is one the most abundant base lesions in pro-and eukaryotic DNA. In mamm... more 8-Oxo-7,8-dihydroguanine is one the most abundant base lesions in pro-and eukaryotic DNA. In mammalian cells, it is excised by the 8-oxoguanine DNA glycosylases (OGG1) during DNA base excision repair, and the generated free 8-oxoG base (8-oxoG) is one of the DNA-derived biomarkers of oxidative stress in biological samples. The modification of 8-oxoG in the context of nucleoside and DNA has been the subject of many studies; however, the oxidative transformation of the free 8-oxoG base has not been described. By using biochemical and cell biological assays, we showed that in the presence of molecular oxygen, the free 8-oxoG base transformed to a highly reactive hydroperoxide (8-oxoG*). Specifically, 8-oxoG* oxidizes Amplex Red to resorufin, H 2 DCF to DCF, Fe 2+ to Fe 3+ , and GSH to GSSG. This property of 8-oxoG* was diminished by treatment with catalase, glutathione peroxidase, but not superoxide dismutase. 8-oxoG* formation was prevented by reducing agents or nitrogen atmosphere. Its addition to H 2 DCF-DA-loaded cells rapidly increased intracellular DCF fluorescence. There were no such properties observed for 8oxodeoxyguanosine, 2,6-diamino-4-hydroxy-5-formamidopyrimidine, 2'-deoxyguanosine, guanine, adenine, guanosine and 8-hydroxyadenine. These data imply that a free 8-oxoG base is more susceptible to oxidation than is its nucleoside form and, consequently, it stands as unique among intact and oxidatively modified purines.
Regular physical exercise retards a number of age-associated disorders, in spite of the paradox t... more Regular physical exercise retards a number of age-associated disorders, in spite of the paradox that free radical generation is significantly enhanced with exercise. Eight weeks of treadmill running resulted in nearly a 40% increase in maximal oxygen uptake in both middle-aged (20-month-old) and aged (30-month-old) rats. The ageassociated increase in 8-hydroxy-2'-deoxyguanosine (8-OHdG) content was significantly attenuated in gastrocnemius muscle by exercise. The 8-OHdG repair, as measured by the excision of 32 P-labeled damaged oligonucleotide, increased in muscle of exercising animals. The reactive carbonyl derivatives (RCD) of proteins did not increase with aging. However, when the muscle homogenate was exposed to a mixture of 1 mM iron sulfate and 50 mM ascorbic acid, the muscle of old control animals accumulated more RCD than that of the trained or adult groups. The chymotrypsin-like activity of proteasome complex increased in muscle of old trained rats. We suggest that regular exercise-induced adaptation attenuates the age-associated increase in 8-OHdG levels, and increases the activity of DNA repair and resistance against oxidative stress in proteins.
International Journal of Molecular Sciences, 2014
Many, if not all, environmental pollutants/chemicals and infectious agents increase intracellular... more Many, if not all, environmental pollutants/chemicals and infectious agents increase intracellular levels of reactive oxygen species (ROS) at the site of exposure. ROS not only function as intracellular signaling entities, but also induce damage to cellular molecules including DNA. Among the several dozen ROS-induced DNA base lesions generated in the genome, 8-oxo-7,8-dihydroguanine (8-oxoG) is one of the most abundant because of guanine&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s lowest redox potential among DNA bases. In mammalian cells, 8-oxoG is repaired by the 8-oxoguanine DNA glycosylase-1 (OGG1)-initiated DNA base excision repair pathway (OGG1-BER). Accumulation of 8-oxoG in DNA has traditionally been associated with mutagenesis, as well as various human diseases and aging processes, while the free 8-oxoG base in body fluids is one of the best biomarkers of ongoing pathophysiological processes. In this review, we discuss the biological significance of the 8-oxoG base and particularly the role of OGG1-BER in the activation of small GTPases and changes in gene expression, including those that regulate pro-inflammatory chemokines/cytokines and cause inflammation.
Innate Immunity, 2009
Lactoferrin is a non-heme iron-binding glycoprotein, produced by mucosal epithelial cells and gra... more Lactoferrin is a non-heme iron-binding glycoprotein, produced by mucosal epithelial cells and granulocytes in most mammalian species. It is involved in regulation of immune responses, possesses anti-oxidant, anti-carcinogenic, anti-inflammatory properties, and provides protection against various microbial infections. In addition, lactoferrin has been implicated in protection against the development of insult-induced systemic inflammatory response syndrome (SIRS) and its progression into septic conditions in vivo. Here we show a potential mechanism by which lactoferrin lessens oxidative insult at the cellular and tissue levels after lipopolysaccharide (LPS) exposure. Lactoferrin pretreatment of cells decreased LPS-mediated oxidative insults in a dosedependent manner. Lipopolysaccharide-induced oxidative burst was found to be of mitochondrial origin, and release of reactive oxygen species (ROS) was localized to the respiratory complex III. Importantly, lactoferrin nearly abolished LPS-induced increases in mitochondrial ROS generation and the accumulation of oxidative damage in the DNA. In vivo, pretreatment of experimental animals with lactoferrin significantly (P<0.05) lowered LPS-induced mitochondrial dysfunction as shown by both decreased release of H 2 O 2 and DNA damage in the mitochondria. In contrast, deferoxamine, an iron chelating compound, provided only partial protection in LPS-treated animals. Together, these data suggest that lactoferrin protects against oxidative insult at the mitochondrial level, and indicate a potential utility of lactoferrin in prevention and treatment of SIRS.
Dose-Response, 2013
ᮀ Low capacity runner (LCR) rats have been developed by divergent artificial selection for treadm... more ᮀ Low capacity runner (LCR) rats have been developed by divergent artificial selection for treadmill endurance capacity to explore an aerobic biology-disease connection. The beneficial effects of resveratrol supplementation have been demonstrated in endurance running. In this study it was examined whether 12 weeks of treadmill exercise training and/or resveratrol can retrieve the low running performance of the LCR and impact mitochondrial biogenesis and quality control. Resveratrol regressed running performance in trained LCR (p<0.05). Surprisingly, exercise and resveratrol treatments significantly decreased pAMPK/AMPK, SIRT1, SIRT4, forkhead transcription factor 1 (FOXO1) and mitochondrial transcription factor A (TFAM) levels in these animals (p<0.05). Mitochondrial fusion protein, HSP78 and polynucleotide phosphorylase were significantly induced in LCR-trained, LCR-resveratrol treated, LCR-trained and resveratol treated groups compared to LCR-controls. The data indicate that the AMPK-SIRT1-NAMPT-FOXO1 axis could be important to the limited aerobic endurance capacity of low running capacity rats. Resveratrol supplementation was not beneficial in terms of aerobic endurance performance, mitochondrial biogenesis, or quality control.
Journal of immunology (Baltimore, Md. : 1950), 2014
8-Oxoguanine-DNA glycosylase-1 (OGG1) is the primary enzyme for repairing 7,8-dihydro-8-oxoguanin... more 8-Oxoguanine-DNA glycosylase-1 (OGG1) is the primary enzyme for repairing 7,8-dihydro-8-oxoguanine (8-oxoG) via the DNA base excision repair pathway (OGG1-BER). Accumulation of 8-oxoG in the genomic DNA leads to genetic instability and carcinogenesis and is thought to contribute to the worsening of various inflammatory and disease processes. However, the disease mechanism is unknown. In this study, we proposed that the mechanistic link between OGG1-BER and proinflammatory gene expression is OGG1's guanine nucleotide exchange factor activity, acquired after interaction with the 8-oxoG base and consequent activation of the small GTPase RAS. To test this hypothesis, we used BALB/c mice expressing or deficient in OGG1 in their airway epithelium and various molecular biological approaches, including active RAS pulldown, reporter and Comet assays, small interfering RNA-mediated depletion of gene expression, quantitative RT-PCR, and immunoblotting. We report that the OGG1-initiated rep...
Free radical biology & medicine, Jan 19, 2015
Reactive oxygen species inflict oxidative modifications on various biological molecules, includin... more Reactive oxygen species inflict oxidative modifications on various biological molecules, including DNA. One of the most abundant DNA base lesions 8-oxo-7,8-dihydroguanine (8-oxoG) is repaired by 8-oxoguanine DNA glycosylase-1 (OGG1) during DNA base excision repair (OGG1-BER). 8-OxoG accumulation in DNA has been associated with various pathological and aging processes, while its role is unclear. The lack of OGG1-BER in Ogg1-/- mice resulted in decreased inflammatory responses, increased susceptibility to infections and metabolic disorders. Therefore, we proposed that OGG1 and/or 8-oxoG base may have a role in immune and homeostatic processes. To test our hypothesis, we challenged mouse lungs with OGG1-BER product 8-oxoG base and changes in gene expression were determined by RNA sequencing and data were analyzed by gene ontology and statistical tools. RNA-Seq analysis identified 1592 differentially expressed (≥ 3-fold change) transcripts. The upregulated mRNAs were related to biologic...
Respiratory Physiology & Neurobiology, 2007
Exposure to high altitude, which is associated with decreased oxygen pressure, could result in ox... more Exposure to high altitude, which is associated with decreased oxygen pressure, could result in oxidative/reductive stress, enhanced generation of reactive oxygen and nitrogen species (RONS), and related oxidative damage to lipids, proteins, and DNA. The severity of oxidative challenge is related to the degree of altitude. A wide range of RONS generating systems are activated during exposure to high altitude, including the mitochondrial electron transport chain, xanthine oxidase, and nitric oxide synthase. High altitude appears to weaken the enzymatic and non-enzymatic antioxidant systems, and increased nutritional uptake of antioxidant vitamins are beneficial to reduce the altitude-induced oxidative damage. The pattern of high altitude exposure-associated oxidative damage resembles ischemia/reperfusion injury. The adaptive process to this oxidative challenge requires a relatively long period of time. Physical exercise or an enhanced level of physical activity at high altitude, exacerbates the extent of the oxidative challenge. Therefore, special attention is necessary to curb the degree of oxidative stress.
Pfl�gers Archiv European Journal of Physiology, 2002
Regular physical exercise retards a number of age-associated disorders, in spite of the paradox t... more Regular physical exercise retards a number of age-associated disorders, in spite of the paradox that free radical generation is significantly enhanced with exercise. Eight weeks of treadmill running resulted in nearly a 40% increase in maximal oxygen uptake in both middle-aged (20-month-old) and aged (30-month-old) rats. The ageassociated increase in 8-hydroxy-2'-deoxyguanosine (8-OHdG) content was significantly attenuated in gastrocnemius muscle by exercise. The 8-OHdG repair, as measured by the excision of 32 P-labeled damaged oligonucleotide, increased in muscle of exercising animals. The reactive carbonyl derivatives (RCD) of proteins did not increase with aging. However, when the muscle homogenate was exposed to a mixture of 1 mM iron sulfate and 50 mM ascorbic acid, the muscle of old control animals accumulated more RCD than that of the trained or adult groups. The chymotrypsin-like activity of proteasome complex increased in muscle of old trained rats. We suggest that regular exercise-induced adaptation attenuates the age-associated increase in 8-OHdG levels, and increases the activity of DNA repair and resistance against oxidative stress in proteins.
Pfl�gers Archiv European Journal of Physiology, 1998
It is known that acute physical exercise may have diverse pathophysiological consequences in vari... more It is known that acute physical exercise may have diverse pathophysiological consequences in various organs due to free radical formation. We have investigated whether a period of anaerobic running to exhaustion in rats results in oxidative modification of proteins in the lungs. Six rats of an exercised group (E) ran for two periods of 5 min at a speed of 30 m·min -1 followed by a recovery period of 5 min, and then by a third period of running to exhaustion. Reactive carbonyl derivatives (RCD) were measured by the Western blot technique on lungs of E and control (C) rats. In addition, the activity of glutamine synthetase (GS) was also monitored as marker of oxidative damage to proteins. This investigation revealed significant exercise-induced increases in accumulation of RCD in the lungs of the E group compared with the C group. The RCD signals were visibly stronger in proteins with molecular weight of 55 kDa and 32 kDa. The activity of GS was higher by about 30% in E rats than in C rats. The present data suggest that anaerobic exercise induces protein oxidation in the lungs.