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Howard T. Petrie - One of the best experts on this subject based on the ideXlab platform.
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Metabolic Damage and Premature Thymus Aging Caused by Stromal Catalase Deficiency
Cell reports, 2015Co-Authors: Ann V. Griffith, Thomas Venables, Jianjun Shi, Andrew G. Farr, Holly Van Remmen, Luke I. Szweda, Mohammad Fallahi, Peter S. Rabinovitch, Howard T. PetrieAbstract:T lymphocytes are essential mediators of immunity that are produced by the thymus in proportion to its size. The thymus atrophies rapidly with age, resulting in progressive diminution of new T cell production. This decreased output is compensated by duplication of existing T cells, but it results in gradual dominance by memory T cells and decreased ability to respond to new pathogens or vaccines. Here, we show that accelerated and irreversible thymic atrophy results from stromal Deficiency in the reducing enzyme Catalase, leading to increased damage by hydrogen peroxide generated by aerobic metabolism. Genetic complementation of Catalase in stromal cells diminished atrophy, as did chemical antioxidants, thus providing a mechanistic link between antioxidants, metabolism, and normal immune function. We propose that irreversible thymic atrophy represents a conventional aging process that is accelerated by stromal Catalase Deficiency in the context of an intensely anabolic (lymphoid) environment.
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Metabolic damage and premature thymus aging caused by stromal Catalase Deficiency (LYM2P.722)
Journal of Immunology, 2015Co-Authors: Ann Griffith, Thomas Venables, Jianjun Shi, Andrew G. Farr, Holly Van Remmen, Luke I. Szweda, Mohammad Fallahi, Peter S. Rabinovitch, Howard T. PetrieAbstract:T lymphocytes are essential mediators of immunity produced by the thymus in proportion to mass. The thymus atrophies rapidly with age, resulting in diminished new T cell production. Decreased thymic output is compensated by duplication of existing cells, but results in progressive dominance by memory T cells, and decreased ability to respond to new pathogens or vaccines. We find that accelerated thymic atrophy results from stromal Deficiency in the reducing enzyme Catalase, leading to increased damage by reactive oxygen species (ROS) generated during aerobic metabolism. Genetic complementation of Catalase diminished atrophy, as did chemical antioxidants, providing a mechanistic link between antioxidants, metabolism, and normal immune function. Progenitor lymphoblasts represent the primary source of thymic ROS, likely acting on stromal cells in trans. We propose that thymic atrophy represents a conventional aging process that is accelerated by stromal Catalase Deficiency in the context of an intensely metabolic lymphoid environment.
László Góth - One of the best experts on this subject based on the ideXlab platform.
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Inherited Catalase Deficiency: is it benign or a factor in various age related disorders?
Mutation research, 2013Co-Authors: László Góth, Teréz NagyAbstract:Hydrogen peroxide was - and is still - considered toxic for a wide range of living organisms. Oxidative stress occurs when there is an excess of pro-oxidants over antioxidants and it has been implicated in several diseases. Catalase is involved in hydrogen peroxide catabolism and is important in defense against oxidative stress. ACatalasemia means the inherited near-total Deficiency of Catalase activity, usually in reference to red cell Catalase. ACatalasemia was thought at first to be an asymptotic disorder. In the absence of Catalase, neither the Japanese, or Hungarian aCatalasemics nor aCatalasemic mice had significantly increased blood glutathione peroxidase activity. In animal models, Catalase deficient tissues show much slower rates of removal of extracellular hydrogen peroxide. In Catalase knock-out mice, a decreased hydrogen peroxide removing capacity and increased reactive oxygen species formation were reported. Hydrogen peroxide may cause methemoglobinemia in patients with Catalase Deficiency. During anesthesia for a Japanese aCatalasemic patient the disinfection with hydrogen peroxide solution caused severe methemoglobinemia. Patients with inherited Catalase Deficiency, who are treated with uric acid oxidase (rasburicase) may experience very high concentrations of hydrogen peroxide and may suffer from methemoglobinemia and hemolysis. The high (18.5%) prevalence of diabetes mellitus in inherited Catalase deficient individuals and the earlier (10 years) manifestation of the disease may be attributed to the oxidative damage of oxidant sensitive, insulin producing pancreatic beta-cells. Ninety-seven of 114 aCatalasemics had diseases related to oxidative stress and aging. The oxidative stress due to Catalase Deficiency could contribute to the manifestation of diabetes while for the other diseases it may be one of the factors in their causations. In summary, inherited Catalase Deficiency is associated with clinical features, pathologic laboratory test results, age and oxidative stress related disorders. Rather than considering it a benign condition, it should be considered as a complicating condition for aging and oxidative stress.
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ACatalasemia and diabetes mellitus
Archives of biochemistry and biophysics, 2012Co-Authors: László Góth, Teréz NagyAbstract:The enzyme Catalase catalyzes the breakdown of hydrogen peroxide into oxygen and water. It is the main regulator of hydrogen peroxide metabolism. Hydrogen peroxide is a highly reactive small molecule formed as a natural byproducts of energy metabolism. Excessive concentrations may cause significant damages to protein, DNA, RNA and lipids. Low levels in muscle cells, facilitate insulin signaling. ACatalasemia is a result of the homozygous mutations in the Catalase gene, has a worldwide distribution with 12 known mutations. Increased hydrogen peroxide, due to Catalase Deficiency, plays a role in the pathogenesis of several diseases such as diabetes mellitus. Diabetes mellitus is a disorder caused by multiple genetic and environmental factors. Examination of Hungarian diabetic and aCatalasemic patients showed that an increased frequency of Catalase gene mutations exists among diabetes patients. Inherited Catalase Deficiency may increase the risk of type 2 diabetes mellitus, especially for females. Early onset of type 2 diabetes occurs with inherited Catalase Deficiency. Low levels of SOD and glutathione peroxidase could contribute to complications caused by increased oxidative stress.
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A kataláz enzim génje polimorfizmusának hatása az enzim expressziójára = Association of Catalase gene and Catalase protein expression
2012Co-Authors: László Góth, Eszter Sükei, Miklós Káplár, Amir H. Shemirani, Enikő Simics, Ildikó TarnaiAbstract:1. Katalaz gen exon 9 C111T polimorfizmus kismertekű ver katalaz csokkenessel jar vitiligos nők eseteben (CEMED 2011) 2. Csokkent ver katalaz aktivitas volt merhető magyar beta-thalassemia trait betegeknel. 6 uj Magarorszagon meg nem detektalt mutaciot detektaltunk. (Int J Lab Hematol 2012) 3. A -C262T polmorfizmus vizsgalata Magyarorszagi vitiligos betegeknel es kontroll egyeneknel a CC genotipus gyakorisaganak csokkenest mutatta. Ket uj akatalazemia mutacio (exon 9: C37T es G113 ) volt detektalhato Magyarorszagi egyeneknel (Mol Biol Rep 2012) 4. Egyszeru szűrő modszer kifejlesztese tortent a katalaz gen 9. exon polimorfizmusainak vizsgalatara. Ezzel modszerrel azt talaltak, hogy a C111T polimorfizmusban a TT genotipus mutatta legalacsonyabb katalaz aktivitast microciter anemaban es beta-thallassemiaban. (Arch Biochem Biophys 2012) 5. A veleszuletett katalaz hianyos egyeneknel fokozottan fordul elő a 2-es tipusu diabetes. Magyarorszagon mar 7 akatalazemia mutaciorol szamoltak be a szerzők.(Arch Biochem Biophys 2012) 6. A 2-es tipusu diabetesben a C-262T polimorfizmus TT genotipusa csokkent eletkorral, HDL-el es emelkedett glukoz, HbA1c, koleszterin, Apob B koncentraciokkal es a legkisebb letszamu sulphonylure kezelsesel jaro csoportot mutatott . A TT gentipus ezeknel a betegeknel fokozott diabetes komlpikaciokra utlhat (Free Radic Res 2012 in press) | 1. C111T polymoprhism of Catalase gene exon 9 has a weak effect on blood Catalase activity in female vitiligo patients (CEMED 2011) 2. Decreased blood Catalase activity was detected in beta-thalassemia trait patients in Hugary. Six new beta-thalassemia trait mutation was reported in Hungary (Int J Lab Hematol 2012) 3.Examination of -262C toT polymorphism in Hungarian vitiligo patients and in controls showed decrease frequency of CC genotype. Two new aCatalasemia mutations (exon 9: C37T and G113 T) were reported in Hungarian subjects (Mol Biol Rep 2012) 4.A simple screening method was developed for examinations of polymorphisms in Catalase exon 9. With this method the examination of C111T polymorphism the TT genotype yielded the lowest blood Catalase in microcyter anemia and beta-thalassemia trait patients (Arch Bichem Biophys 2012) 5. Inherited Catalase Deficiency is associated with increased frequency of type 2 diabetes. In Hungary, seven aCatalasemia mutations have been reported. (Arch Bioche Biophys 2012) 6.In type 2 diabetes the TT genotype of C-262T polymorphism was associated with decreased age, HDL and increased glucose, HbA1c, cholesterol, ApoB and the smallest group of patients treated with sulphonyurea.TT genotype of this polymorphism may mean a higher risk of diabetes complications (Free Radic Res 2012 in press)
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Catalase Deficiency and Type 2 Diabetes
Diabetes care, 2008Co-Authors: László GóthAbstract:Recent data suggest that at low concentrations hydrogen peroxide acts as a cellular messenger in insulin signaling, whereas at high concentrations it is toxic, particularly in pancreatic cells, which are Catalase poor. Erythrocyte Catalase is the main regulator of hydrogen peroxide metabolism; any inherited or acquired deficiencies in erythrocyte Catalase may cause increased hydrogen peroxide concentrations with both toxic and physiological effects. Examination of 23,150 Hungarian subjects detected 2 aCatalasemic homozygotes and 63 hypoCatalasemic heterozygotes. The two aCatalasemic subjects and five of the hypoCatalasemic subjects had type 2 diabetes, and one hypoCatalasemic subject had type 1 diabetes. The 11% frequency of type 2 diabetes among the 65 Catalase-deficient subjects was significantly different ( P < 0.005) from the 0% frequency among their normoCatalasemic relatives and the 1.75% frequency …
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Az öröklött és szerzett kataláz hiány klinikai és klinikai biokémiai vonatkozásai = Clinical and biochemical consequences of inherited and acquired forms of Catalase Deficiency
2007Co-Authors: László Góth, Eszter Sükei, Sándor Imre, Ildikó TarnaiAbstract:A hidrogenperoxid az előszervezetekre gyakorolt oxidativ, toxikus hatasarol volt ismert, mig szerepe az ujabb irodalmi adatok alapjan atertekelődott. A hidrogenperoxid paradoxon azt jelenti, hogy kis koncentracioban fiziologias feladatai vannak, mig nagy koncentracioban toxikus a sejtekre. A hidrogenperoxid metabolizmus fő szabalyozo enzime a katalaz, amelynek hianya tobb patologias folyamat kialakulasanak kockazati tenyezője lehet. A megnovekedett plazma homocisztein es veleszuletett katalaz hiany a fokozott hidrogenperoxid reven novelhet az oxidativ stresszt. Ez az oxidaciora erzekeny folsavon keresztul csokkentheti a verkepzest. Vizsgalataink soran csokkent ver katalazt detektaltunk 1-es tipus,. 2-es tipusu es gestacios diabetesben. Az utobbi megbetegedesben az ismert katalaz mutaciokak nem talaltuk es a jelenseget a katalaz szintezis csokkenesenek tulajdonitottuk. 3 missense mutacio (kettő a 2. exonban: 96, 135, egy a 9. exonban: 111), amely a katalaz aktivitast csokkentette hozzajarulhat a diabetes mellitus pathomechanizmusahoz. Vizsgalati eredmenyeinkből arra kovetkeztethetunk, hogy nem a mutacio tipusa, hanem az annak kovetkezteben kialakult katalaz csokkenes lehet a felelős a pathologies elvaltozasokert. Irodalmi es sajat adataink alapjan elemeztuk a katalaz gen polimorfizmusait es mutacioit. A Magyarorszag akatalazemia ket (D es E) uj tipusat irtuk le. | Hydrogen peroxide was known as a toxic agent for human organs. Due to the recent findings its role has been reevaluated. The hydrogen peroxide paradox means that its low concentration is vital for some physiological processes while its high concentration is toxic for human cells. The main regulator of hydrogen peroxide is the enzyme Catalase and its Deficiency may be a risk factor for some pathological changes. The increased plasma homocysteine and inherited Catalase Deficiency could promote oxidative stress via hydrogen peroxide. This stress may be responsible for the decreased blood hemoglobin via the oxidation sensitive folate. We found decreased blood Catalase in different forms (type 1, type 2 and gestational) of diabetes mellitus. For this, the dysregulation of Catalase synthesis may be responsible in gestational diabetes as we could not detect the known mutations in the Catalase gene. Three missense mutations (on exon 2: 96 and 135 and on exon 9: 111) could cause to the decreased blood Catalase activity and may contribute to the pathomechanism of diabetes mellitus. Our data suggest that it is not the type of mutation but rather its effect, the decreased blood Catalase activity, that may be responsible for the development of diabetes mellitus. We analyzed the Catalase gene polymorphisms and two new types (Hungarian D and E) were added to the Hungarian types of the inherited Catalase deficiencies.
Xilin Zhao - One of the best experts on this subject based on the ideXlab platform.
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Reactive oxygen species play a dominant role in all pathways of rapid quinolone-mediated killing.
The Journal of antimicrobial chemotherapy, 2019Co-Authors: Yuzhi Hong, Karl Drlica, Qiong Gao, Jianping Xie, Haihui Huang, Xilin ZhaoAbstract:Background Quinolones have been thought to rapidly kill bacteria in two ways: (i) quinolone-topoisomerase-DNA lesions stimulate the accumulation of toxic reactive oxygen species (ROS); and (ii) the lesions directly cause lethal DNA breaks. Traditional killing assays may have underestimated the ROS contribution by overlooking the possibility that ROS continue to accumulate and kill cells on drug-free agar after quinolone removal. Methods Quinolone-induced, ROS-mediated killing of Escherichia coli was measured by plating post-treatment samples on agar with/without anti-ROS agents. Results When E. coli cultures were treated with ciprofloxacin or moxifloxacin in the presence of chloramphenicol (to accentuate DNA-break-mediated killing), lethal activity, revealed by plating on quinolone-free agar, was inhibited by supplementing agar with ROS-mitigating agents. Moreover, norfloxacin-mediated lethality, observed with cells suspended in saline, was blocked by inhibitors of ROS accumulation and exacerbated by a katG Catalase Deficiency that impairs peroxide detoxification. Unlike WT cells, the katG mutant was killed by nalidixic acid or norfloxacin with chloramphenicol present and by nalidixic or oxolinic acid with cells suspended in saline. ROS accumulated after quinolone removal with cultures either co-treated with chloramphenicol or suspended in saline. Deficiencies in recA or recB reduced the protective effects of ROS-mitigating agents, supporting the idea that repair of quinolone-mediated DNA lesions suppresses the direct lethal effects of such lesions. Conclusions ROS are the dominant factor in all modes of quinolone-mediated lethality, as quinolone-mediated primary DNA lesions are insufficient to kill without triggering ROS accumulation. ROS-stimulating adjuvants may enhance the lethality of quinolones and perhaps other antimicrobials.
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Suppression of Reactive Oxygen Species Accumulation Accounts for Paradoxical Bacterial Survival at High Quinolone Concentration.
Antimicrobial agents and chemotherapy, 2017Co-Authors: Gan Luan, Yuzhi Hong, Karl Drlica, Xilin ZhaoAbstract:When bacterial cells are exposed to increasing concentrations of quinolone-class antibacterials, survival drops, reaches a minimum, and then recovers, sometimes to 100%. Despite decades of study, events underlying this paradoxical high-concentration survival remain obscure. Since reactive oxygen species (ROS) have been implicated in antimicrobial lethality, conditions generating paradoxical survival were examined for diminished ROS accumulation. Escherichia coli cultures were treated with various concentrations of nalidixic acid, followed by measurements of survival, rate of protein synthesis, and ROS accumulation. The last measurement used a dye (carboxy-H2DCFDA) that fluoresces in the presence of ROS; fluorescence was assessed by microscopy (individual cells) and flow cytometry (batch cultures). High, nonlethal concentrations of nalidixic acid induced lower levels of ROS than moderate, lethal concentrations. Sublethal doses of exogenous hydrogen peroxide became lethal and eliminated the nalidixic acid-associated paradoxical survival. Thus, quinolone-mediated lesions needed for ROS-executed killing persist at high, nonlethal quinolone concentrations, thereby implicating ROS as a key factor in cell death. Chloramphenicol suppressed nalidixic acid-induced ROS accumulation and blocked lethality, further supporting a role for ROS in killing. Nalidixic acid also inhibited protein synthesis, with extensive inhibition at high concentrations correlating with lower ROS accumulation and paradoxical survival. A Catalase Deficiency, which elevated ROS levels, overcame the inhibitory effect of chloramphenicol on nalidixic acid-mediated killing, emphasizing the importance of ROS. The data collectively indicate that ROS play a dominant role in the lethal action of narrow-spectrum quinolone-class compounds; a drop in ROS levels accounted for the quinolone tolerance observed at very high concentrations.
Noriyoshi Masuoka - One of the best experts on this subject based on the ideXlab platform.
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Protective effect of vitamin E against alloxan-induced mouse hyperglycemia.
Biochimica et biophysica acta, 2015Co-Authors: Kazunori Takemoto, Wakana Doi, Noriyoshi MasuokaAbstract:Abstract Background Alloxan induces oxidative stress and hyperglycemia in animal models. ACatalasemic (Catalase Deficiency) mice are susceptible to alloxan-induced hyperglycemia. As the incidence of hyperglycemia induced by alloxan was reportedly improved when mice were fed a vitamin E supplemented diet, this protective effect was examined. Methods ACatalasemic and normal mice fed a vitamin E supplemented diet were treated with alloxan. The pancreas were examined with microscopy. We also isolated pancreatic islets of normal mice treated with alloxan. The glucose stimulated insulin secretion was examined. Results Vitamin E powerfully ameliorated the increase in apoptosis. Vitamin E increases insulin amounts secreted from pancreatic cells, but does not ameliorate the regulation of the glucose stimulated insulin secretion. Conclusions It is suggested that the difference in the mice fed vitamin E supplemented diet is due to an increase of insulin secretion and that vitamin E supplementation may have a role in helping to slow the stages of diabetes mellitus.
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Insulin Release from the Beta Cells in ACatalasemic Mice Is Highly Susceptible to Alloxan-Induced Oxidative Stress
Journal of Database Management, 2015Co-Authors: Kazunori Takemoto, Hitoshi Sugiyama, Da Hong Wang, Kohji Ishihara, Wakana Doi, Ken Kataoka, Noriyoshi MasuokaAbstract:Background: Catalase Deficiency (aCatalasemia) is sensitive to alloxan, and the administration to aCatalasemic mice develops hyperglycemia under mild conditions. However, the mechanism is still poorly understood. Methods: Alloxan was used to induce the oxidative stress and intraperitoneally administered to aCatalasemic and normal mice. The blood samples of these mice after 1, 3, 5 and 7 days were examined. The pancreatic islets 7 days after alloxan administration were isolated, and the insulin released under 3 mM and 20 mM glucose was examined. Results: After alloxan administration, increase of oxidative markers in blood and pancreatic apoptosis in aCatalasemic mice were observed immediately. Insulin in blood was lowered after 3 days, and the insulin in aCatalasemic mice was lower than that in normal mice. Hyperglycemia in the aCatalasemic mice was observed after 3 days. The pancreatic islets after 7 days were isolated. A reduction of the insulin released from the islets under glucose stimulation was observed. The stimulation indexes of the normal and aCatalasemic mice were 1.4 ± 0.6 and 0.7 ± 0.3, respectively. Conclusions: Alloxan induced a deterioration of glucose-dependent insulin secretion ability from the islets, and the deterioration mostly contributed to hyperglycemia, rather than apoptosis.
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ACatalasemic mice are mildly susceptible to adriamycin nephropathy and exhibit increased albuminuria and glomerulosclerosis
BMC nephrology, 2012Co-Authors: Keiichi Takiue, Hitoshi Sugiyama, Da Hong Wang, Yohei Maeshima, Tatsuyuki Inoue, Hiroshi Morinaga, Yoko Kikumoto, Masashi Kitagawa, Shinji Kitamura, Noriyoshi MasuokaAbstract:Background Catalase is an important antioxidant enzyme that regulates the level of intracellular hydrogen peroxide and hydroxyl radicals. The effects of Catalase Deficiency on albuminuria and progressive glomerulosclerosis have not yet been fully elucidated. The adriamycin (ADR) nephropathy model is considered to be an experimental model of focal segmental glomerulosclerosis. A functional Catalase Deficiency was hypothesized to exacerbate albuminuria and the progression of glomerulosclerosis in this model.
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ACatalasemic mice are mildly susceptible to adriamycin nephropathy and exhibit increased albuminuria and glomerulosclerosis
BMC Nephrology, 2012Co-Authors: Keiichi Takiue, Hitoshi Sugiyama, Yohei Maeshima, Tatsuyuki Inoue, Hiroshi Morinaga, Yoko Kikumoto, Masashi Kitagawa, Shinji Kitamura, Da-hong Wang, Noriyoshi MasuokaAbstract:Background Catalase is an important antioxidant enzyme that regulates the level of intracellular hydrogen peroxide and hydroxyl radicals. The effects of Catalase Deficiency on albuminuria and progressive glomerulosclerosis have not yet been fully elucidated. The adriamycin (ADR) nephropathy model is considered to be an experimental model of focal segmental glomerulosclerosis. A functional Catalase Deficiency was hypothesized to exacerbate albuminuria and the progression of glomerulosclerosis in this model. Methods ADR was intravenously administered to both homozygous aCatalasemic mutant mice (C3H/AnLCs^bCs^b) and control wild-type mice (C3H/AnLCs^aCs^a). The functional and morphological alterations of the kidneys, including albuminuria, renal function, podocytic, glomerular and tubulointerstitial injuries, and the activities of Catalase were then compared between the two groups up to 8 weeks after disease induction. Moreover, the presence of a mutation of the toll-like receptor 4 ( tlr4 ) gene, which was previously reported in the C3H/HeJ strain, was investigated in both groups. Results The ADR-treated mice developed significant albuminuria and glomerulosclerosis, and the degree of these conditions in the ADR-treated aCatalasemic mice was higher than that in the wild-type mice. ADR induced progressive renal fibrosis, renal atrophy and lipid peroxide accumulation only in the aCatalasemic mice. In addition, the level of Catalase activity was significantly lower in the kidneys of the aCatalasemic mice than in the wild-type mice during the experimental period. The Catalase activity increased after ADR injection in wild-type mice, but the aCatalasemic mice did not have the ability to increase their Catalase activity under oxidative stress. The C3H/AnL strain was found to be negative for the tlr4 gene mutation. Conclusions These data indicate that Catalase Deficiency plays an important role in the progression of renal injury in the ADR nephropathy model.
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Low Catalase activity in blood is associated with the diabetes caused by alloxan.
Clinica chimica acta; international journal of clinical chemistry, 2009Co-Authors: Kazunori Takemoto, Da-hong Wang, Miho Tanaka, Hiroshi Iwata, Ryou Nishihara, Kohji Ishihara, Keiki Ogino, Koji Taniuchi, Noriyoshi MasuokaAbstract:Hydrogen peroxide is enzymatically processed by Catalase, and Catalase Deficiency in blood is known as aCatalasemia. We examined whether low Catalase activity is a risk factor for diabetes mellitus. Blood glucose, insulin and glucose tolerance test were examined in aCatalasemic and normal mice under non-stress and oxidative stress conditions. Alloxan administration was used as oxidative stress. Alloxan, which was a drug that caused diabetes mellitus, mostly generated hydrogen peroxide by the reaction of alloxan and reduced glutathione, in vitro. Incidence of hyperglycemia in alloxan-untreated aCatalasemic mice was as low as that in the normal mice. However, the incidence of aCatalasemia mice treated with alloxan was higher than that in normal mice, and the number of pancreatic beta-cells in the aCatalasemic mice was less than that in normal mice. These results indicate that low Catalase activity in the blood is associated with the diabetes mellitus caused by alloxan administration.
Peter S. Rabinovitch - One of the best experts on this subject based on the ideXlab platform.
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Metabolic Damage and Premature Thymus Aging Caused by Stromal Catalase Deficiency
Cell reports, 2015Co-Authors: Ann V. Griffith, Thomas Venables, Jianjun Shi, Andrew G. Farr, Holly Van Remmen, Luke I. Szweda, Mohammad Fallahi, Peter S. Rabinovitch, Howard T. PetrieAbstract:T lymphocytes are essential mediators of immunity that are produced by the thymus in proportion to its size. The thymus atrophies rapidly with age, resulting in progressive diminution of new T cell production. This decreased output is compensated by duplication of existing T cells, but it results in gradual dominance by memory T cells and decreased ability to respond to new pathogens or vaccines. Here, we show that accelerated and irreversible thymic atrophy results from stromal Deficiency in the reducing enzyme Catalase, leading to increased damage by hydrogen peroxide generated by aerobic metabolism. Genetic complementation of Catalase in stromal cells diminished atrophy, as did chemical antioxidants, thus providing a mechanistic link between antioxidants, metabolism, and normal immune function. We propose that irreversible thymic atrophy represents a conventional aging process that is accelerated by stromal Catalase Deficiency in the context of an intensely anabolic (lymphoid) environment.
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Metabolic damage and premature thymus aging caused by stromal Catalase Deficiency (LYM2P.722)
Journal of Immunology, 2015Co-Authors: Ann Griffith, Thomas Venables, Jianjun Shi, Andrew G. Farr, Holly Van Remmen, Luke I. Szweda, Mohammad Fallahi, Peter S. Rabinovitch, Howard T. PetrieAbstract:T lymphocytes are essential mediators of immunity produced by the thymus in proportion to mass. The thymus atrophies rapidly with age, resulting in diminished new T cell production. Decreased thymic output is compensated by duplication of existing cells, but results in progressive dominance by memory T cells, and decreased ability to respond to new pathogens or vaccines. We find that accelerated thymic atrophy results from stromal Deficiency in the reducing enzyme Catalase, leading to increased damage by reactive oxygen species (ROS) generated during aerobic metabolism. Genetic complementation of Catalase diminished atrophy, as did chemical antioxidants, providing a mechanistic link between antioxidants, metabolism, and normal immune function. Progenitor lymphoblasts represent the primary source of thymic ROS, likely acting on stromal cells in trans. We propose that thymic atrophy represents a conventional aging process that is accelerated by stromal Catalase Deficiency in the context of an intensely metabolic lymphoid environment.