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Li W, Wu M, Li Y, Shen J. Reactive nitrogen species as therapeutic targets for autophagy/mitophagy modulation to relieve neurodegeneration in multiple sclerosis: Potential application for drug discovery. Free Radic Biol Med 2023; 208:37-51. [PMID: 37532065 DOI: 10.1016/j.freeradbiomed.2023.07.032] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Revised: 07/28/2023] [Accepted: 07/31/2023] [Indexed: 08/04/2023]
Abstract
Multiple sclerosis (MS) is a neuroinflammatory disease with limited therapeutic effects, eventually developing into handicap. Seeking novel therapeutic strategies for MS is timely important. Active autophagy/mitophagy could mediate neurodegeneration, while its roles in MS remain controversial. To elucidate the exact roles of autophagy/mitophagy and reveal its in-depth regulatory mechanisms, we conduct a systematic literature study and analyze the factors that might be responsible for divergent results obtained. The dynamic change levels of autophagy/mitophagy appear to be a determining factor for final neuron fate during MS pathology. Excessive neuronal autophagy/mitophagy contributes to neurodegeneration after disease onset at the active MS phase. Reactive nitrogen species (RNS) serve as key regulators for redox-related modifications and participate in autophagy/mitophagy modulation in MS. Nitric oxide (•NO) and peroxynitrite (ONOO-), two representative RNS, could nitrate or nitrosate Drp1/parkin/PINK1 pathway, activating excessive mitophagy and aggravating neuronal injury. Targeting RNS-mediated excessive autophagy/mitophagy could be a promising strategy for developing novel anti-MS drugs. In this review, we highlight the important roles of RNS-mediated autophagy/mitophagy in neuronal injury and review the potential therapeutic compounds with the bioactivities of inhibiting RNS-mediated autophagy/mitophagy activation and attenuating MS progression. Overall, we conclude that reactive nitrogen species could be promising therapeutic targets to regulate autophagy/mitophagy for multiple sclerosis treatment.
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Affiliation(s)
- Wenting Li
- Department of Pharmacy, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China.
| | - Meiling Wu
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
| | - Yuzhen Li
- Department of Pharmacy, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China.
| | - Jiangang Shen
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
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Sun X, Jiao H, Zhao J, Wang X, Lin H. Rule of UA on Cardiac Myocytes Uric Acid Differently Influence the Oxidative Damage Induced by Acute Exposure of High Level of Glucose in Chicken Cardiac Myocytes. Front Vet Sci 2020; 7:602419. [PMID: 33426022 PMCID: PMC7785973 DOI: 10.3389/fvets.2020.602419] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 11/30/2020] [Indexed: 12/26/2022] Open
Abstract
Background: Uric acid (UA) is a potent scavenger of oxidants in mammalian and avian species. In humans, hyperglycemia with simultaneous hyperuricemia may exert additional damage to the cardiovascular system. Chickens naturally have hyperglycemia (10.1–11.0 mmol/L) and hyperuricemia (100–900 μmol/L), which makes them an interesting model. Methods: The aim of this study was to investigate the effects of UA on the oxidative damage induced by acute exposure of high level of glucose in chicken cardiac myocytes. Results: Cell viability and the concentrations of thiobarbituric acid reactive substance (TBARS) were decreased by glucose treatment in a dose- and time-dependent manner. After acute exposure to high level of glucose (300 mM), a moderate level of UA (300 μM) increased cell viability and reduced TBARS and glutathione (GSH) content. Compared to the control or to independent high glucose (300 mM) or UA (1,200 μM) treatment, the concurrent treatment of high glucose and high UA significantly increased the TBARS, protein carbonyl contents, and ROS concentration, whereas it decreased the cell viability, superoxide dismutase (SOD) activity, and GSH content. In the presence of high glucose and UA, the nucleic protein expression of nuclear factor erythroid 2-related factor 2 (Nrf2) was decreased and the mRNA levels of the genes cat, sod1, sod2, gss, and gclc were downregulated. Conclusion: In conclusion, acute exposure of high level of glucose induced oxidative damage in the cardiac myocytes of chicken. The present result suggests that an adequate level of uric acid is helpful in alleviating the acute oxidative damage that is induced by high glucose, whereas the inhibition of the Nrf2 pathway by a high level of uric acid may render the cardiac myocytes more vulnerable to suffering from oxidative damage.
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Affiliation(s)
- Xiaolong Sun
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an, China.,Shandong Key Lab of Animal Bioengineering and Disease Control and Prevention, Tai'an, China
| | - Hongchao Jiao
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an, China.,Shandong Key Lab of Animal Bioengineering and Disease Control and Prevention, Tai'an, China
| | - Jingpeng Zhao
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an, China.,Shandong Key Lab of Animal Bioengineering and Disease Control and Prevention, Tai'an, China
| | - Xiaojuan Wang
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an, China.,Shandong Key Lab of Animal Bioengineering and Disease Control and Prevention, Tai'an, China
| | - Hai Lin
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an, China.,Shandong Key Lab of Animal Bioengineering and Disease Control and Prevention, Tai'an, China
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Coleto I, Pineda M, Alamillo JM. Molecular and biochemical analysis of XDH from Phaseolus vulgaris suggest that uric acid protects the enzyme against the inhibitory effects of nitric oxide in nodules. PLANT PHYSIOLOGY AND BIOCHEMISTRY : PPB 2019; 143:364-374. [PMID: 31542638 DOI: 10.1016/j.plaphy.2019.09.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/14/2019] [Revised: 09/04/2019] [Accepted: 09/04/2019] [Indexed: 06/10/2023]
Abstract
Xanthine dehydrogenase (XDH) is essential for the assimilation of symbiotically fixed nitrogen in ureidic legumes. Uric acid, produced in the reaction catalyzed by XDH, is the precursor of the ureides, allantoin and allantoate, which are the main N-transporting molecules in these plants. XDH and uric acid have been reported to be involved in the response to stress, both in plants and animals. However, the physiological role of XDH under stressful conditions in ureidic legumes remains largely unexplored. In vitro assays showed that Phaseolus vulgaris XDH (PvXDH) can behave as a dehydrogenase or as an oxidase. Therefore, it could potentially protect against oxidative radicals or, in contrast, it could increase their production. In silico analysis of the upstream genomic region of XDH coding gene from P. vulgaris revealed the presence of several stress-related cis-regulatory elements. PvXDH mRNA and enzymatic activity in plants treated with stress-related phytohormones or subjected to dehydration and stressful temperatures showed several fold induction. However, PvXDH activity was in vivo and in vitro inhibited by nitric oxide in leaves but not in nodules. In extracts from RNAi PvXDH silenced nodules, with lower levels of uric acid, XDH activity was inhibited by SNP which indicates that uric acid produced by XDH in the nodules of this ureidic legume could help to protect XDH against the inhibitory effects of nitric oxide.
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Affiliation(s)
- Inmaculada Coleto
- Departamento de Botánica, Ecología y Fisiología Vegetal, Grupo de Fisiología Molecular y Biotecnología de Plantas, Campus de Excelencia Internacional Agroalimentario, CEIA3, Campus de Rabanales, Edif. Severo Ochoa, Universidad de Córdoba, 14071, Córdoba, Spain.
| | - Manuel Pineda
- Departamento de Botánica, Ecología y Fisiología Vegetal, Grupo de Fisiología Molecular y Biotecnología de Plantas, Campus de Excelencia Internacional Agroalimentario, CEIA3, Campus de Rabanales, Edif. Severo Ochoa, Universidad de Córdoba, 14071, Córdoba, Spain.
| | - Josefa M Alamillo
- Departamento de Botánica, Ecología y Fisiología Vegetal, Grupo de Fisiología Molecular y Biotecnología de Plantas, Campus de Excelencia Internacional Agroalimentario, CEIA3, Campus de Rabanales, Edif. Severo Ochoa, Universidad de Córdoba, 14071, Córdoba, Spain.
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Roumeliotis S, Roumeliotis A, Dounousi E, Eleftheriadis T, Liakopoulos V. Dietary Antioxidant Supplements and Uric Acid in Chronic Kidney Disease: A Review. Nutrients 2019; 11:nu11081911. [PMID: 31443225 PMCID: PMC6723425 DOI: 10.3390/nu11081911] [Citation(s) in RCA: 83] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 08/10/2019] [Accepted: 08/12/2019] [Indexed: 02/07/2023] Open
Abstract
Increased serum levels of uric acid have been associated with the onset and development of chronic kidney disease (CKD), cardiovascular disease, and mortality, through several molecular pathogenetic mechanisms, such as inflammation and oxidative stress. Oxidative stress is present even in the early stages of CKD, progresses parallelly with the deterioration of kidney function, and is even more exacerbated in end-stage renal disease patients undergoing maintenance hemodialysis. Although acting in the plasma as an antioxidant, once uric acid enters the intracellular environment; it behaves as a powerful pro-oxidant. Exogenous intake of antioxidants has been repeatedly shown to prevent inflammation, atherosclerosis and oxidative stress in CKD patients. Moreover, certain antioxidants have been proposed to exert uric acid-lowering properties. This review aims to present the available data regarding the effects of antioxidant supplements on both oxidative stress and uric acid serum levels, in a population particularly susceptible to oxidative damage such as CKD patients.
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Affiliation(s)
- Stefanos Roumeliotis
- Division of Nephrology and Hypertension, 1st Department of Internal Medicine, AHEPA Hospital, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki 54636, Greece
| | - Athanasios Roumeliotis
- Division of Nephrology and Hypertension, 1st Department of Internal Medicine, AHEPA Hospital, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki 54636, Greece
| | - Evangelia Dounousi
- Department of Nephrology, School of Medicine, University of Ioannina, Ioannina 45110, Greece
| | | | - Vassilios Liakopoulos
- Division of Nephrology and Hypertension, 1st Department of Internal Medicine, AHEPA Hospital, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki 54636, Greece.
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Uric Acid Provides Protective Role in Red Blood Cells by Antioxidant Defense: A Hypothetical Analysis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:3435174. [PMID: 31049132 PMCID: PMC6458867 DOI: 10.1155/2019/3435174] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Revised: 12/16/2018] [Accepted: 01/12/2019] [Indexed: 01/15/2023]
Abstract
Uric acid (UA) is a major antioxidant molecule in the human blood, and it has been linked with cell longevity. However, it is unclear whether serum UA levels are associated with red blood cell (RBC) indexes. This cross-sectional study included 10,759 Chinese subjects, recruited from the Shanghai Xuhui Central Hospital from January 2014 to December 2017. The participants were categorized into gender groups and then further divided into three different subgroups according to their UA reference range as follows: low (male (UA < 0.202 mmol/l), female (UA < 0.143 mmol/l)), normal (male (0.417 mmol/l > UA ≥ 0.202 mmol/l), female (0.339 mmol/l > UA ≥ 0.143 mmol/l)), and high (male (UA ≥ 0.417 mmol/l), female (UA ≥ 0.339 mmol/l)). The associations of UA levels with RBC parameters were analyzed using 1-way ANOVA, Pearson correlations, and multivariate linear regression. The levels of mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, RBCs, and hemoglobin were lowest in the low UA group, followed by the normal UA group and high UA group (p < 0.001). Pearson analysis showed that there was a statistically significant correlation between UA levels with mean corpuscular hemoglobin, mean corpuscular hemoglobin concentrations, mean corpuscular volumes, RBC counts, and hemoglobin (p < 0.05). Multiple linear regression analysis suggested that there were statistically significant positive correlations between UA levels and RBC counts (B = 0.245, p < 0.001, 95% CI = 0.003 to 0.092), as well as UA levels and hemoglobin concentrations (B = 0.138, p < 0.001, 95% CI = 0.002 to 0.082). Furthermore, similar results were observed in both the male and female subgroups. The serum UA levels may be independently associated with RBC parameters, regardless of sex, and UA may protect RBCs owing to its antioxidant effect.
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6
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Sun X, Jiao H, Zhao J, Wang X, Lin H. Unexpected effect of urate on hydrogen peroxide-induced oxidative damage in embryonic chicken cardiac cells. Free Radic Res 2017; 51:693-707. [DOI: 10.1080/10715762.2017.1362106] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Affiliation(s)
- Xiaolong Sun
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai’an, Shandong, PR China
- Shandong Key Laboratory of Animal Bioengineering and Disease Control and Prevention, Tai’an, Shandong, PR China
| | - Hongchao Jiao
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai’an, Shandong, PR China
- Shandong Key Laboratory of Animal Bioengineering and Disease Control and Prevention, Tai’an, Shandong, PR China
| | - Jingpeng Zhao
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai’an, Shandong, PR China
- Shandong Key Laboratory of Animal Bioengineering and Disease Control and Prevention, Tai’an, Shandong, PR China
| | - Xiaojuan Wang
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai’an, Shandong, PR China
- Shandong Key Laboratory of Animal Bioengineering and Disease Control and Prevention, Tai’an, Shandong, PR China
| | - Hai Lin
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai’an, Shandong, PR China
- Shandong Key Laboratory of Animal Bioengineering and Disease Control and Prevention, Tai’an, Shandong, PR China
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Dual release behavior of atorvastatin and alpha-lipoic acid from PLGA microspheres for the combination therapy in peripheral nerve injury. J Drug Deliv Sci Technol 2017. [DOI: 10.1016/j.jddst.2017.04.028] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
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Ramachandran J, Peluffo RD. Threshold levels of extracellular l-arginine that trigger NOS-mediated ROS/RNS production in cardiac ventricular myocytes. Am J Physiol Cell Physiol 2016; 312:C144-C154. [PMID: 27903582 DOI: 10.1152/ajpcell.00150.2016] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2016] [Revised: 11/14/2016] [Accepted: 11/17/2016] [Indexed: 12/19/2022]
Abstract
l-Arginine (L-Arg) is the substrate for nitric oxide synthase (NOS) to produce nitric oxide (NO), a signaling molecule that is key in cardiovascular physiology and pathology. In cardiac myocytes, L-Arg is incorporated from the circulation through the functioning of system-y+ cationic amino acid transporters. Depletion of L-Arg leads to NOS uncoupling, with O2 rather than L-Arg as the terminal electron acceptor, resulting in superoxide formation. The reactive oxygen species (ROS) superoxide (O2˙-), combined with NO, may lead to the production of the reactive nitrogen species (RNS) peroxynitrite (ONOO-), which is recognized as a major contributor to myocardial depression. In this study we aimed to determine the levels of external L-Arg that trigger ROS/RNS production in cardiac myocytes. To this goal, we used a two-step experimental design in which acutely isolated cardiomyocytes were loaded with the dye coelenterazine that greatly increases its fluorescence quantum yield in the presence of ONOO- and O2˙- Cells were then exposed to different concentrations of extracellular L-Arg and changes in fluorescence were followed spectrofluorometrically. It was found that below a threshold value of ~100 µM, decreasing concentrations of L-Arg progressively increased ONOO-/ O2˙--induced fluorescence, an effect that was not mimicked by d-arginine or l-lysine and was fully blocked by the NOS inhibitor l-NAME. These results can be explained by NOS aberrant enzymatic activity and provide an estimate for the levels of circulating L-Arg below which ROS/RNS-mediated harmful effects arise in cardiac muscle.
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Affiliation(s)
- Jayalakshmi Ramachandran
- Department of Pharmacology, Physiology and Neuroscience, Rutgers Biomedical and Health Sciences, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey
| | - R Daniel Peluffo
- Department of Pharmacology, Physiology and Neuroscience, Rutgers Biomedical and Health Sciences, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey
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Abstract
Cerium oxide nanoparticles (CeO2 NPs) have been shown to possess a substantial oxygen storage capacity via the interchangeable surface reduction and oxidation of cerium atoms, cycling between the Ce(4+) and Ce(3+) redox states. It has been well established in many studies that depending on their reactivity and surface chemistry, CeO2 NPs can effectively convert both reactive oxygen species (superoxide, O2 (•-), and hydrogen peroxide) into more inert species and scavenge reactive nitrogen species (RNS)(nitric oxide, •NO), both in vitro and in vivo. Since much of damage attributed to •NO and O2 (•-) is actually the result of oxidation or nitration by peroxynitrite or its breakdown products and due to the multiple species that these nanoparticles target in vivo, it was logical to test their interaction with the highly reactive molecule peroxynitrite (ONOO(-)). Here, we report that CeO2 NPs significantly accelerated the decay of ONOO(-) by three independent methods. Additionally, our data suggest the ability of CeO2 NPs to interact with ONOO(-) is independent of the Ce(3+)/Ce(4+) ratio on the surface of the CeO2 NPs. The accelerated decay was not observed when reactions were carried out in an inert gas (argon), suggesting strongly that the decay of peroxynitrite is being accelerated due to a reaction of CeNPs with the carbonate radical anion. These results suggest that one of the protective effects of CeO2 NPs during RNS is likely due to reduction in peroxynitrite or its reactive breakdown products.
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Comparison of some antioxidant properties of plant extracts from Origanum vulgare, Salvia officinalis, Eleutherococcus senticosus and Stevia rebaudiana. In Vitro Cell Dev Biol Anim 2014; 50:614-22. [DOI: 10.1007/s11626-014-9751-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2013] [Accepted: 03/17/2014] [Indexed: 10/25/2022]
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Abstract
Peroxynitrite, a reactive oxidant formed by the reaction of nitric oxide with superoxide at sites of inflammation in multiple sclerosis (MS), is capable of damaging tissues and cells. Uric acid, a natural scavenger of peroxynitrite, reduces inflammatory demyelination in experimental allergic encephalomyelitis. Some studies reported lower serum levels of uric acid in MS patients compared with controls, whereas other studies found no difference. A critical appraisal of these studies favors the view that reduced uric acid in MS is secondary to its peroxynitrite scavenging activity during inflammatory disease activity, rather than a primary deficiency. Serum uric acid levels could be used as a biomarker for monitoring disease activity in MS. Therapeutic strategies aimed at raising serum uric acid levels may have a glial/neuroprotective effect on MS patients.
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Affiliation(s)
- Marcus Koch
- Department of Neurology, University Medical Centre Groningen, University of Groningen, The Netherlands
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Wang CC, Weng TI, Lu MY, Yang RS, Lin KH, Wu MH, Liu SH. Hemorrhagic cystitis in children treated with alkylating agent cyclophosphamide: The experience of a medical center in Taiwan. J Formos Med Assoc 2013; 114:691-7. [PMID: 23880225 DOI: 10.1016/j.jfma.2013.06.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2013] [Revised: 06/03/2013] [Accepted: 06/03/2013] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND/PURPOSE Hemorrhagic cystitis is a common complication with chemotherapeutic alkylating agents. We investigated the possible prognostic factors of cyclophosphamide-induced hemorrhagic cystitis in children. METHODS Medical records of children (< 18 years old) with cyclophosphamide-related hemorrhagic cystitis were collected retrospectively from January 2000 to December 2010 in a tertiary care center. We also prospectively enrolled children (< 18 years old) with cyclophosphamide treatment. RESULTS The retrospective study consisted of 23 patients whose median age was 11 years. The median day of onset time was 1 day after cyclophosphamide usage. The hemato-oncological diseases included acute leukemia (39.1%), lymphoma (13%), blastoma (13%), sarcoma (13%), aplastic anemia (13%), and others (8.7%). Patients who received bone marrow transplantation (BMT) had significantly longer duration of hemorrhagic cystitis than those who did not receive BMT (p < 0.05). Serum uric acid, checked prior to and after the onset of hemorrhage cystitis, was significantly lower after the development of hemorrhagic cystitis (p < 0.05). In the prospective study, 11 children were enrolled with a median age of 5 years. The urinary nitrite/nitrate and 8-iso-prostaglandin F2α levels increased significantly after cyclophosphamide usage (p < 0.05). CONCLUSION Alteration serum uric acid level and BMT could be indicators for severe hemorrhagic cystitis. The elevated levels of urinary nitrite/nitrate and 8-iso-prostaglandin F2α may indicate the essential roles played by nitric oxide syntheses and reactive oxidative stress in cyclophosphamide-induced hemorrhagic cystitis. These findings may help clinicians formulate a better strategy for treating cyclophosphamide-induced hemorrhagic cystitis.
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Affiliation(s)
- Ching-Chia Wang
- Department of Pediatrics, Division of Critical Care Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Te-I Weng
- Department of Forensic Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Meng-Yao Lu
- Department of Pediatrics, Division of Critical Care Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Rong-Sen Yang
- Department of Orthopaedics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Kai-Hsin Lin
- Department of Pediatrics, Division of Critical Care Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Mei-Hwan Wu
- Department of Pediatrics, Division of Critical Care Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Shing-Hwa Liu
- Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
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Chen X, Wu G, Schwarzschild MA. Urate in Parkinson's disease: more than a biomarker? Curr Neurol Neurosci Rep 2012; 12:367-75. [PMID: 22580741 DOI: 10.1007/s11910-012-0282-7] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Parkinson's disease (PD) is a progressive neurodegenerative disease with characteristic motor manifestations. Although appreciation of PD as a multisystem disorder has grown, loss of dopaminergic neurons in the substantia nigra remains a pathological and neurochemical hallmark, accounting for the substantial symptomatic benefits of dopamine replacement therapies. However, currently no treatment has been shown to prevent or forestall the progression of the disease in spite of tremendous efforts. Among multiple environmental and genetic factors that have been implicated in the pathogenesis of PD, oxidative stress is proposed to play a critical role. A recent confluence of clinical, epidemiological, and laboratory evidence identified urate, an antioxidant and end product of purine metabolism, as not only a molecular predictor for both reduced risk and favorable progression of PD but also a potential neuroprotectant for the treatment of PD. This review summarizes recent findings on urate in PD and their clinical implications.
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Affiliation(s)
- Xiqun Chen
- Department of Neurology, Massachusetts General Hospital, Harvard Medical School, 114 16th Street, Charlestown, MA 02129, USA.
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14
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Wang R. Physiological implications of hydrogen sulfide: a whiff exploration that blossomed. Physiol Rev 2012; 92:791-896. [PMID: 22535897 DOI: 10.1152/physrev.00017.2011] [Citation(s) in RCA: 1421] [Impact Index Per Article: 109.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
The important life-supporting role of hydrogen sulfide (H(2)S) has evolved from bacteria to plants, invertebrates, vertebrates, and finally to mammals. Over the centuries, however, H(2)S had only been known for its toxicity and environmental hazard. Physiological importance of H(2)S has been appreciated for about a decade. It started by the discovery of endogenous H(2)S production in mammalian cells and gained momentum by typifying this gasotransmitter with a variety of physiological functions. The H(2)S-catalyzing enzymes are differentially expressed in cardiovascular, neuronal, immune, renal, respiratory, gastrointestinal, reproductive, liver, and endocrine systems and affect the functions of these systems through the production of H(2)S. The physiological functions of H(2)S are mediated by different molecular targets, such as different ion channels and signaling proteins. Alternations of H(2)S metabolism lead to an array of pathological disturbances in the form of hypertension, atherosclerosis, heart failure, diabetes, cirrhosis, inflammation, sepsis, neurodegenerative disease, erectile dysfunction, and asthma, to name a few. Many new technologies have been developed to detect endogenous H(2)S production, and novel H(2)S-delivery compounds have been invented to aid therapeutic intervention of diseases related to abnormal H(2)S metabolism. While acknowledging the challenges ahead, research on H(2)S physiology and medicine is entering an exponential exploration era.
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Affiliation(s)
- Rui Wang
- Department of Biology, Lakehead University, Thunder Bay, Ontario, Canada.
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Abstract
The human eye is subjected constantly to oxidative stress due to daily exposure to sunlight, high metabolic activities, and oxygen tension. Reactive oxygen species generated from environmental insults and pathological conditions render the human eye particularly vulnerable to oxidative damage. The ocular surface composed of the tear film, the cornea, and the aqueous humor forms the first physical and biochemical barrier of the eye and plays a pivotal role in combating free radicals. These ocular compartments are enriched in certain antioxidants in the form of metabolic enzymes or small molecules. Such an antioxidant defense system in the ocular surface is essential for the maintenance of redox homeostasis in the eye and protection against oxidative damage. Herein, we review the properties and functions of key constituent antioxidants of the ocular surface.
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Affiliation(s)
- Ying Chen
- Molecular Toxicology and Environmental Health Sciences Program, Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO 80045, USA
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Marchitti SA, Chen Y, Thompson DC, Vasiliou V. Ultraviolet radiation: cellular antioxidant response and the role of ocular aldehyde dehydrogenase enzymes. Eye Contact Lens 2011; 37:206-13. [PMID: 21670692 PMCID: PMC3356694 DOI: 10.1097/icl.0b013e3182212642] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Solar ultraviolet radiation (UVR) exposes the human eye to near constant oxidative stress. Evidence suggests that UVR is the most important environmental insult leading to the development of a variety of ophthalmoheliosis disorders. UVR-induced reactive oxygen species (ROS) are highly reactive with DNA, proteins, and cellular membranes, resulting in cellular and tissue damage. Antioxidant defense systems present in ocular tissues function to combat ROS and protect the eye from oxidative damage. Important enzymatic antioxidants are the superoxide dismutases, catalase, glutathione peroxidases, glutathione reductase, and members of the aldehyde dehydrogenase (ALDH) superfamily. Glutathione, ascorbic and uric acids, α-tocopherol, nicotinamide-adenine dinucleotide phosphate, and ferritin serve as small molecule, nonenzymatic antioxidants. Ocular tissues have high levels of these antioxidants, which are essential for the maintenance of reduction-oxidation homeostasis in the eye and protection against oxidative damage. ALDH1A1 and ALDH3A1, present abundantly in the cornea and lens, have been shown to have unique roles in the defense against UVR and the downstream effects of oxidative stress. This review presents the properties and functions of ocular antioxidants that play critical roles in the cellular response to UVR exposure, including a focused discussion of the unique roles that the ALDH1A1 and ALDH3A1 enzymes have as multifunctional ocular antioxidants.
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Affiliation(s)
- Satori A. Marchitti
- Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO, USA
| | - Ying Chen
- Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO, USA
| | - David C. Thompson
- Department of Clinical Pharmacology, University of Colorado Denver, Aurora, CO, USA
| | - Vasilis Vasiliou
- Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO, USA
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Berski S, Latajka Z, Gordon AJ. Electron localization function and electron localizability indicator applied to study the bonding in the peroxynitrous acid HOONO. J Comput Chem 2011; 32:1528-40. [DOI: 10.1002/jcc.21731] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2010] [Accepted: 11/10/2010] [Indexed: 11/06/2022]
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18
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Heiss RS, Cohen AA, Bowman R, Boughton RK, Bridge E, McGraw KJ, Schoech SJ. Circulating carotenoid concentrations are positively correlated with later clutch initiation in Florida Scrub-Jays (Aphelocoma coerulescens). ACTA ACUST UNITED AC 2011; 315A:101-10. [PMID: 21328560 DOI: 10.1002/jez.654] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2010] [Revised: 09/30/2010] [Accepted: 10/21/2010] [Indexed: 02/04/2023]
Abstract
Antioxidants play key roles in preventing free radical damage to various molecules, cells, and tissues, but it is not well understood how variation in antioxidant levels may relate to the reproductive success or health of wild animals. We explored the relationship between circulating antioxidant concentrations and both body condition and timing of reproduction in male and female Florida Scrub-Jays (Aphelocoma coerulescens), a cooperatively breeding passerine bird. We examined whether levels of uric acid, vitamin E, and carotenoids (all potentially important antioxidants) were linked to body condition and timing of reproduction, two measures that are directly related to reproductive success. Antioxidant concentrations were not correlated with body condition, but they were related to timing of first clutch initiation, though not always in the predicted direction. Elevated circulating levels of carotenoids were associated with delayed clutch initiation in female breeders. Relatively higher vitamin E levels in control birds were associated with earlier clutch initiation, whereas male breeders that received long-term food supplementation had elevated levels of vitamin E and delayed reproduction. Several potential explanations for the link between elevated levels of antioxidants and delayed clutch initiation are discussed. Separate explanations for each sex include, but are not limited to, oxidative stress as a result of territory defense efforts in males, different dietary regimes due to supplementation, and mobilized plasma antioxidants in females that were coping with a stressor.
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Affiliation(s)
- Rebecca S Heiss
- Department of Biological Sciences, University of Memphis, Memphis, Tennessee 38152, USA.
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20
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Imaram W, Gersch C, Kim KM, Johnson RJ, Henderson GN, Angerhofer A. Radicals in the reaction between peroxynitrite and uric acid identified by electron spin resonance spectroscopy and liquid chromatography mass spectrometry. Free Radic Biol Med 2010; 49:275-81. [PMID: 20406679 PMCID: PMC2916040 DOI: 10.1016/j.freeradbiomed.2010.04.010] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2009] [Revised: 03/22/2010] [Accepted: 04/13/2010] [Indexed: 02/04/2023]
Abstract
Peroxynitrite is a reactive oxidant produced in vivo in response to oxidative and other stress by the diffusion-limited reaction of nitric oxide and superoxide. This article is focused on the identification of free radical intermediates of uric acid formed during its reaction with peroxynitrite. The experimental approach included the ESR spin trapping of the radical generated from the reaction between uric acid and peroxynitrite at pH 7.4 and mass spectrometry studies of the trapped radicals. Using PBN (N-tert-butyl-alpha-phenylnitrone) as the spin trapping agent, a six-line ESR spectrum was obtained and its hyperfine coupling constants, a(N)=15.6 G and a(H)=4.4 G, revealed the presence of carbon-based radicals. Further structural identification of the PBN-radical adducts was carried out using liquid chromatography-mass spectrometry. After comparison with the control reactions, two species were identified that correspond to the protonated molecules (M+1) at m/z 352 and 223, respectively. The ions of m/z 352 were characterized as the PBN-triuretcarbonyl radical adduct and the m/z 223 ion was identified as the PBN-aminocarbonyl radical adduct. Their mechanism of formation is discussed.
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Affiliation(s)
- Witcha Imaram
- Department of Chemistry, University of Florida, Gainesville, FL 32611, USA.
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21
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Self-sufficient control of urate homeostasis in mice by a synthetic circuit. Nat Biotechnol 2010; 28:355-60. [DOI: 10.1038/nbt.1617] [Citation(s) in RCA: 201] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2010] [Accepted: 02/19/2010] [Indexed: 02/07/2023]
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22
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Yokozawa T, Rhyu DY, Cho EJ. (–)-Epicatechin 3-O-gallate ameliorates the damages related to peroxynitrite production by mechanisms distinct from those of other free radical inhibitors. J Pharm Pharmacol 2010; 56:231-9. [PMID: 15005882 DOI: 10.1211/0022357022601] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Abstract
Abstract
This study was carried out to elucidate whether the protective activity of (–)-epicatechin 3-O-gallate (ECg) against excessive peroxynitrite (ONOO−) production, is distinct from the activity of several well-known free radical inhibitors, the ONOO− inhibitors ebselen and uric acid, the superoxide anion (O2−) scavenger copper zinc superoxide dismutase (CuZnSOD) and the selective inducible nitric oxide synthase inhibitor l-N6-(1-iminoethyl)lysine hydrochloride (l-NIL). To generate ONOO−, male Wistar rats (n = 6/group) were subjected to ischaemia–reperfusion process together with lipopolysaccharide (LPS) injection. Although ECg did not scavenge the ONOO− precursors nitric oxide (NO) and O2−, it reduced the 3-nitrotyrosine level, a property similar to that of uric acid, but distinct from l-NIL. In addition, the elevation in myeloperoxidase activity was reversed by the administration of ECg, uric acid and SOD, but not by that of l-NIL. Furthermore, ECg was the more potent scavenger of the ONOO− decomposition product, the hydroxyl radical (·OH), than any other free radical inhibitor tested. The LPS plus ischaemia–reperfusion process resulted in renal dysfunction, estimated by measuring the parameters of renal function – serum urea nitrogen and creatinine levels. However, administration of ECg ameliorated renal dysfunction more than that of the other free radical inhibitors. Moreover, ECg reduced the excessive uric acid level, while the others did not, suggesting a property of ECg distinct from the others. Furthermore, proteinuria, which was demonstrated by the low- and high-molecular weight (LMW and HMW) protein bands of the sodium dodecyl sulfate-polyacrylamide gel electrophoresis pattern, caused by LPS plus ischaemia–reperfusion, was attenuated by administration of ECg and l-NIL, after which the HMW band intensities decreased and LMW protein bands were absent. This study indicates that, in an in-vivo model of ONOO− generation, ECg, l-NIL and uric acid exert stronger protective activity against ONOO−-induced oxidative damage than SOD and ebselen, and that the mechanism whereby ECg protects against ONOO− is distinct from that of l-NIL or uric acid.
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Affiliation(s)
- Takako Yokozawa
- Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan.
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Lu N, Zhou G, Pei D, Yi L, Gao Z. Peroxynitrite and heme protein – Mediated nitrative/oxidative modification of human plasma protein: The role of free radical scavenging vs. complex forming. Toxicol In Vitro 2009; 23:1227-33. [DOI: 10.1016/j.tiv.2009.07.034] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2009] [Revised: 06/03/2009] [Accepted: 07/30/2009] [Indexed: 10/20/2022]
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Massa J, O'Reilly E, Munger KL, Delorenze GN, Ascherio A. Serum uric acid and risk of multiple sclerosis. J Neurol 2009; 256:1643-8. [PMID: 19468784 PMCID: PMC2834535 DOI: 10.1007/s00415-009-5170-y] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2009] [Revised: 05/04/2009] [Accepted: 05/05/2009] [Indexed: 10/20/2022]
Abstract
Because of evidence implicating oxidative stress in multiple sclerosis pathogenesis, it has been postulated that high levels of urate, a potent antioxidant, could reduce risk or favorably influence disease progression. We conducted a prospective study to determine whether serum urate levels contribute to prediction of multiple sclerosis risk. Analyses included 31 cases with blood collected a median of 1.9 years before multiple sclerosis onset from the Nurses' Health Study and Nurses' Health Study II cohorts, and 42 cases with collection a median of 14.5 years before onset from the Kaiser Permanente Northern California health plan cohort. Relative risks were estimated by unconditional logistic regression, including 26 controls in the Nurses' cohorts and 130 controls in the Kaiser cohort. In analyses including only cases in the Nurses' cohorts where blood was collected shortly before onset, there was a trend toward a lower risk of multiple sclerosis among individuals with higher serum urate, but the association was not significant (multivariable relative risk 0.52, 95% CI 0.22, 1.20, p value 0.13). In contrast, there was no evidence of a decline in risk with increasing serum urate in the Kaiser cohort where there was a longer period of time between blood collection and onset (multivariable relative risk 1.36, 95% CI 0.87, 2.14, p value 0.18). The results of this study suggest that serum urate is not a strong predictor of MS risk. This lack of association is consistent with the interpretation that the lower urate levels among multiple sclerosis cases are a consequence rather than a cause of the disease.
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Affiliation(s)
- Jennifer Massa
- Departments of Epidemiology and Nutrition, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115, USA.
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25
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Lü JM, Lin PH, Yao Q, Chen C. Chemical and molecular mechanisms of antioxidants: experimental approaches and model systems. J Cell Mol Med 2009; 14:840-60. [PMID: 19754673 PMCID: PMC2927345 DOI: 10.1111/j.1582-4934.2009.00897.x] [Citation(s) in RCA: 682] [Impact Index Per Article: 42.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Free radicals derived from oxygen, nitrogen and sulphur molecules in the biological system are highly active to react with other molecules due to their unpaired electrons. These radicals are important part of groups of molecules called reactive oxygen/nitrogen species (ROS/RNS), which are produced during cellular metabolism and functional activities and have important roles in cell signalling, apoptosis, gene expression and ion transportation. However, excessive ROS attack bases in nucleic acids, amino acid side chains in proteins and double bonds in unsaturated fatty acids, and cause oxidative stress, which can damage DNA, RNA, proteins and lipids resulting in an increased risk for cardiovascular disease, cancer, autism and other diseases. Intracellular antioxidant enzymes and intake of dietary antioxidants may help to maintain an adequate antioxidant status in the body. In the past decades, new molecular techniques, cell cultures and animal models have been established to study the effects and mechanisms of antioxidants on ROS. The chemical and molecular approaches have been used to study the mechanism and kinetics of antioxidants and to identify new potent antioxidants. Antioxidants can decrease the oxidative damage directly via reacting with free radicals or indirectly by inhibiting the activity or expression of free radical generating enzymes or enhancing the activity or expression of intracellular antioxidant enzymes. The new chemical and cell-free biological system has been applied in dissecting the molecular action of antioxidants. This review focuses on the research approaches that have been used to study oxidative stress and antioxidants in lipid peroxidation, DNA damage, protein modification as well as enzyme activity, with emphasis on the chemical and cell-free biological system.
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Affiliation(s)
- Jian-Ming Lü
- Molecular Surgeon Research Center, Division of Vascular Surgery and Endovascular Therapy, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA
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26
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Gruber J, Tang SY, Jenner AM, Mudway I, Blomberg A, Behndig A, Kasiman K, Lee CYJ, Seet RCS, Zhang W, Chen C, Kelly FJ, Halliwell B. Allantoin in human plasma, serum, and nasal-lining fluids as a biomarker of oxidative stress: avoiding artifacts and establishing real in vivo concentrations. Antioxid Redox Signal 2009; 11:1767-76. [PMID: 19388825 DOI: 10.1089/ars.2008.2364] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Urate is the terminal product of purine metabolism in primates, including humans. Urate is also an efficient scavenger of oxidizing species and is thought to be an important antioxidant in human body fluids. Allantoin, the major oxidation product of urate, has been suggested as a candidate biomarker of oxidative stress because it is not produced metabolically. Although urate is converted to allantoin under strongly alkaline pH, such conditions have been used in the past to facilitate extraction of allantoin. We evolved a method for the determination of allantoin concentrations in human plasma and serum by gas chromatography-mass spectrometry without such artifact. With this method, we show that alkaline conditions do indeed cause breakdown of urate, leading to significant overestimation of allantoin concentration in human samples. By using our alternative method, serum samples from 98 volunteers were analyzed, and allantoin levels were found to be significantly lower than was previously reported. The in vivo utility and sensitivity of our method was further evaluated in human nasal-lining fluids. We were able to demonstrate an ozone-induced increase in allantoin, in the absence of increases in either ascorbate or glutathione oxidation products.
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Affiliation(s)
- Jan Gruber
- Centre for Life Sciences, Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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Cete S, Yaşar A, Arslan F. An Amperometric Biosensor for Uric Acid Determination Prepared from Uricase Immobilized in Polypyrrole Film. ACTA ACUST UNITED AC 2009; 34:367-80. [PMID: 16809136 DOI: 10.1080/10731190600684116] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
In order to prepare a biosensor for the determination of uric acid, electropolymerization of pyrrole on Pt surface was carried out with an electrochemical cell containing pyrrole, ferrocene (as a electron mediator) and tetrabutylammonium tetrafluoroborat in acetonitrile by cyclic voltammetry between 0.0 and 1.0 V (vs. Ag/AgCl) at a scan rate of 50 mV/s upon Pt electrode. Uricase was immobilized by a glutaraldehyde/gelatine croslinking procedure on to polypyrrole film after the electropolymerization processes. The response of the biosensor against uric acid was measured after 330 seconds following the application of a constant potential of +0.7 V (vs. Ag/AgCl). The resulting biosensor exhibits excellent electrocatalysis for the uric acid. The amperometric determination is based on the electrochemical detection of H2O2, which is generated in enzymatic reaction of uric acid. The sensor responds to uric acid with a detection limit of 5.0 x 10(-7) M. The sensor remains relatively stable for 5 weeks. Interference effect were investigated on the amperometric response of the biosensor. Determination of uric acid was carried out in the biological fluids by biosensor.
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Affiliation(s)
- Servet Cete
- Department of Chemistry, Faculty of Arts and Sciences, Gazi University, Ankara, Turkey.
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28
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Guerreiro S, Ponceau A, Toulorge D, Martin E, Alvarez-Fischer D, Hirsch EC, Michel PP. Protection of midbrain dopaminergic neurons by the end-product of purine metabolism uric acid: potentiation by low-level depolarization. J Neurochem 2009; 109:1118-28. [DOI: 10.1111/j.1471-4159.2009.06040.x] [Citation(s) in RCA: 70] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
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Urtasun R, Cubero FJ, Vera M, Nieto N. Reactive nitrogen species switch on early extracellular matrix remodeling via induction of MMP1 and TNFalpha. Gastroenterology 2009; 136:1410-22, e1-4. [PMID: 19250650 DOI: 10.1053/j.gastro.2008.12.065] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2008] [Revised: 12/04/2008] [Accepted: 12/29/2008] [Indexed: 01/09/2023]
Abstract
BACKGROUND & AIMS Liver injury leads to generation of reactive oxygen and nitrogen species, which can react to produce peroxynitrite (ONOO-). We investigated whether ONOO- and its metabolites modulate extracellular matrix remodeling. METHODS Stellate cells (HSC) were incubated with pure ONOO- or SIN-1 (a ONOO- donor). Western blot, nuclear in vitro transcription, Northern blot, qPCR, and promoter transactivation analysis for COL1A1 and COL1A2 were carried out. Rats were fed alcohol or injected with CCl4 to cause alcohol-induced liver injury and an early fibrogenic response. RESULTS HSC incubated with ONOO- or SIN-1 showed similar viability, proliferation, COL1A1 and COL1A2 transcription rates, and mRNA levels as controls. There was a time- and dose-dependent down-regulation of collagen I and alpha-Sma proteins and up-regulation of MMP1 and TNFalpha, indicating decreased HSC activation. These effects were blocked by ONOO- scavengers. SIN-1 or ONOO- increased nitrosylation of MMP1/MMP13 and transactivation of the MMP1, MMP13, and TNFalpha promoters. A TNFalpha neutralizing antibody or GSH-ethyl ester blocked MMP1 promoter transactivation; whereas TNFalpha or l-buthionine sulfoximine, which depletes GSH, further enhanced it. Pretreatment with SIN-1 or ONOO- reduced the TGFbeta pro-fibrogenic response in HSC. In vivo experiments validated the protective role of ONOO- on the early fibrogenic response. However, highly activated HSC, such as myofibroblasts and HSC from chronic alcohol-fed rats, were resistant to the anti-fibrogenic actions of ONOO- due to higher levels of GSH, a ONOO- scavenger, overproduction of pro-fibrogenic TGFbeta, and reactive oxygen species. CONCLUSION ONOO- could induce a protective mechanism in HSC in early stages of liver injury.
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Affiliation(s)
- Raquel Urtasun
- Department of Medicine, Division of Liver Diseases, Mount Sinai School of Medicine, New York, New York 10029, USA
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Johnson RJ, Sautin YY, Oliver WJ, Roncal C, Mu W, Sanchez-Lozada LG, Rodriguez-Iturbe B, Nakagawa T, Benner SA. Lessons from comparative physiology: could uric acid represent a physiologic alarm signal gone awry in western society? J Comp Physiol B 2009; 179:67-76. [PMID: 18649082 PMCID: PMC2684327 DOI: 10.1007/s00360-008-0291-7] [Citation(s) in RCA: 97] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2008] [Revised: 06/18/2008] [Accepted: 06/23/2008] [Indexed: 02/07/2023]
Abstract
Uric acid has historically been viewed as a purine metabolic waste product excreted by the kidney and gut that is relatively unimportant other than its penchant to crystallize in joints to cause the disease gout. In recent years, however, there has been the realization that uric acid is not biologically inert but may have a wide range of actions, including being both a pro- and anti-oxidant, a neurostimulant, and an inducer of inflammation and activator of the innate immune response. In this paper, we present the hypothesis that uric acid has a key role in the foraging response associated with starvation and fasting. We further suggest that there is a complex interplay between fructose, uric acid and vitamin C, with fructose and uric acid stimulating the foraging response and vitamin C countering this response. Finally, we suggest that the mutations in ascorbate synthesis and uricase that characterized early primate evolution were likely in response to the need to stimulate the foraging "survival" response and might have inadvertently had a role in accelerating the development of bipedal locomotion and intellectual development. Unfortunately, due to marked changes in the diet, resulting in dramatic increases in fructose- and purine-rich foods, these identical genotypic changes may be largely responsible for the epidemic of obesity, diabetes and cardiovascular disease in today's society.
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Affiliation(s)
- Richard J. Johnson
- Division of Nephrology, Hypertension and Transplantation, University of Florida, PO Box 100224, Gainesville, FL 32610, USA, e-mail:
| | - Yuri Y. Sautin
- Division of Nephrology, Hypertension and Transplantation, University of Florida, PO Box 100224, Gainesville, FL 32610, USA, e-mail:
| | | | - Carlos Roncal
- Division of Nephrology, Hypertension and Transplantation, University of Florida, PO Box 100224, Gainesville, FL 32610, USA, e-mail:
| | - Wei Mu
- Division of Nephrology, Hypertension and Transplantation, University of Florida, PO Box 100224, Gainesville, FL 32610, USA, e-mail:
| | | | | | - Takahiko Nakagawa
- Division of Nephrology, Hypertension and Transplantation, University of Florida, PO Box 100224, Gainesville, FL 32610, USA, e-mail:
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M. Al-Nime M, A. Ali E. Dual Effects of Interaction Between Meloxicam, Diclofenac Sodium or Tramadol and Nitrogen Species Radicals: In vitro Comparative Study. INT J PHARMACOL 2008. [DOI: 10.3923/ijp.2009.86.89] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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Nakagawa T, Cirillo P, Sato W, Gersch M, Sautin Y, Roncal C, Mu W, Sánchez-Lozada LG, Johnson RJ. The conundrum of hyperuricemia, metabolic syndrome, and renal disease. Intern Emerg Med 2008; 3:313-8. [PMID: 18320146 PMCID: PMC2895906 DOI: 10.1007/s11739-008-0141-3] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2007] [Accepted: 02/20/2008] [Indexed: 02/07/2023]
Abstract
The level of serum uric acid in human has been increasing over the last decades, and correlates with an increase prevalence of renal disease and metabolic syndrome. Understanding the role of uric acid in these conditions may provide clues for preventing the current epidemic of renal disease. Controversy still remains if hyperuricemia is simply a consequence or a cause of renal disease although epidemiological studies have attempted to resolve this issue. In this review, we discuss the clinical and experimental evidence for a causal role of hyperuricemia in renal diseases and potential relationships of hyperuricemia with metabolic syndrome.
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Affiliation(s)
- Takahiko Nakagawa
- Division of Nephrology, Hypertension and Transplantation, University of Florida, PO Box 100224, Gainesville, FL, 32610, USA,
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Abstract
Neutrophils are key effectors of the innate immune response. Reduction of neutrophil migration to infection sites is associated with a poor outcome in sepsis. We have demonstrated a failure of neutrophil migration in lethal sepsis. Together with this failure, we observed more bacteria in both peritoneal exudates and blood, followed by a reduction in survival rate. Furthermore, neutrophils obtained from severe septic patients displayed a marked reduction in chemotactic response compared with neutrophils from healthy subjects. The mechanisms of neutrophil migration failure are not completely understood. However, it is known that they involve systemic Toll-like receptor activation by bacteria and/or their products and result in excessive levels of circulating cytokines/chemokines. These mediators acting together with LPS stimulate expression of iNOS that produces high amounts of NO, which in turn mediates the failure of neutrophil migration. NO reduced expression of CXCR2 on neutrophils and the levels of adhesion molecules on both endothelial cells and neutrophils. These events culminate in decreased endothelium-leukocyte interactions, diminished neutrophil chemotactic response, and neutrophil migration failure. Additionally, the NO effect, at least in part, is mediated by peroxynitrite. In this review, we summarize what is known regarding the mechanisms of neutrophil migration impairment in severe sepsis.
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González D, Marquina R, Rondón N, Rodriguez-Malaver AJ, Reyes R. Effects of aerobic exercise on uric acid, total antioxidant activity, oxidative stress, and nitric oxide in human saliva. Res Sports Med 2008; 16:128-37. [PMID: 18569946 DOI: 10.1080/15438620802103700] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
The aim of this study was to determine the effect of aerobic exercise on uric acid (UA), total antioxidant activity (TAA), lipid hydroperoxides, and nitric oxide (NO) metabolites in human saliva. Twenty-four healthy male and female subjects were studied during a 10,000-m race. Saliva samples were collected 1 h before and immediately after exercise. The NO concentration was determined by the Griess reaction, UA by enzymatic method, TAA by the ABTS method, and lipid hydroperoxide by the ferrous iron/xylenol orange (FOX) method. A repeated measures ANOVA was used to examine the effect of aerobic exercise on salivary UA, TAA, lipid hydroperoxides, and NO metabolites. Aerobic exercise caused an increase in both salivary UA and TAA, and a decrease in salivary lipid hydroperoxide. There was no, however, change in nitrite concentration. These results suggested that aerobic exercise-induced increment in both UA and TAA seems to inhibit lipid hydroperoxide generation, a marker of oxidative stress in human saliva.
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Affiliation(s)
- David González
- Facultad de Medicina, Laboratorio de Bioquimica Adaptativa, Departamento de Bioquímica, Mérida, Venezuela
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Reinehr R, Sommerfeld A, Häussinger D. CD95 ligand is a proliferative and antiapoptotic signal in quiescent hepatic stellate cells. Gastroenterology 2008; 134:1494-506. [PMID: 18471522 DOI: 10.1053/j.gastro.2008.02.021] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2007] [Accepted: 01/31/2008] [Indexed: 12/21/2022]
Abstract
BACKGROUND & AIMS Despite expression of CD95 (Fas) receptor, hepatic stellate cells (HSCs) are fairly resistant toward CD95 ligand (CD95L)-induced cell death. The underlying mechanisms and the function of the CD95 system in quiescent HSCs, however, are unknown. METHODS The effects of CD95L on quiescent, 1- to 2-day cultured rat HSCs were studied with regard to CD95 activation, signal transduction, proliferation, and apoptosis. RESULTS In quiescent HSCs, CD95L led to a rapid phosphorylation of the epidermal growth factor receptor (EGFR), extracellular signal-regulated kinase (Erk), and c-Src, but not of c-Jun-N-terminal kinase and p47(phox), an activating subunit of reduced nicotinamide adenine dinucleotide phosphate oxidase. CD95L-induced EGFR and Erk phosphorylation were abolished after proteinase inhibition by GM6001 and in the presence of neutralizing epidermal growth factor antibodies, suggestive of a ligand-dependent EGFR phosphorylation in response to CD95L. In quiescent HSCs, CD95L did not induce apoptotic cell death but stimulated HSC proliferation and triggered a rapid inactivating CD95 tyrosine nitration that was not detected in activated HSCs (10-14 days of culture). EGFR phosphorylation, HSC proliferation, and CD95 tyrosine nitration were also triggered by tumor necrosis factor alpha and tumor necrosis factor-related apoptosis-inducing ligand. CONCLUSIONS In quiescent HSCs, CD95L and other death receptor ligands are mitogens through a ligand-dependent EGFR phosphorylation. Simultaneously, an antiapoptotic signaling is triggered by CD95L-induced CD95 tyrosine nitration. This unusual response to death receptor ligands may help quiescent HSCs to participate in liver regeneration following liver injury.
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Affiliation(s)
- Roland Reinehr
- Clinic for Gastroenterology, Hepatology and Infectiology, Heinrich Heine University, Düsseldorf, Germany
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36
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Methodological aspects about in vitro evaluation of antioxidant properties. Anal Chim Acta 2008; 613:1-19. [DOI: 10.1016/j.aca.2008.02.047] [Citation(s) in RCA: 405] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2007] [Revised: 02/18/2008] [Accepted: 02/21/2008] [Indexed: 01/17/2023]
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Kim JY, Kim HS, Kang HS, Choi JS, Yokozawa T, Chung HY. Antioxidant Potential of Dimethyl Lithospermate Isolated fromSalvia miltiorrhiza(Red Sage) Against Peroxynitrite. J Med Food 2008; 11:21-8. [DOI: 10.1089/jmf.2007.040] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Affiliation(s)
- Ji Young Kim
- College of Pharmacy, Aging Tissue Bank, Pusan National University, Busan, Republic of Korea
| | - Hyung Seok Kim
- College of Pharmacy, Aging Tissue Bank, Pusan National University, Busan, Republic of Korea
| | - Hye Sook Kang
- Faculty of Food Science and Biotechnology, Pukyong National University, Busan, Republic of Korea
| | - Jae Sue Choi
- Faculty of Food Science and Biotechnology, Pukyong National University, Busan, Republic of Korea
| | - Takako Yokozawa
- Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, Toyama, Japan
| | - Hae Young Chung
- College of Pharmacy, Aging Tissue Bank, Pusan National University, Busan, Republic of Korea
- Longevity Life Science and Technology Institutes, Pusan National University, Busan, Republic of Korea
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Abstract
In the past decade, a growing number of evidence has implicated free radicals in a variety of pathophysiological conditions including aging, cancer, and coronary heart disease. Analyses of different aspects of multiple sclerosis (MS) pathology with respect to oxidative damage have also revealed evidence of free radical injury to the central nervous system (CNS), although attempts to protect the CNS using various antioxidants have met with only moderate success. Several recent studies have reported lower levels of uric acid (UA), a major scavenger of reactive nitrogen species, in MS patients, while other studies found no such correlation. Here, we discuss these studies as well as current efforts to manipulate serum UA levels in MS patients.
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Affiliation(s)
- S Spitsin
- Thomas Jefferson University, 1020 Locust St, JAH Room M85, Philadelphia, PA 19107, USA
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Torres-Dueñas D, Celes MRN, Freitas A, Alves-Filho JC, Spiller F, Dal-Secco D, Dalto VF, Rossi MA, Ferreira SH, Cunha FQ. Peroxynitrite mediates the failure of neutrophil migration in severe polymicrobial sepsis in mice. Br J Pharmacol 2007; 152:341-52. [PMID: 17641671 PMCID: PMC2042948 DOI: 10.1038/sj.bjp.0707393] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
BACKGROUND AND PURPOSE Sepsis is a systemic inflammatory response resulting from the inability of the host to restrict local infection. The failure of neutrophil migration to the infection site is one of the mechanisms involved in this process. Recently, it was demonstrated that this event is mediated by nitric oxide (NO). The present study addresses the possibility that peroxynitrite (ONOO(-)), a NO-derived powerful oxidizing and nitrating compound, could also be involved in neutrophil migration failure. EXPERIMENTAL APPROACH Male C57Bl/6 mice were subjected to moderate (MSI) or severe (SSI) septic injury, both induced by cecal ligation and puncture (CLP). The leukocyte rolling and adhesion in the mesentery was evaluated by intravital microscopy. Cytokines (TNF-alpha and MIP-1alpha) were measured by ELISA and 3-nitrotyrosine (3-NT) by immunofluorescence. KEY RESULTS Compared with saline pretreatment of SSI mice, pre-treatment with uric acid, a ONOO(-) scavenger, partially restored the failure of neutrophil rolling, adhesion and migration to the site of infection. These mice also presented low circulating bacterial counts and diminished systemic inflammatory response. Pretreatment with uric acid reduced 3-NT labelling in leukocytes in mesenteric tissues and in neutrophils obtained from peritoneal exudates. Finally, uric acid pretreatment enhanced significantly the survival rate in the SSI mice. Similarly, treatment with FeTPPs, a more specific ONOO(-) scavenger, re-established neutrophil migration and increased mice survival rate. CONCLUSIONS AND IMPLICATIONS These results indicate that ONOO(-) contributed to the reduction of neutrophil/endothelium interaction and the consequent failure of neutrophil migration into infection foci and hence susceptibility to severe sepsis.
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Affiliation(s)
- D Torres-Dueñas
- Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, University of São Paulo São Paulo, Brazil
- Department of Pharmacology, School of Medicine of Bucaramanga, University Autonoma of Bucaramanga, UNAB Bucaramanga, Colombia
| | - M R N Celes
- Department of Pathology, Faculty of Medicine of Ribeirão Preto, University of São Paulo São Paulo, Brazil
| | - A Freitas
- Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, University of São Paulo São Paulo, Brazil
| | - J C Alves-Filho
- Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, University of São Paulo São Paulo, Brazil
| | - F Spiller
- Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, University of São Paulo São Paulo, Brazil
| | - D Dal-Secco
- Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, University of São Paulo São Paulo, Brazil
| | - V F Dalto
- Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, University of São Paulo São Paulo, Brazil
| | - M A Rossi
- Department of Pathology, Faculty of Medicine of Ribeirão Preto, University of São Paulo São Paulo, Brazil
| | - S H Ferreira
- Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, University of São Paulo São Paulo, Brazil
| | - F Q Cunha
- Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, University of São Paulo São Paulo, Brazil
- Author for correspondence:
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40
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Aitken RJ, Wingate JK, De Iuliis GN, McLaughlin EA. Analysis of lipid peroxidation in human spermatozoa using BODIPY C11. Mol Hum Reprod 2007; 13:203-11. [PMID: 17327268 DOI: 10.1093/molehr/gal119] [Citation(s) in RCA: 141] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Lipid peroxidation is known to be a major factor in the aetiology of defective sperm function. Although biochemical assays for this process exist, they are relatively insensitive and require large numbers of spermatozoa; a condition that cannot be met with many infertility specimens. Recently, a new approach for monitoring peroxidative damage has been introduced, involving the probe BODIPY (581/591) C(11), which readily incorporates into cells and undergoes a spectral emission shift when attacked by reactive oxygen metabolites. We have examined the applicability of this probe as an indicator of oxidative stress in human sperm populations using flow cytometry as an end point. The measurement of peroxidation with BODIPY C(11) demonstrated significant dependence on the presence of a ferrous ion promoter (P < 0.001), which was significantly enhanced in sperm recovered from low-density Percoll fractions (P < 0.05) and was particularly damaging to the sperm midpiece. Iron-induced radical formation was suppressed by ascorbate in a dose-dependent manner (P < 0.001) and could only be promoted by Fe(II) and Cu(II); nickel, zinc and Fe(III) were ineffective. The Fe(II)-promoted BODIPY C(11) signal was significantly correlated with the measurement of reactive oxygen species generation with dihydroethidium. We conclude that BODIPY C(11) is an extremely useful probe for indexing peroxidative damage in human spermatozoa.
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Affiliation(s)
- R John Aitken
- ARC Centre of Excellence in Biotechnology and Development, Discipline of Biological Sciences, University of Newcastle, NSW, Australia.
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41
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Abstract
The discovery that mammalian cells have the ability to synthesize the free radical nitric oxide (NO) has stimulated an extraordinary impetus for scientific research in all the fields of biology and medicine. Since its early description as an endothelial-derived relaxing factor, NO has emerged as a fundamental signaling device regulating virtually every critical cellular function, as well as a potent mediator of cellular damage in a wide range of conditions. Recent evidence indicates that most of the cytotoxicity attributed to NO is rather due to peroxynitrite, produced from the diffusion-controlled reaction between NO and another free radical, the superoxide anion. Peroxynitrite interacts with lipids, DNA, and proteins via direct oxidative reactions or via indirect, radical-mediated mechanisms. These reactions trigger cellular responses ranging from subtle modulations of cell signaling to overwhelming oxidative injury, committing cells to necrosis or apoptosis. In vivo, peroxynitrite generation represents a crucial pathogenic mechanism in conditions such as stroke, myocardial infarction, chronic heart failure, diabetes, circulatory shock, chronic inflammatory diseases, cancer, and neurodegenerative disorders. Hence, novel pharmacological strategies aimed at removing peroxynitrite might represent powerful therapeutic tools in the future. Evidence supporting these novel roles of NO and peroxynitrite is presented in detail in this review.
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Affiliation(s)
- Pál Pacher
- Section on Oxidative Stress Tissue Injury, Laboratory of Physiologic Studies, National Institutes of Health, National Institute of Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.
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42
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Hartman S, Taleb SA, Geng T, Gyenai K, Guan X, Smith E. Comparison of Plasma Uric Acid Levels in Five Varieties of the Domestic Turkey, Meleagris gallopavo. Poult Sci 2006; 85:1791-4. [PMID: 17012170 DOI: 10.1093/ps/85.10.1791] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
Plasma uric acid (PUA) is a consensus physiological biomarker for many phenotypes in vertebrates because it is a reliable indicator for processes such as oxidative stress and tubular function. In birds, it is considered a major antioxidant and is also the primary endproduct of nitrogen metabolism. Despite this importance, knowledge of baseline levels of PUA in physiologically normal birds, including the turkey, Meleagris gallopavo, is limited. Here, we compared PUA levels in a total of 106 apparently normal male and female birds at 8 and 32 wk of age from 5 strains of the domestic turkey, including Bourbon Red, Narragansett, Blue Slate, Royal Palm, and Spanish Black. Though differences in PUA were not significant at 8 and 32 wk of age, BW, variety, and sex effects were highly significant. When adjusted for BW, female birds had, on average, a higher PUA per kilogram of BW than male birds. When adjusted for both sex and BW, Royal Palm birds had the lowest average PUA, and Blue Slate had the highest PUA. Results of these investigations represent the first comparative analysis of PUA in physiologically normal turkey varieties. They suggest that differences in basal plasma levels of uric acid in physiologically normal turkeys are influenced by sex, weight, and genetic background but may be independent of age.
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Affiliation(s)
- S Hartman
- Comparative Genomics Laboratory, Department of Animal and Poultry Sciences, Virginia Tech, Blacksburg 24061, USA
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43
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Olmos A, Giner RM, Máñez S. Drugs modulating the biological effects of peroxynitrite and related nitrogen species. Med Res Rev 2006; 27:1-64. [PMID: 16752428 DOI: 10.1002/med.20065] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The term "reactive nitrogen species" includes nitrogen monoxide, commonly called nitric oxide, and some other remarkable chemical entities (peroxynitrite, nitrosoperoxycarbonate, etc.) formed mostly from nitrogen monoxide itself in biological environments. Regardless of the specific mechanisms implicated in their effects, however, it is clear that an integrated pharmacological approach to peroxynitrite and related species is only just beginning to take shape. The array of affected chemical and pathological processes is extremely broad. One of the most conspicuous mechanisms observed thus far has been the scavenging of the peroxynitrite anion by molecules endowed with antioxidant activity. This discovery has in turn lent great significance to several naturally occurring and synthetic antioxidants, which usually protect not only against oxidative reactions, but also from nitrating ones, both in vitro and in vivo. This has proven to be beneficial in different tissues, especially within the central nervous system. Taking these results and those of other biochemical investigations into account, many research lines are currently in progress to establish the true potential of reactive nitrogen species deactivators in the therapy of neurological diseases, ischemia-reperfusion damage, renal failure, and lung injury, among others.
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Affiliation(s)
- Ana Olmos
- Departament de Farmacologia, Universitat de València, València, Spain
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44
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Rose P, Ong CN, Whiteman M. Protective effects of Asian green vegetables against oxidant induced cytotoxicity. World J Gastroenterol 2006; 11:7607-14. [PMID: 16437686 PMCID: PMC4727240 DOI: 10.3748/wjg.v11.i48.7607] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the antioxidant and phase II detoxification enzyme inducing ability of green leaf vegetables consumed in Asia. METHODS The antioxidant properties of six commonly consumed Asian vegetables were determined using the ABTS, DPPH, deoxyribose, PR bleaching and iron- ascorbate induced lipid peroxidation assay. Induce of phase II detoxification enzymes was also determined for each respective vegetable extract. Protection against authentic ONOO- and HOCl mediated cytotoxicity in human colon HCT116 cells was determined using the MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrasodium bromide) viability assay. RESULTS All of the extracts derived from green leaf vegetables exhibited antioxidant properties, while also having cytoprotective effects against ONOO- and HOCl mediated cytotoxicity. In addition, evaluation of the phase II enzyme inducing ability of each extract, as assessed by quinone reductase and glutathione-S-transferase activities, showed significant variation between the vegetables analyzed. CONCLUSION Green leaf vegetables are potential sources of antioxidants and phase II detoxification enzyme inducers in the Asian diet. It is likely that consumption of such vegetables is a major source of beneficial phytochemical constituents that may protect against colonic damage.
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Affiliation(s)
- Peter Rose
- Department of Biochemistry, National University of Singapore, 8 Medical Drive, 117597 Singapore.
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45
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Jansson PJ, Lindqvist C, Nordström T. Iron prevents ascorbic acid (vitamin C) induced hydrogen peroxide accumulation in copper contaminated drinking water. Free Radic Res 2006; 39:1233-9. [PMID: 16298750 DOI: 10.1080/10715760500249861] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Ascorbic acid (vitamin C) induced hydrogen peroxide (H(2)O(2)) formation was measured in household drinking water and metal supplemented Milli-Q water by using the FOX assay. Here we show that ascorbic acid readily induces H(2)O(2) formation in Cu(II) supplemented Milli-Q water and poorly buffered household drinking water. In contrast to Cu(II), iron was not capable to support ascorbic acid induced H(2)O(2) formation during acidic conditions (pH: 3.5-5). In 12 out of the 48 drinking water samples incubated with 2 mM ascorbic acid, the H(2)O(2) concentration exceeded 400 microM. However, when trace amounts of Fe(III) (0.2 mg/l) was present during incubation, the ascorbic acid/Cu(II)-induced H(2)O(2) accumulation was totally blocked. Of the other common divalent or trivalent metal ions tested, that are normally present in drinking water (calcium, magnesium, zinc, cobalt, manganese or aluminum), only calcium and magnesium displayed a modest inhibitory activity on the ascorbic acid/Cu(II)-induced H(2)O(2) formation. Oxalic acid, one of the degradation products from ascorbic acid, was confirmed to actively participate in the iron induced degradation of H(2)O(2). Ascorbic acid/Cu(II)-induced H(2)O(2) formation during acidic conditions, as demonstrated here in poorly buffered drinking water, could be of importance in host defense against bacterial infections. In addition, our findings might explain the mechanism for the protective effect of iron against vitamin C induced cell toxicity.
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Affiliation(s)
- Patric J Jansson
- Department of Biochemistry and Pharmacy, Abo Akademi University, BioCity, Turku, Finland
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46
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Messmer K, Reynolds GP. An in vitro model of inflammatory neurodegeneration and its neuroprotection. Neurosci Lett 2005; 388:39-44. [PMID: 16102901 DOI: 10.1016/j.neulet.2005.06.047] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2005] [Revised: 06/09/2005] [Accepted: 06/13/2005] [Indexed: 10/25/2022]
Abstract
Inflammation has been implicated in a variety of acute and chronic neurodegenerative diseases in which the inflammatory processes are considered not only to result from neurodegenerative effects, but also to contribute to these effects. To investigate the primary effect of inflammation on neuronal survival, a co-culture system of neuronal cells (differentiated SH SY5Y human neuroblastoma cells or primary cortical/striatal neurons) and monocytic cells (THP-1) in direct cell-cell contact was set up. After 5 days, THP-1 activation by lipopolysaccharide and phorbol 12-myristate 13-acetate resulted in a significant increase of neuronal cell death compared to co-culture without activation. In neuroprotection studies using this model, ascorbic acid and EDTA demonstrated a highly significant reduction in activated THP-1 induced cell death. Glutathione and NBQX, but not the protease inhibitor, PMSF, and catalase, also significantly reduced this inflammatory neurotoxicity. Indomethacin was protective of the primary cultured neurons but not the SH SY5Y cells. This co-culture of neuronal cells and activated THP-1 provides a useful model for the study of inflammatory mechanisms resulting in neuronal cell death.
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Affiliation(s)
- Kirsten Messmer
- University of Sheffield, Department of Biomedical Science, Western Bank, Sheffield S10 2TN, UK.
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47
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Rentzos M, Nikolaou C, Anagnostouli M, Rombos A, Tsakanikas K, Economou M, Dimitrakopoulos A, Karouli M, Vassilopoulos D. Serum uric acid and multiple sclerosis. Clin Neurol Neurosurg 2005; 108:527-31. [PMID: 16202511 DOI: 10.1016/j.clineuro.2005.08.004] [Citation(s) in RCA: 70] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2005] [Revised: 08/02/2005] [Accepted: 08/08/2005] [Indexed: 10/25/2022]
Abstract
UNLABELLED Peroxynitrite (PN) has been implicated in multiple sclerosis (MS) and its animal model experimental allergic encephalomyelitis. Uric acid (UA) serum levels of MS patients, a natural scavenger of PN, were found lowered in some recent studies. OBJECTIVE/PURPOSE The objective of our study was to correlate UA serum levels and several clinical parameters of MS. We also tried to investigate serum UA changes during treatment with immunomodulating or immunosuppressing drugs in the last 6 months. PATIENTS AND METHODS We measured UA serum levels in 190 patients with MS and 58 age and gender matched patients with inflammatory (IND) and non-inflammatory diseases (NIND) studied as control groups. UA levels were correlated with clinical parameters as type of the disease, duration, disability, magnetic resonance imaging (MRI) activity and female gender. RESULTS In the overall MS group, patients were found to have significantly lower mean serum uric acid levels compared with the IND (p = 0.0029) and the NIND group (p < 0.0001). UA serum concentrations were not inversely correlated with duration of the disease (p = 0.87), with disability as assessed by Expanded Disability Status Scale (EDSS) score (p = 0.67) and MRI activity (p = 0.36). Treatment with immunomodulating or immunosuppressing drugs had no influence in UA levels (p = 0.85). Patients with Clinically Isolated Syndromes (CIS) were found to have significantly lower UA concentrations compared with IND and NIND patients (p = 0.009 and <0.001, respectively). CONCLUSIONS Our findings suggest that lower serum UA levels in MS patients may represent a primary, constitutive loss of protection against nitric oxide and the development of CNS inflammation and tissue damage may not have a direct effect to UA serum levels. They also provide support that the earlier increase of UA serum levels might be beneficial in the future treatment of MS.
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Affiliation(s)
- M Rentzos
- Department of Neurology, Aeginition Hospital-Athens Medical School, 72-74 Vas.Sophias Av, Greece.
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48
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Ghavami S, Hashemi M, Shahriari HA, Bajestani SN, de Serres FJ, Moghaddam EM, Kazemi M, Alavian SM, Taheri M, Blanco I, Fernandez Bustillo E. Alpha-1-antitrypsin phenotypes and HLA-B27 typing in uveitis patients in southeast Iran. Clin Biochem 2005; 38:425-32. [PMID: 15820772 DOI: 10.1016/j.clinbiochem.2005.02.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2004] [Revised: 02/05/2005] [Accepted: 02/17/2005] [Indexed: 12/30/2022]
Abstract
OBJECTIVES Uveitis is an eye disease that affects humans worldwide. Inflammation of the uveal tract is termed uveitis. Alpha-1-antitrypsin (AAT) deficiency is one of many factors that may be involved in abnormalities such as liver and lung disease, inflammatory joint diseases, and inflammatory eye diseases. In this study, the role of AAT in uveitis is analyzed. DESIGN AND METHODS AAT phenotyping and serum-trypsin inhibitory capacity (S-TIC) experiments were performed on 103 patients who were referred to the ALZAHRA eye center in Zahedan (southeast of Iran). The same experiments were performed on 167 people who did not suffer from any eye or systemic diseases and served as a control group. RESULTS The results revealed that the frequency of M1S, M2S, M1Z, and MV phenotypes were significantly higher in uveitis patients (P < 0.001). There was no difference in AAT phenotype frequencies between various types of uveitis (P = 0.1). CONCLUSION AAT deficiency appears to be a risk factor for uveitis in southeast Iran. More investigation is needed to establish potential benefits of AAT phenotyping tests and AAT therapy in the diagnosis and treatment of uveitis cases with unclear etiology.
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Affiliation(s)
- Saeid Ghavami
- Department of Clinical Biochemistry, School of Medicine, Zahedan Medical University, Zahedan, Iran.
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Kamiya Y, Ohta Y, Imai Y, Arisawa T, Nakano H. A critical role of gastric mucosal ascorbic acid in the progression of acute gastric mucosal lesions induced by compound 48/80 in rats. World J Gastroenterol 2005; 11:1324-32. [PMID: 15761970 PMCID: PMC4250679 DOI: 10.3748/wjg.v11.i9.1324] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the role of gastric mucosal ascorbic acid (AA) in the progression of acute gastric mucosal lesions induced by compound 48/80 (C48/80), a mast cell degranulator, in rats.
METHODS: C48/80 (0.75 mg/kg) was intraperitoneally injected to fasted Wistar rats. Oral administration of AA (10, 50 or 100 mg/kg) was performed 0.5 h after C48/80 treatment. Determinations for gastric mucosal lesion severity and blood flow, and assays for gastric mucosal total AA, reduced AA, oxidized AA, vitamin E, thiobarbituric acid reactive substances (TBARS), adherent mucus, nitrite/nitrate (NOx), non-protein SH (NPSH), and myeloperoxidase (MPO), and serum total AA, reduced AA, oxidized AA, and NOx were conducted 0.5 and 3 h after C48/80 treatment.
RESULTS: Gastric mucosal lesions occurred 0.5 h after C48/80 treatment and progressed at 3 h. Gastric mucosal blood flow decreased 0.5 h after C48/80 treatment but the decrease was recovered at 3 h. Gastric mucosal total AA, reduced AA, vitamin E, and adherent mucus concentrations decreased 3 h after C48/80 treatment. Gastric mucosal oxidized AA concentration remained unchanged after C48/80 treatment. Gastric mucosal NPSH concentration decreased 0.5 h after C48/80 treatment, but the decrease was recovered at 3 h. Gastric mucosal TBARS concentration and MPO activity increased 0.5 h after C48/80 treatment and further increased at 3 h. Serum total AA and reduced AA concentrations increased 0.5 h after C48/80 treatment and further increased at 3 h, while serum oxidized AA concentration increased at 0.5 h. Serum and gastric mucosal NOx concentrations increased 3 h after C48/80 treatment. AA administration to C48/80-treated rats at 0.5 h after the treatment prevented the gastric mucosal lesion progression and the changes in gastric mucosal total AA, reduced AA, vitamin E, adherent mucus, NOx, and TBARS concentrations and MPO activity and serum NOx concentration found at 3 h after the treatment dose-dependently. The AA administration to C48/80-treated rats caused further increases in serum total AA and reduced AA concentrations at 3 h after the treatment dose-dependently.
CONCLUSION: Gastric mucosal AA plays a critical role in the progression of C48/80-induced acute gastric mucosal lesions in rats.
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Affiliation(s)
- Yoshio Kamiya
- Department of Internal Medicine, School of Medicine, Fujita Health University, Toyoake, Aichi 470-1192, Japan
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50
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Gianfrancesco F, Esposito T, Casu G, Maninchedda G, Roberto R, Pirastu M. Emergence of Talanin protein associated with human uric acid nephrolithiasis in the Hominidae lineage. Gene 2004; 339:131-8. [PMID: 15363853 DOI: 10.1016/j.gene.2004.06.030] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2004] [Revised: 06/06/2004] [Accepted: 06/17/2004] [Indexed: 02/04/2023]
Abstract
Recently, we identified a susceptibility locus for human uric acid nephrolithiasis (UAN) on 10q21-q22 and demonstrated that a novel gene (ZNF365) included in this region produces through alternative splicing several transcripts coding for four protein isoforms. Mutation analysis showed that one of them (Talanin) is associated with UAN. We examined the evolutionary conservation of ZNF365 gene through a comparative genomic approach. Searching for mouse homologs of ZNF365 transcripts, we identified a highly conserved mouse ortholog of ZNF365A transcript, expressed specifically in brain. We did not found a mouse homolog for ZNF365D transcript encoding the Talanin protein, even if we were able to identify the corresponding genomic region in mouse and rat not yet organized in canonical gene structure suggesting that ZNF365D was originated after the branching of hominoid from rodent lineage. In mouse and in most mammals, a functional uricase degrades the uric acid to allantoin, but uricase activity was lost during the Miocene epoch in hominoids. Searching for the presence of Talanin in Primates, we found a canonical intron-exon structure with several stop codons preventing protein production in Old World and New World monkeys. In humans, we observe expression and we have evidence that ZNF365D transcript produces a functional protein. It seems therefore that ZNF365D transcript emerged during primate evolution from a noncoding genomic sequence that evolved in a standard gene structure and assumed its role in parallel with the disappearance of uricase, probably against a disadvantageous excessive hyperuricemia.
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MESH Headings
- Alternative Splicing
- Amino Acid Sequence
- Animals
- Base Sequence
- Chromosomes, Human, Pair 10/genetics
- Chromosomes, Mammalian/genetics
- Cloning, Molecular
- DNA, Complementary/chemistry
- DNA, Complementary/genetics
- DNA, Complementary/isolation & purification
- DNA-Binding Proteins/genetics
- Evolution, Molecular
- Humans
- Kidney Diseases/blood
- Kidney Diseases/genetics
- Kidney Diseases/pathology
- Mice
- Molecular Sequence Data
- Phylogeny
- Primates/genetics
- Protein Isoforms/genetics
- Sequence Alignment
- Sequence Analysis, DNA
- Sequence Homology, Amino Acid
- Sequence Homology, Nucleic Acid
- Synteny
- Transcription Factors/genetics
- Uric Acid/blood
- Zinc Fingers/genetics
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