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Cell Oct 2019Physical or mental stress leads to neuroplasticity in the brain and increases the risk of depression and anxiety. Stress exposure causes the dysfunction of peripheral T...
Physical or mental stress leads to neuroplasticity in the brain and increases the risk of depression and anxiety. Stress exposure causes the dysfunction of peripheral T lymphocytes. However, the pathological role and underlying regulatory mechanism of peripheral T lymphocytes in mood disorders have not been well established. Here, we show that the lack of CD4 T cells protects mice from stress-induced anxiety-like behavior. Physical stress-induced leukotriene B4 triggers severe mitochondrial fission in CD4 T cells, which further leads to a variety of behavioral abnormalities including anxiety, depression, and social disorders. Metabolomic profiles and single-cell transcriptome reveal that CD4 T cell-derived xanthine acts on oligodendrocytes in the left amygdala via adenosine receptor A1. Mitochondrial fission promotes the de novo synthesis of purine via interferon regulatory factor 1 accumulation in CD4 T cells. Our study implicates a critical link between a purine metabolic disorder in CD4 T cells and stress-driven anxiety-like behavior.
Topics: Amygdala; Animals; Anxiety; Behavior, Animal; Brain Diseases, Metabolic; CD4-Positive T-Lymphocytes; Disease Models, Animal; Humans; Mice; Mitochondrial Dynamics; Oligodendroglia; Single-Cell Analysis; Stress, Psychological; Transcriptome; Xanthine
PubMed: 31675497
DOI: 10.1016/j.cell.2019.10.001 -
Redox Biology Jul 2020The innate immune system in mammals is the first-line defense that plays an important protective role against a wide spectrum of pathogens, especially during early life... (Review)
Review
The innate immune system in mammals is the first-line defense that plays an important protective role against a wide spectrum of pathogens, especially during early life before the adaptive immune system develops. The enzymes xanthine oxidase (XO) and lactoperoxidase (LPO) are widely distributed in mammalian tissues and secretions, and have a variety of biological functions including in innate immunity, provoking much interest for both in vitro and in vivo applications. The enzymes are characterized by their generation of reactive oxygen and nitrogen species, including hydrogen peroxide, hypothiocyanite, nitric oxide, and peroxynitrite. XO is a major generator of hydrogen peroxide and superoxide that subsequently trigger a cascade of oxidative radical pathways, including those produced by LPO, which have bactericidal and bacteriostatic effects against pathogens including opportunistic bacteria. In addition to their role in host microbial defense, reactive oxygen and nitrogen species play important physiological roles as second messenger cell signaling molecules, including cellular proliferation, differentiation and gene expression. There are several indications that the reactive species generated by peroxide have positive effects on human health, particularly in neonates; however, some important in vivo aspects of this system remain obscure. The primary dependence of the system on hydrogen peroxide has led us to propose it is particularly relevant to neonate mammals during milk feeding.
Topics: Animals; Humans; Hydrogen Peroxide; Immunity, Innate; Infant, Newborn; Lactoperoxidase; Superoxides; Xanthine; Xanthine Oxidase
PubMed: 32334145
DOI: 10.1016/j.redox.2020.101524 -
Clinical Pharmacokinetics Nov 2022Previously, we developed a pharmacokinetic-pharmacodynamic model of allopurinol, oxypurinol, and biomarkers, hypoxanthine, xanthine, and uric acid, in neonates with...
BACKGROUND AND OBJECTIVE
Previously, we developed a pharmacokinetic-pharmacodynamic model of allopurinol, oxypurinol, and biomarkers, hypoxanthine, xanthine, and uric acid, in neonates with hypoxic-ischemic encephalopathy, in which high initial biomarker levels were observed suggesting an impact of hypoxia. However, the full pharmacodynamics could not be elucidated in our previous study. The current study included additional data from the ALBINO study (NCT03162653) placebo group, aiming to characterize the dynamics of hypoxanthine, xanthine, and uric acid in neonates with hypoxic-ischemic encephalopathy.
METHODS
Neonates from the ALBINO study who received allopurinol or placebo mannitol were included. An extended population pharmacokinetic-pharmacodynamic model was developed based on the mechanism of purine metabolism, where synthesis, salvage, and degradation via xanthine oxidoreductase pathways were described. The initial level of the biomarkers was a combination of endogenous turnover and high disease-related amounts. Model development was accomplished by nonlinear mixed-effects modeling (NONMEM, version 7.5).
RESULTS
In total, 20 neonates treated with allopurinol and 17 neonates treated with mannitol were included in this analysis. Endogenous synthesis of the biomarkers reduced with 0.43% per hour because of precursor exhaustion. Hypoxanthine was readily salvaged or degraded to xanthine with rate constants of 0.5 1/h (95% confidence interval 0.33-0.77) and 0.2 1/h (95% confidence interval 0.09-0.31), respectively. A greater salvage was found in the allopurinol treatment group consistent with its mechanism of action. High hypoxia-induced initial levels of biomarkers were quantified, and were 1.2-fold to 2.9-fold higher in neonates with moderate-to-severe hypoxic-ischemic encephalopathy compared with those with mild hypoxic-ischemic encephalopathy. Half-maximal xanthine oxidoreductase inhibition was achieved with a combined allopurinol and oxypurinol concentration of 0.68 mg/L (95% confidence interval 0.48-0.92), suggesting full xanthine oxidoreductase inhibition during the period studied.
CONCLUSIONS
This extended pharmacokinetic-pharmacodynamic model provided an adequate description of the complex hypoxanthine, xanthine, and uric acid metabolism in neonates with hypoxic-ischemic encephalopathy, suggesting a positive allopurinol effect on these biomarkers. The impact of hypoxia on their dynamics was characterized, underlining higher hypoxia-related initial exposure with a more severe hypoxic-ischemic encephalopathy status.
Topics: Humans; Infant, Newborn; Allopurinol; Hypoxanthine; Hypoxia; Hypoxia-Ischemia, Brain; Mannitol; Oxypurinol; Uric Acid; Xanthine; Xanthine Dehydrogenase; Clinical Studies as Topic
PubMed: 36040612
DOI: 10.1007/s40262-022-01164-9 -
BMC Plant Biology Jan 2021Soil salinity is a critical threat to global agriculture. In plants, the accumulation of xanthine activates xanthine dehydrogenase (XDH), which catalyses the...
BACKGROUND
Soil salinity is a critical threat to global agriculture. In plants, the accumulation of xanthine activates xanthine dehydrogenase (XDH), which catalyses the oxidation/conversion of xanthine to uric acid to remove excess reactive oxygen species (ROS). The nucleobase-ascorbate transporter (NAT) family is also known as the nucleobase-cation symporter (NCS) or AzgA-like family. NAT is known to transport xanthine and uric acid in plants. The expression of MdNAT is influenced by salinity stress in apple.
RESULTS
In this study, we discovered that exogenous application of xanthine and uric acid enhanced the resistance of apple plants to salinity stress. In addition, MdNAT7 overexpression transgenic apple plants showed enhanced xanthine and uric acid concentrations and improved tolerance to salinity stress compared with nontransgenic plants, while opposite phenotypes were observed for MdNAT7 RNAi plants. These differences were probably due to the enhancement or impairment of ROS scavenging and ion homeostasis abilities.
CONCLUSION
Our results demonstrate that xanthine and uric acid have potential uses in salt stress alleviation, and MdNAT7 can be utilized as a candidate gene to engineer resistance to salt stress in plants.
Topics: Antioxidants; Gene Expression Regulation, Plant; Homeostasis; Hydrogen Peroxide; Malus; Nucleobase Transport Proteins; Plant Leaves; Plant Proteins; Plants, Genetically Modified; Potassium; Salt Tolerance; Sodium; Uric Acid; Xanthine
PubMed: 33468049
DOI: 10.1186/s12870-021-02831-y -
Nucleic Acids Research Jul 2021Riboswitches are conserved functional domains in mRNA that mostly exist in bacteria. They regulate gene expression in response to varying concentrations of metabolites...
Riboswitches are conserved functional domains in mRNA that mostly exist in bacteria. They regulate gene expression in response to varying concentrations of metabolites or metal ions. Recently, the NMT1 RNA motif has been identified to selectively bind xanthine and uric acid, respectively, both are involved in the metabolic pathway of purine degradation. Here, we report a crystal structure of this RNA bound to xanthine. Overall, the riboswitch exhibits a rod-like, continuously stacked fold composed of three stems and two internal junctions. The binding-pocket is determined by the highly conserved junctional sequence J1 between stem P1 and P2a, and engages a long-distance Watson-Crick base pair to junction J2. Xanthine inserts between a G-U pair from the major groove side and is sandwiched between base triples. Strikingly, a Mg2+ ion is inner-sphere coordinated to O6 of xanthine and a non-bridging oxygen of a backbone phosphate. Two further hydrated Mg2+ ions participate in extensive interactions between xanthine and the pocket. Our structure model is verified by ligand binding analysis to selected riboswitch mutants using isothermal titration calorimetry, and by fluorescence spectroscopic analysis of RNA folding using 2-aminopurine-modified variants. Together, our study highlights the principles of metal ion-mediated ligand recognition by the xanthine riboswitch.
Topics: Binding Sites; Cations, Divalent; Crystallography, X-Ray; Ligands; Magnesium; Models, Molecular; Mutation; Nucleic Acid Conformation; RNA Folding; Riboswitch; Xanthine
PubMed: 34125892
DOI: 10.1093/nar/gkab486 -
International Journal of Molecular... May 2020Flavonoids are natural phenolic compounds, which are the active ingredients in several dietary supplements. It is well-known that some flavonoid aglycones are potent...
Flavonoids are natural phenolic compounds, which are the active ingredients in several dietary supplements. It is well-known that some flavonoid aglycones are potent inhibitors of the xanthine oxidase (XO)-catalyzed uric acid formation . However, the effects of conjugated flavonoid metabolites are poorly characterized. Furthermore, the inhibition of XO-catalyzed 6-mercaptopurine oxidation is an important reaction in the pharmacokinetics of this antitumor drug. The inhibitory effects of some compounds on xanthine vs. 6-mercaptopurine oxidation showed large differences. Nevertheless, we have only limited information regarding the impact of flavonoids on 6-mercaptopurine oxidation. In this study, we examined the interactions of flavonoid aglycones and some of their conjugates with XO-catalyzed xanthine and 6-mercaptopurine oxidation . Diosmetin was the strongest inhibitor of uric acid formation, while apigenin showed the highest effect on 6-thiouric acid production. Kaempferol, fisetin, geraldol, luteolin, diosmetin, and chrysoeriol proved to be similarly strong inhibitors of xanthine and 6-mercaptopurine oxidation. While apigenin, chrysin, and chrysin-7-sulfate were more potent inhibitors of 6-mercaptopurine than xanthine oxidation. Many flavonoids showed similar or stronger (even 5- to 40-fold) inhibition of XO than the positive control allopurinol. Based on these observations, the extremely high intake of flavonoids may interfere with the elimination of 6-mercaptopurine.
Topics: Allopurinol; Catalysis; Dose-Response Relationship, Drug; Flavonoids; Mercaptopurine; Oxidation-Reduction; Xanthine; Xanthine Oxidase
PubMed: 32380641
DOI: 10.3390/ijms21093256 -
Journal of Clinical Laboratory Analysis Jun 2019Hyperuricemia is the only biochemical index in the classification of acute gouty arthritis in American Rheumatism Association 1977 and the main basis of clinical...
BACKGROUND
Hyperuricemia is the only biochemical index in the classification of acute gouty arthritis in American Rheumatism Association 1977 and the main basis of clinical diagnosis for most doctors. However, nearly half of the time gout occurs without hyperuricemia, especially in an acute attack,which leads to an urgent need to find a new substitute diadynamic criteria of gout. Xanthine and hypoxanthine, as precursors of uric acid, have been reported to be high in gout patients with hyperuricemia and presumed to be gout biomarkers.
OBJECTIVES
To further explore the possibility of xanthine and hypoxanthine to be gout biomarkers as substitutes for uric acid.
METHODS
A reversed-phase HPLC-UV method was employed for simultaneous quantitative detection of uric acid (UA), xanthine (X), and hypoxanthine (HX) in gout patients' (with and without hyperuricemia) and healthy persons' serum.
RESULTS
The xanthine and hypoxanthine concentrations in gout patients with hyperuricemia and without hyperuricemia are higher than in healthy persons with a P < 0.001.
CONCLUSIONS
This study supplements previous researches by confirming that xanthine and hypoxanthine are significantly elevated in gout patients' serum especially in patients' with normouricemia, which supported xanthine and hypoxanthine may have clinical application for the diagnosis of gout.
Topics: Blood Chemical Analysis; Chromatography, High Pressure Liquid; Gout; Humans; Hyperuricemia; Hypoxanthine; Limit of Detection; Male; Reproducibility of Results; Uric Acid; Xanthine
PubMed: 30803031
DOI: 10.1002/jcla.22868 -
Journal of Diabetes Investigation Jul 2020Uric acid is synthesized by oxidation of hypoxanthine and xanthine using a catalyzing enzyme, xanthine oxidoreductase (XOR), which can be a source of reactive oxygen...
AIMS/INTRODUCTION
Uric acid is synthesized by oxidation of hypoxanthine and xanthine using a catalyzing enzyme, xanthine oxidoreductase (XOR), which can be a source of reactive oxygen species. Plasma XOR activity is a metabolic biomarker associated with obesity, hyperuricemia, liver dysfunction and insulin resistance. However, it has recently been reported that XOR activity in fat tissue is low in humans, unlike in rodents, and that hypoxanthine is secreted from human fat tissue.
MATERIALS AND METHODS
The associations of obesity with hypoxanthine, xanthine and plasma XOR activity were investigated in 484 participants (men/women: 224/260) of the Tanno-Sobetsu Study.
RESULTS
Levels of hypoxanthine, xanthine and plasma XOR activity were significantly higher in men than in women. In 59 participants with hyperuricemia, 11 (men/women: 11/0) participants were being treated with an XOR inhibitor and had a significantly higher level of xanthine, but not hypoxanthine, than that in participants without treatment. In all of the participants, hypoxanthine concentration in smokers was significantly higher than that in non-smokers. Stepwise and multivariate regression analyses showed that body mass index, smoking habit and xanthine were independent predictors of hypoxanthine after adjustment of age, sex and use of antihyperuricemic drugs. Whereas, alanine transaminase, hypoxanthine and plasma XOR activity were independent predictors for xanthine, and alanine transaminase, triglycerides and xanthine were independent predictors for plasma XOR activity.
CONCLUSIONS
The concentration of hypoxanthine, but not that of xanthine, is independently associated with obesity and smoking habit, indicating differential regulation of hypoxanthine and xanthine in a general population.
Topics: Adipose Tissue; Aged; Alanine Transaminase; Biomarkers; Body Mass Index; Enzyme Inhibitors; Female; Humans; Hyperuricemia; Hypoxanthine; Japan; Liver; Male; Middle Aged; Obesity; Regression Analysis; Signal Transduction; Triglycerides; Xanthine; Xanthine Dehydrogenase
PubMed: 31916414
DOI: 10.1111/jdi.13207 -
Current Pharmaceutical Design 2013Xanthine oxidoreductase (XOR), a complex flavoprotein, catalyzes the metabolic reactions leading from hypoxanthine to xanthine and from xanthine to urate, and both... (Review)
Review
Xanthine oxidoreductase (XOR), a complex flavoprotein, catalyzes the metabolic reactions leading from hypoxanthine to xanthine and from xanthine to urate, and both reactions take place at the molybdenum cofactor. The enzyme is a target of drugs for therapy of gout or hyperuricemia. We review the chemical nature and reaction mechanisms of the molybdenum cofactor of XOR, focusing on molybdenum-dependent reactions of actual or potential medical importance, including nitric oxide (NO) synthesis. It is now generally accepted that XOR transfers the water-exchangeable -OH ligand of the molybdenum atom to the substrate. The hydroxyl group at OH-Mo(IV) can be replaced by urate, oxipurinol and FYX-051 derivatives and the structures of these complexes have been determined by xray crystallography under anaerobic conditions. Although formation of NO from nitrite or formation of xanthine from urate by XOR ischemically feasible, it is not yet clear whether these reactions have any physiological significance since the reactions are catalyzed at a slow rate even under anaerobic conditions.
Topics: Animals; Coenzymes; Drug Discovery; Electron Transport; Humans; Hydrogen Bonding; Hydroxylation; Metalloproteins; Models, Molecular; Molybdenum Cofactors; Nitric Oxide; Oxidation-Reduction; Protein Binding; Pteridines; Substrate Specificity; Uric Acid; Xanthine; Xanthine Dehydrogenase
PubMed: 23116398
DOI: 10.2174/1381612811319140010 -
Scientific Reports Jul 2022The enzyme xanthine oxidoreductase (XOR) catalyzes the synthesis of uric acid (UA) from hypoxanthine and xanthine, which are products of purine metabolism starting from...
The enzyme xanthine oxidoreductase (XOR) catalyzes the synthesis of uric acid (UA) from hypoxanthine and xanthine, which are products of purine metabolism starting from ribose-5-phosphate. Several studies suggested a relationship between hyperuricemia and hepatic steatosis; however, few previous studies have directly examined the relationship between XOR activity and hepatic steatosis. A total of 223 subjects with one or more cardiovascular risk factors were enrolled. The liver-to-spleen (L/S) ratio on computed tomography and the hepatic steatosis index (HSI) were used to assess hepatic steatosis. We used a newly developed highly sensitive assay based on [C, N] xanthine and liquid chromatography/triple quadrupole mass spectrometry to measure plasma XOR activity. Subjects with the L/S ratio of < 1.1 and the HSI of < 36 had increased XOR activity and serum UA levels. Independent of insulin resistance and serum UA levels, multivariate logistic regression analysis revealed that plasma XOR activity was associated with the risk of hepatic steatosis as assessed by the L/S ratio and HSI. According to the findings of this study, plasma XOR activity is associated with hepatic steatosis independent of insulin resistance and serum UA levels.
Topics: Chromatography, Liquid; Fatty Liver; Humans; Insulin Resistance; Mass Spectrometry; Xanthine; Xanthine Dehydrogenase
PubMed: 35854080
DOI: 10.1038/s41598-022-16688-0