Uric Acid Synthesis Research Articles

Relationship between plasma xanthine oxidoreductase activity and left ventricular ejection fraction and hypertrophy among cardiac patients.

Background and purposeXanthine oxidoreductase (XOR), which catalyzes purine catabolism, has two interconvertible forms, xanthine dehydrogenase and xanthine oxidase, the latter of which produces superoxide during uric acid (UA) synthesis. An association between plasma XOR activity and cardiovascular and renal outcomes has been previously suggested. We investigated the potential association between cardiac parameters and plasma XOR activity among cardiology patients.Methods and resultsPlasma XOR activity was measured by [13C2,15N2]xanthine coupled with liquid chromatography/triplequadrupole mass spectrometry. Among 270 patients who were not taking UA-lowering drugs, XOR activity was associated with body mass index (BMI), alanine aminotransferase (ALT), HbA1c and renal function. Although XOR activity was not associated with serum UA overall, patients with chronic kidney disease (CKD), those with higher XOR activity had higher serum UA among patients without CKD. Compared with patients with the lowest XOR activity quartile, those with higher three XOR activity quartiles more frequently had left ventricular hypertrophy. In addition, plasma XOR activity showed a U-shaped association with low left ventricular ejection fraction (LVEF) and increased plasma B-type natriuretic peptide (BNP) levels, and these associations were independent of age, gender, BMI, ALT, HbA1C, serum UA, and CKD stages.ConclusionsAmong cardiac patients, left ventricular hypertrophy, low LVEF, and increased BNP were significantly associated with plasma XOR activity independent of various confounding factors. Whether pharmaceutical modification of plasma XOR activity might inhibit cardiac remodeling and improve cardiovascular outcome should be investigated in future studies.

Xanthine oxidoreductase activity is correlated with insulin resistance and subclinical inflammation in young humans

Background and AimsThe enzyme xanthine oxidoreductase (XOR) catalyzes the formation of uric acid (UA) from hypoxanthine and xanthine, which in turn are products of purine metabolism starting from ribose-5-phosphate. Besides the synthesis of UA, basic research has suggested that XOR is involved in the regulation of reactive oxygen species, adipogenesis, and peroxisome proliferator-activated receptor-γ (PPAR-γ). XOR activity has shown to be much lower in humans than in rodents, which makes its accurate measurement difficult. Recently, a novel human plasma XOR activity assay has been established using a combination of liquid chromatography (LC) and triple quadrupole mass spectrometry (TQMS) to detect [13C2,15N2]UA using [13C2,15N2]xanthine as a substrate. Using this novel assay, we for the first time determine plasma XOR activity in humans, and evaluate its association with insulin resistance, high-sensitivity C-reactive protein (hsCRP) levels, and other parameters. MethodsOf the 29 volunteers who wished to participate in the study, 3 were excluded; of the remaining, 11 were female and 15 were male with a mean age of 25.9±3.3years. Blood samples were collected under fasting conditions in the early morning to measure XOR activity and other parameters. ResultsThe natural logarithmic value of XOR activity (ln-XOR) in plasma was 3.4±0.8pmol/h/mL. Ln-XOR had a positive correlation with UA and body mass index (BMI) and a negative correlation with quantitative insulin sensitivity check index (QUICKI) and adiponectin. In addition, ln-XOR had a positive correlation with hsCRP levels, which serves as a marker of chronic inflammation. ConclusionsThe present study has shown that XOR activity is correlated with serum UA levels in humans. Furthermore, even in young subjects, XOR activity is correlated with insulin resistance, BMI, and subclinical inflammation. Thus, XOR activity may be potentially involved in adiposity and subclinical inflammation in humans.

Effective uric acid-lowering treatment for hypertensive patients with hyperuricemia.

Uric acid (UA) has been associated with hypertension, renal disease and cardiovascular disease. The aim of the present study was to compare the UA-lowering effects of a standard dose of the UA synthesis inhibitor febuxostat to a standard dose of the uricosuric agent benzbromarone, and to investigate the effects of a low-dose combination of both agents in hypertensive patients with hyperuricemia. Twenty hypertensive patients with inadequate UA control were administered febuxostat 40 mg (Feb), benzbromarone 50 mg (Ben) and febuxostat 20 mg and benzbromarone 25 mg (feb/ben) for 3 months each in a randomized modified crossover manner. UA metabolism, blood pressure (BP) and the indices of organ damage were assessed at baseline and the end of each treatment period. No significant changes were observed in BP or estimated glomerular filtration rate (eGFR) after the treatment with each UA-lowering regimen. The change in UA was significantly greater with feb/ben than with Feb. The excretion of UA and clearance of UA were higher with Ben than with Feb and feb/ben. Urinary 8-hydroxydeoxyguanosine and liver-type fatty-acid-binding protein levels were slightly lower with Ben, whereas flow-mediated dilation was slightly higher with feb/ben and Ben. The UA-lowering effects of the low-dose combination of the UA synthesis inhibitor and uricosuric agent were greater than those of the standard dose of each agent alone. The uricosuric agent may be more effective at improving vascular function than the UA synthesis inhibitor. Thus, the appropriate management of hyperuricemia with uricosuric drugs appears to be useful for hypertensive patients with hyperuricemia.

BIOCHEMICAL ROLE OF XANTHINE OXIDOREDUCTASE AND ITS NATURAL INHIBITORS: AN OVERVIEW

<p>Xanthine oxidoreductase (XOR) is a widely distributed housekeeping enzyme in mammals that catalyzes the last two steps in human purine catabolism to produce uric acid. The enzyme exists as a homodimer with independent electron transfer in each monomer. This has been studied extensively as a major constituent of the milk fat globule membrane (MFGM) which surrounds fat globules in cow's milk even though purine catabolism is the most accepted function of XOR. A huge number of literature highlights on the different catalytic forms of XOR and their importance in the generation of reactive oxygen species/reactive nitrogen species (ROS/RNS) and synthesis of uric acid which are involved in many physiological and pathological processes. However, a slight ambiguity resides in their biochemical functions. The aim of this article was to review the literature published on the structural, catalytical, physiological and pathological role of XOR and to resolve the ambiguity in biochemical processes and to firm up various natural inhibitors of XOR collectively. Uric acid, the product of purine catabolism shows antioxidant activity, and XOR-derived ROS and RNS play a role in innate immunity, milk secretion and also be involved in signaling and metabolism of xenobiotics. Furthermore, XOR is likely to be engaged in pathology because of excessive production of uric acid and ROS/RNS. This review also reports natural XOR inhibitors in plants which inhibit the enzyme to treat XOR associated pathology.</p>

Effects of xanthine oxidase inhibition with febuxostat on the development of nephropathy in experimental type 2 diabetes.

Elevated serum uric acid (UA) is a risk factor for the development of kidney disease. Inhibitors of xanthine oxidase (XOi), an enzyme involved in UA synthesis, have protective effects at early stages of experimental diabetic nephropathy (DN). However, long-term effects of XOi in models of DN remain to be determined. The development of albuminuria, renal structure and molecular markers of DN were studied in type 2 diabetic Zucker obese (ZO) rats treated for 18weeks with the XOi febuxostat and compared with vehicle-treated ZO rats, ZO rats treated with enalapril or a combination of both agents, and lean Zucker rats without metabolic defects. Febuxostat normalized serum UA and attenuated the development of albuminuria, renal structural changes, with no significant effects on BP, metabolic control or systemic markers of oxidative stress (OS). Most of these actions were comparable with those of enalapril. Combination treatment induced marked decreases in BP and was more effective in ameliorating structural changes, expression of profibrotic genes and systemic OS than either monotherapy. Febuxostat attenuated renal protein expression of TGF-ß, CTGF, collagen 4, mesenchymal markers (FSP1 and vimentin) and a tissue marker of OS nitrotyrosine. Moreover, febuxostat attenuated TGF-ß- and S100B-induced increased expression of fibrogenic molecules in renal tubular cells in vitro in UA-free media in an Akt kinase-dependent manner. Febuxostat is protective and enhances the actions of enalapril in experimental DN. Multiple mechanisms might be involved, such as a reduction of UA, renal OS and inhibition of profibrotic signalling.

Maternal fructose drives placental uric acid production leading to adverse fetal outcomes.

Maternal metabolic diseases increase offspring risk for low birth weight and cardiometabolic diseases in adulthood. Excess fructose consumption may confer metabolic risks for both women and their offspring. However, the direct consequences of fructose intake per se are unknown. We assessed the impact of a maternal high-fructose diet on the fetal-placental unit in mice in the absence of metabolic syndrome and determined the association between maternal serum fructose and placental uric acid levels in humans. In mice, maternal fructose consumption led to placental inefficiency, fetal growth restriction, elevated fetal serum glucose and triglyceride levels. In the placenta, fructose induced de novo uric acid synthesis by activating the activities of the enzymes AMP deaminase and xanthine oxidase. Moreover, the placentas had increased lipids and altered expression of genes that control oxidative stress. Treatment of mothers with the xanthine oxidase inhibitor allopurinol reduced placental uric acid levels, prevented placental inefficiency, and improved fetal weights and serum triglycerides. Finally, in 18 women delivering at term, maternal serum fructose levels significantly correlated with placental uric acid levels. These findings suggest that in mice, excess maternal fructose consumption impairs placental function via a xanthine oxidase/uric acid-dependent mechanism, and similar effects may occur in humans.

Effect of glycine supplementation in low protein diets with amino acids from soy protein isolate or free amino acids on broiler growth and nitrogen utilisation

Here, it was investigated whether substitution of amino acids (AA) from soy protein isolate with free AA in low crude protein diets influences the growth performance and N utilisation in broilers, and whether interactions with dietary glycine equivalent (Glyequi) concentration exist.Birds were distributed in two 2 × 2 factorial arrangements of 48 floor pens containing 10 birds each, plus 48 metabolism cages containing two birds each. Experimental feed was provided for ad libitum consumption from d 7 to 22. Diets contained either a soy protein isolate at 79 g/kg or a mix of free AA, which supplied the same amount of 18 proteinogenic AA. A mix of free glycine and l-serine was used to obtain low and high (12.0 and 20.5 g/kg dry matter) levels of dietary Glyequi.Substitution of soy protein isolate with free AA reduced the average daily gain and feed efficiency, mainly due to reduced feed intake. Efficiency of N accretion was not influenced by the AA source or Glyequi concentration on d 21, possibly due to the lower AA digestibility of soy protein isolate and higher urinary excretion of nitrogenous substances in the treatments with the AA mix.The average daily weight gain of the treatments with high Glyequi concentration was higher for both AA sources. This increase was due to higher average daily feed intake by broilers in the treatments with soy protein isolate and due to the increased feed efficiency in the treatments with the AA mix. Broilers exhibited different growth responses to dietary Glyequi between the AA sources; however, these responses could not be attributed to the different utilisation of Glyequi for uric acid synthesis.

Molybdenum cofactor deficiency causes translucent integument, male-biased lethality, and flaccid paralysis in the silkworm Bombyx mori

Uric acid accumulates in the epidermis of Bombyx mori larvae and renders the larval integument opaque and white. Yamamoto translucent (oya) is a novel spontaneous mutant with a translucent larval integument and unique phenotypic characteristics, such as male-biased lethality and flaccid larval paralysis. Xanthine dehydrogenase (XDH) that requires a molybdenum cofactor (MoCo) for its activity is a key enzyme for uric acid synthesis. It has been observed that injection of a bovine xanthine oxidase, which corresponds functionally to XDH and contains its own MoCo activity, changes the integuments of oya mutants from translucent to opaque and white. This finding suggests that XDH/MoCo activity might be defective in oya mutants. Our linkage analysis identified an association between the oya locus and chromosome 23. Because XDH is not linked to chromosome 23 in B. mori, MoCo appears to be defective in oya mutants. In eukaryotes, MoCo is synthesized by a conserved biosynthesis pathway governed by four loci (MOCS1, MOCS2, MOCS3, and GEPH). Through a candidate gene approach followed by sequence analysis, a 6-bp deletion was detected in an exon of the B. mori molybdenum cofactor synthesis-step 1 gene (BmMOCS1) in the oya strain. Moreover, recombination was not observed between the oya and BmMOCS1 loci. These results indicate that the BmMOCS1 locus is responsible for the oya locus. Finally, we discuss the potential cause of male-biased lethality and flaccid paralysis observed in the oya mutants.

Heat Stress Nephropathy From Exercise-Induced Uric Acid Crystalluria: A Perspective on Mesoamerican Nephropathy

Mesoamerican nephropathy (MeN), an epidemic in Central America, is a chronic kidney disease of unknown cause. In this article, we argue that MeN may be a uric acid disorder. Individuals at risk for developing the disease are primarily male workers exposed to heat stress and physical exertion that predisposes to recurrent water and volume depletion, often accompanied by urinary concentration and acidification. Uric acid is generated during heat stress, in part consequent to nucleotide release from muscles. We hypothesize that working in the sugarcane fields may result in cyclic uricosuria in which uric acid concentrations exceed solubility, leading to the formation of dihydrate urate crystals and local injury. Consistent with this hypothesis, we present pilot data documenting the common presence of urate crystals in the urine of sugarcane workers from El Salvador. High end-of-workday urinary uric acid concentrations were common in a pilot study, particularly if urine pH was corrected to 7. Hyperuricemia may induce glomerular hypertension, whereas the increased urinary uric acid may directly injure renal tubules. Thus, MeN may result from exercise and heat stress associated with dehydration-induced hyperuricemia and uricosuria. Increased hydration with water and salt, urinary alkalinization, reduction in sugary beverage intake, and inhibitors of uric acid synthesis should be tested for disease prevention.

Bipolar affective disorder: A review of novel forms of therapy

Abstract Normothymic, antidepressant and antipsychotic pharmaceutics are, in accordance with international guidelines, employed both in the therapy and the prevention of bipolar disorder (BD). Long-term studies on the mechanisms of action of such medications, as well as on the pathogenetic background of BD, have led to the discovery of effective, albeit unconventional pharmacotherapeutic approaches. These methods have the potential to successfully treat mania and depression, as well as to counter affective episode relapse. Allopurinol - commonly used to treat gout, secondary hyperuricemia and Lesch-Nyhan syndrome, acts by inhibiting the synthesis of uric acid, levels of which are often increased in manic patients. Due to this, an evaluation of the potential effect of allopurinol on the reduction of mania symptoms seems to be reasonable. Additionally, the numerable research papers coming out of research regarding the role of purine neurotransmitters in mood alterations, indicate that adenosine agonists act analogously to dopamine antagonists. N-acetylcysteine (NAC), a supporting agent in the pharmacotherapy of depressive episodes in bipolar disorder, substantially accelerates mood stabilization in patients. In turn, memantine, known for its procognitive effect, not only has antimanic and normothymic properties, but also boosts the neuroprotective action of traditional lithium therapy. In view of the latest opinions, the subtle pro-inflammatory process is typical for the pathophysiology of bipolar disease. Acetylsalicylic acid (ASA) (a popular analgesic, antipyretic and antiphlogistic agent) may be useful in BD therapy. This is because that, via its effect upon cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), ASA modulates leukocyte recruitment in neuro-inflammation. Apart from the above-mentioned medications, this article introduces the results of recent investigations of ketamine, modafinil and tamoxifen, including their receptor mechanisms, as well as certain genetic aspects or elements of their pharmacodynamics, for use in BD therapy. We put forward that, possibly, more insightful cognition of these drugs will allow significant enrichment in the range of pharmacotherapy for BD in the near future.

Rats hyperuricemia model established by lipid emulsion simulating irregular of diet

Due to the irregular of diet and overfeeding greasy and surfeit flavor closely associated with hyperuricemia disease, the lipid emulsion containing high cholesterol was used to model. To obtain a more stable and sustained animal model for the efficacy evaluation of traditional Chinese herbs, we observed the influence on the serum uric acid of rat induced by the lipid emulsion compared with high purine diet. 36 SD male rats were randomized to the normal control group, high purine diet group and lipid emulsion group respectively. The general behavior, body weight and daily food intake of rats were observed. The orbital blood was taken to separate into the serum and 24 hours urine was collected. The serum indexes such as UA, BUN, Cr, ALT, AST, TC, TG, LDL-c were determined every 2 weeks, and XOD, ADA enzyme activity were determined at the 4th week. The urine indexes such as UA, Cr and Cua/Ccr were determined at the 4th week. After stopping modeling, the serum UA were determined two weeks and four weeks later respectively. At the 2nd week, the body weight and daily food intake of rats in the lipid emulsion group reduced significantly, and the level of serum UA, BUN, Cr, TC, LDL-c, ATL, AST raised significantly meanwhile TG reduced. At the 4th week, the serum UA in high purine diet group did not raise, and the serum XOD raised obviously while ADA did not; the serum UA in lipid emulsion group was higher significantly, and the serum XOD and ADA raised while Cua/Ccr reduced obviously. At the 6th weeks, the serum UA in both the high purine diet group and lipid emulsion group raised obviously. After stopping modeling, the serum UA in lipid emulsion group still maintained a high level at the 2nd week and back to the normal level at the 4th week. Compared with high purine diet, the hyperuricemia model induced by lipid emulsion forms earlierand more stable. It maybe has great value to study the pharmacodynamics of traditional Chinese medicine treatment to hyperuricemia disease. Its mechanism may be related to increasing XOD and ADA enzyme activity which can promote uric acid synthesis, meanwhile inhibiting of uric acid excretion.

Polymorphism of rs7688672 and rs10033237 in cGKII/PRKG2 and gout susceptibility of Han population in northern China

Gout is a genetic or acquired metabolic disease caused by increase of uric acid synthesis resulted from purine metabolic abnormalities. Whether cGMP-dependent protein kinase 2 (cGKII/PRKG2) is correlated with gout remains controversial. The objective of the present study was to investigate whether there is a correlation between polymorphism of cGKII/PRKG2 and gout susceptibility of Han population in northern China. Four hundred and five male patients with gout in the case group and 429 controls in the control group were collected from the Department of Endocrinology and Metabolic Disease, the Fourth Affiliated Hospital of Harbin Medical University. A case–control study method was used to study the correlation between cGKII/PRKG2 polymorphism rs7688672 and rs10033237 and gout susceptibility. The genotype frequencies of rs7688672 and rs10033237 polymorphisms of cGKII/PRKG2 in the case group and the control group both were in accordance with Hardy–Weinberg equilibrium. There were significant differences of rs10033237 in the allele frequencies and genotype distributions (P<0.05) between the two groups, while no association was found between rs7688672 and gout. Combined mutation sites AA⁎ from rs7688672 and rs10033237 were negatively correlated with gout susceptibility, whereas haplotype GG⁎ was positively correlated with gout susceptibility. In conclusion, patients with rs10033237 polymorphism of cGKII/PRKG2 gene are more likely to suffer from gout. With regard to haplotypes of rs10033237 and rs7688672, both AA⁎ and GG⁎ are related to gout. AA⁎ is a gout susceptible gene, whereas GG⁎ is a protective gene.

Effect of High-Fat Diet on Hepatic Proteomics of Hamsters

A high-fat diet contributes to the etiology of metabolic diseases. As the liver plays a crucial role in metabolism, an insight into the hepatic proteomics will help to illustrate the physiological effect of a high-fat diet. Fourteen nine-week old male Syrian hamsters were maintained on either control (C) or high-fat (HF) diets (0.2% cholesterol +22% fat) for 8 weeks. Hamsters were chosen because they show close similarity to human lipid metabolism. At the end of study, blood and livers were collected for analysis. Liver proteins were fractionated by electrophoresis, digested by trypsin, and then separated by label-free nano-LC/MS/MS. The TurboSequest algorithm was used to identify the peptide sequences against the hamster database in Universal Proteins Resource Knowledgebase (UniProt). The results indicate that 1191 hepatic proteins were identified and 135 of them were expressed differentially in the high-fat group (p < 0.05). Some of these 135 proteins that involve in metabolic diseases were further validated by Western blotting. The animals maintained on the high-fat diet had significantly (p < 0.05) higher serum triglyceride, cholesterol, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and uric acid. Animals consuming a high-fat diet also had significantly (p < 0.05) more accumulation of triglyceride and cholesterol in livers. Xanthine dehydrogenase (XDH), which plays an important role in uric acid synthesis, was up-regulated by the high-fat diet (p < 0.05). The α-subunit of hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase (HADHA), which catalyzes the second and third reactions of β-oxidation, was down-regulated by the high-fat diet (p < 0.05). Aconitate hydratase 2 (ACO2), which catalyzes the conversion of citrate to isocitrate in TCA cycle, was down-regulated in animals of the high-fat group (p < 0.05). Inflammatory markers annexin A3 (ANXA3) and annexin A5 (ANXA5) were up-regulated by the high-fat diet (p < 0.05). Moreover, enzymes involved in the urea cycle were suppressed by high-fat diet, including carbamoyl phosphate synthase 1 (CPS1), ornithine transcarbamoylase (OTC), argininosuccinate synthase (ASS), argininosuccinate lyase (ASL), and arginase 1 (ARG 1). Post-translational modifications (PTM) of ANXA3, ANXA5, and XDH were also analyzed. A set of differentially expressed proteins were identified as molecular markers for elucidating the pathological mechanism of high-fat diet.

Urate synthesis and oxidative stress in phenytoin hepatotoxicity: the role of antioxidant vitamins.

Phenytoin is known to induce microsomal enzymes including xanthine oxidase which catalyzes uric acid synthesis with superoxides as byproducts, thus contributing to the oxidative stress of phenytoin hepatotoxicity. To investigate the role of antioxidant vitamins in ameliorating phenytoin induced hepatic changes through possible actions on xanthine oxidase activities as measured by urate concentration. Growing albino rats of Wistar strain were randomly divided into 8 groups of 7 rats each. Group 2, 3, 4, 5, 6, 7 and 8 were treated with phenytoin alone, phenytoin + folic acid, phenytoin + vitamin E, phenytoin + vitamin E + vitamin C, phenytoin + vitamin C, phenytoin + folic acid + vitamin E and phenytoin + vitamin E + vitamin C + folic acid respectively while animals in group 1 were given normal saline to serve as control. Serum concentrations of uric acid, albumin, total protein and the activities of aspartate and alanine aminotransferases (AST and ALT) and catalase were measured spectrophotometrically using appropriate commercial reagent kits. Result showed that administration of phenytoin alone caused significant (p < 0.05) increase in serum levels of globulin, uric acid, AST and ALT activities while the levels of albumin and catalase were reduced significantly (p < 0.05). Supplementation of phenytoin treatment with vitamins resulted in various degrees of protection. However, the elevated level of uric acid in serum was not significantly (p < 0.05) affected by any of the vitamins used and there was no significant correlation between the activities of aminotransferases and uric acid concentration in the vitamin treated animals as was observed between aminotransferases and catalase. The findings in this study suggest that antioxidant vitamins were able to ameliorate phenytoin hepatotoxic effects by improving oxidant radicals removal in the animals but would not inhibit further generation of the superoxides by xanthine oxidase activity and that xanthine oxidase may contribute significantly to the oxidative stress of phenytoin therapy.

Uric acid as a predictor of in-hospital mortality in acute myocardial infarction: a meta-analysis.

Uric acid (UA) is generalized as a byproduct the terminal steps of purine catabolism, which are catalyzed by xanthine oxidoreductase. Xanthine oxidase activity and uric acid synthesis are reported to be increased under tissue ischemia. Therefore, elevated uric acid may act as a prognostic marker of acute myocardial infarction (AMI). A few studies have showed that UA is associated with therapeutic outcomes in patients with acute myocardial infarction. The purpose of this meta-analysis is to evaluate the prognostic significance of the UA as a predictor of in-hospital mortality. We performed a systematic review and included studies that used both UA and in-hospital mortality from Embase and PubMed. Six studies have been included in this review with totally 5,686 patients. During the follow-up, high UA level was found to be associated with an increased risk of in-hospital mortality [risk ratios (RR) 2.10 (1.03-4.26), number needed to harm (NNH) 37], MACE [RR 3.44 (2.33-5.08), NNH 17]. High UA level has the potential to be an important prognostic marker for in-hospital mortality in individuals with AMI.

Basic science: Pathophysiology: the CardioRenal Metabolic Syndrome

Basic science: Pathophysiology: the CardioRenal Metabolic Syndrome

The cockroach Blattella germanica obtains nitrogen from uric acid through a metabolic pathway shared with its bacterial endosymbiont.

Uric acid stored in the fat body of cockroaches is a nitrogen reservoir mobilized in times of scarcity. The discovery of urease in Blattabacterium cuenoti, the primary endosymbiont of cockroaches, suggests that the endosymbiont may participate in cockroach nitrogen economy. However, bacterial urease may only be one piece in the entire nitrogen recycling process from insect uric acid. Thus, in addition to the uricolytic pathway to urea, there must be glutamine synthetase assimilating the released ammonia by the urease reaction to enable the stored nitrogen to be metabolically usable. None of the Blattabacterium genomes sequenced to date possess genes encoding for those enzymes. To test the host's contribution to the process, we have sequenced and analysed Blattella germanica transcriptomes from the fat body. We identified transcripts corresponding to all genes necessary for the synthesis of uric acid and its catabolism to urea, as well as for the synthesis of glutamine, asparagine, proline and glycine, i.e. the amino acids required by the endosymbiont. We also explored the changes in gene expression with different dietary protein levels. It appears that the ability to use uric acid as a nitrogen reservoir emerged in cockroaches after its age-old symbiotic association with bacteria.

Uric acid and central nervous system functioning (a literature review)

The high level of uric acid in blood distinguishes humans from other studied species of mammals. The reason behind this is the absence of the enzyme uricase, which is evolutionary determined. Today, hyperuricemia can be considered as a factor of “diseases of civilization.” However, uric acid can also have positive effects, because it intensifies cognitive processes. The high level of uric acid in blood probably facilitated the emergence of intellectually advanced primates. Later, it enhanced the human’s motivation for active work. In the present review, these points are substantiated using data by V.P. Efroimson on the role of hyperuricemia and gout in the development of genius, V.S. Rotenberg’s Search Activity Concept, and the R. Johnson’s hypothesis on the role of uric acid as a messenger when it is necessary to change the behavioral responses of animals upon transition to active feeding. The nonspecific activating role of hyperuricemia is the factor that links all three hypotheses together. In addition, the enhancement of cognitive functions and motivations in hyperuricemia has been confirmed in different population samples. The biochemical basis for such effects is the potential for uric acid synthesis in the central nervous system and the penetration of the blood-brain barrier by its precursors, the interrelations between the metabolism of uric acid in the central nervous system and the metabolism of catecholamines and dopamine, and the neuroprotective and antioxidative properties of uric acid.

Airway Uric Acid Is a Sensor of Inhaled Protease Allergens and Initiates Type 2 Immune Responses in Respiratory Mucosa

Although type 2 immune responses to environmental Ags are thought to play pivotal roles in asthma and allergic airway diseases, the immunological mechanisms that initiate the responses are largely unknown. Many allergens have biologic activities, including enzymatic activities and abilities to engage innate pattern-recognition receptors such as TLR4. In this article, we report that IL-33 and thymic stromal lymphopoietin were produced quickly in the lungs of naive mice exposed to cysteine proteases, such as bromelain and papain, as a model for allergens. IL-33 and thymic stromal lymphopoietin sensitized naive animals to an innocuous airway Ag OVA, which resulted in production of type 2 cytokines and IgE Ab, and eosinophilic airway inflammation when mice were challenged with the same Ag. Importantly, upon exposure to proteases, uric acid (UA) was rapidly released into the airway lumen, and removal of this endogenous UA by uricase prevented type 2 immune responses. UA promoted secretion of IL-33 by airway epithelial cells in vitro, and administration of UA into the airways of naive animals induced extracellular release of IL-33, followed by both innate and adaptive type 2 immune responses in vivo. Finally, a potent UA synthesis inhibitor, febuxostat, mitigated asthma phenotypes that were caused by repeated exposure to natural airborne allergens. These findings provide mechanistic insights into the development of type 2 immunity to airborne allergens and recognize airway UA as a key player that regulates the process in respiratory mucosa.

Clec12a: Quieting the Dead

Immune activation as a result of the recognition of damage-associated molecular patterns needs to be controlled. In this issue of Immunity, Neumann etal. (2014) demonstrates that Clec12a is a receptor for dead cells through the recognition of uric acid crystals and contributes to the dampening of the responses.