Cluster analysis of uric acid exchange parameters in female rats

Background. Uric acid is traditionally considered as the final product of human and primate DNA/RNA degradation, devoid ofuseful physiological activity. However, there is an opinion that theuric acid molecule, by analogy with methylxanthines (caffeine, theophylin, theobromine) has physiological activity. The acquired experience allows us to offer a topic for future research: “Neurotropic and immunotropic activity of endogenous uric acid”. Working hypothesis. Uric acid, interacting with A1 and A2a adenosine receptors as well as phosphodiesterase and Na,K-ATPase of neurons, modulates the activity of nerve centers, which in turn modulate immunocytes. Perhaps the direct effect of uric acid on immunocytes, since the existence oftheophylline-resistant and theophylline-sensitive subpopulations of T-lymphocytes has long been known. The proposed article is the first swallow of the announced project.Material and Methods. Experiment was performed on 58 healthy female Wistar rats 220-300 g. Among them 10 animals remained intact, using tap water from drinking ad libitum. The rats of others groups for 6 days administered through the tube various fluids at a dose of 1,5 mL/100 g of body mass.The day after the completion of the drinking course the plasma and urine levels of the uric acid (uricase method) were determined. Results. We obtained a wide range of uric acid metabolism parameters, divided into four clusters, quantitatively and qualitatively different from each other. On the basis of the accepted criteria, 29,3% of animals state normouricemia in combination with normal or slightly increased excretion of uric acid. In 24,1% of rats, hypouricemia is combined with normal or slightly reduced uricosuria. In 31,0% of animals normal or slightly elevated levels of plasma uric acid are accompanied by a very marked dispersion of uricosuria. The remaining 15,5% of rats expressed hyperuricemia combined with normal or slightly increased uricosuria. In the following articles, functional relationships of uricemia and uricosuria with the parameters of autonomic regulation, immunity and metabolism will be analyzed

Uric acid, metabolism, neuro-endocrine-immune complex, 258 s.

LITERATURE 1. Avtandylov H.G. Medical morphometry. Moscow. Medicine; 1990: 384 p. 2. Baevsky R.M., Kirillov O.I., Kletskin S.Z. Mathematical analysis of heart rate changes during stress. Moscow. Science; 1984: 221 p. 3. Baevsky R.M., Ivanov H.G. Variability of the heart rhythm: theoretical aspects and opportunities for clinical application. Ultrasound and functional diagnostics. 2001; 3: 106-127. 4. Bazarnova M.A. Cytological examination of punctate spleen. Guide to practical classes in clinical laboratory diagnostics. K.: Higher school; 1988: 263-264. 5. Balanovsky V.P., Popovych I.L., Karpynets SV. About the ambivalent-equilibrator nature of the influence of Naftusya medicinal water on the human body. ANU reports. Mat., prop., tech. science 1993; 3: 154-158. 6. Belousova OI, Fedotova MY. Comparative data on changes in the number of lymphocytes of the spleen, goiter and bone marrow in the early stages after irradiation in a wide range of doses. Radiobiology-radiotherapy. 1968; 9(3): 309-313. 7. Bilas V.R., Popovych I.L. The role of microflora and organic substances of Naftusya water in its modulating effect on the neuroendocrine-immune complex and metabolism. Medical hydrology and rehabilitation. 2009; 7(1): 68-102. 8. Biloshitsky P.V. Temperature, information, water, anabiosis, immortality. Health and longevity. Kyiv; 2007: 46-47. 9. Harkavy L.H., Kvakina E.B., Kuzmenko T.S. Antistress reactions and activating therapy. Moscow. Imedis; 1998: 654 p. 10. Harkavy L.H., Kvakina E.B., Ukolova M.A. Adaptation reactions and resistance of the body. Rostov-on-Don. Rostov University Publishing House, 3rd ed.; 1990: 224 p. 11. Harkavy L.H., Romasyuk S.I., Barantsev F.G., Kuzmenko T.S., Otkydach S.A., Tattsov O.V., Barantseva L.P. Activation therapy in the sanatorium-resort stage of rehabilitation of patients with internal organ diseases. Sochi; 2000: 94 p. 12. Gozhenko A.I. Theory of disease. Odesa. Phoenix; 2018: 236 p. 13. Gozhenko A.I. Dysregulation as the basis of the pathophysiology of homeostasis. Clinical and experimental pathology. 2004; 3 (2): 191-193. 14. Gozhenko A.I. Functional-metabolic continuum. The National Academy of Sciences of Ukraine. 2016; 22(1): 3-8. 15. Gozhenko A.I., Korda M.M., Popadynets O.O., Popovych I.L. Entropy, harmony, synchronization and their neuro-endocrine-immune correlates. Odesa. Phoenix; 2021: 232 p. 16. Horyachkovsky A.M. Clinical biochemistry. Odesa: Astroprint; 1998: 608 p. 17. Datsko O.R., Bubnyak A.B., Ivasivka S.V. The organic component of Naftusya mineral water. Development of an idea about its composition and origin. Medical hydrology and rehabilitation. 2008; 6(1): 168-174. 18. Ivasivka S.V., Popovych I.L., Aksentiychuk B.I., Flunt I.S. Physiological activity of uric acid and its role in the mechanism of action of Naftusya water. K. Computer Press; 2004: 163 p. 19. Lapovets L.Y., Lutsik B.D. Laboratory immunology. Kyiv. 2004. 173 p. 20. Perederiy V.G., Zemskov A.M., Bychkova N.G., Zemskov V.M. Immune status, principles of its evaluation and correction of immune disorders. K. Health; 1995: 211 p. 21. Popovych I.L. Informational effects of Naftusya bioactive water in rats: modulation of entropy, reversal of desynchronizing and limitation of disharmonizing effect of water-immersion stress on informational components of the neuro-endocrine-immune system and metabolism, which correlates with a gastroprotective effect. Medical hydrology and rehabilitation. 2007; 5(3): 50-70. 22. I.L. Popovych Concept of neuro-endocrine-immune complex. Medical hydrology and rehabilitation. 2009; 7(2): 9-18. 23. I.L. Popovych Stress-limiting adaptogenic mechanism of biological and therapeutic activity of Naftusya water. Kyiv. Computer press; 2011: 300 c. 24. Popovich I.L., Flunt I.S., Alekseev O.I. etc. Sanogenetic principles of rehabilitation at the Truskavets resort of urological patients of the Chernobyl contingent. Kyiv. Computer press; 2003: 192 p. 25. Popovich I.L., Flunt I.S., Nischeta I.V., Loboda M.V., Aksentiychuk B.I., Pryima B.G., Tserkovnyuk R.G. General adaptation reactions and resistance of the organism of liquidators of the Chernobyl accident. Kyiv. Computer press; 2000: 117 p. 26. Portnychenko A.G. Ukrainian balneology: scientific trends of the last decade (scientometric analysis). Medical hydrology and rehabilitation. 2015; 13(4): 41-52. 27. Smagliy V.S., Gozhenko A.I., Badyuk N.S., Popovych I.L. Variants of uric acid metabolism and their immune and microbial accompaniments in patients with complex neuro-endocrine-immune dysfunction. In: VIII National Congress of Pathophysiologists of Ukraine "Pathological Physiology - Health Care of Ukraine" (Odesa, May 13-15, 2020). Odesa; 2020: 314-315. 28. Khaitov R.M., Pinegin B.V., Istamov K.I. Ecological immunology. Moscow. INWARD; 1995: 219 p. 29. Khmelevsky Yu.V., Usatenko O.K. Basic biochemical constants of a person in normal and pathological conditions. Kyiv. Health; 1987: 160 p. 30. Efroimson V.P. Some biological factors of mental activity. VIET. 1987; 4: 74-84. 31. Yushkovska O.H. The use of information theory to study the adaptive reactions of athletes' bodies. Medical rehabilitation Spa therapy Physiotherapy. 2001; 1 (25): 40-43. 32. Abdel Aziz N., Tallima H., Hafez E.A., El Ridi R. Papain-based vaccination modulates Schistosoma mansoni infection-induced cytokine signals. Scand J Immunol. 2016;83(2):128–138. 33. Ahbap E., Sakaci T., Kara E., Sahutoglu T., Koc Y., Basturk T. Serum uric acid levels and inflammatory markers with respect to dipping status: a retrospective analysis of hypertensive patients with or without chronic kidney disease . Clin Exp Hypertens. 2016;38(6):555–563. 34. Akbar S.R., Long D.M., Hussain K., Alhajhusain A., Ahmed U.S., Iqbal H.I. Hyperuricemia: an early marker for severity of illness in sepsis. Int J Nephrol. 2015; 301021. 35. Alberti K.G., Eckel R.H., Grundy S.M., Zimmet P.Z., Cleeman J.I., Donato K.A. Harmonizing the metabolic syndrome: a joint interim statement of the international diabetes federation task force on epidemiology and prevention; national heart, lung, and blood institute; american heart association; world heart federation; international atherosclerosis society; and international association for the study of obesity. Circulation. 2009;120(16):1640–1645. 36. Aldenderfer M.S., Blashfield R.K. Cluster analysis (Second printing, 1985) [transl. from English in Russian]. In: Factor, Discriminant and Cluster Analysis. Moscow. Finance and Statistics; 1989: 139-214. 37. Alvarez-Lario B., Macarrón-Vicente J. Is there anything good in uric acid? QJM. 2011;104(12):1015–1024.] 38. Alvarez-Lario B., Macarron-Vicente J. Uric acid and evolution. Rheumatology. 2010;49(11):2010–2015. 39. Amaral F.A., Costa V.V., Tavares L.D., Sachs D., Coelho F.M., Fagundes C.T. NLRP3 inflammasome-mediated neutrophil recruitment and hypernociception depend on leukotriene B(4) in a murine model of gout. Arthritis Rheum. 2012;64(2):474–484. 40. Amaral K.B., Silva T.P., Malta K.K., Carmo L.A.S., Dias F.F., Almeida M.R. Natural Schistosoma mansoni infection in the wild reservoir Nectomys squamipes leads to excessive lipid droplet accumulation in hepatocytes in the absence of liver functional impairment. Plos One. 2016;11(11):e0166979. 41. Amaral L.M., Cunningham M.W., Jr, Cornelius D.C., LaMarca B. Preeclampsia: long-term consequences for vascular health. Vasc Health Risk Manage. 2015; 11: 403–415. 42. Ames B.N., Cathcart R., Schwiers E., Hochstein P. Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis. Proc Natl Acad Sci U S A. 1981;78(11):6858–6862. 43. Amsellem V., Abid S., Poupel L., Parpaleix A., Rodero M., Gary-Bobo G., Latiri M., Dubois-Rande J.L., Lipskaia L., Combadiere C., et al. Roles for the CX3CL1/CX3CR1 and CCL2/CCR2 Chemokine Systems in Hypoxic Pulmonary Hypertension. Am. J. Respir. Cell. Mol. Biol. 2017; 56:597–608. 44. Ando K., Takahashi H., Watanabe T., Daidoji H., Otaki Y., Nishiyama S. Impact of serum uric acid levels on coronary plaque stability evaluated using integrated backscatter intravascular ultrasound in patients with coronary artery disease. J Atheroscler Thromb. 2016;23(8):932–939. 45. Andreadou E., Nikolaou C., Gournaras F., Rentzos M., Boufidou F., Tsoutsou A. Serum uric acid levels in patients with Parkinson's disease: their relationship to treatment and disease duration. Clin Neurol Neurosurg. 2009;111(9):724–728. 46. Annanmaki T., Muuronen A., Murros K. Low plasma uric acid level in Parkinson's disease. Mov Disord. 2007;22(8):1133–1137. 47. Anthony R.M., Rutitzky L.I., Urban J.F., Jr., Stadecker M.J., Gause W.C. Protective immune mechanisms in helminth infection. Nat Rev Immunol. 2007;7(12):975–987. Review. 48. Anzai N., Ichida K., Jutabha P., Kimura T., Babu E., Jin C.J. Plasma urate level is directly regulated by a voltage-driven urate efflux transporter URATv1 (SLC2A9) in humans. J Biol Chem. 2008;283(40):26834–26838. 49. Apasov S, Chen JF, Smith P, Sitkovsky M. A2A receptor dependent and A2A receptor independent effects of extracellular adenosine on murine thymocytes in the condition of adenosine deaminase deficiency. Blood. 2000; 95(12): 3859-3867. 50. Araya J., Rodrigo R., Videla L.A., Thielemann L., Orellana M., Pettinelli P. Increase in long-chain polyunsaturated fatty acid n - 6/n - 3 ratio in relation to hepatic steatosis in patients with non- alcoholic fatty liver disease. Clin Sci (Lond) 2004;106(6):635–643. 51. Aribas A., Kayrak M., Ulucan S., Keser A., Demir K., Alibasic H. The relationship between uric acid and erectile dysfunction in hypertensive subjects. Blood Press. 2014;23: 370–376. 52. Arvola L, Bertelsen G, Hassaf D, Ytrehus K. Positive inotropic and sustained anti-beta-adrenergic effect of diadenosine pentaphosphate in human and guinea pig hearts. Role of dinucleotide receptors and adenosine receptors. Acta Physiol Scand. 2004;182(3):277-285. 53. Arnold I.C., Mathisen S., Schulthess J., Danne C., Hegazy A.N., Powrie F. CD11c(+) monocyte/macrophages promote chronic Helicobacter hepaticus-induced intestinal inflammation through the production of IL-23. Mucosal Immunol. 2016; 9:352–363. 54. Auerbach A. Dose-ResponseAnalysis When There Is a Correlation between Affinity and Efficacy. Mol. Pharmacol. 2016; 89:297–302. 55. Babio N., Martínez-González M.A., Estruch R., Wärnberg J., Recondo J., Ortega-Calvo M. Associations between serum uric acid concentrations and metabolic syndrome and its components in the PREDIMED study. Nutr Metab Cardiovasc Dis. 2015;25(2):173–180. 56. Bakhtiari S., Toosi P., Samadi S., Bakhshi M. Assessment of uric acid level in the saliva of patients with oral lichen planus. Med Princ Pract. 2017;26(1):57–60. 57. Barabé F, Gilbert C, Liao N, Bourgoin SG, Naccache PH. Crystal-induced neutrophil activationVI. Involvement of FcgammaRIIIB (CD16) and CD11b in response to inflammatory microcrystals. FASEB J. 1998;12(2):209-220. doi:10.1096/fasebj.12.2.209 58. Barakat R., Abou El-Ela N.E., Sharaf S., El Sagheer O., Selim S., Tallima H. Efficacy and safety of arachidonic acid for treatment of school-age children in Schistosoma mansoni high-endemic regions. Am J Trop Med Hyg. 2015;92(4):797–804. 59. Bardin T., Richette P. Definition of hyperuricemia and gouty conditions. Curr. Opin. Rheumatol. 2014;26: 186–191. 60. Barikbin B., Yousefi M., Rahimi H., Hedayati M., Razavi S.M., Lotfi S. Antioxidant status in patients with lichen planus. Clin Exp Dermatol. 2011;36(8):851–854. 61. Bartáková V., Kuricová K., Pácal L., Nová Z., Dvořáková V., Švrčková M. Hyperuricemia contributes to the faster progression of diabetic kidney disease in type 2 diabetes mellitus. J Diabetes Complications. 2016;30(7):1300–1307. 62. Barylyak L.G., Malyuchkova R.V., Tolstanov O.B., Tymochko O.B., Hryvnak R.F., Uhryn M.R. Comparative estimation of informativeness of leukocytary index of adaptation by Garkavi and by Popovych. Medical Hydrology and Rehabilitation. 2013; 11(1): 5-20. 63. Basseville A., Bates S. Gout, genetics and ABC transporters. F1000 Biology Reports. 2011;3: 23. 64. Beck L.H. Requiem for gouty nephropathy. Kidney Int. 1986;30(2):280–287. 65. Becker B.F. Towards the physiological function of uric acid. Free Radical Biol Med. 1993;14(6):615–631. 66. Bellomo G., Venanzi S., Verdura C., Saronio P., Esposito A., Timio M. Association of uric acid with changes in kidney function in healthy normotensive individuals. Am J Kidney Dis. 2010;56(2):264–272. 67. Berntson GG, Bigger JT jr, Eckberg DL, Grossman P, Kaufman PG, Malik M, Nagaraja HN, Porges SW, Saul JP, Stone PH, Van der Molen MW. Heart Rate Variability: Origins, methods, and interpretive caveats. Psychophysiology. 1997; 34: 623-648. 68. Bianco C. Population of lymphocytes bearing a membrane receptor for antigen-antibody complex. J Exp Med. 1970; 134(4): 702-720. 69. Bjorkander S., Heidari-Hamedani G., Bremme K., Gunnarsson I., Holmlund U. Peripheral monocyte expression of the chemokine receptors CCR2, CCR5 and CXCR3 is altered at parturition in healthy women and in women with systemic lupus erythematosus. Scand. J. Immunol. 2013;77: 200–212. 70. Birch RE, Rosenthal AK, Polmer SH. Pharmacological modification of immunoregulatory T lymphocytes. II. Modulation of T lymphocyte cell surface characteristics. Clin Exp Immunol. 1982; 48(1): 231-238. 71. Bjornstad P., Lanaspa M.A., Ishimoto T., Kosugi T., Kume S., Jalal D. Fructose and uric acid in diabetic nephropathy. Diabetology. 2015;58(9):1993–2002. 72. Bjornstad P., Maahs D.M., Johnson R.J., Rewers M., Snell-Bergeon J.K. Estimated insulin sensitivity predicts regression of albuminuria in Type 1 diabetes. Diabetes Med. 2015;32(2):257–261. 73. Bjornstad P., Roncal C., Milagres T., Pyle L., Lanaspa M.A., Bishop F.K. Hyperfiltration and uricosuria in adolescents with type 1 diabetes. Pediatr Nephrol. 2016;(5):787–793. 74. Bjornstad P., Snell-Bergeon J.K., McFann K., Wadwa R.P., Rewers M., Rivard C.J. Serum uric acid and insulin sensitivity in adolescents and adults with and without type 1 diabetes. J Diabetes Complications. 2014;28(3):298–304. 75. Bobulescu I.A., Moe O.W. Renal transport of uric acid: evolving concepts and uncertainties. Adv Chronic Kidney Dis. 2012;19(6):358–371. 76. Bocarsly M.E., Powell E.S., Avena N.M., Hoebel B.G. High-fructose corn syrup causes characteristics of obesity in rats: increased body weight, body fat and triglyceride levels. Pharmacol Biochem Behav. 2010;97: 101–106. 77. Broz P., Dixit V.M. Inflammasomes: mechanism of assembly, regulation and signaling. Nat Rev Immunol. 2016;16(7):407–420. 78. Bruno C.M., Pricoco G., Cantone D., Elisa Marino E., Bruno F. Tubular handling of uric acid and factors influencing its renal excretion: a short review. EMJ Nephrol. 2016;4(1):92–97. 79. Busso N., Ea H.K. The mechanisms of inflammation in gout and pseudogout (CPP-induced arthritis) Rheumatismo. 2012;63(4):230–237. 80. Busso N., So A. Mechanisms of inflammation in gout. Arthritis Res Ther. 2010;12(2):206. 81. Busso N., So A. Microcrystals as DAMPs and their role in joint inflammation. Rheumatology (Oxford) 2012;51(7):1154–1160. 82. Cammalleri L., Malaguarnera M. Rasburicase represents a new tool for hyperuricemia in tumor lysis syndrome and in gout. International Journal of Medical Sciences. 2007;4(2):83–93. doi: 10.7150/ijms.4.83. 83. Campion E.W., Glynn R.J., DeLabry L.O. Asymptomatic hyperuricemia. Risks and consequences in the Normative Aging Study. Am J Med. 1987; 82:421. 84. Carito V., Ceccanti M., Tarani L., Ferraguti G., Chaldakov G. N., Fiore M. Neurotrophins' modulation by olive polyphenols. Current Medicinal Chemistry. 2016;23(28):3189–3197. 85. Carvalho LAC, Lopes JPPB, Kaihami GH, Silva RP, Bruni-Cordoso A, Baldini RL, Meotti FC. Uric acid disrupts hypochlorous acid production and bactericidal activity of HL-60 cells. Redox Biology. 2018; 16: 179-188. 86. Chakraborti G., Biswas R., Chakraborti S., Sen P.K. Altered serum uric acid level in lichen planus patients. Indian J Dermatol. 2014;59(6):558–561. 87. Chang B.S. Ancient insights into uric acid metabolism in primates. Proc Natl Acad Sci USA. 2014;111(10):3657–3658. 88. Chaudhary K., Malhotra K., Sowers J., Aroor A. Uric Acid - key ingredient in the recipe for cardiorenal metabolic syndrome. Cardiorenal Med. 2013;3(3):208–220. 89. Chen CJ, Shi Y, Hearn A, et al. MyD88-dependent IL-1 receptor signaling is essential for gouty inflammation stimulated by monosodium urate crystals. J Clin Invest. 2006;116(8):2262-2271. 90. Chen H., Cao G., Chen D. Q., et al. Metabolomics insights into activated redox signaling and lipid metabolism dysfunction in chronic kidney disease progression. Redox Biology. 2016; 10:168–178. 91. Chen Y., Xu B., Sun W., Sun J., Wang T., Xu Y. Impact of the serum uric acid level on subclinical atherosclerosis in middle-aged and elderly Chinese. J Atheroscler Thromb. 2015;22(8):823–832. 92. Chen-Xu M., Yokose C., Rai S.K., Pillinger M.H., Choi H.K. Contemporary Prevalence of Gout and Hyperuricemia in the United States and Decadal Trends: The National Health and Nutrition Examination Survey, 2007–2016. Arthritis Rheumatol. 2019; 71:991–999. 93. Cheung K.J., Tzameli I., Pissios P., Rovira I., Gavrilova O., Ohtsubo T. Xanthine oxidoreductase is a regulator of adipogenesis and PPARγ activity. Cell Metab. 2007; 5:115–128. 94. Cheungpasitporn W., Thongprayoon C., Harrison A.M., Erickson S.B. Admission hyperuricemia increases the risk of acute kidney injury in hospitalized patients. Clin Kidney J. 2016;9(1):51–56. 95. Chiquete E., Ruiz-Sandoval J.L., Murillo-Bonilla L.M., Arauz A., Orozco-Valera D.R., Ochoa-Guzmán A. Serum uric acid and outcome after acute ischemic stroke: PREMIER study. Cerebrovasc Dis. 2013;35(2):168–174. 96. Cho J., Kim C., Kang D.R., Park J. Hyperuricemia and uncontrolled hypertension in treated hypertensive patients: K-MetS study. Medicine (Baltimore) 2016;95(28): e4177. 97. Choi H.K., Curhan G. Independent impact of gout on mortality and risk for coronary heart disease. Circulation. 2007;116(8):894–900. 98. Choi H.K., Ford E.S. Prevalence of the metabolic syndrome in individuals with hyperuricemia. Am J Med. 2007;120(5):442–447. 99.Choi Y.J., Shin H.S., Choi H.S., Park J.W., Jo I., Oh E.S. Uric acid induces fat accumulation via generation of endoplasmic reticulum stress and SREBP-1c activation in hepatocytes. Lab Invest. 2014;94(10):1114–1125. 100.Chou Y.C., Kuan J.C., Yang T., Chou W.Y., Hsieh P.C., Bai C.H. Elevated uric acid level as a significant predictor of chronic kidney disease: a cohort study with repeated measurements. J Nephrol. 2015;28(4):457–462. 101. Cicerchi C., Li N., Kratzer J., Garcia G., Roncal-Jimenez C.A., Tanabe K. Uric acid-dependent inhibition of AMP kinase induces hepatic glucose production in diabetes and starvation: evolutionary implications of the uricase loss in hominids FASEB J. 2014;(8):3339–3350. 102. Cicero A., Rosticci M., Tartagni E., Parini A., Grandi E., D'Addato S. Serum uric acid level, but not renal function or arterial stiffness, is associated to worse blood pressure control in general practice : data from the brisighella heart study. J Hypertens. 2015;33(Suppl 1):e22. 103. Cicero A.F., Rosticci M., Fogacci F., Grandi E., D'Addato S., Borghi C. High serum uric acid is associated with poorly controlled blood pressure and higher arterial stiffness in hypertensive subjects. Eur J Intern Med. 2017;37: 38–42. 104. Cinel I, Gür S. Direct inotropic effects of propofol and adenosine on rat atrial muscle: possible mechanisms. Pharmacol Res. 2000;42(2):123-128. 105. Clarson L.E., Chandratre P., Hider S.L., Belcher J., Heneghan C., Roddy E. Increased cardiovascular mortality associated with gout: a systematic review and meta-analysis. Eur J Prev Cardiol. 2015;22(3):335–343. 106. Clémençon B., Lüscher B.P., Fine M., Baumann M.U., Surbek D.V., Bonny O. Expression, purification, and structural insights for the human uric acid transporter, GLUT9, using the Xenopus laevis oocytes system. PLoS ONE. 2014;9(10):e108852. 107. Cleophas M. C., Joosten L. A., Stamp L. K., Dalbeth N., Woodward O. M., Merriman T. R. ABCG2 polymorphisms in gout: insights into disease susceptibility and treatment approaches. Ph. DArmacogenomics and Personalized Medicine. 2017; 10:129–142. 108. Conen D, Wietlisbach V, Bovet P, Shamlaye C, Riesen W, Paccaud F, et al. Prevalence of hyperuricemia and relationship of serum uric acid with cardiovascular risk factors in a developing country. BMC public health. 2004; 4:9. 109. Convento M.S., Pessoa E., Dalboni M.A., Borges F.T., Schor N. Pro-inflammatory and oxidative effects of noncrystalline uric acid in human mesangial cells: contribution to hyperuricemic glomerular damage. Urol Res. 2011;39(1):21–27. 110.Cristóbal-García M., García-Arroyo F.E., Tapia E., Osorio H., Arellano-Buendía A.S., Madero M. Renal oxidative stress induced by long-term hyperuricemia alters mitochondrial function and maintains systemic hypertension. Oxid Med Cell Longev. 2015; 535686. 111. Culleton B.F., Larson M.G., Kannel W.B., Levy D. Serum uric acid and risk for cardiovascular disease and death: the Framingham Heart Study. Ann Intern Med. 1999;131(1):7–13. 112. Dalbeth N., Merriman T. Crystal ball gazing: new therapeutic targets for hyperuricemia and gout. Rheumatology (Oxford). 2009;48(3):222–226. 113. De Cosmo S., Viazzi F., Pacilli A., Giorda C., Ceriello A., Gentile S. Serum uric acid and risk of CKD in Type 2 diabetes. Clin J Am Soc Nephrol. 2015;10(11):1921–1929. 114. De Duve C, Wattiaux R. Functions of lysosomes. Annu Rev Physiol. 1966; 28:435–492. 115. De Vera M., Rahman M.M., Rankin J., Kopec J., Gao X., Choi H. Gout and the risk of Parkinson's disease: a cohort study. Art