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Molecular Pathophysiology of Primary Hyperuricemia and Gout
Bohatá, Jana ; Stibůrková, Blanka (advisor) ; Hrnčíř, Zbyněk (referee) ; Friedecký, David (referee)
Primary hyperuricemia, as a condition of elevated serum uric acid levels, is caused by various factors and necessarily precedes a form of inflammatory arthritis referred to as gout. Uric acid is the end product of purine catabolism and requires specialized proteins for its transport. Pathogenic variants in the genes for these transport proteins can have a major negative impact on their function, thereby affecting the resulting serum uric acid levels. However, chronically elevated uric acid levels are not the only predisposition to the development of gout. Other factors, such as epigenetic mechanisms or genetic predispositions to inflammatory conditions caused by immune dysregulation, are likely to play a role in disease progression. The aim of the study was to analyse damaging variants in genes for important urate transporters ABCG2, SLC22A12 and SLC2A9, which may cause impaired excretion or reabsorption of uric acid and thus contribute to the development of primary hyperuricemia and gout, or rare hereditary renal hypouricemia. We also focused on circulating miRNAs in the plasma of patients with primary hyperuricemia, gout and gout attack. We identified and functionally characterized over ten rare nonsynonymous variants in the ABCG2 gene. Most of these variants had a negative impact on protein...
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Pathophysiology of urate transporters in primary gout
Pavelcová, Kateřina ; Stibůrková, Blanka (advisor) ; Doležel, Zdeněk (referee) ; Hrnčíř, Zbyněk (referee)
There are localised proteins (so-called urate transporters) in the renal proximal tubules and in the intestine, which excrete and reabsorb uric acid. Polymorphisms in the genes coding these proteins can result in the disruption of the transport function and development of hyperuricemia and gout. However the serum level of uric acid is also determined by other factors which include the intake of exogenous purines in food, synthesis of endogenous purines and degradation of nucleic acids, but also certain conditions. In 250 patients with primary hyperuricemia and gout we used Sanger sequencing to analyse the exons and adjacent intron regions in ten genes coding urate transporters: ABCG2, ABCC4, SLC2A9, SLC22A12, SLC22A11, SLC22A13, SLC17A1, SLC17A3, SLC22A6 and SLC22A8. We examined a possible connection between the identified genetic variants and primary hyperuricemia and gout based on a comparison of allele frequencies with the European population, according to topological models, according to programs predicting the functional impacts of variants and searches in specialised literature. We also took into account the conclusions of functional studies analysing the impact of nonsynonymous variants in the ABCG2 and SLC2A9 genes. We also focused on the effect of the concomitant occurrence of several...
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Role of uric acid in the pathogenesis of cardiovascular diseases
Vlková, Kateřina ; Kovařík, Miroslav (advisor) ; Kudláčková, Zděnka (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Biological and Medical Sciences Student: Kateřina Vlková Supervisor: PharmDr. Miroslav Kovařík, PhD. Title of the bachelor thesis: The role of uric acid in the pathogenesis of cardiovascular diseases The basic biological function of uric acid in the human body is to protect cells from oxidative damage. More precisely, its behavior depends on the physico-chemical environment in which it is located. Under certain conditions and higher concentration in serum, it may act as a prooxidant and participate in the pathophysiology of a variety of diseases. These are mainly kidney disease, non-alcoholic steatosis of the liver, diabetes mellitus II. type and metabolic syndrome. These diseases can precede cardiovascular risk. Cardiovascular failure may be caused by some mechanisms. These mechanisms include especially oxidative stress, inflammation, reduced availability of nitric oxide and endothelial dysfunction, proliferation of smooth muscle cells in blood vessels, insulin resistance or metabolic disorders. The cause of cardiovascular disease associated with uric acid has not been proved. It can only serve as a intermediator of harmful effects on vascular tissue and myocardium. Keywords: uric acid, oxidative stress, inflammation,...
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Nutraceuticals: possibilities in decreasing of hyperuricemia and alleviating gout
Lorencová, Štěpánka ; Hošťálková, Anna (advisor) ; Opletal, Lubomír (referee)
1 ABSTRACT Lorencová Š.: Nutraceuticals: possibilities in decreasing of hyperuricemia and alleviating gout. Diploma thesis, Charles University in Prague, Faculty of Pharmacy in Hradec Kralove, Department of Pharmaceutical Botany and Ecology, Hradec Kralove 2020, 82 p. This research work was conducted on the basis of literature analysis, reviewing papers mainly from international but also domestic journals. The review describes pathophysiology of gout and discusses options to mitigate the disease with the aid of dietary supplements. This work presents symptoms and a clinical picture of the disease as well as its origin and risk factors, pathological processes leading to the development of the disease, and a short overview of current pharmacotherapy. Furthermore this work summarises natural substances including plant extracts that may be utilised in the prevention and support of gout treatment. In particular, these include vitamins, unsaturated fatty acids, polyphenols and peptides. This work also describes plants used in the traditional treatment of gout and gives a brief overview of natural substances including plant extracts contained in food supplements that are available on the market in Czech Republic. This work also describes the role of purines, fructose, alcoholic drinks and tomatoes in triggering...
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