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1.
Uric acid extrarenal excretion: the gut microbiome as an evident yet understated factor in gout development.
Méndez-Salazar, EO, Martínez-Nava, GA
Rheumatology international. 2022;(3):403-412
Abstract
Humans do not produce uricase, an enzyme responsible for degrading uric acid. However, some bacteria residing in the gut can degrade one-third of the dietary and endogenous uric acid generated daily. New insights based on metagenomic and metabolomic approaches provide a new interest in exploring the involvement of gut microbiota in gout. Nevertheless, the exact mechanisms underlying this association are complex and have not been widely discussed. In this study, we aimed to review the evidence that suggests uric acid extrarenal excretion and gut microbiome are potential risk factors for developing gout. A literature search was performed in PubMed, Web of Science, and Google Scholar using several keywords, including "gut microbiome AND gout". A remarkable intestinal dysbiosis and shifts in abundance of certain bacterial taxa in gout patients have been consistently reported among different studies. Under this condition, bacteria might have developed adaptive mechanisms for de novo biosynthesis and salvage of purines, and thus, a concomitant alteration in uric acid metabolism. Moreover, gut microbiota can produce substrates that might cross the portal vein so the liver can generate de novo purinogenic amino acids, as well as uric acid. Therefore, the extrarenal excretion of uric acid needs to be considered as a factor in gout development. Nevertheless, further studies are needed to fully understand the role of gut microbiome in uric acid production and its extrarenal excretion, and to point out possible bacteria or bacterial enzymes that could be used as probiotic coadjutant treatment in gout patients.
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2.
The biology of urate.
Keenan, RT
Seminars in arthritis and rheumatism. 2020;(3S):S2-S10
Abstract
Urate is the end-product of the purine metabolism in humans. The dominant source of urate is endogenous purines and the remainder comes through diet. Approximately two thirds of urate is eliminated via the kidney with the rest excreted in the feces. While the transporter BCRP, encoded by ABCG2, has been found to play a role in both the gut and kidney, SLC22A12 and SLC2A9 encoding URAT1 and GLUT9, respectively, are the two transporters best characterized. Only 8-12% of the filtered urate is excreted by the kidney. Renal elimination of urate depends substantially on specific transporters, including URAT1, GLUT9 and BCRP. Studies that have assessed the biologic effects of urate have produced highly variable results. Although there is a suggestion that urate may have anti-oxidant properties in some circumstances, the majority of evidence indicates that urate is pro-inflammatory. Hyperuricemia can result in the formation of monosodium urate (MSU) crystals that may be recognized as danger signals by the immune system. This immune response results in the activation of the NLRP3 inflammasome and ultimately in the production and release of interleukin-1β, and IL-18, that mediate both inflammation, pyroptotic cell death, and necroinflammation. It has also been demonstrated that soluble urate mediates effects on the kidney to induce hypertension and can induce long term epigenetic reprogramming in myeloid cells to induce "trained immunity." Together, these sequelae of urate are thought to mediate most of the physiological effects of hyperuricemia and gout, illustrating this biologically active molecule is more than just an "end-product" of purine metabolism.
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3.
Hyperuricemia: a novel old disorder-relationship and potential mechanisms in heart failure.
Borghi, C, Palazzuoli, A, Landolfo, M, Cosentino, E
Heart failure reviews. 2020;(1):43-51
Abstract
Uric acid, the metabolic mediator of gout and urate renal stones, is associated with increased cardiovascular risk burden. Hyperuricemia is an old emerging metabolic disorder, and interaction among uric acid and cardiovascular diseases has been clearly described. Several illness including hypertension, myocardial infarction, metabolic syndrome, and heart failure, are related with uric acid levels increase. In this review, we will discuss the pathophysiology of hyperuricemia and describe the biological plausibility for this metabolite to participate in the pathogenesis of cardiovascular disorders. In particular, we will focus on the implications of hyperuricemia in the onset and progression of heart failure, paying special attention to the pathophysiology and the possible clinical implications. We will conclude by discussing the effects of lowering plasma uric acid concentration on the prognosis of heart failure by reviewing most of available data on the different classes of drugs directly or indirectly involved in the hyperuricemia management.
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4.
Regulation of Catechins in Uric Acid Metabolism Disorder Related Human Diseases.
Wu, D, Zhang, W, Lai, X, Li, Q, Sun, L, Chen, R, Sun, S, Cao, F
Mini reviews in medicinal chemistry. 2020;(18):1857-1866
Abstract
Uric acid is the end product of purine metabolism in humans. High uric acid levels form sodium urate crystals that trigger biological processes, which lead to the development of several diseases, including diabetes, hyperuricemia, gout, inflammatory disease, kidney disease, cardiovascular disease and hypertension. Catechins have been suggested to be beneficial for the regulation of uric acid metabolic disorders due to their powerful antioxidant and anti-inflammatory properties. To identify an effective and safe natural substance that can decrease levels of serum uric acid to improve uric acid metabolism disorders. A search was performed on PubMed, Web of Science and Google Scholar to identify comprehensive studies that presented summarized data on the use of catechins in lowering uric acid levels in diseases. This review details the role of catechins in inhibiting the activity of xanthine oxidase to decrease uric acid overproduction in the liver and in regulating expressions of uric acid transporters, URAT1, OAT1, OAT3, ABCG2 and GLUT9, to balance levels of uric acid secretion and reabsorption through the kidney and intestine. Additionally, Catechins were also found to prevent monosodium urate-induced inflammatory reactions. In vivo, catechins can be used to decrease high uric acid levels that result from hyperuricemia and related diseases. Catechins can be used to maintain the balance of uric acid metabolism.
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5.
A novel mutation in gene of PRPS1 in a young Chinese woman with X-linked gout: a case report and review of the literature.
Yang, BY, Yu, HX, Min, J, Song, XX
Clinical rheumatology. 2020;(3):949-956
Abstract
Pyrophosphate synthetase-1(PRS-1) is a crucial enzyme that catalyzes the synthesis of phosphoribosylpyrophosphate (PRPP) with substrate: adenosine triphosphate (ATP) and ribose-5-phophate(R5P) in the de novo pathways of purine and pyrimidine nucleotide synthesis. Mutation in PRPS1 can result in a series of diseases of purine metabolism, which includes PRS-1 superactivity. The common clinical phenotypes are hyperuricemia and hyperuricosuria. We identified a novel missense mutation in X-chromosomal gene PRPS1 in a young Chinese woman while her mother has heterogeneous genotype and phenotype. A 24-year-old Chinese female patient suffered hyperuricemia, gout, and recurrent hyperpyrexia for more than 6 years, and then was diagnosed with hyperandrogenism, insulin resistance (IR), and polycystic ovary syndrome (PCOS). A novel missense mutation, c.521(exon)G>T, p.(Gly174Val) was detected by next-generation sequencing (NGS) and confirmed by Sanger sequencing in the patient and her parents. Interestingly, her mother has the same heterozygous missense mutation but without uric acid overproduction which can be explained by the phenomenon of the skewed X-chromosome inactivation. The substituted amino acid Val for Gly174 is positioned in the pyrophosphate (PPi) binding loop, and this mutation impacts the binding rate of Mg2+-ATP complex to PRS-1, thus the assembling of homodimer is affected by changed Val174 leading to the instability of the allosteric site. Our report highlights the X-linked inheritance of gout in females caused by mutation in PRPS1 accompanied with severe metabolic disorders and recurrent hyperpyrexia.
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6.
Uric Acid Elevation by Favipiravir, an Antiviral Drug.
Mishima, E, Anzai, N, Miyazaki, M, Abe, T
The Tohoku journal of experimental medicine. 2020;(2):87-90
Abstract
In light of the recent pandemic, favipiravir (Avigan®), a purine nucleic acid analog and antiviral agent approved for use in influenza in Japan, is being studied for the treatment of coronavirus disease 2019 (COVID-19). Increase in blood uric acid level is a frequent side effect of favipiravir. Here, we discussed the mechanism of blood uric acid elevation during favipiravir treatment. Favipiravir is metabolized to an inactive metabolite M1 by aldehyde oxidase and xanthine oxidase, and excreted into urine. In the kidney, uric acid handling is regulated by the balance of reabsorption and tubular secretion in the proximal tubules. Favipiravir and M1 act as moderate inhibitors of organic anion transporter 1 and 3 (OAT1 and OAT3), which are involved in uric acid excretion in the kidney. In addition, M1 enhances uric acid reuptake via urate transporter 1 (URAT1) in the renal proximal tubules. Thus, favipiravir is thought to decrease uric acid excretion into urine, resulting in elevation of uric acid levels in blood. Elevated uric acid levels were returned to normal after discontinuation of favipiravir, and favipiravir is not used for long periods of time for the treatment of viral infection. Thus, the effect on blood uric acid levels was subclinical in most studies. Nevertheless, the adverse effect of favipiravir might be clinically important in patients with a history of gout, hyperuricemia, kidney function impairment (in which blood concentration of M1 increases), and where there is concomitant use of other drugs affecting blood uric acid elevation.
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7.
Dietary Antioxidant Supplements and Uric Acid in Chronic Kidney Disease: A Review.
Roumeliotis, S, Roumeliotis, A, Dounousi, E, Eleftheriadis, T, Liakopoulos, V
Nutrients. 2019;(8)
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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8.
Combinational effect of angiotensin receptor blocker and folic acid therapy on uric acid and creatinine level in hyperhomocysteinemia-associated hypertension.
Singh, Y, Samuel, VP, Dahiya, S, Gupta, G, Gillhotra, R, Mishra, A, Singh, M, SreeHarsha, N, Gubbiyappa, SK, Tambuwala, MM, et al
Biotechnology and applied biochemistry. 2019;(5):715-719
Abstract
Homocysteine [HSCH2 CH2 CH(NH2 )COOH] (Hcy) is a sulfur-containing amino acid of 135.18 Da of molecular weight, generated during conversion of methionine to cysteine. If there is a higher accumulation of Hcy in the blood, that is usually above 15 µmol/L, it leads to a condition referred to as hyperhomocysteinemia. A meta-analysis of observational study suggested an elevated concentration of Hcy in blood, which is termed as the risk factors leading to ischemic heart disease and stroke. Further experimental studies stated that Hcy can lead to an increase in the proliferation of vascular smooth muscle cells and functional impairment of endothelial cells. The analyses confirmed some of the predictors for Hcy presence, such as serum uric acid (UA), systolic blood pressure, and hematocrit. However, angiotensin-converting enzyme inhibitors angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) alone are inadequate for controlling UA and creatinine level, although the addition of folic acid may be beneficial in hypertensive patients who are known to have a high prevalence of elevated Hcy. We hypothesized that combination therapy with an ARB (olmesartan) and folic acid is a promising treatment for lowering the UA and creatinine level in hyperhomocysteinemia-associated hypertension.
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9.
Pharmacological urate-lowering approaches in chronic kidney disease.
Li, X, Liu, J, Ma, L, Fu, P
European journal of medicinal chemistry. 2019;:186-196
Abstract
Chronic kidney disease (CKD) has become a global public health issue and uric acid (UA) remains a major risk factor of CKD. As the main organ for the elimination of UA, kidney owned a group of urate transporters in tubular epithelium. Kidney disease hampered the UA excretion, and the accumulation of serum UA in return harmed the renal function. Commercially, there are three kinds of agents targeting at urate-lowering, xanthine oxidoreductase inhibitor which prevents the production of UA, uricosuric which increases the concentration of UA in urine thus decreasing serum UA level, and uricase which converts UA to allantoin resulting in the dramatic decrement of serum UA. Of note, in patients with CKD, administration of above-mentioned agents, alone or combined, needs special attention. New evidence is emerging for the efficacy of several urate-lowering drugs for the treatment of hyperuricemia in patients with CKD. Besides, loads of novel and promising drug candidates and phytochemicals are in the different phases of research and development. As of today, there is insufficient evidence to recommend the widespread use of UA-lowering therapy to prevent or slow down the progression of CKD. The review summarized the evidence and perspectives about the treatment of hyperuricemia with CKD for medicinal chemist and nephrologist.
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10.
Diagnostic advances in synovial fluid analysis and radiographic identification for crystalline arthritis.
Zell, M, Zhang, D, FitzGerald, J
Current opinion in rheumatology. 2019;(2):134-143
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Abstract
PURPOSE OF REVIEW The present review addresses diagnostic methods for crystalline arthritis including synovial fluid analysis, ultrasound, and dual energy CT scan (DECT). RECENT FINDINGS There are new technologies on the horizon to improve the ease, sensitivity, and specificity of synovial fluid analysis. Raman spectroscopy uses the spectral signature that results from a material's unique energy absorption and scatter for crystal identification. Lens-free microscopy directly images synovial fluid aspirate on to a complementary metal-oxide semiconductor chip, providing a high-resolution, wide field of view (∼20 mm) image. Raman spectroscopy and lens-free microscopy may provide additional benefit over compensated polarized light microscopy synovial fluid analysis by quantifying crystal density in synovial fluid samples. Ultrasound and DECT have good sensitivity and specificity for the identification of monosodium urate (MSU) and calcium pyrophosphate (CPP) crystals. However, both have limitations in patients with recent onset gout and low urate burdens. SUMMARY New technologies promise improved methods for detection of MSU and CPP crystals. At this time, limitations of these technologies do not replace the need for synovial fluid aspiration for confirmation of crystal detection. None of these technologies address the often concomitant indication to rule out infectious arthritis.