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International Journal of Molecular... Aug 2021Uric acid (UA) is synthesized mainly in the liver, intestines, and vascular endothelium as the end product of an exogenous purine from food and endogenously from... (Review)
Review
Molecular Biological and Clinical Understanding of the Pathophysiology and Treatments of Hyperuricemia and Its Association with Metabolic Syndrome, Cardiovascular Diseases and Chronic Kidney Disease.
Uric acid (UA) is synthesized mainly in the liver, intestines, and vascular endothelium as the end product of an exogenous purine from food and endogenously from damaged, dying, and dead cells. The kidney plays a dominant role in UA excretion, and the kidney excretes approximately 70% of daily produced UA; the remaining 30% of UA is excreted from the intestine. When UA production exceeds UA excretion, hyperuricemia occurs. Hyperuricemia is significantly associated with the development and severity of the metabolic syndrome. The increased urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) expression, and glycolytic disturbances due to insulin resistance may be associated with the development of hyperuricemia in metabolic syndrome. Hyperuricemia was previously thought to be simply the cause of gout and gouty arthritis. Further, the hyperuricemia observed in patients with renal diseases was considered to be caused by UA underexcretion due to renal failure, and was not considered as an aggressive treatment target. The evidences obtained by basic science suggests a pathogenic role of hyperuricemia in the development of chronic kidney disease (CKD) and cardiovascular diseases (CVD), by inducing inflammation, endothelial dysfunction, proliferation of vascular smooth muscle cells, and activation of the renin-angiotensin system. Further, clinical evidences suggest that hyperuricemia is associated with the development of CVD and CKD. Further, accumulated data suggested that the UA-lowering treatments slower the progression of such diseases.
Topics: Animals; Biomarkers; Cardiovascular Diseases; Disease Management; Disease Susceptibility; Humans; Hyperuricemia; Metabolic Syndrome; Renal Insufficiency, Chronic; Severity of Illness Index
PubMed: 34502127
DOI: 10.3390/ijms22179221 -
Current Opinion in Rheumatology Mar 2022The global burden of gout is rising, as are the prevalence of associated comorbidities, all-cause mortality and societal costs. In this review, we discuss recent... (Review)
Review
PURPOSE OF REVIEW
The global burden of gout is rising, as are the prevalence of associated comorbidities, all-cause mortality and societal costs. In this review, we discuss recent advances in epidemiology and treatment strategies for gout.
RECENT FINDINGS
Genetic factors and obesity are prominent contributors to hyperuricemia and gout, while dietary factors contribute to less variance in serum urate, though can still have some contribution to population attributable risk. A consensus statement by the Gout, Hyperuricemia and Crystal-Associated Disease Network outlined appropriate terminology regarding gout, which will aid in communication about various aspects of the disease. The 2020 American College of Rheumatology gout guideline offers comprehensive evidence-based recommendations for the management of hyperuricemia using urate-lowering therapy, prophylaxis when initiating urate-lowering therapy, treatment of gout flare and adjunctive management strategies. There is improved understanding of risk factors for allopurinol hypersensitivity syndrome and well tolerated use of allopurinol in chronic kidney disease. Trial data have provided new insights regarding cardiovascular risk with febuxostat. Several new drug therapies are being tested for both urate-lowering efficacy and gout flare management.
SUMMARY
Although there have been significant advances in understanding of risk factors and treatment approaches, gout remains suboptimally managed. There is substantial need for improving gout management efforts and gout education among patients and clinicians.
Topics: Allopurinol; Febuxostat; Gout; Gout Suppressants; Humans; Hyperuricemia; Symptom Flare Up
PubMed: 34907116
DOI: 10.1097/BOR.0000000000000861 -
BioMed Research International 2020Uric acid is the end product of purine metabolism in humans, and its excessive accumulation leads to hyperuricemia and urate crystal deposition in tissues including... (Review)
Review
Uric acid is the end product of purine metabolism in humans, and its excessive accumulation leads to hyperuricemia and urate crystal deposition in tissues including joints and kidneys. Hyperuricemia is considered an independent risk factor for cardiovascular and renal diseases. Although the symptoms of hyperuricemia-induced renal injury have long been known, the pathophysiological molecular mechanisms are not completely understood. In this review, we focus on the research advances in the mechanisms of hyperuricemia-caused renal injury, primarily on oxidative stress, endothelial dysfunction, renal fibrosis, and inflammation. Furthermore, we discuss the progress in hyperuricemia management.
Topics: Fibrosis; Humans; Hyperuricemia; Inflammation; Kidney; Kidney Diseases; Oxidative Stress
PubMed: 32685502
DOI: 10.1155/2020/5817348 -
Nutricion Hospitalaria Apr 2014From ancient times, gout has been related with excessive eating and drinking; however, it has not been until the last decade that a broader knowledge on dietary factors... (Review)
Review
From ancient times, gout has been related with excessive eating and drinking; however, it has not been until the last decade that a broader knowledge on dietary factors associated with hyperuricemia and gout has been achieved. Obesity, excessive intake of red meats and alcoholic beverages were already recognized as causal factors from Antiquity. Legumes and purine rich vegetables have been exculpated after the studies. New risk factors, not previously recognized, have been described such as fructose and sweetened beverages. Finally, protective factors have also been described, such as skimmed dairy products. Gout is characterized not only by an increase in uric acid, eventual episodes of arthritis, and chronic joint damage, but also by association with several comorbidities and increased cardiovascular risk. The adoption of more healthier dietary habits may contribute to better management of uricemia and also to a reduction of associated diseases. The most common practice recommendations according to current knowledge and the main treatment guidelines are reviewed. Additional studies are needed on the actual efficacy in clinical practice of the adoption of specific dietary measures on the management and clinical course of patients with hyperuricemia and gout.
Topics: Diet; Gout; Humans; Hyperuricemia
PubMed: 24679016
DOI: 10.3305/nh.2014.29.4.7196 -
Renal Failure Nov 2020Hyperuricemia is a state in which the serum levels of uric acid are elevated. As such it has a pronounced effect on vascular and renal function with their consequences,... (Review)
Review
BACKGROUND
Hyperuricemia is a state in which the serum levels of uric acid are elevated. As such it has a pronounced effect on vascular and renal function with their consequences, while also showing some antioxidant effects that show to be beneficial.
SUMMARY
Hyperuricemia has shown to have a J-shaped relationship with mortality, is frequently associated with development and progression of heart and kidney disease, and is correlated with malnutrition-inflammation-atherosclerosis syndrome, although several Mendelian studies have failed to show an association with morbidity and mortality. Hyperuricemia is usually associated with gout flares and tophi development but can also present as asymptomatic hyperuricemia. It is still uncertain whether asymptomatic hyperuricemia is an independent risk factor for cardiovascular or renal disease and as such its treatment is questionable.
KEY MESSAGES
Some possible tools for future decision making are the use of noninvasive techniques such as pulse wave analysis, urinary sediment analysis, and joint ultrasound, which could help identify individuals with asymptomatic hyperuricemia that could benefit from urate lowering therapy most.
Topics: Cardiovascular Diseases; Gout; Humans; Hyperuricemia; Kidney; Myocardium; Renal Insufficiency, Chronic; Uric Acid
PubMed: 32972284
DOI: 10.1080/0886022X.2020.1822185 -
Nutrients Jul 2019Plant-based diets (PBDs) are associated with decreased risk of morbidity and mortality associated with important noncommunicable chronic diseases. Similar to... (Review)
Review
Plant-based diets (PBDs) are associated with decreased risk of morbidity and mortality associated with important noncommunicable chronic diseases. Similar to animal-based food sources (e.g, meat, fish, and animal visceral organs), some plant-based food sources (e.g, certain soy legume products, sea vegetables, and brassica vegetables) also contain a high purine load. Suboptimally designed PBDs might consequently be associated with increased uric acid levels and gout development. Here, we review the available data on this topic, with a great majority of studies showing reduced risk of hyperuricemia and gout with vegetarian (especially lacto-vegetarian) PBDs. Additionally, type of ingested purines, fiber, vitamin C, and certain lifestyle factors work in concordance to reduce uric acid generation in PBDs. Recent limited data show that even with an exclusive PBD, uric acid concentrations remain in the normal range in short- and long-term dieters. The reasonable consumption of plant foods with a higher purine content as a part of PBDs may therefore be safely tolerated in normouricemic individuals, but additional data is needed in hyperuricemic individuals, especially those with chronic kidney disease.
Topics: Biomarkers; Diet, Healthy; Diet, Vegetarian; Gout; Humans; Hyperuricemia; Nutritive Value; Protective Factors; Recommended Dietary Allowances; Risk Assessment; Risk Factors; Risk Reduction Behavior; Uric Acid
PubMed: 31357560
DOI: 10.3390/nu11081736 -
The Korean Journal of Internal Medicine Nov 2021Previous research has investigated whether hyperuricemia serves as an independent risk factor for cardiovascular and renal diseases. Hyperuricemia is defined as an... (Review)
Review
Previous research has investigated whether hyperuricemia serves as an independent risk factor for cardiovascular and renal diseases. Hyperuricemia is defined as an abnormally high level of uric acid (UA; i.e., serum urate level > 6.8 mg/dL). Hyperuricemia has been considered a complication of chronic kidney disease (CKD). However, it seems to play a pathogenic role in the progression of renal diseases. There has been increasing focus on the link between hyperuricemia and CKD. The results of randomized controlled trials have implied independent associations between hyperuricemia and the progression of cardiovascular and renal morbidities. These associations may be mediated by renin-angiotensin system activation, nitric oxide synthase inhibition, and macrovascular/microvascular disease development. There remains controversy regarding the use of serum UA level as an indirect index of renal vascular disease. This literature review focuses on the role of asymptomatic hyperuricemia in the progression of CKD, as well as the association between hyperuricemia and cardiovascular disease. It also provides a general overview of the physiological metabolism of UA.
Topics: Cardiovascular Diseases; Gout Suppressants; Humans; Hyperuricemia; Renal Insufficiency, Chronic; Uric Acid
PubMed: 33045808
DOI: 10.3904/kjim.2020.340 -
International Journal of Molecular... Jun 2021Urate homeostasis in humans is a complex and highly heritable process that involves i.e., metabolic urate biosynthesis, renal urate reabsorption, as well as renal and... (Review)
Review
Urate homeostasis in humans is a complex and highly heritable process that involves i.e., metabolic urate biosynthesis, renal urate reabsorption, as well as renal and extrarenal urate excretion. Importantly, disturbances in urate excretion are a common cause of hyperuricemia and gout. The majority of urate is eliminated by glomerular filtration in the kidney followed by an, as yet, not fully elucidated interplay of multiple transporters involved in the reabsorption or excretion of urate in the succeeding segments of the nephron. In this context, genome-wide association studies and subsequent functional analyses have identified the ATP-binding cassette (ABC) transporter ABCG2 as an important urate transporter and have highlighted the role of single nucleotide polymorphisms (SNPs) in the pathogenesis of reduced cellular urate efflux, hyperuricemia, and early-onset gout. Recent publications also suggest that ABCG2 is particularly involved in intestinal urate elimination and thus may represent an interesting new target for pharmacotherapeutic intervention in hyperuricemia and gout. In this review, we specifically address the involvement of ABCG2 in renal and extrarenal urate elimination. In addition, we will shed light on newly identified polymorphisms in ABCG2 associated with early-onset gout.
Topics: ATP Binding Cassette Transporter, Subfamily G, Member 2; Age of Onset; Alleles; Animals; Disease Susceptibility; Genetic Association Studies; Genetic Predisposition to Disease; Genetic Variation; Genotype; Gout; Humans; Hyperuricemia; Neoplasm Proteins; Phenotype; Polymorphism, Single Nucleotide
PubMed: 34206432
DOI: 10.3390/ijms22136678 -
Phytomedicine : International Journal... Jul 2023α-Viniferin, the major constituent of the roots of Caragana sinica (Buc'hoz) Rehder with a trimeric resveratrol oligostilbenoid skeleton, was demonstrated to possess a...
BACKGROUND
α-Viniferin, the major constituent of the roots of Caragana sinica (Buc'hoz) Rehder with a trimeric resveratrol oligostilbenoid skeleton, was demonstrated to possess a strong inhibitory effect on xanthine oxidase in vitro, suggesting it to be a potential anti-hyperuricemia agent. However, the in vivo anti-hyperuricemia effect and its underlying mechanism were still unknown.
PURPOSE
The current study aimed to evaluate the anti-hyperuricemia effect of α-viniferin in a mouse model and to assess its safety profile with emphasis on its protective effect on hyperuricemia-induced renal injury.
METHODS
The effects were assessed in a potassium oxonate (PO)- and hypoxanthine (HX)-induced hyperuricemia mice model by analyzing the levels of serum uric acid (SUA), urine uric acid (UUA), serum creatinine (SCRE), serum urea nitrogen (SBUN), and histological changes. Western blotting and transcriptomic analysis were used to identify the genes, proteins, and signaling pathways involved.
RESULTS
α-Viniferin treatment significantly reduced SUA levels and markedly mitigated hyperuricemia-induced kidney injury in the hyperuricemia mice. Besides, α-viniferin did not show any obvious toxicity in mice. Research into the mechanism of action of α-viniferin revealed that it not only inhibited uric acid formation by acting as an XOD inhibitor, but also reduced uric acid absorption by acting as a GLUT9 and URAT1 dual inhibitor as well as promoted uric acid excretion by acting as a ABCG2 and OAT1 dual activator. Then, 54 differentially expressed (log FPKM ≥ 1.5, p ≤ 0.01) genes (DEGs) repressed by the treatment of α-viniferin in the hyperuricemia mice were identified in the kidney. Finally, gene annotation results revealed that downregulation of S100A9 in the IL-17 pathway, of CCR5 and PIK3R5 in the chemokine signaling pathway, and of TLR2, ITGA4, and PIK3R5 in the PI3K-AKT signaling pathway were involved in the protective effect of α-viniferin on the hyperuricemia-induced renal injury.
CONCLUSIONS
α-Viniferin inhibited the production of uric acid through down-regulation of XOD in hyperuricemia mice. Besides, it also down-regulated the expressions of URAT1 and GLUT9 and up-regulated the expressions of ABCG2 and OAT1 to promote the excretion of uric acid. α-Viniferin could prevent hyperuricemia mice from renal damage by regulating the IL-17, chemokine, and PI3K-AKT signaling pathways. Collectively, α-viniferin was a promising antihyperuricemia agent with desirable safety profile. This is the first report of α-viniferin as an antihyperuricemia agent.
Topics: Mice; Animals; Uric Acid; Interleukin-17; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Hyperuricemia; Kidney; Xanthine Oxidase
PubMed: 37209608
DOI: 10.1016/j.phymed.2023.154868 -
Molecular Medicine Reports Nov 2019Gout is a type of serious arthritis that is caused by hyperuricemia. Celery is an umbelliferous plant that was shown to exhibit anti‑inflammatory activity in rodent....
Gout is a type of serious arthritis that is caused by hyperuricemia. Celery is an umbelliferous plant that was shown to exhibit anti‑inflammatory activity in rodent. The present study aimed to investigate the effects and potential preliminary mechanisms of celery seed aqueous extract (CSAE) and celery seed oil extract (CSOL) for gout treatment. The components of CSAE and CSOL were systematically analyzed. In mice with hyperuricemia induced by potassium oxonate and yeast extract, CSAE and CSOL treatment reduced the serum levels of uric acid and xanthine oxidase. In addition, CSAE and CSOL reduced the levels of reactive oxygen species and increased the serum levels of superoxide dismutase and glutathione peroxidase in mouse serum. In rats with acute gouty arthritis induced by intra‑articular injection of monosodium urate crystals, CSAE and CSOL treatment alleviated the swelling of the ankle joints and reduced inflammatory cell infiltration around the ankle joints. In addition, CSAE and CSOL reduced the levels of interleukin (IL)‑1β and tumor necrosis factor α and increased the levels of IL‑10. The results of the present study suggested that celery seed extracts may have anti‑gout properties, partially through anti‑inflammatory and antioxidative effects.
Topics: Animals; Apium; Arthritis, Gouty; Hyperuricemia; Interleukin-10; Interleukin-1beta; Male; Mice; Mice, Inbred BALB C; Plant Extracts; Seeds
PubMed: 31702020
DOI: 10.3892/mmr.2019.10708