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1.
Int J Mol Sci ; 22(17)2021 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-34502127

RESUMO

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.


Assuntos
Doenças Cardiovasculares/etiologia , Suscetibilidade a Doenças , Hiperuricemia/complicações , Hiperuricemia/metabolismo , Síndrome Metabólica/etiologia , Insuficiência Renal Crônica/etiologia , Animais , Biomarcadores , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/terapia , Gerenciamento Clínico , Humanos , Hiperuricemia/diagnóstico , Hiperuricemia/terapia , Síndrome Metabólica/diagnóstico , Síndrome Metabólica/metabolismo , Síndrome Metabólica/terapia , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/terapia , Índice de Gravidade de Doença
2.
FASEB J ; 35(9): e21808, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34390515

RESUMO

The link between serum uric acid (SUA) and the risk of venous thromboembolism (VTE) is well established. Recent data suggested a causative role of UA in endothelial cells (ECs) dysfunction. However, the molecular mechanism of high UA on thrombogenesis is unknown. We investigate whether high UA induce phosphatidylserine (PS) externalization and microparticle (MP) shedding in cultured EC, and contribute to UA-induced hypercoagulable state. In the present study, we demonstrate that UA induces PS exposure and EMP release of EC in a concentration- and time-dependent manner, which enhances the procoagulant activity (PCA) of EC and inhibited over 90% by lactadherin in vitro. Furthermore, hyperuricemic rat model was used to evaluate the development of thrombi following by flow stasis in the inferior vena cava (IVC). Hyperuricemia group is more likely to form large and hard thrombi compared with control. Importantly, we found that TMEM16F expression is significantly upregulated in UA-treated EC, which is crucial for UA-induced PS exposure and MP formation. Additionally, UA increases the generation of reactive oxygen species (ROS), lipid peroxidation, and cytosolic Ca2+ concentration in EC, which might contribute to increased TMEM16F expression. Using confocal microscopy, we also observed disruption of the actin cytoskeleton, suggesting that depolymerization of actin filaments might be required for TMEM16F activation and followed by PS exposure and membrane blebbing in UA-treated EC. Our results demonstrate a thrombotic role of EC in hyperuricemia through TMEM16F-mediated PS exposure and MPs release.


Assuntos
Anoctaminas/metabolismo , Micropartículas Derivadas de Células/metabolismo , Células Endoteliais/metabolismo , Hiperuricemia/metabolismo , Fosfatidilserinas/metabolismo , Proteínas de Transferência de Fosfolipídeos/metabolismo , Citoesqueleto de Actina/metabolismo , Animais , Cálcio/metabolismo , Células Cultivadas , Células Endoteliais da Veia Umbilical Humana , Humanos , Hiperuricemia/sangue , Peroxidação de Lipídeos/fisiologia , Masculino , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Ácido Úrico/sangue
3.
Int J Mol Sci ; 22(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206432

RESUMO

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.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Suscetibilidade a Doenças , Gota/etiologia , Hiperuricemia/etiologia , Proteínas de Neoplasias/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Idade de Início , Alelos , Animais , Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Genótipo , Gota/diagnóstico , Gota/metabolismo , Gota/terapia , Humanos , Hiperuricemia/diagnóstico , Hiperuricemia/metabolismo , Hiperuricemia/terapia , Proteínas de Neoplasias/metabolismo , Fenótipo , Polimorfismo de Nucleotídeo Único
4.
Expert Rev Cardiovasc Ther ; 19(6): 547-556, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34112023

RESUMO

Introduction: The role of serum uric acid as a connector in cardiorenal interactions has been long debated and studied extensively in the past decade. Epidemiological, and clinical data suggest that hyperuricemia may be an independent risk factor as well as a strong predictor of morbidity and mortality in cardiovascular diseases (CVD) and renal diseases. New data suggesting that urate lowering therapies may improve outcomes in cardiovascular diseases have generated interest.Areas Covered: This review attempts to summarize the pathophysiological mechanisms by which hyperuricemia causes cardiorenal dysfunction. It also provides a summary of the recent evidence for urate lowering therapies and the possible underlying mechanisms which lead to cardiovascular benefits. This was a narrative review with essential references or cross references obtained via expert opinion.Expert Opinion: Emphasis on newer drugs that address the cardio-renal metabolic axis and the relation to their effects on uric acid may help further elucidate underlying mechanisms responsible for their cardiovascular and renal benefits. Once these benefits are well established, we will be able to come up with guidelines for targeting hyperuricemia. This can potentially lead to a change in clinical practice and can possibly lead to improved cardiovascular and renal outcomes.


Assuntos
Doenças Cardiovasculares/etiologia , Insuficiência Cardíaca/etiologia , Hiperuricemia/fisiopatologia , Nefropatias/sangue , Doenças Cardiovasculares/sangue , Insuficiência Cardíaca/sangue , Humanos , Hiperuricemia/complicações , Hiperuricemia/metabolismo , Ácido Úrico/sangue , Ácido Úrico/metabolismo
5.
J Food Sci ; 86(7): 3265-3276, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34160066

RESUMO

Hyperuricemia contributes to chronic kidney disease development. However, it has been historically viewed with limited research interest. In this study, we mimicked the development of hyperuricemic nephropathy by using a potassium oxonate-induced hyperuricemia rat model. We found that administering vitamin C at 10 mg/kg/day effectively ameliorated hyperuricemic nephropathy. Compared to the control group, rats with hyperuricemia had significantly increased serum uric acid level, xanthine oxidase activity, and urine microalbumin level, by 5-fold, 1.5-fold, and 4-fold, respectively. At the same time, vitamin C supplementation reverted these values by 20% for serum uric acid level and xanthine oxidase activity and 50% for microalbumin level. Vitamin C also alleviated renal pathology and decreased the expression of pro-inflammatory and pro-fibrotic markers. A further mechanistic study suggested that vitamin C might attenuate hyperuricemic nephropathy in renal tubular epithelial cells induced by monosodium urate (MSU) crystal, at least in part, by directly inhibiting IL-6/JAK2/STAT3 signaling pathway. Meanwhile, in macrophages, vitamin C inhibited the expression of TGF-ß, and reduced ROS level induced by MSU by about 35%. In short, our results suggest that vitamin C supplementation delay the progression of hyperuricemic nephropathy.


Assuntos
Antioxidantes/farmacologia , Ácido Ascórbico/farmacologia , Fibrose/prevenção & controle , Hiperuricemia/tratamento farmacológico , Inflamação/prevenção & controle , Nefropatias/tratamento farmacológico , Animais , Fibrose/etiologia , Fibrose/patologia , Hiperuricemia/induzido quimicamente , Hiperuricemia/metabolismo , Hiperuricemia/patologia , Inflamação/etiologia , Inflamação/patologia , Nefropatias/induzido quimicamente , Nefropatias/metabolismo , Nefropatias/patologia , Masculino , Ácido Oxônico/toxicidade , Ratos , Ratos Sprague-Dawley
6.
Int J Mol Sci ; 22(6)2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33801813

RESUMO

Several polymorphisms and mutations in the human ABCG2 multidrug transporter result in reduced plasma membrane expression and/or diminished transport function. Since ABCG2 plays a pivotal role in uric acid clearance, its malfunction may lead to hyperuricemia and gout. On the other hand, ABCG2 residing in various barrier tissues is involved in the innate defense mechanisms of the body; thus, genetic alterations in ABCG2 may modify the absorption, distribution, excretion of potentially toxic endo- and exogenous substances. In turn, this can lead either to altered therapy responses or to drug-related toxic reactions. This paper reviews the various types of mutations and polymorphisms in ABCG2, as well as the ways how altered cellular processing, trafficking, and transport activity of the protein can contribute to phenotypic manifestations. In addition, the various methods used for the identification of the impairments in ABCG2 variants and the different approaches to correct these defects are overviewed.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Predisposição Genética para Doença/genética , Gota/genética , Hiperuricemia/genética , Mutação , Polimorfismo de Nucleotídeo Único , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Gota/metabolismo , Humanos , Hiperuricemia/metabolismo , Modelos Genéticos , Transporte Proteico/genética
7.
Am J Physiol Endocrinol Metab ; 320(6): E1032-E1043, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33900847

RESUMO

Uric acid is the end metabolite derived from the oxidation of purine compounds. Overwhelming evidence shows the vital interrelationship between hyperuricemia (HUA) and nonalcoholic fatty liver disease (NAFLD). However, the mechanisms for this association remain unclear. In this study, we established a urate oxidase-knockout (Uox-KO) mouse model by clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 technology. To study the correlation between HUA and NAFLD, human HepG2 hepatoma cells were treated in culture medium with high level of uric acid. In vivo, the Uox-KO mice spontaneously developed hyperuricemia and aberrant lipid-metabolism, concomitant with abnormal hepatic fat accumulation. HUA activated c-Jun N-terminal kinase (JNK) in vivo and in vitro. Furthermore, inhibiting JNK activation by a JNK-specific inhibitor, SP600125, decreased fat accumulation and lipogenic gene expression induced by HUA. Overexpression of the lipogenic enzymes fatty acid synthase and acetyl-CoA carboxylase 1 was via activation of JNK, which was blocked by the JNK inhibitor SP600125. HUA activated AP-1 to upregulate lipogenic gene expression via JNK activation. In addition, HUA caused mitochondrial dysfunction and reactive oxygen species production. Pretreatment with the antioxidant N-acetyl-l-cysteine could ameliorate HUA-activated JNK and hepatic steatosis. These data suggest that ROS/JNK/AP-1 signaling plays an important role in HUA-mediated fat accumulation in liver.NEW & NOTEWORTHY Hyperuricemia and nonalcoholic fatty liver disease are global public health problems, which are strongly associated with metabolic syndrome. In this study, we demonstrate that uric acid induces hepatic fat accumulation via the ROS/JNK/AP-1 pathway. This study identifies a new mechanism of NAFLD pathogenesis and new potential therapeutic strategies for HUA-induced NAFLD.


Assuntos
Hiperuricemia/metabolismo , Fígado/efeitos dos fármacos , Ácido Úrico/farmacologia , Animais , Células Hep G2 , Humanos , Hiperuricemia/patologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipogênese/efeitos dos fármacos , Fígado/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição AP-1/metabolismo , Ácido Úrico/metabolismo
8.
Biomed Chromatogr ; 35(8): e5118, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33749891

RESUMO

Hyperuricemia (HUM) is a major risk factor for the development of gout. The traditional Chinese medicine (TCM) complex prescription Tongfengxiaofang (TFXF) is composed of a variety of TCMs. To study the therapeutic effect of TFXF on HUM mice and the mechanisms by which it exerts a therapeutic effect, the biochemical indices were measured and qPCR technique was used. In addition, plasma metabolomics analysis was carried out based on UPLC-Q-TOF/MS to evaluate the characteristics of the metabolic spectrum changes. TFXF significantly downregulated the contents of uric acid, urea nitrogen and creatinine in serum and the concentration of xanthine oxidase in liver of HUM mice. In addition, TFXF significantly inhibited the overexpression of uric acid transporter 1 and glucose transporter 9 and upregulated the expression of organic anion transporter 1 in the kidney. A total of 152 metabolites were identified and 11 key biomarkers were further selected from these pathways to understand the mechanism of TFXF on the arginine biosynthesis, galactose metabolism, pyrimidine metabolism, glycerophospholipid metabolism, tryptophan metabolism and the citrate cycle (TCA cycle). The results of this confirmed the effect of TFXF on HUM and revealed the metabolic activity mechanism.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas/farmacologia , Hiperuricemia/metabolismo , Metaboloma/efeitos dos fármacos , Metabolômica/métodos , Animais , Modelos Animais de Doenças , Fígado/efeitos dos fármacos , Fígado/enzimologia , Masculino , Camundongos , Espectrometria de Massas por Ionização por Electrospray/métodos , Ácido Úrico/sangue , Ácido Úrico/metabolismo , Xantina Oxidase/análise , Xantina Oxidase/metabolismo
9.
Arthritis Rheumatol ; 73(9): 1738-1748, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33760368

RESUMO

OBJECTIVE: To systematically profile metabolic alterations and dysregulated metabolic pathways in hyperuricemia and gout, and to identify potential metabolite biomarkers to discriminate gout from asymptomatic hyperuricemia. METHODS: Serum samples from 330 participants, including 109 with gout, 102 with asymptomatic hyperuricemia, and 119 normouricemic controls, were analyzed by high-resolution mass spectrometry-based metabolomics. Multivariate principal components analysis and orthogonal partial least squares discriminant analysis were performed to explore differential metabolites and pathways. A multivariate methods with Unbiased Variable selection in R (MUVR) algorithm was performed to identify potential biomarkers and build multivariate diagnostic models using 3 machine learning algorithms: random forest, support vector machine, and logistic regression. RESULTS: Univariate analysis demonstrated that there was a greater difference between the metabolic profiles of patients with gout and normouricemic controls than between the metabolic profiles of individuals with hyperuricemia and normouricemic controls, while gout and hyperuricemia showed clear metabolomic differences. Pathway enrichment analysis found diverse significantly dysregulated pathways in individuals with hyperuricemia and patients with gout compared to normouricemic controls, among which arginine metabolism appeared to play a critical role. The multivariate diagnostic model using MUVR found 13 metabolites as potential biomarkers to differentiate hyperuricemia and gout from normouricemia. Two-thirds of the samples were randomly selected as a training set, and the remainder were used as a validation set. Receiver operating characteristic analysis of 7 metabolites yielded an area under the curve of 0.83-0.87 in the training set and 0.78-0.84 in the validation set for distinguishing gout from asymptomatic hyperuricemia by 3 machine learning algorithms. CONCLUSION: Gout and hyperuricemia have distinct serum metabolomic signatures. This diagnostic model has the potential to improve current gout care through early detection or prediction of progression to gout from hyperuricemia.


Assuntos
Gota/metabolismo , Hiperuricemia/metabolismo , Metabolômica , Adulto , Algoritmos , Doenças Assintomáticas , Biomarcadores/metabolismo , Estudos de Casos e Controles , Feminino , Gota/diagnóstico , Humanos , Hiperuricemia/diagnóstico , Aprendizado de Máquina , Masculino , Espectrometria de Massas , Redes e Vias Metabólicas , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Adulto Jovem
10.
J Sci Food Agric ; 101(12): 4916-4924, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33543494

RESUMO

BACKGROUND: Hyperuricemia (HUA) is a serious public health concern globally that needs to be solved. It is closely related to gout and other metabolic diseases. To develop a safe and effective dietary supplementation for alleviating HUA, we investigated the effects of whey protein hydrolysate (WPH) on HUA and associated renal dysfunction and explored their underlying mechanism. RESULTS: Potassium oxonate was used to induce HUA in model rats, who were then administered WPH for 21 days. The results showed that WPH significantly inhibited xanthine oxidase and adenosine deaminase activity in serum and liver, decreased uric acid (UA), creatinine, and blood urea nitrogen levels in serum, and increased the UA excretion in urine. In addition, WPH downregulated the expression of urate transporter 1 and upregulated the expression of organic anion transporter 1, adenosine triphosphate binding cassette subfamily G member 2, organic cation/carnitine transporters 1 and 2, and organic cation transporter 1 in kidneys. CONCLUSION: These findings demonstrated for the first time that WPH could alleviate HUA by inhibiting UA production and promoting UA excretion, and improve the renal dysfunction caused by HUA. Thus, WPH may be a potential functional ingredient for the prevention and treatment of HUA and associated renal dysfunction. © 2021 Society of Chemical Industry.


Assuntos
Hiperuricemia/dietoterapia , Proteínas do Soro do Leite/metabolismo , Adenosina Desaminase/metabolismo , Animais , Creatinina/sangue , Humanos , Hiperuricemia/induzido quimicamente , Hiperuricemia/metabolismo , Rim/metabolismo , Fígado/metabolismo , Masculino , Ácido Oxônico/efeitos adversos , Hidrolisados de Proteína/administração & dosagem , Ratos , Ratos Sprague-Dawley , Ácido Úrico/sangue , Soro do Leite/química , Xantina Oxidase/metabolismo
11.
J Food Sci ; 86(3): 1081-1088, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33565626

RESUMO

Hyperuricemia is related to plenty of diseases, seriously damaging human health. Current clinical drugs used to treat hyperuricemia have many adverse effects. In this study, kidney bean hydrolysate (KBH) was found to exert high xanthine oxidase inhibitory (XOI) activity. Compared to KBH (50.31 ± 2.73%), XOI activities of three fractions (Mw <5 kDa, Mw <3 kDa, Mw  < 1 kDa) by ultrafiltration were higher and increased to 58.58 ± 3.57%, 59.34 ± 1.78%, and 55.05 ± 5.00%, respectively (P < 0.05). A total of 69 peptides were identified by HPLC-ESI-MS/MS and analyzed binding affinities with XO with the help of molecular docking. AVDSLVPIGR, DWYDIK, LDNLLR, ISPIPVLK, ISSLEMTR showed well binding affinities with XO and DWYDIK presented the highest XOI activity (68.63 ± 5.07%) among five synthetic peptides (P < 0.05). Additionally, visual analysis results indicated that DWYDIK was pushed into the hydrophobic channel and formed hydrogen bonds with pivotal amino acids of xanthine oxidase. Overall, KBH could be a promising candidate as anti- hyperuricemia functional food. PRACTICAL APPLICATION: This research initially revealed that kidney bean peptides could significantly inhibit the activity of xanthine oxidase, indicating kidney bean peptides could be a treatment for hyperuricemia. Kidney bean peptides may have commercial potentials as a safer alternative with few side effects to drugs.


Assuntos
Simulação por Computador , Inibidores Enzimáticos/farmacologia , Fragmentos de Peptídeos/farmacologia , Phaseolus/química , Extratos Vegetais/farmacologia , Xantina Oxidase/antagonistas & inibidores , Cromatografia Líquida de Alta Pressão , Inibidores Enzimáticos/análise , Inibidores Enzimáticos/isolamento & purificação , Humanos , Hiperuricemia/tratamento farmacológico , Hiperuricemia/metabolismo , Fragmentos de Peptídeos/análise , Fragmentos de Peptídeos/isolamento & purificação , Extratos Vegetais/análise , Extratos Vegetais/isolamento & purificação , Espectrometria de Massas em Tandem , Ultrafiltração
12.
Biomed Pharmacother ; 135: 111194, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33395608

RESUMO

The increasing incidence of gout poses a very challenging management problem. However, the currently available drugs often have various toxic side effects. As a traditional edible and medicinal macrofungus, Sanghuangporus vaninii presents high medical research value. Therefore, to improve fermentation efficiency and identify novel anti-gout drugs, we optimized the culture medium of S. vaninii with lignin and further investigated its anti-gout effects. The results indicated that 0.06 g/L of lignin was most favorable for S. vaninii growth. In the hyperuricemia cell model, we found that S. vaninii could significantly induce the downregulation of xanthine oxidoreductase and the upregulation of hypoxanthine-guanine phosphoribosyltransferase. Furthermore, following oral administration of the extracts, the serum uric acid levels of mice with hyperuricemia were effectively reduced. In a gouty arthritis rat model, S. vaninii also achieved strong suppression of synovial swelling, indicating its anti-inflammatory activity. In addition, the antioxidant assays suggested that S. vaninii shows a strong free radical scavenging capacity and can effectively alleviate cellular oxidative stress. This activity further enhances its anti-inflammatory activity and reduces the incidence of comorbidities. In summary, our results provide the basis for the utilization of S. vaninii to develop anti-gout drugs.


Assuntos
Artrite Gotosa/tratamento farmacológico , Técnicas Bacteriológicas , Basidiomycota/metabolismo , Meios de Cultura/metabolismo , Supressores da Gota/farmacologia , Hiperuricemia/tratamento farmacológico , Lignina/metabolismo , Animais , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Antioxidantes/isolamento & purificação , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Artrite Gotosa/metabolismo , Artrite Gotosa/microbiologia , Basidiomycota/crescimento & desenvolvimento , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Supressores da Gota/isolamento & purificação , Humanos , Hiperuricemia/genética , Hiperuricemia/metabolismo , Hipoxantina Fosforribosiltransferase/genética , Hipoxantina Fosforribosiltransferase/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Xantina Desidrogenase/genética , Xantina Desidrogenase/metabolismo
13.
Artigo em Inglês | MEDLINE | ID: mdl-33454442

RESUMO

Concentration of uric acid (UA) in serum is one of the markers used to diagnose gout and hyperuricemia. However, serum treatment and storage are cumbersome, and wounds are susceptible to infection. Therefore, a new sampling and analysis method using noninvasive biological samples has been developed, called the dried spot method of UA in human saliva (DSM-UHS). Saliva (5 µL) was dropped on filter paper (a spot with a diameter of 5 mm) containing hypoxanthine (IS) (5 µL) and dried at room temperature for 30 min. The filter paper was immersed in 200 µL of lithium carbonate solution and shaken in a block bath shaker for 5 min at 30 °C. Afterward, the extraction was concentrated and reconstituted with 100 µL of lithium carbonate solution analyzed by HPLC-UV. When comparing the concentration of UA in the human saliva of hyperuricemia patients (HPs) and with that of healthy volunteers (HVs), we observed the concentration of UA was higher in the HPs than in the HVs (p < 0.0001). In addition, the results showed a significant linear relationship between the content of UA in saliva and the content of UA in the serum (r = 0.6243). The content of UA in human saliva could indirectly reflect the content of UA in human serum. Then DSM-UHS could be used to determine the content of UA in the saliva of HVs and HPs. This study provides a new research method and strategy for the determination of human UA content and the clinical prewiring of hyperuricemia.


Assuntos
Testes de Química Clínica/métodos , Hiperuricemia , Saliva/química , Ácido Úrico , Adulto , Cromatografia Líquida de Alta Pressão , Teste em Amostras de Sangue Seco , Feminino , Humanos , Hiperuricemia/sangue , Hiperuricemia/diagnóstico , Hiperuricemia/metabolismo , Limite de Detecção , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Ácido Úrico/análise , Ácido Úrico/sangue , Ácido Úrico/química , Adulto Jovem
14.
Mol Cell Biochem ; 476(3): 1377-1386, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33389490

RESUMO

Hyperuricemic nephropathy (HN) is a common clinical complication of hyperuricemia. High-serum uric acid can trigger renal inflammation. The inflammasome family has several members and shows a significant effect on inflammatory responses. NLRP3 (NOD-, LRR-, and pyrin domain-containing 3) senses the stimuli signal of excessive uric acid and then it recruits apoptosis-related specular protein (ASC) as well as aspartic acid-specific cysteine protease (caspase)-1 precursor to form NLRP3 inflammasome. NLRP3 inflammasome is activated in acute kidney injury (AKI), chronic kidney diseases (CKD), diabetic nephropathy (DN), and HN. This review focuses on important role for the involvement of NLRP3 inflammasome and associated signaling pathways in the pathogenesis of hyperuricemia-induced renal injury and the potential therapeutic implications. Additionally, several inhibitors targeting NLRP3 inflammasome are under development, most of them for experiment. Therefore, researches into NLRP3 inflammasome modulators may provide novel therapies for HN.


Assuntos
Nefropatias Diabéticas/metabolismo , Hiperuricemia/metabolismo , Inflamassomos/metabolismo , Transdução de Sinais , Injúria Renal Aguda/metabolismo , Animais , Citocinas/metabolismo , Humanos , Inflamação , Falência Renal Crônica/metabolismo , Medicina Tradicional Chinesa , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Espécies Reativas de Oxigênio , Ácido Úrico/metabolismo
15.
Gene ; 765: 145120, 2021 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-32896590

RESUMO

BACKGROUND: Gout is an inflammatory arthritis resulting from precipitation of monosodium urate (MSU) crystals in joints and surrounding tissues. However, the mechanism underlying high levels of uric acid inducing gouty arthritis has not been clarified. OBJECTIVE: The purpose was to investigate the role of Matrix Metalloproteinase-3 (MMP-3) in the development of gouty arthritis from hyperuricemia. METHOD: MSU crystal-induced gouty arthritis model and chondrocytes were used to evaluate changes of MMP-3 levels. Western blot, qPCR and ELISA were performed to detect MMP-3, Tissue Inhibitors of Metalloproteinase-1 (TIMP-1) and A Disintegrin and Metalloproteinase with Thrombospondin Motifs-4 (ADAMTS-4) expressions in rabbit chondrocytes. Expression of proteoglycan was determined through toluidine blue staining. Concentrations of glycosaminoglycan, Interleukin-6 (IL-6), Interleukin-1ß (IL-1ß) and Tumor Necrosis Factor-α (TNF-α) in chondrocytes were assessed via ELISA kits. Concentration of uric acid in supernate was tested by Automatic Analyzer. RESULTS: MMP-3 was significantly increased in rat serum, synovial fluid, cartilages and chondrocytes treated with high-level uric acid. Increased concentration of glycosaminoglycancould be observed in chondrocytes incubated with MMP-3, as well as the remarkable downregulation of proteoglycan expression. Furthermore, high-level uric acid contributed to the degradation of proteoglycan via the activation of MMP-3. IL-6, IL-1ß and TNF-α concentrations were increased significantly in 35 °C compared to 37 °C with MMP-3 and high-level uric acid. CONCLUSION: Our study showed that MMP-3 was enhanced by high levels of uric acid, which promoted proteoglycan degradation, and induced MSU crystallization in turn. A low temperature environment is an important factor in the development of gout.


Assuntos
Artrite Gotosa/metabolismo , Metaloproteinase 3 da Matriz/metabolismo , Proteoglicanas/metabolismo , Animais , Artrite Gotosa/induzido quimicamente , Artrite Gotosa/patologia , Condrócitos/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Hiperuricemia/metabolismo , Interleucina-6/metabolismo , Macrófagos/metabolismo , Masculino , Metaloproteinase 3 da Matriz/fisiologia , Coelhos , Ratos , Ratos Sprague-Dawley , Líquido Sinovial/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Ácido Úrico/metabolismo
16.
Endocrinology ; 161(11)2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32941616

RESUMO

Over the past decade, noncoding ribonucleic acids (ncRNAs) have been shown to have crucial functional importance in health and disease. ncRNAs have been well studied and may be involved in the development of inflammatory arthritis, including gouty arthritis. Gout is also associated with metabolic pathway disorders, such as hyperuricemia, due to disturbed purine nucleotide metabolism or excretion of uric acid through the kidney. Moreover, their presence in the circulation has led to the idea that ncRNAs might serve as biomarkers for specific disease states to guide clinical decision-making. Therefore, we summarize the emerging evidence and review the current literature on the regulatory role of miRNAs and lncRNAs in gout pathophysiology. We further discuss the opportunities and challenges of ncRNAs as new blood-based biomarkers for future studies aimed at translation into clinical applications in the diagnosis and therapy of gout.


Assuntos
Gota/diagnóstico , Gota/terapia , RNA Longo não Codificante/fisiologia , Biomarcadores/análise , Biomarcadores/metabolismo , Gota/genética , Gota/metabolismo , Humanos , Hiperuricemia/complicações , Hiperuricemia/genética , Hiperuricemia/metabolismo , Redes e Vias Metabólicas/genética , MicroRNAs/genética , MicroRNAs/metabolismo , MicroRNAs/fisiologia
17.
J Am Soc Nephrol ; 31(12): 2773-2792, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32938648

RESUMO

BACKGROUND: The roles of asymptomatic hyperuricemia or uric acid (UA) crystals in CKD progression are unknown. Hypotheses to explain links between UA deposition and progression of CKD include that (1) asymptomatic hyperuricemia does not promote CKD progression unless UA crystallizes in the kidney; (2) UA crystal granulomas may form due to pre-existing CKD; and (3) proinflammatory granuloma-related M1-like macrophages may drive UA crystal-induced CKD progression. METHODS: MALDI-FTICR mass spectrometry, immunohistochemistry, 3D confocal microscopy, and flow cytometry were used to characterize a novel mouse model of hyperuricemia and chronic UA crystal nephropathy with granulomatous nephritis. Interventional studies probed the role of crystal-induced inflammation and macrophages in the pathology of progressive CKD. RESULTS: Asymptomatic hyperuricemia alone did not cause CKD or drive the progression of aristolochic acid I-induced CKD. Only hyperuricemia with UA crystalluria due to urinary acidification caused tubular obstruction, inflammation, and interstitial fibrosis. UA crystal granulomas surrounded by proinflammatory M1-like macrophages developed late in this process of chronic UA crystal nephropathy and contributed to the progression of pre-existing CKD. Suppressing M1-like macrophages with adenosine attenuated granulomatous nephritis and the progressive decline in GFR. In contrast, inhibiting the JAK/STAT inflammatory pathway with tofacitinib was not renoprotective. CONCLUSIONS: Asymptomatic hyperuricemia does not affect CKD progression unless UA crystallizes in the kidney. UA crystal granulomas develop late in chronic UA crystal nephropathy and contribute to CKD progression because UA crystals trigger M1-like macrophage-related interstitial inflammation and fibrosis. Targeting proinflammatory macrophages, but not JAK/STAT signaling, can attenuate granulomatous interstitial nephritis.


Assuntos
Hiperuricemia/complicações , Hiperuricemia/patologia , Nefrite Intersticial/etiologia , Nefrite Intersticial/patologia , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/patologia , Animais , Doenças Assintomáticas , Modelos Animais de Doenças , Progressão da Doença , Granuloma/etiologia , Granuloma/metabolismo , Granuloma/patologia , Hiperuricemia/metabolismo , Camundongos , Nefrite Intersticial/sangue , Insuficiência Renal Crônica/sangue
18.
Eur J Pharmacol ; 888: 173490, 2020 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-32827538

RESUMO

Increasing evidence shows that the intestinal tract plays an important role in maintaining urate homeostasis and might be a potential therapeutic target for hyperuricaemia. However, uric acid-lowering drugs available in the clinic do not target intestinal excretion as a therapeutic strategy. We previously reported that mangiferin had potent hypouricaemic effects in hyperuricaemic animals. However, the underlying mechanisms are not completely clear. Here, we investigated the effects of mangiferin on the intestinal excretion of urate and its underlying mechanisms. The data revealed that mangiferin concentration-dependently promoted the intestinal secretion of endogenous urate in in situ intestinal closed loops in normal and hyperuricaemic mice, as well as inhibited the absorption of exogenous uric acid perfused into the intestinal loops in rats. Administration of mangiferin not only decreased the serum urate levels in the hyperuricaemic mice but also increased the protein expression of ATP-binding cassette transporter, subfamily G, member 2 (ABCG2) and inhibited the protein expression of glucose transporter 9 (GLUT 9) in the intestine. These findings suggested that intestinal ABCG2 and GLUT9 might be pivotal and possible action sites for the observed hypouricaemic effects. Moreover, no significant changes in intestinal xanthine oxidoreductase activities were observed, suggesting that mangiferin did not affect intestinal uric acid generation in the hyperuricaemic mice. Overall, promoting intestinal elimination of urate by upregulating ABCG2 expression and downregulating GLUT9 expression might be an important mechanism underlying mangiferin lowering serum uric acid levels. Mangiferin supplementation might be beneficial for the prevention and treatment of hyperuricaemia.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/biossíntese , Eliminação Intestinal/efeitos dos fármacos , Proteínas de Transporte de Monossacarídeos/biossíntese , Ácido Úrico/metabolismo , Xantonas/farmacologia , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/agonistas , Animais , Hiperuricemia/tratamento farmacológico , Hiperuricemia/metabolismo , Eliminação Intestinal/fisiologia , Masculino , Camundongos , Proteínas de Transporte de Monossacarídeos/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley , Xantonas/uso terapêutico
19.
FASEB J ; 34(10): 13474-13493, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32780898

RESUMO

Potential underlying molecular mechanisms for uric acid-induced lipid metabolic disturbances had not been elucidated clearly. This study investigated the effects and underlying mechanisms of uric acid on the development of lipid metabolic disorders. We collected blood samples from 100 healthy people and 100 patients with hyperuricemia for whom serum lipid analysis was performed. Meanwhile, a mouse model of hyperuricemia was generated, and lipidomics was performed on liver tissues, comparing control and hyperuricemia groups, to analyze lipid profiles and key metabolic enzymes. Uric acid directly induced serum lipid metabolic disorders in both humans and mice based on triglycerides, total cholesterol, and low-density lipoprotein cholesterol. Through lipidomic analysis, 46 lipids were differentially expressed in hyperuricemic mouse livers, and the phosphatidylcholine composition was altered, which was mediated by LPCAT3 upregulation. High-uric acid levels-induced p-STAT3 inhibition and SREBP-1c activation in vivo and in vitro. Moreover, LPCAT3-knockdown significantly attenuated uric acid-induced p-STAT3 inhibition, SREBP-1c activation, and lipid metabolic disorders in L02 cells. In conclusion, uric acid induces lipid metabolic disturbances through LPCAT3-mediated p-STAT3 inhibition and SREBP-1c activation. LPCAT3 could be a key regulatory factor linking hyperuricemia and lipid metabolic disorders. These results might provide novel insights into the clinical treatment of hyperuricemia.


Assuntos
1-Acilglicerofosfocolina O-Aciltransferase/fisiologia , Hiperuricemia/metabolismo , Fígado/metabolismo , Triglicerídeos/metabolismo , Ácido Úrico/metabolismo , Adulto , Animais , Estudos de Casos e Controles , Colesterol/metabolismo , Feminino , Técnicas de Silenciamento de Genes , Células Hep G2 , Humanos , Lipoproteínas LDL/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Fator de Transcrição STAT3/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
20.
Int J Mol Sci ; 21(15)2020 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-32707836

RESUMO

Hyperuricemia is an important risk factor of chronic kidney disease, metabolic syndrome and cardiovascular disease. We aimed to assess the time-feature relationship of hyperuricemia mouse model on uric acid excretion and renal function. A hyperuricemia mouse model was established by potassium oxonate (PO) and adenine for 21 days. Ultra Performance Liquid Chromatography was used to determine plasma uric acid level. Hematoxylin-eosin staining was applied to observe kidney pathological changes, and Western blot was used to detect renal urate transporters' expression. In hyperuricemia mice, plasma uric acid level increased significantly from the 3rd day, and tended to be stable from the 7th day, and the clearance rate of uric acid decreased greatly from the 3rd day. Further study found that the renal organ of hyperuricemia mice showed slight damage from the 3rd day, and significantly deteriorated renal function from the 10th day. In addition, the expression levels of GLUT9 and URAT1 were upregulated from the 3rd day, while ABCG2 and OAT1 were downregulated from the 3rd day, and NPT1 were downregulated from the 7th day in hyperuricemia mice kidney. This paper presents a method suitable for experimental hyperuricemia mouse model, and shows the time-feature of each index in a hyperuricemia mice model.


Assuntos
Modelos Animais de Doenças , Hiperuricemia/sangue , Hiperuricemia/fisiopatologia , Rim/patologia , Ácido Úrico/sangue , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/sangue , Adenina/toxicidade , Animais , Cromatografia Líquida de Alta Pressão , Creatinina/sangue , Proteínas Facilitadoras de Transporte de Glucose/sangue , Hiperuricemia/induzido quimicamente , Hiperuricemia/metabolismo , Rim/metabolismo , Camundongos , Proteína 1 Transportadora de Ânions Orgânicos/sangue , Transportadores de Ânions Orgânicos/sangue , Transportadores de Ânions Orgânicos/metabolismo , Ácido Oxônico/toxicidade , Proteínas Cotransportadoras de Sódio-Fosfato Tipo I/sangue , Fatores de Tempo
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