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1.
J Agric Food Chem ; 69(37): 10932-10942, 2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34505780

RESUMO

The intestinal flora serves a critical role in the development of hyperuricemia-induced chronic kidney disease (CKD). We previously found that natural flavonol fisetin exhibited nephroprotective effects in hyperuricemic mice. However, the mechanism remains largely unknown. To investigate the underlying mechanism of fisetin, mice were fed with potassium oxonate and adenine to introduce hyperuricemia-induced CKD. Fisetin improved kidney function, ameliorated renal fibrosis, and restored enteric dysbacteriosis in hyperuricemia-induced CKD mice. Meanwhile, gut microbiota-derived tryptophan metabolites, especially l-kynurenine, showed correlations with nephroprotective profiles of fisetin. Additionally, the kidney expression of the aryl hydrocarbon receptor (AHR), an endogenous receptor of l-kynurenine, was enhanced in hyperuricemic mice and further reduced in fisetin-treated mice. Finally, in vitro results showed that inhibition of AHR activation attenuated l-kynurenine-induced fibrosis. These results highlighted that fisetin protected against hyperuricemia-induced CKD via modulating gut microbiota-mediated tryptophan metabolism and AHR activation.


Assuntos
Microbioma Gastrointestinal , Hiperuricemia , Insuficiência Renal Crônica , Animais , Flavonóis , Hiperuricemia/tratamento farmacológico , Camundongos , Receptores de Hidrocarboneto Arílico/genética , Insuficiência Renal Crônica/tratamento farmacológico , Triptofano
2.
Arq Bras Cardiol ; 117(2): 378-384, 2021 08.
Artigo em Inglês, Português | MEDLINE | ID: mdl-34495236

RESUMO

BACKGROUND: Hyperuricemia is a frequent finding in patients with arterial hypertension, and there is increasing evidence that this entity is also a risk factor for cardiovascular disease. OBJECTIVE: In the context of an aging population, this study aims to evaluate serum uric acid levels and arterial hypertension prevalence and control in a subgroup of Romanian adults (>65 years), concerning the influence of age on these parameters. METHOD: The study sample consists of 1,920 adults included in SEPHAR III survey, of whom 447 were elderly patients (>65 years of age). During the two study visits, three blood pressure (BP) measurements were performed at 1-min intervals and serum uric acid levels, kidney function by estimated glomerular filtration rate, blood pressure, and intima media thickness measurements were conducted. Hypertension and controls were defined according to the current guidelines. Intima-media thickness evaluation was assessed by B-mode Doppler ultrasound evaluation. A significance level p < 0.05 was adopted for the statistical analysis. RESULTS: Adult patients had a significant lower serum uric acid levels, compared to elderly patients, regardless of glomerular filtration rate levels. Adult patients showed a significantly lower intima-media thickness levels, when compared to elderly patients. CONCLUSION: Similar to previous studies, in the present study, age represented one of the factors contributing to the increased level of serum uric acid. An increasing prevalence of arterial hypertension with age, together with a poor control of blood pressure, was also obtained.


Assuntos
Hipertensão , Hiperuricemia , Adulto , Idoso , Pressão Sanguínea , Espessura Intima-Media Carotídea , Humanos , Hipertensão/epidemiologia , Hiperuricemia/epidemiologia , Fatores de Risco , Ácido Úrico
4.
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
5.
J Agric Food Chem ; 69(38): 11225-11235, 2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34549578

RESUMO

A novel polysaccharide from Ulva lactuca (ULP) was purified using a Sepharose CL-4B column. Fourier transform infrared spectroscopy, high-performance liquid chromatography, and nuclear magnetic resonance spectroscopy were employed to analyze the structure of ULP. It consisted of rhamnose (Rha), glucuronic acid (GluA), galactose (Gal), and xylose (Xyl) at a molar ratio of 32.75:22.83:1.07:6.46 with the molecular weight of 2.24 × 105 Da. The four major glycosidic residues found in ULP were →2,3)-α-l-Rhap-(1→, →4)-ß-d-GlcpA-(1→, →2,6)-ß-d-Galp-(1→, and →4)-ß-d-Xylp-(1→. The antihyperuricemic activity of ULP was exhibited by detecting related biochemical indexes, urate transporter gene expressions, renal histopathology, and intestinal microbiota shifts. ULP obviously decreased the levels of serum uric acid (UA), blood urea nitrogen, and creatinine, while inhibited serum and hepatic xanthine oxidase activities as well as improved renal injury in hyperuricemic mice. Furthermore, the upregulation of UA excretion genes ABCG2/OAT1 and downregulation of UA resorption genes URAT1 and GLUT9 were detected. In addition, ULP exerted its antihyperuricemic effect through regulating the intestinal microbiome, characterized by elevating the helpful microbial abundance, meanwhile declining the harmful bacterial abundance and restoring the gut microbiome homeostasis. This study demonstrates the antihyperuricemic activity of ULP and its potential effect for the treatment of hyperuricemia-related diseases.


Assuntos
Hiperuricemia , Ulva , Animais , Supressores da Gota/uso terapêutico , Hiperuricemia/tratamento farmacológico , Rim , Camundongos , Transportadores de Ânions Orgânicos , Polissacarídeos/uso terapêutico , Ácido Úrico
6.
J Assoc Physicians India ; 69(4): 11-12, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34470189

RESUMO

BACKGROUND: Hyperuricemia is found to be associated with the development and progression of gout, chronic kidney disease, cardiovascular diseases and several others. However, consistent recommendation in the management of hyperuricemia among physicians in India is absent. This study was done to assess the knowledge, attitude, practice (KAP) and barriers in the management of hyperuricemia among physicians in India. METHODS: A cross-sectional study using a telephonically-administered questionnaire was distributed to 350 physicians treating hyperuricemia patients with co-morbidities like hypertension, diabetes mellitus, metabolic syndrome etc. The questionnaire included 25 questions on qualitative and quantitative aspects. Descriptive statistics were used for demographic characteristics. Inferential statistics (binary logistic regression) was used to identify the relationship between knowledge scores across different physician factors. RESULTS: A total of 350 responses were obtained with a response rate of 100%. Majority of the physicians (90%) were male and 10% were female with median age of 45.5 ± 12.2 years. Mean scores for knowledge and attitude were 7.4 ± 2.35 and 12.1 ± 1.6, respectively. 66.1% (230) of physicians had adequate knowledge score, while the remaining 33.9% (118) had inadequate score. Irrespective of comorbidity status, no change in the attitude of physicians towards management of hyperuricemia was found. CONCLUSION: This study demonstrated that the majority of physicians demonstrated adequate level of knowledge, positive/favourable attitude and reported optimal treatment practices for the management of hyperuricemia while exhibiting a few perceived barriers. Nevertheless, facilitating widespread physician awareness about the benefits of optimal management of hyperuricemia is warranted.


Assuntos
Hiperuricemia , Médicos , Adulto , Estudos Transversais , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Hiperuricemia/epidemiologia , Hiperuricemia/terapia , Índia/epidemiologia , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários
7.
Molecules ; 26(15)2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34361599

RESUMO

The present study aimed to develop an amorphous solid dispersion of nobiletin (ASD/NOB) using hydroxypropyl cellulose-SSL (HPC-SSL) to improve the pharmacokinetic properties and hypouricemic effect of NOB. ASD/NOB was prepared by the freeze-drying method (ASD/NOB). ASD/NOB was characterized with a focus on crystallinity, dissolution, pharmacokinetic behavior, and hypouricemic action in a rat model of hyperuricemia. ASD/NOB showed significant improvement in dissolution behavior, as evidenced by a 4.4-fold higher dissolved NOB concentration than crystalline NOB at 2 h in distilled water. After the oral administration of ASD/NOB (50 mg NOB/kg) in rats, higher systemic exposure to NOB was observed with an 18-fold enhancement in oral bioavailability, and the Tmax value of orally administered ASD/NOB was 60% shorter than that of orally administered crystalline NOB. In a rat model of hyperuricemia, orally dosed ASD/NOB showed an improved hypouricemic effect by a 16% reduction in the plasma uric acid level compared with orally administered crystalline NOB. Based on these findings, ASD/NOB may be an efficacious dosage option to improve the nutraceutical potential of NOB for the treatment of hyperuricemia.


Assuntos
Flavonas , Hiperuricemia/tratamento farmacológico , Animais , Disponibilidade Biológica , Química Farmacêutica/métodos , Flavonas/farmacocinética , Flavonas/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley
8.
Nutr Metab Cardiovasc Dis ; 31(10): 2756-2765, 2021 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-34348878

RESUMO

AIM: Increasing evidence supports the hypothesis that high serum uric acid (SUA) levels are related to atrial fibrillation (AF). However, the incidence of AF in patients with hyperuricemia and SUA levels in different types of AF is not entirely clear. This meta-analysis was designed to evaluate the relationship between SUA and incidence of AF, and the variation in SUA levels in different types of AF. DATA SYNTHESIS: Relevant reports were searched for in Embase, PubMed and the Cochrane Library. A fixed-effects model combining relative risk (RR) and the corresponding 95% confidence interval (95% CI) was used to evaluate the correlation between SUA and AF. The standardized mean differences (SMDs) of SUA values were calculated using a random-effects model to evaluate the differences in SUA levels among different types of AF. A total of 31 studies with 504,958 participants were included in this research. The results from 8 cohort studies showed that high SUA levels significantly increased the incidence of AF [RR (95% CI): 1.92 (1.68-2.20); P < 0.01]. The results from 29 studies revealed that SUA levels elevated in patients with AF [SMD (95% CI): 0.55 (0.43-0.66); P < 0.001]. Meanwhile, SUA levels in new-onset AF [SMD (95%CI): 0.24 (0.10-0.38); P = 0.001], paroxysmal AF [SMD (95%CI): 0.52 (0.33-0.72); P < 0.001] and persistent AF [SMD (95%CI): 1.23 (0.98-1.48); P < 0.001] were significantly higher than that in patients without AF. CONCLUSIONS: High SUA levels had an obvious correlation with the occurrence rate of AF. In addition, SUA levels were significantly different among patients with new-onset, paroxysmal and persistent AF.


Assuntos
Fibrilação Atrial/fisiopatologia , Frequência Cardíaca , Hiperuricemia/sangue , Ácido Úrico/sangue , Adulto , Idoso , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/epidemiologia , Biomarcadores/sangue , Feminino , Humanos , Hiperuricemia/diagnóstico , Hiperuricemia/epidemiologia , Incidência , Masculino , Pessoa de Meia-Idade , Prognóstico , Medição de Risco , Fatores de Risco , Regulação para Cima
9.
Nutr Metab Cardiovasc Dis ; 31(10): 2912-2920, 2021 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-34454825

RESUMO

BACKGROUND AND AIMS: Increased serum uric acid (SUA) is common in type 2 diabetes mellitus (T2DM) and is associated with left ventricular (LV) myocardial dysfunction. Nonetheless the association of SUA with right ventricular (RV) function in T2DM has not been studied. This study aimed to investigate the association of SUA with biventricular myocardial function in patients with T2DM. METHODS AND RESULTS: A total of 560 patients with T2DM were enrolled and divided into four groups according to sex-specific quartiles of SUA. Transthoracic echocardiography was performed and two-dimensional speckle tracking was used to measure biventricular myocardial strain, including LV global longitudinal strain (GLS), circumferential strain (CS), radial strain (RS), and RV free wall longitudinal strain (RV-FWLS). The absolute value of all biventricular strain parameters showed a stepwise decrease across SUA quartiles (all P < 0.01). In particular, LV assessment by GLS, CS and RS demonstrated that those in the 4th quartile were impaired compared with the other quartiles (all P < 0.05). Similarly, RV-FWLS of the 4th quartile was significantly impaired compared with the 1st and 2nd quartiles (all P < 0.05). The same reduction in biventricular strain across SUA quartiles was observed in patients with estimated glomerular filtration rate < or ≥60 ml/min/1.73 m2, and glycated hemoglobin < or ≥7.0% (all P < 0.05). Multivariable linear regression analysis demonstrated that higher quartile of SUA was independently associated with impaired biventricular myocardial strain (all P < 0.05). CONCLUSIONS: SUA was independently associated with biventricular myocardial dysfunction in asymptomatic T2DM patients, regardless of renal function or diabetic control.


Assuntos
Diabetes Mellitus Tipo 2/epidemiologia , Hiperuricemia/epidemiologia , Ácido Úrico/sangue , Disfunção Ventricular Esquerda/epidemiologia , Disfunção Ventricular Direita/epidemiologia , Idoso , Biomarcadores/sangue , Estudos Transversais , Diabetes Mellitus Tipo 2/diagnóstico , Ecocardiografia , Feminino , Hong Kong/epidemiologia , Humanos , Hiperuricemia/sangue , Hiperuricemia/diagnóstico , Masculino , Pessoa de Meia-Idade , Prevalência , Prognóstico , Medição de Risco , Fatores de Risco , Fatores Sexuais , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/fisiopatologia , Disfunção Ventricular Direita/diagnóstico por imagem , Disfunção Ventricular Direita/fisiopatologia , Função Ventricular Esquerda , Função Ventricular Direita
11.
Afr Health Sci ; 21(1): 82-95, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34394285

RESUMO

Objectives: This meta-analysis aimed to investigate whether uric acid lowering treatment can improve ß-cell function and insulin sensitivity. Methods: PubMed, Cochrane Library, EMBASE and China Biology Medicine were searched up to March 1, 2020. Randomized controlled clinical trials of urate lowering therapy in hyperuricemia patients were included in meta-analysis. Effect size was estimated as mean difference with 95% confidence interval (CI). Results: Our search yielded 7 eligible trials with 503 participants. This meta-analysis showed that uric acid-lowering therapy decreased fasting insulin -1.43 µIU/ml (weighted mean differences (WMD, 95% CI -2.78 to -0.09), homeostasis model assessment of insulin resistance -0.65 (WMD, 95% CI -1.05 to -0.24), systolic blood pressure -2.45 mm Hg (WMD, 95%CI -4.57 to -0.33) and diastolic blood pressure -3.41 mm Hg (WMD, 95%CI -3.87 to -2.95). However, the treatment had no significant effect on fasting plasma glucose (WMD -0.19 mmol/L, 95%CI -0.42 to 0.05), homeostasis model assessment of ß-cell function index (WMD -0.02, 95%CI -0.28 to 0.24), total cholesterol (WMD 0.18 mg/dl; 95%CI, -1.39 to 1.75) and triglyceride (WMD 3.15 mg/dl, 95% CI -9.83 to 16.14). Conclusion: Uric acid-lowering therapies might improve insulin sensitivity and lower blood pressure, but had no significant effect on HOMA-ß and serum lipids.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hiperuricemia/tratamento farmacológico , Uricosúricos/uso terapêutico , Glicemia , Pressão Sanguínea/fisiologia , China , Jejum , Feminino , Humanos , Hiperuricemia/complicações , Insulina/administração & dosagem , Insulina/uso terapêutico , Resistência à Insulina , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Ácido Úrico/sangue
12.
Nutrients ; 13(8)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34444825

RESUMO

Camellia japonica bee pollen is one of the major types of bee pollen in China and exhibits antioxidant and anti-inflammatory activities. The aims of our study were to evaluate the effects and the possible mechanism of Camellia japonica bee pollen polyphenols on the treatment of hyperuricemia induced by potassium oxonate (PO). The results showed that Camellia japonica bee pollen ethyl acetate extract (CPE-E) owned abundant phenolic compounds and strong antioxidant capabilities. Administration with CPE-E for two weeks greatly reduced serum uric acid and improved renal function. It inhibited liver xanthine oxidase (XOD) activity and regulated the expression of urate transporter 1 (URAT1), glucose transporter 9 (GLUT9), organic anion transporter 1 (OAT1), organic cation transporter 1 (OCT1) and ATP-binding cassette superfamily gmember 2 (ABCG2) in kidneys. Moreover, CPE-E suppressed the activation of the toll-like receptor 4/myeloid differentiation factor 88/nuclear factor-κB (TLR4/MyD88/NF-κB) signaling pathway and nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome in PO-treated mice, and related inflammatory cytokines were reduced. CPE-E also modulated gut microbiota structure, showing that the abundance of Lactobacillus and Clostridiaceae increased in hyperuicemic mice. This study was conducted to explore the protective effect of CPE-E on hyperuricemia and provide new thoughts for the exploitation of Camellia japonica bee pollen.


Assuntos
Abelhas , Camellia/química , Hiperuricemia/tratamento farmacológico , Ácido Oxônico/efeitos adversos , Pólen/química , Polifenóis/farmacologia , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Anti-Inflamatórios , Antioxidantes , China , Modelos Animais de Doenças , Proteínas Facilitadoras de Transporte de Glucose , Humanos , Hiperuricemia/induzido quimicamente , Inflamassomos/metabolismo , Rim/metabolismo , Fígado/metabolismo , Camundongos , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Fator 1 de Transcrição de Octâmero , Proteína 1 Transportadora de Ânions Orgânicos/metabolismo , Transportadores de Ânions Orgânicos , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like , Ácido Úrico
13.
Front Public Health ; 9: 689219, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34458222

RESUMO

Importance: High uric acid (UA) is hypothesized to worsen kidney and cardiovascular disease morbidity via activation of systemic inflammation. Clinical trials of UA modification report reduction of the inflammatory marker high sensitivity C-reactive protein (hs-CRP) as an outcome measure, but studies have not demonstrated that hyperuricemia independently increases hs-CRP when adjusted for important confounders such as body mass index (BMI), sex, and age. Objective: To identify clinical risk factors for elevated hs-CRP, including but not limited to hyperuricemia, through a cross-sectional analysis of the National Health and Nutrition Examination Survey (NHANES) 2015-2018. Results: In the final multivariate logistic regression model, the exposure with the strongest effect on the odds of elevated hs-CRP was BMI in the fourth quartile, OR = 13.1 (95% CI 6.25-27.42), followed by female sex (OR = 4.9, 95% CI 2.92-8.34), hyperuricemia (OR = 2.2, 95% CI 1.36-3.45), urine albumin creatinine ratio (ACR; OR = 1.5, 95% CI 1.09-2.18), poor overall health (OR = 1.4, 95% CI 1.18-1.58), and interactions between hyperuricemia and sex (OR = 1.4, 95% CI 1.05-1.83), and between BMI and sex (OR = 1.2, 95% CI 1.03-1.47). Notably, chronic kidney disease (CKD) and CKD surrogates were not associated with hs-CRP despite urine ACR maintaining a significant independent effect. Conclusions: In this national population-based study, we demonstrated that hyperuricemia significantly increases the odds of elevated hs-CRP, independent from BMI, female sex, urine ACR, and overall health status. Further study is recommended to better understand the sex difference in this association and the role of albuminuria, but not CKD, in systemic inflammation.


Assuntos
Proteína C-Reativa , Hiperuricemia , Albuminúria , Índice de Massa Corporal , Proteína C-Reativa/análise , Estudos Transversais , Feminino , Humanos , Hiperuricemia/epidemiologia , Masculino , Inquéritos Nutricionais , Fatores de Risco
14.
J Pak Med Assoc ; 71(8): 1930-1934, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34418003

RESUMO

OBJECTIVE: To study the association of hyperuricaemia with clinical and pathological characteristics of patients with IgA nephropathy, and to clarify adverse effects of hyperuricaemia on the onset and progression of IgA nephropathy. METHODS: A total of 244 patients with IgA nephropathy enrolled in Jiangjin Center Hospital were divided into a group with normal serum uric acid level and a group with elevated level. Age, gender, course of disease, blood pressure, liver function, renal function, blood lipid levels, blood glucose level, 24-hour urine protein level and pathological grades were recorded. The correlations of serum uric acid level with clinical indices and pathological grades were analyzed. RESULTS: The incidence rate of IgA nephropathy complicated with hyperuricaemia was 25.4%. The two groups had significantly different course of disease, body mass index (BMI), and levels of urea nitrogen, creatinine, triglyceride and urine protein (p<0.05). The group with elevated serum uric acid level had higher Lee's grade, tubulointerstitial lesion grade and renal arteriolar lesion grade. Patients with IgA nephropathy were prone to hyperuricaemia, being closely correlated with BMI, course of disease, blood pressure, triglyceride level and renal function. High pathological grades were important indices for poor prognosis. CONCLUSIONS: The serum uric acid levels of patients with IgA nephropathy should be monitored to effectively control hyperuricaemia and to avoid its complications.


Assuntos
Glomerulonefrite por IGA , Hiperuricemia , Creatinina , Glomerulonefrite por IGA/complicações , Glomerulonefrite por IGA/epidemiologia , Humanos , Hiperuricemia/complicações , Hiperuricemia/epidemiologia , Rim , Ácido Úrico
15.
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
16.
Int J Mol Sci ; 22(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34360886

RESUMO

Xanthine oxidase (XO) is an important target for the effective treatment of hyperuricemia-associated diseases. A series of novel 2-substituted 6-oxo-1,6-dihydropyrimidine-5-carboxylic acids (ODCs) as XO inhibitors (XOIs) with remarkable activities have been reported recently. To better understand the key pharmacological characteristics of these XOIs and explore more hit compounds, in the present study, the three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking, pharmacophore modeling, and molecular dynamics (MD) studies were performed on 46 ODCs. The constructed 3D-QSAR models exhibited reliable predictability with satisfactory validation parameters, including q2 = 0.897, R2 = 0.983, rpred2 = 0.948 in a CoMFA model, and q2 = 0.922, R2 = 0.990, rpred2 = 0.840 in a CoMSIA model. Docking and MD simulations further gave insights into the binding modes of these ODCs with the XO protein. The results indicated that key residues Glu802, Arg880, Asn768, Thr1010, Phe914, and Phe1009 could interact with ODCs by hydrogen bonds, π-π stackings, or hydrophobic interactions, which might be significant for the activity of these XOIs. Four potential hits were virtually screened out using the constructed pharmacophore model in combination with molecular dockings and ADME predictions. The four hits were also found to be relatively stable in the binding pocket by MD simulations. The results in this study might provide effective information for the design and development of novel XOIs.


Assuntos
Ácidos Carboxílicos/química , Inibidores Enzimáticos/química , Simulação de Acoplamento Molecular/métodos , Simulação de Dinâmica Molecular , Xantina Oxidase/antagonistas & inibidores , Xantina Oxidase/química , Desenho de Fármacos , Inibidores Enzimáticos/uso terapêutico , Humanos , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Hiperuricemia/tratamento farmacológico , Estrutura Molecular , Ligação Proteica , Relação Quantitativa Estrutura-Atividade
18.
Int J Clin Pract ; 75(11): e14674, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34324762

RESUMO

OBJECTIVE: Hyperuricemia increases the risk of gout and cardiovascular diseases. Obesity increases the risk of hyperuricemia while weight loss (>5 kg) has been reported to decrease urate. The effects of orlistat on serum uric acid (SUA) are still controversial. The aim of this meta-analysis was to evaluate the influence of orlistat on SUA levels in adults. METHODS: Relevant studies, published up to May 2020, were searched systematically through PubMed/Medline, Scopus and Google Scholar. All relevant randomised controlled clinical trials were included. Meta-analysis was performed using random-effect model. Subgroup analysis, sensitivity analysis and meta-regression were also carried out. RESULTS: Overall 7 trials (9 datasets) that enrolled 1786 subjects were included. Orlistat showed in a significant change in SUA level (Difference in means: -17.661 µmol, 95% CI: -31.615 to -3.707, P = .01). A low heterogeneity observed across the studies (I2 = 25.119%). After categorising studies on the basis of duration and sample size, the effect of orlistat on SUA was significant. The results of meta-regression were showed that significant relationships were not found between orlistat and SUA in the duration of intervention. CONCLUSION: We found a significant reduction in SUA following orlistat therapy in adults.


Assuntos
Gota , Hiperuricemia , Adulto , Humanos , Orlistate , Ensaios Clínicos Controlados Aleatórios como Assunto , Ácido Úrico , Perda de Peso
19.
Iran J Kidney Dis ; 15(4): 256-262, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34278996

RESUMO

INTRODUCTION: Many factors, such as increased serum creatinine, increased blood pressure and abnormal urine protein, may lead to poor prognosis of IgA nephropathy (IgAN). The features of IgAN are also affected by uric acid, but its effect on the prognosis is less reported. We therefore systematically investigated the possible correlation of IgAN with hyperuricemia (HUA) and their prognosis. METHODS: Two groups (HUA group and uric acid normal group) were included of 178 IgAN patients. The indexes in the clinic and pathology were compared; logistic regression and renal survival were used to speculate the correlated factors of HUA in IgAN and their prognosis. RESULTS: HUA group had higher serum urea nitrogen, serum creatinine, total cholesterol, 24-hour urinary protein quantity, percentage of CKD3⁃5, the thickness of arteriole, glomerular mesangial hyperplasia, tubular atrophy, glomerulosclerosis, interstitial fibrosis and the area of infiltration of inflammatory cells (ICI), lower eGFR and serum albumin-to-creatinine ratios (P < .05). Total cholesterol and ICI in X2 were independent related factors of HUA given by the analysis of logistic regression (P < .05). No correlation was found in HUA and normal group used by Kaplan- Meier (P > .05). CONCLUSION: Severer renal pathological injures (glomeruli, tubules or interstitium) were found in IgAN. Besides, total cholesterol and the area of infiltration of inflammatory cells were independent related factors of hyperuricemia in IgAN.


Assuntos
Glomerulonefrite por IGA , Hiperuricemia , Taxa de Filtração Glomerular , Glomerulonefrite por IGA/complicações , Glomerulonefrite por IGA/diagnóstico , Humanos , Hiperuricemia/diagnóstico , Rim , Estudos Retrospectivos
20.
Andrologia ; 53(10): e14184, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34255383

RESUMO

This study is to identify the differentially expressed miRNAs in testicular tissues of rats with hyperuricaemia-induced male infertility. We found that the hyperuricaemia model group had significantly increased serum uric acid, while significantly decreased sperm concentration and motile sperm percentage than normal group (p < .05). A total of 39 differentially expressed miRNAs were identified in the testicular tissues of hyperuricaemia rats compared with the control rats, ten of which were validated by real-time PCR. The target mRNAs of 7 differentially expressed miRNAs (miR-10b-5p, miR-26a-5p, miR-136-5p, miR-151-3p, miR-183-5p, miR-362-3p and miR-509-5p) from 3'-untranslated region binding perspective were enriched in signalling pathways of Wnt, Jak-STAT, mTOR and MAPK. The target mRNAs of 6 differentially expressed miRNAs (miR-136-5p, miR-144-3p, miR-99a-5p, miR-509-5p, miR-451-5p and miR-362-3p) from coding sequence binding perspective were enriched in signalling pathways of Calcium, Notch and MAPK. The functions of miRNAs in testicular tissues of rats with hyperuricaemia were revealed by the differentially expressed miRNAs (miR-183-5p, miR-99a-5p, miR-10b-5p, miR-151-3p, miR-26a-5p, miR-451-5p, miR-362-3p, miR-136-5p, miR-144-3p and miR-509-5p)-mRNAs interaction network. The differentially expressed miRNAs in the testicular tissues of hyperuricaemia rats might shed light on the mechanism of hyperuricaemia-induced male infertility.


Assuntos
Hiperuricemia , MicroRNAs , Animais , Perfilação da Expressão Gênica , Hiperuricemia/genética , Masculino , MicroRNAs/genética , RNA Mensageiro , Ratos , Transdução de Sinais , Testículo , Ácido Úrico
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