BACKGROUND Previous studies have indicated bidirectional associations between urate levels and inflammatory bowel disease(IBD),including ulcerative colitis(UC)and Crohn’s disease(CD).However,it remains unclear whethe...BACKGROUND Previous studies have indicated bidirectional associations between urate levels and inflammatory bowel disease(IBD),including ulcerative colitis(UC)and Crohn’s disease(CD).However,it remains unclear whether the observations are causal because of confounding factors.AIM To investigate the causal associations between urate levels and IBD using bidirec-tional Mendelian randomization(MR).METHODS Independent genetic variants for urate levels and IBD were selected as instru-mental variables from published genome-wide association studies(GWASs).Summary statistics for instrument-outcome associations were retrieved from three separate databases for IBD(the UK Biobank,the FinnGen database and a large GWAS meta-analysis)and one for urate levels(a large GWAS meta-analysis).MR analyses included the inverse-variance-weighted method,weighted-median estimator,MR-Egger and sensitivity analyses(MR-PRESSO).A meta-analysis was also conducted to merge the data from separate outcome databases using a fixed-effects model.RESULTS Genetically higher serum urate levels were strongly associated with an increased risk of UC[odds ratio(OR):1.95,95%confidence interval(CI):1.86-2.05]after outlier correction,and the ORs(95%CIs)for IBD and CD were 0.94(95%CI:0.86-1.03)and 0.91(95%CI:0.80-1.04),respectively.Animal studies have confirmed the positive association between urate levels and UC.Moreover,genetically predicted IBD was inversely related to urate levels(OR:0.97,95%CI:0.94-0.99).However,no association was observed between genetically influenced UC or CD and urate levels.CONCLUSION Urate levels might be risk factors for UC,whereas genetically predicted IBD was inversely associated with urate levels.These findings provide essential new insight for treating and preventing IBD.展开更多
Gout is caused by the deposition of uric acid as monosodium urate（MSU）. Chronic hyperuricemia is the necessary condition for MSU deposition, which arises from over-production and/or under-excretion of uric acid. Ren...Gout is caused by the deposition of uric acid as monosodium urate（MSU）. Chronic hyperuricemia is the necessary condition for MSU deposition, which arises from over-production and/or under-excretion of uric acid. Renal under-excretion of uric acid accounts for greater than 90% of the patients with hyperuricemia, making URAT1 inhibitors, which act through uricosuric effect a promising class of urate-lowering therapy（ULT）. This review aims at the summary and discussion of the latest development of URAT1 inhibitors for the treatment of hyperuricemia and gout and providing an insight into their structure-activity relationship（SAR）, which will be helpful to the design of URAT1 inhibitors for both academic research and pharmaceutical industry. The current development pipeline of URAT1 inhibitors is promising and encouraging.展开更多
Background: More and more chronic kidney disease (CKD) patients are accompanied with hyperuricaemia. As is known, hyperuricaemia is an independent hazard of both cardiovascular diseases (CVD) and chronic kidney diseas...Background: More and more chronic kidney disease (CKD) patients are accompanied with hyperuricaemia. As is known, hyperuricaemia is an independent hazard of both cardiovascular diseases (CVD) and chronic kidney diseases. We aim at identifying Single Nucleotide Polymorphism (SNP) difference of hURAT1 (rs7932775) and ABCG2 (rs3825016) on CKD patient with hyperuricemia and/or gout. Methods: All forty-two CKD patients were divided into two groups: hyperuricemia, and control group. 24 hours urine sample and serum were prepared for testing biochemistry parameters. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method is used to analyze hURAT1 and ABCG2 single nucleotide polymorphisms in different groups. Results: 17 patients have CT SNP of hURAT1 (rs7932775) and 13 patients have CT SNP of ABCG2 (rs3825016) in hyperuricemia group, while only 5 persons and 6 persons have the same mutations in control group respectively. 7 patients have CT SNP of both hURAT1 (rs7932775) and ABCG2 (rs3825016) in hyperuricemia group, while only 2 persons have the same mutations in control group. CT mutation rates of hURAT1 (rs7932775) and ABCG2 (rs3825016) in hyperuricemia group were 60.7% (17/28) and 50% (13/28) respectively, higher than that of control group (35.7% (5/14) and 42.8% (6/14)). What is more, Double SNP mutations in both hURAT1 (rs7932775) and ABCG2 (rs3825016) in hyperuricemia group were 25% (7/28), higher than that of control group (14.2%, 2/14). Conclusion: There are higher mutation rates of CT SNP in hURAT1 (rs7932775) and/or ABCG2 (rs3825016) in hyperuricemia group. We can conclude that hyperuricemia is a high risk factor in progress of CKD, which is necessary to take measures of decreasing serum uric acid to delay CKD progress.展开更多
Objective:Hyperuricemia is an excess of urate in blood.The kidneys play important parts in urate excretion,which involves handling reabsorption and secretion.A series of urate transporters is responsible for this proc...Objective:Hyperuricemia is an excess of urate in blood.The kidneys play important parts in urate excretion,which involves handling reabsorption and secretion.A series of urate transporters is responsible for this process:urate transporter (URAT)1,glucose transporter (GLUT)9,organic anion transporter (OAT)1 and OAT3.Excessive fructose intake may result in increased serum urate levels.Chicory (Cichorium intybus L.) has been used as an edible vegetable and traditional Chinese medicine.Studies have shown that chicory is a promising anti-hyperuricemia agent and we explored the mechanism of its uricosuric effect via a renal pathway.Methods:Hyperuricemia was induced in rats by administration of 10% fructose.The uricosuric effect was evaluated by determining the serum urate level.Renal excretory function was detected by the clearance rate of creatinine,clearance rate of uric acid and histology.The location and expression of URAT1,GLUT9,OAT1 and OAT3 their mRNA expression in kidneys were analyzed.Results:Chicory decreased serum levels of urate and creatinine significantly,and promoted the clearance of creatinine and urate,as well as improving renal pathologic changes due to hyperuricemia.Chicory inhibited expression of URAT1 and GLUT9 markedly in a dosedependent manner,but showed no influence on expression of OAT1 or OAT3.Conclusion:Chicory might be a promising anti-hyperuricemia agent.It can promote renal excretion of urate by inhibiting urate reabsorption,which may be related to downregulation of mRNA and protein expression of URAT1 and GLUT9.展开更多
There has long been a recognised association between non-alcoholic fatty liver disease(NAFLD)and the composite aspects of the metabolic syndrome.Part of this association highlighted the supposed co-existence of elevat...There has long been a recognised association between non-alcoholic fatty liver disease(NAFLD)and the composite aspects of the metabolic syndrome.Part of this association highlighted the supposed co-existence of elevated uric acid levels in those with NAFLD.There is interest in exploitation of this as a putative diagnostic and prognostic biomarker in NAFLD.Given the increased economic and health burden associated with the NAFLD epidemic,improved methods of population-based,minimally-invasive methods and biomarkers are clearly highly sought and necessary.In this opinion review we review the proposed role of uric acid in the pathogenesis of NAFLD and its potential utilisation in the diagnosis and monitoring of the disease process.展开更多
基金Supported by National Natural Science Foundation of China,No.82170567,No.81873546,No.82170568,and No.82300627Program of Shanghai Academic/Technology Research Leader,No.22XD1425000+4 种基金The"Shu Guang"project of Shanghai Municipal Education Commission and Shanghai Education Development Foundation,No.19SG30,ChinaDeep Blue Project of Naval Medical University(Pilot Talent Plan)The Chenguang Program of Shanghai Education Development Foundation and Shanghai Municipal Education Commission,No.22CGA42The Shanghai Sailing Program,No.23YF1458600and Shanghai Natural Science Foundation,No.23ZR1478700.
文摘BACKGROUND Previous studies have indicated bidirectional associations between urate levels and inflammatory bowel disease(IBD),including ulcerative colitis(UC)and Crohn’s disease(CD).However,it remains unclear whether the observations are causal because of confounding factors.AIM To investigate the causal associations between urate levels and IBD using bidirec-tional Mendelian randomization(MR).METHODS Independent genetic variants for urate levels and IBD were selected as instru-mental variables from published genome-wide association studies(GWASs).Summary statistics for instrument-outcome associations were retrieved from three separate databases for IBD(the UK Biobank,the FinnGen database and a large GWAS meta-analysis)and one for urate levels(a large GWAS meta-analysis).MR analyses included the inverse-variance-weighted method,weighted-median estimator,MR-Egger and sensitivity analyses(MR-PRESSO).A meta-analysis was also conducted to merge the data from separate outcome databases using a fixed-effects model.RESULTS Genetically higher serum urate levels were strongly associated with an increased risk of UC[odds ratio(OR):1.95,95%confidence interval(CI):1.86-2.05]after outlier correction,and the ORs(95%CIs)for IBD and CD were 0.94(95%CI:0.86-1.03)and 0.91(95%CI:0.80-1.04),respectively.Animal studies have confirmed the positive association between urate levels and UC.Moreover,genetically predicted IBD was inversely related to urate levels(OR:0.97,95%CI:0.94-0.99).However,no association was observed between genetically influenced UC or CD and urate levels.CONCLUSION Urate levels might be risk factors for UC,whereas genetically predicted IBD was inversely associated with urate levels.These findings provide essential new insight for treating and preventing IBD.
基金Supported by Key Projects of Tianjin Science and Technology Support Plan(16YFZCSY00910)Natural Science Foundation of Shandong Province(ZR2015BM028)
文摘Gout is caused by the deposition of uric acid as monosodium urate（MSU）. Chronic hyperuricemia is the necessary condition for MSU deposition, which arises from over-production and/or under-excretion of uric acid. Renal under-excretion of uric acid accounts for greater than 90% of the patients with hyperuricemia, making URAT1 inhibitors, which act through uricosuric effect a promising class of urate-lowering therapy（ULT）. This review aims at the summary and discussion of the latest development of URAT1 inhibitors for the treatment of hyperuricemia and gout and providing an insight into their structure-activity relationship（SAR）, which will be helpful to the design of URAT1 inhibitors for both academic research and pharmaceutical industry. The current development pipeline of URAT1 inhibitors is promising and encouraging.
文摘Background: More and more chronic kidney disease (CKD) patients are accompanied with hyperuricaemia. As is known, hyperuricaemia is an independent hazard of both cardiovascular diseases (CVD) and chronic kidney diseases. We aim at identifying Single Nucleotide Polymorphism (SNP) difference of hURAT1 (rs7932775) and ABCG2 (rs3825016) on CKD patient with hyperuricemia and/or gout. Methods: All forty-two CKD patients were divided into two groups: hyperuricemia, and control group. 24 hours urine sample and serum were prepared for testing biochemistry parameters. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method is used to analyze hURAT1 and ABCG2 single nucleotide polymorphisms in different groups. Results: 17 patients have CT SNP of hURAT1 (rs7932775) and 13 patients have CT SNP of ABCG2 (rs3825016) in hyperuricemia group, while only 5 persons and 6 persons have the same mutations in control group respectively. 7 patients have CT SNP of both hURAT1 (rs7932775) and ABCG2 (rs3825016) in hyperuricemia group, while only 2 persons have the same mutations in control group. CT mutation rates of hURAT1 (rs7932775) and ABCG2 (rs3825016) in hyperuricemia group were 60.7% (17/28) and 50% (13/28) respectively, higher than that of control group (35.7% (5/14) and 42.8% (6/14)). What is more, Double SNP mutations in both hURAT1 (rs7932775) and ABCG2 (rs3825016) in hyperuricemia group were 25% (7/28), higher than that of control group (14.2%, 2/14). Conclusion: There are higher mutation rates of CT SNP in hURAT1 (rs7932775) and/or ABCG2 (rs3825016) in hyperuricemia group. We can conclude that hyperuricemia is a high risk factor in progress of CKD, which is necessary to take measures of decreasing serum uric acid to delay CKD progress.
基金The authors thank Mrs.Meijuan Yang for her technical support on the preparation of paraffin sections.This work was supported by National Natural Science Foundation of China(81673618)Beijing Natural Science Foundation(7162117)National Science and Technology Major Projects for'Major New Drugs Innovation and Development'(2017ZX09301024).
文摘Objective:Hyperuricemia is an excess of urate in blood.The kidneys play important parts in urate excretion,which involves handling reabsorption and secretion.A series of urate transporters is responsible for this process:urate transporter (URAT)1,glucose transporter (GLUT)9,organic anion transporter (OAT)1 and OAT3.Excessive fructose intake may result in increased serum urate levels.Chicory (Cichorium intybus L.) has been used as an edible vegetable and traditional Chinese medicine.Studies have shown that chicory is a promising anti-hyperuricemia agent and we explored the mechanism of its uricosuric effect via a renal pathway.Methods:Hyperuricemia was induced in rats by administration of 10% fructose.The uricosuric effect was evaluated by determining the serum urate level.Renal excretory function was detected by the clearance rate of creatinine,clearance rate of uric acid and histology.The location and expression of URAT1,GLUT9,OAT1 and OAT3 their mRNA expression in kidneys were analyzed.Results:Chicory decreased serum levels of urate and creatinine significantly,and promoted the clearance of creatinine and urate,as well as improving renal pathologic changes due to hyperuricemia.Chicory inhibited expression of URAT1 and GLUT9 markedly in a dosedependent manner,but showed no influence on expression of OAT1 or OAT3.Conclusion:Chicory might be a promising anti-hyperuricemia agent.It can promote renal excretion of urate by inhibiting urate reabsorption,which may be related to downregulation of mRNA and protein expression of URAT1 and GLUT9.
文摘There has long been a recognised association between non-alcoholic fatty liver disease(NAFLD)and the composite aspects of the metabolic syndrome.Part of this association highlighted the supposed co-existence of elevated uric acid levels in those with NAFLD.There is interest in exploitation of this as a putative diagnostic and prognostic biomarker in NAFLD.Given the increased economic and health burden associated with the NAFLD epidemic,improved methods of population-based,minimally-invasive methods and biomarkers are clearly highly sought and necessary.In this opinion review we review the proposed role of uric acid in the pathogenesis of NAFLD and its potential utilisation in the diagnosis and monitoring of the disease process.
