scholarly journals Chinese Herbal Formulas Si-Wu-Tang and Er-Miao-San Synergistically Ameliorated Hyperuricemia and Renal Impairment in Rats Induced by Adenine and Potassium Oxonate

2015 ◽  
Vol 37 (4) ◽  
pp. 1491-1502 ◽  
Author(s):  
Yongping Guo ◽  
Qian Jiang ◽  
Dingkun Gui ◽  
Niansong Wang
Keyword(s):  
Uric Acid ◽  
Renal Impairment ◽  
Serum Uric Acid ◽  
Organic Anion ◽  
Organic Anion Transporter ◽  
Protective Effects ◽  
Chinese Herbal ◽  
Renal Histopathology ◽  
Anion Transporter ◽  
Potassium Oxonate

Background/Aims: Hyperuricemia is an independent risk factor for chronic kidney disease and cardiovascular disease. Here, we examined the combined protective effects of Chinese herbal formula Si-Wu-Tang and Er-Miao-San on hyperuricemia and renal impairment in rats. Methods: Rats were randomly divided into normal rats, hyperuricemic rats, and hyperuricemic rats orally administrated with benzbromarone (4.5 mg·kg-1·d-1), Si-Wu-Tang (3.78 g·kg-1·d-1) and Si-Wu-Tang plus Er-Miao-San (6.48 g·kg-1·d-1) for 4 weeks. Hyperuricemic rats were orally gavaged with adenine (0.1 g·kg-1·d-1) and potassium oxonate (1.5 g·kg-1·d-1) daily for 4 weeks. Serum uric acid, creatinine, total cholesterol (TCH), triglyceride and blood urea nitrogen (BUN) concentrations, as well as urinary uric acid and microalbuminuria were measured weekly. Serum xanthine oxidase (XOD) activity and renal histopathology were also evaluated. The renal expression of organic anion transporter 1 (OAT1) and organic anion transporter 3 (OAT3) was detected by western blot. Results: Si-Wu-Tang plus Er-Miao-San lowered serum uric acid, creatinine, triglyceride and BUN levels to a greater degree than did Si-Wu-Tang alone. Si-Wu-Tang plus Er-Miao-San ameliorated microalbuminuria and renal histopathology, as well as decreased serum TCH concentration and XOD activity in hyperuricemic rats. Combination of Si-Wu-Tang and Er-Miao-San also led to a greater increase in OAT1 and OAT3 expression than did Siwutang alone. Conclusion: Si-Wu-Tang and Er-Miao-San synergistically ameliorated hyperuricemia and renal impairment in rats through upregulation of OAT1 and OAT3.

Effect of bempedoic acid on uric acid and gout in 3621 patients with hypercholesterolemia: pooled analyses from phase 3 trials

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
K.K Ray ◽  
G.L Bakris ◽  
M Banach ◽  
A Catapano ◽  
P.B Duell ◽  
...  
Keyword(s):  
Uric Acid ◽  
Serum Uric Acid ◽  
Organic Anion ◽  
Organic Anion Transporter ◽  
Lipid Lowering ◽  
Funding Source ◽  
Lipid Lowering Therapy ◽  
Private Company ◽  
Anion Transporter ◽  
History Of

Abstract Background Bempedoic acid (BA), an oral ATP-citrate lyase inhibitor, significantly lowers low-density lipoprotein cholesterol levels in patients with hypercholesterolemia. In clinical trials of BA, small mean increases in uric acid have been reported. BA weakly inhibits organic anion transporter 2 (OAT2) in vitro, which may account for small elevations in serum uric acid. Purpose To assess uric acid levels and incidence of gout with BA treatment. Methods Data were pooled from 4 randomized (2:1), double-blind studies of BA (180 mg daily) vs placebo for 12 weeks to 52 weeks in patients with hypercholesterolemia on stable background lipid-lowering therapy. Safety assessments included adverse events of special interest (elevation in uric acid levels, gout) and laboratory assessments. Results A total of 2424 patients treated with BA and 1197 patients on placebo were included in this analysis. Mean (SD) baseline uric acid levels were 6.0 (1.4) mg/dL for both groups. History of gout was reported by 5.2% (127/2424) and 5.8% (69/1197) in the BA and placebo groups, respectively. At week 12, mean (SD) serum uric acid levels (% change from baseline) increased from baseline with BA treatment by 0.82 (0.97) mg/dL (14.8%) vs –0.02 (0.82) mg/dL (0.67%) for placebo. Elevations in serum uric acid levels typically occurred within the first 4 weeks of treatment, remained stable during treatment, and returned to baseline after treatment discontinuation. Gout was reported in 1.4% (BA) and 0.4% (placebo) of patients, and hyperuricemia was reported in 1.7% (BA) and 0.6% (placebo) of patients. Other potential clinical consequences of elevated uric acid levels (eg, events associated with nephrolithiasis), were similar between groups (0.7% vs 0.8%). In both groups, patients who reported gout during the studies were more likely to have a medical history of gout or elevated baseline uric acid levels (Table). Few patients discontinued treatment due to gout (n=1, <0.1% [BA]) or uric acid increases (n=2, <0.1% [BA]). Conclusion Mean increases in uric acid levels were small, remained stable while patients continued to receive treatment, were infrequently associated with AEs, and were reversible on discontinuation of BA Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Esperion Therapeutics funded the research for this study and provided writing support for this abstract. Medical writing assistance was provided by Agnella Izzo Matic, PhD, CMPP, and Kelly M Cameron, PhD, CMPP, of JB Ashtin.

Hypouricemic and Nephroprotective Effects of Emodinol in Oxonate-Induced Hyperuricemic Mice are Mediated by Organic Ion Transporters and OIT3

Planta Medica ◽  
2015 ◽  
Vol 82 (04) ◽  
pp. 289-297 ◽  
Author(s):  
Wu Hui ◽  
Yuan Yongliang ◽  
Chen Yongde ◽  
Lu Guo ◽  
Lan Li ◽  
...  
Keyword(s):  
Uric Acid ◽  
Renal Dysfunction ◽  
Xanthine Oxidase ◽  
Oxidase Activity ◽  
Glucose Transporter ◽  
Organic Anion ◽  
Organic Anion Transporter ◽  
Xanthine Oxidase Activity ◽  
Anion Transporter ◽  
Potassium Oxonate

AbstractEmodinol, 1β,3β,23-trihydroxyolean-12-en-28-acid, as the main active ingredient firstly extracted from the rhizomes of Elaeagus pungens by our research group, has been demonstrated to exhibit uricosuric activity by our previous study. The aim of this study was to evaluate the uricosuric and nephroprotective effects of emodinol and explore its possible mechanisms in potassium oxonate-induced hyperuricemic mice with renal dysfunction. Mice were orally administrated 250 mg/kg of potassium oxonate once daily for 7 consecutive days to induce hyperuricemia with renal dysfunction. Emodinol was given at doses of 25, 50, and 100 mg/kg on the same day 1 h after oxonate treatment, and allopurinol (10 mg/kg) was given as a positive control. After 1 week, serum uric acid, serum creatinine, urine uric acid, urine creatinine, blood urea nitrogen, and hepatic xanthine oxidase activity were determined. The mRNA and protein levels of urate transporter 1, glucose transporter 9, ATP-binding cassette subfamily G member 2, organic anion transporter 1, oncoprotein-induced transcript 3, and organic cation/carnitine transporters in the kidney were detected by real-time polymerase chain reaction and Western blot analysis. In addition, urinary and renal Tamm-Horsfall glycoprotein concentrations were examined by ELISA assays. Emodinol significantly reduced serum urate levels, increased urinary urate levels and fractional excretion of uric acid, and inhibited hepatic xanthine oxidase activity in hyperuricemic mice. Moreover, potassium oxonate administration led to dys expressions of renal urate transporter 1, glucose transporter 9, ATP-binding cassette subfamily G member 2, organic anion transporter 1, and oncoprotein-induced transcript 3 as well as alternations of uromodulin concentrations, which could be reversed by emodinol. On the other hand, treatment of emodinol caused upregulated expressions of organic cation/carnitine transporters, resulting in an improvement of renal function characterized by decreased serum creatinine and blood urea nitrogen levels. Emodinol exhibited hypouricemic and nephroprotective actions by inhibiting xanthine oxidase activity and regulating renal ion transporters and oncoprotein-induced transcript 3, which may be a potential therapeutic agent in hyperuricemia and renal dysfunction.

scholarly journals Probenecid, a gout remedy, inhibits pannexin 1 channels

2008 ◽  
Vol 295 (3) ◽  
pp. C761-C767 ◽  
Author(s):  
William Silverman ◽  
Silviu Locovei ◽  
Gerhard Dahl
Keyword(s):  
Uric Acid ◽  
Organic Anion ◽  
Atp Release ◽  
Transport Processes ◽  
Organic Anion Transporter ◽  
Acid Excretion ◽  
Dye Uptake ◽  
Uric Acid Excretion ◽  
Pannexin 1 ◽  
Anion Transporter

Probenecid is a well-established drug for the treatment of gout and is thought to act on an organic anion transporter, thereby affecting uric acid excretion in the kidney by blocking urate reuptake. Probenecid also has been shown to affect ATP release, leading to the suggestion that ATP release involves an organic anion transporter. Other pharmacological evidence and the observation of dye uptake, however, suggest that the nonvesicular release of ATP is mediated by large membrane channels, with pannexin 1 being a prominent candidate. In the present study we show that probenecid inhibited currents mediated by pannexin 1 channels in the same concentration range as observed for inhibition of transport processes. Probenecid did not affect channels formed by connexins. Thus probenecid allows for discrimination between channels formed by connexins and pannexins.

scholarly journals Effects of Renal Impairment on the Pharmacokinetics of Morinidazole: Uptake Transporter-Mediated Renal Clearance of the Conjugated Metabolites

2014 ◽  
Vol 58 (7) ◽  
pp. 4153-4161 ◽  
Author(s):  
Kan Zhong ◽  
Xiuli Li ◽  
Cen Xie ◽  
Yifan Zhang ◽  
Dafang Zhong ◽  
...  
Keyword(s):  
Renal Impairment ◽  
Renal Clearance ◽  
Healthy Subjects ◽  
Severe Renal Impairment ◽  
Organic Anion ◽  
Organic Anion Transporter ◽  
Anion Transporter ◽  
Plasma And Urine Samples ◽  
Conjugated Metabolites

ABSTRACTMorinidazole is a novel 5-nitroimidazole antimicrobial drug that undergoes extensive metabolism in humans viaN+-glucuronidation (N+-glucuronide ofS-morinidazole [M8-1] andN+-glucuronide ofR-morinidazole [M8-2]) and sulfation (sulfate conjugate of morinidazole [M7]). Our objectives were to assess the effects of renal impairment on the pharmacokinetics (PK) of morinidazole and to elucidate the potential mechanisms. In this parallel-group study, healthy subjects and patients with severe renal impairment received an intravenous infusion of 500 mg of morinidazole. Plasma and urine samples were collected and analyzed. The areas under the plasma concentration-time curves (AUC) for M7, M8-1, and M8-2 were 15.1, 20.4, and 17.4 times higher, respectively, in patients with severe renal impairment than in healthy subjects, while the AUC for morinidazole was 1.5 times higher. The urinary recovery of the major metabolites was not significantly different between the two groups over 0 to 48 h, but the renal clearances of M7, M8-1, and M8-2 in patients were 85.3%, 92.5%, and 92.2% lower, respectively.In vitrotransporter studies revealed that M7 is a substrate for organic anion transporter 1 (OAT1) and OAT3 (Km= 28.6 and 54.0 μM, respectively). Only OAT3 transported M8-1 and M8-2. Morinidazole was not a substrate for the transporter-transfected cells examined. These results revealed that the function or activity of renal uptake transporters might be impaired in patients with severe renal impairment, which accounted for dramatically increased plasma exposure and reduced renal clearance of the conjugated metabolites of morinidazole, the substrates of renal transporters in patients. It will help clinicians to adjust the dose in patients with severe renal impairment and to predict possible transporter-based drug-drug interactions.

scholarly journals Active Components from Lagotis Brachystachya Maintain Uric Acid Homeostasis by Inhibiting Renal TLR4-NLRP3 Signaling in Hyperuricemic Mice

2021 ◽  
Author(s):  
Ji-Xiao Zhu ◽  
Hai-Yan Yang ◽  
Wei-Qiong Hu ◽  
Jie Cheng ◽  
Yang Liu ◽  
...  
Keyword(s):  
Uric Acid ◽  
Glucose Transporter ◽  
Organic Anion ◽  
Underlying Mechanism ◽  
Organic Anion Transporter ◽  
Active Components ◽  
Inflammatory Signaling ◽  
Anion Transporter ◽  
Glucose Transporter 9

Abstract Lagotis brachystachya Maxim is an herb widely used in traditional Tibet medicine. Our previous study indicated that total extracts from Lagotis brachystachya could lower uric acid levels. This study aimed to further elucidate the active components (luteolin, luteoloside and apigenin) isolated from Lagotis brachystachya and the underlying mechanism in vitro and vivo. The results showed that treatment with luteolin and luteoloside reversed the reduction of organic anion transporter 1 (OAT1) levels, while apigenin attenuated the elevation of urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) levels in uric acid-treated HK-2 cells, which were consistent with the finding in the kidney of potassium oxonate (PO)-induced mice. On the other hand, hepatic xanthine oxidase activity was inhibited by the components. In addition, all of these active components improved the morphology of the kidney in hyperuricemic mice. Moreover, molecular docking showed that luteolin, luteoloside and apigenin could bind TLR4 and NLRP3. Consistently, western blot showed that the components inhibited TLR4/MyD88/NLRP3 signaling. In conclusion, these results indicated that luteolin, luteoloside and apigenin could attenuate hyperuricemia by decreasing the production and increasing the excretion of uric acid, which were mediated by the inhibition of inflammatory signaling pathways.

scholarly journals Hypouricemic Effects of Chrysanthemum indicum L. and Cornus officinalis on Hyperuricemia-Induced HepG2 Cells, Renal Cells, and Mice

Plants ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1668
Author(s):  
Ok-Kyung Kim ◽  
Jeong-Moon Yun ◽  
Minhee Lee ◽  
Dakyung Kim ◽  
Jeongmin Lee
Keyword(s):  
Uric Acid ◽  
Hepg2 Cells ◽  
Glucose Transporter ◽  
Organic Anion ◽  
Organic Anion Transporter ◽  
Expression Levels ◽  
Cornus Officinalis ◽  
Anion Transporter ◽  
Chrysanthemum Indicum ◽  
Primary Mouse

Hyperuricemia, abnormally excess accumulation of uric acid, is caused by an imbalance between the production and excretion of uric acid and is a major cause of gout. We compared the effects of extracts from Chrysanthemum indicum L. (Ci) and Cornus officinalis Siebold and Zucc. (Co) on hyperuricemia, both individually and in combination (FSU-CC), using hypoxanthine-treated human liver cancer (HepG2) cells, primary mouse renal proximal tubule cells, and potassium oxonate induced hyperuricemic mice. The Ci contained 7.62 mg/g luteolin and 0 mg/g loganin, Co contained 0 mg/g luteolin and 4.90 mg/g loganin, and FSH-CC contained 3.95 mg/g luteolin and 2.48 mg/g loganin. We found that treatment with Ci, Co, and FSU-CC suppressed the activity of xanthine oxidase and mRNA expression of xanthine dehydrogenase while inducing an increase in the expression levels of the organic anion transporter 1 (OAT1) and organic anion transporter 3 (OAT3) proteins and a decrease in the expression levels of glucose transporter 9 (GLUT9) and urate transporter 1 (URAT1) proteins. Particularly, treatment and supplementation with FSU-CC showed stronger effects than those of supplementation with either Ci or Co alone. We observed that the excretion of creatinine and uric acid in the combination of Ci and Co was higher than that observed in their individual supplementations and was similar to that of the normal group. Therefore, our data suggest that a combination of Ci and Co may potentially be used for the development of effective natural anti-hyperuricemic functional foods.

scholarly journals Pharmacologic Targeting of BET Proteins Attenuates Hyperuricemic Nephropathy in Rats

2021 ◽  
Vol 12 ◽  
Author(s):  
Chongxiang Xiong ◽  
Jin Deng ◽  
Xin Wang ◽  
Xiaofei Shao ◽  
Qin Zhou ◽  
...  
Keyword(s):  
Uric Acid ◽  
Epithelial To Mesenchymal Transition ◽  
Organic Anion ◽  
Mesenchymal Cell ◽  
Serum Levels ◽  
Organic Anion Transporter ◽  
Vimentin Expression ◽  
Mesenchymal Transition ◽  
Expression Levels ◽  
Anion Transporter

Hyperuricemia is an independent risk factor for renal damage and promotes the progression of chronic kidney disease. In this study, we investigated the effect of I-BET151, a small-molecule inhibitor targeting the bromodomain and extraterminal (BET) proteins, on the development of hyperuricemic nephropathy (HN), and the mechanisms involved. Expression levels of bromodomain-containing protein 2 and 4, but not 3 were increased in the kidney of rats with HN; administration of I-BET151 effectively prevented renal dysfunction, decreased urine microalbumin, and attenuated renal fibrosis as indicated by reduced activation of renal interstitial fibroblasts and expression of fibronectin and collagen I in HN rats. Mechanistic studies show that I-BET151 treatment inhibited transition of renal epithelial cells to a mesenchymal cell type as evidenced by preservation of E-cadherin and reduction of vimentin expression. This was coincident with reduced expression of TGF-β1 and dephosphorylation of Smad3 and ERK1/2. I-BET151 was also effective in inhibiting phosphorylation of NF-κB, expression of multiple cytokines and chemokines, and infiltration of macrophages to the injured kidney. Although there were increased serum levels of uric acid and xanthine oxidase, an enzyme that catalyzes production of uric acid, and decreased expression of renal organic anion transporter 1 and 3 that promote urate excretion in the model of HN, and reduced expression levels of urine uric acid, I-BET151 treatment did not affect these responses. Collectively, our results indicate that I-BET151 alleviates HN by inhibiting epithelial to mesenchymal transition and inflammation in association with blockade of TGF-β, ERK1/2 and NF-κB signaling.

scholarly journals Hypouricemic and Anti-oxidant Effects of Chrysanthemum indicum L. and Cornus officinalis In Vitro and In Vivo Models

2021 ◽  
Author(s):  
Ok-kyung Kim ◽  
Jeong Moon Yun ◽  
Minhee Lee ◽  
Dakyung Kim ◽  
Jeongmin Lee
Keyword(s):  
Uric Acid ◽  
Organic Anion ◽  
Organic Anion Transporter ◽  
In Vivo Models ◽  
Expression Levels ◽  
Cornus Officinalis ◽  
Anion Transporter ◽  
Chrysanthemum Indicum

Abstract Background: Hyperuricemia, abnormally excess accumulation of uric acid, is caused by an imbalance between the production and excretion of uric acid and is a major cause of gout. We compared the effects of extracts from Chrysanthemum indicum L. (Ci) and Cornus officinalis Siebold & Zucc (Co) on hyperuricemia, both individually and in combination (FSU-CC), Methods: We used hypoxanthine-treated human liver cancer (HepG2) cells and primary mouse renal proximal tubule cells for in vitro model, and potassium oxonate-induced hyperuricemic mice for in vivo model.Results: We found that treatment of Ci, Co, and FSU-CC suppressed the activity of xanthine oxidase and mRNA expression of xanthine dehydrogenase, while inducing an increase in the expression levels of the organic anion transporter 1 and organic anion transporter 3 proteins and a decrease in the expression levels of glucose transporter 9 and urate transporter 1 proteins. Particularly, treatment and supplementation with FSU-CC showed stronger effects than those of supplementation with either Ci or Co alone. We observed that the excretion of creatinine and uric acid in the combination of Ci and Co was higher than that observed in their individual supplementations and was similar to that of the normal group.Conclusions: Therefore, our data suggest that a combination of Ci and Co may potentially be used for the development of effective natural anti-hyperuricemic functional foods.

scholarly journals Impact of renal impairment and human organic anion transporter inhibition on pharmacokinetics, safety and tolerability of relebactam combined with imipenem and cilastatin

2020 ◽  
Vol 86 (5) ◽  
pp. 944-957
Author(s):  
Pratik Bhagunde ◽  
Francheska Colon‐Gonzalez ◽  
Yang Liu ◽  
Jin Wu ◽  
Shiyao Sherrie Xu ◽  
...  
Keyword(s):  
Renal Impairment ◽  
Organic Anion ◽  
Organic Anion Transporter ◽  
Anion Transporter

scholarly journals Impact of Camellia japonica Bee Pollen Polyphenols on Hyperuricemia and Gut Microbiota in Potassium Oxonate-Induced Mice

Nutrients ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 2665
Author(s):  
Yuanyuan Xu ◽  
Xirong Cao ◽  
Haoan Zhao ◽  
Erlin Yang ◽  
Yue Wang ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Glucose Transporter ◽  
Organic Anion ◽  
Organic Cation Transporter ◽  
Nuclear Factor Κb ◽  
Organic Anion Transporter ◽  
Camellia Japonica ◽  
Bee Pollen ◽  
Anion Transporter ◽  
Potassium Oxonate

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.

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