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https://www.readbyqxmd.com/read/29656005/the-uricosuric-effects-of-dihydropyridine-calcium-channel-blockers-in-vivo-using-urate-under-excretion-animal-models
#1
Takayuki Hori, Motoshi Ouchi, Naoyuki Otani, Masakatsu Nohara, Asuka Morita, Yusuke Otsuka, Promsuk Jutabha, Ikuko Shibasaki, Yasushi Matsushita, Tomoe Fujita, Hirotsugu Fukuda, Naohiko Anzai
The purpose of this study was to create novel urate under-excretion animal models using pyrazinamide and to evaluate whether dihydropyridine calcium channel blockers (CCBs) have uricosuric effects in vivo. Adult male ICR mice were treated with pyrazinamide, vehicle (dimethyl sulfoxide: DMSO), or tap water. Thirty minutes later, pyrazinamide-treated mice were given benzbromarone, losartan, nilvadipine, nitrendipine, nifedipine or azelnidipine. Six hours after the second administration, urine (by urinary bladder puncture) and plasma were collected to measure uric acid and creatinine levels, and fractional excretion of uric acid (FEUA) and creatinine clearance (Ccr) were calculated and evaluated...
March 8, 2018: Journal of Pharmacological Sciences
https://www.readbyqxmd.com/read/29619007/uric-acid-impairs-insulin-signaling-by-promoting-enpp1-binding-to-insulin-receptor-in-human-umbilical-vein-endothelial-cells
#2
Eliezer J Tassone, Antonio Cimellaro, Maria Perticone, Marta L Hribal, Angela Sciacqua, Francesco Andreozzi, Giorgio Sesti, Francesco Perticone
High levels of uric acid (UA) are associated with type-2 diabetes and cardiovascular disease. Recent pieces of evidence attributed to UA a causative role in the appearance of diabetes and vascular damage. However, the molecular mechanisms by which UA induces these alterations have not been completely elucidated so far. Among the mechanisms underlying insulin resistance, it was reported the role of a transmembrane glycoprotein, named either ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) or plasma cell antigen 1, which is able to inhibit the function of insulin receptor (IR ) and it is overexpressed in insulin-resistant subjects...
2018: Frontiers in Endocrinology
https://www.readbyqxmd.com/read/29531784/pharmacodynamic-and-pharmacokinetic-effects-and-safety-of-verinurad-in-combination-with-allopurinol-in-adults-with-gout-a-phase-iia-open-label-study
#3
Roy Fleischmann, Peter Winkle, Jeffrey N Miner, Xiaohong Yan, Liz Hicks, Shakti Valdez, Jesse Hall, Sha Liu, Zancong Shen, Michael Gillen, Martha Hernandez-Illas
Objectives: Verinurad (RDEA3170) is a high affinity, selective uric acid transporter (URAT1) inhibitor indevelopment for treating gout and asymptomatic hyperuricaemia. This phase IIa study evaluated the pharmacodynamics, pharmacokinetics and safety of verinurad combined with allopurinol versus allopurinol alone in adults with gout. Methods: Forty-one subjects were randomised into two cohorts of verinurad (2.5-20 mg) plus allopurinol (300 mg once daily) versus allopurinol 300 mg once daily, 600 mg once daily or 300 mg twice daily alone...
2018: RMD Open
https://www.readbyqxmd.com/read/29490297/hypouricemic-and-nephroprotective-effects-of-an-active-fraction-from-polyrhachis-vicina-roger-on-potassium-oxonate-induced-hyperuricemia-in-rats
#4
Qibiao Su, Hua Su, Zhihuan Nong, Dongmei Li, Laiyou Wang, Shifeng Chu, Lizhen Liao, Jie Zhao, Xianbiao Zeng, Qikang Ya, Fei He, Wenjie Lu, Baowei Wei, Guining Wei, Naihong Chen
BACKGROUND/AIMS: The objective of this study is to evaluate the hypouricemic and nephroprotective effects of an active fraction from Polyrhachis vicina Roger (AFPR) in potassium oxonate-induced hyperuricemic rats. METHODS: Hyperuricemia was induced by potassium oxonate in male rats. AFPR was orally administered to hyperuricemic rats for 12 consecutive weeks. Serum, liver and kidney samples were collected for effects and mechanism analysis. The levels of serum uric acid (SUA) were measured by the phosphotungstic acid method, xanthine oxidase (XOD) activity in the hepatic and serum samples were measured by ultraviolet spectrophotometry, serum levels of interleukin-1 (IL-1β), interleukin-1 (IL-6) and tumor necrosis factor-α (TNF-α) were measured by ELISA, the levels of serum creatinine (SCr), blood urea nitrogen (BUN), super oxide dismutase (SOD) and malondialdehyde (MDA) in serum were determined by colorimetric method...
February 22, 2018: Kidney & Blood Pressure Research
https://www.readbyqxmd.com/read/29486147/urat1-and-glut9-mutations-in-spanish-patients-with-renal-hypouricemia
#5
Felix Claverie-Martin, Jorge Trujillo-Suarez, Hilaria Gonzalez-Acosta, Cristina Aparicio, Maria L Justa Roldan, Blanka Stiburkova, Kimiyoshi Ichida, Maria A Martín-Gomez, Maria Herrero Goñi, Marta Carrasco Hidalgo-Barquero, Victoria Iñigo, Ricardo Enriquez, Elizabeth Cordoba-Lanus, Victor M Garcia-Nieto
BACKGROUND: Renal hypouricemia (RHUC), a rare inherited disorder characterized by impaired uric acid (UA) reabsorption in the proximal tubule, is caused by mutations in SLC22A12 or SLC2A9. Most mutations have been identified in Japanese patients, and only a few have been detected in Europeans. METHODS: We report clinical, biochemical and genetics findings of fourteen Spanish patients, six Caucasians and eight of Roma ethnia, diagnosed with idiopathic RHUC. Two of the patients presented exercise-induced acute renal failure and another one had several episodes of nephrolithiasis and four of them had progressive deterioration of renal function, while the rest were asymptomatic...
February 24, 2018: Clinica Chimica Acta; International Journal of Clinical Chemistry
https://www.readbyqxmd.com/read/29422889/cordycepin-a-characteristic-bioactive-constituent-in-cordyceps-militaris-ameliorates-hyperuricemia-through-urat1-in-hyperuricemic-mice
#6
Tianqiao Yong, Shaodan Chen, Yizhen Xie, Diling Chen, Jiyan Su, Ou Shuai, Chunwei Jiao, Dan Zuo
Recently, we've reported the anti-hyperuricemic effects of Cordyceps militaris. As a characteristic compound of C. militaris, we hypothesized that cordycepin may play a role in preventing hyperurecimia. Remarkably, cordycepin produced important anti-hyperuricemic actions, decreasing SUA (serum uric acid) to 216, 210, and 203 μmol/L (P < 0.01) at 15, 30, and 60 mg/kg in comparison of hyperuricemic control (337 μmol/L), closing to normal control (202 μmol/L). Elisa, RT-PCR and western blot analysis demonstrated that the actions may be attributed to its downregulation of uric acid transporter 1 (URAT1) in kidney...
2018: Frontiers in Microbiology
https://www.readbyqxmd.com/read/29393127/uric-acid-renal-lithiasis-new-concepts
#7
Fabiola Pazos Pérez
BACKGROUND: Uric acid (UA) stones are responsible for 5-10% of the formation of all kidney stones. Recently, an association between UA stones and insulin resistance, diabetes mellitus, and obesity has been demonstrated and so the incidence has increased. The development of UA stones is dependent on several risk factors, including genetic predisposition, geographical location, dietary indiscretion, and various metabolic characteristics. SUMMARY: UA nephrolithiasis can arise from diverse etiologies, all with distinct underlying defects converging to one or more of 3 defects of hyperuricosuria, acidic urine pH, and low urinary volume...
2018: Contributions to Nephrology
https://www.readbyqxmd.com/read/29393121/time-to-target-uric-acid-to-retard-chronic-kidney-disease-progression
#8
Shunya Uchida, Takanori Kumagai, Wen Xiu Chang, Yoshifuru Tamura, Shigeru Shibata
Uric acid (UA) remains a risk factor for the progression of chronic kidney disease (CKD). Most observational studies showed a slight elevation in the serum UA level and this independently predicts the incidence and development of CKD. The recent meta-analysis, however, did not reach the conclusion that urate-lowering therapy with allopurinol retards the progression of CKD. The target level of serum UA if treated is another issue of debate. Our recent analysis by propensity score analysis has shown that the serum UA should be targeted below 6...
2018: Contributions to Nephrology
https://www.readbyqxmd.com/read/29393102/renal-handling-of-uric-acid
#9
Jorge Andrade Sierra, Milagros M Flores Fonseca
Hyperuricemia occurs in 21.4% of the adult population and is associated with several conditions that increase oxidative stress and contributes to the pathogenesis of inflammatory mechanisms for the development and progression of diseases. Serum blood or urine samples of uric acid levels were used to mainly identify clinical problems, depending on the uric acid pathway alterations, which include synthesis, reabsorption or its excretion. Several proteins that act particularly as transporters (URAT1, GLUT9, 1-NPT1, 1-NPT4, OAT4, 9-MCT9, hUAT1, etc...
2018: Contributions to Nephrology
https://www.readbyqxmd.com/read/29382075/systematic-structure-activity-relationship-sar-exploration-of-diarylmethane-backbone-and-discovery-of-a-highly-potent-novel-uric-acid-transporter-1-urat1-inhibitor
#10
Wenqing Cai, Jingwei Wu, Wei Liu, Yafei Xie, Yuqiang Liu, Shuo Zhang, Weiren Xu, Lida Tang, Jianwu Wang, Guilong Zhao
In order to systematically explore and better understand the structure-activity relationship (SAR) of a diarylmethane backbone in the design of potent uric acid transporter 1 (URAT1) inhibitors, 33 compounds (1a-1x and 1ha-1hi) were designed and synthesized, and their in vitro URAT1 inhibitory activities (IC50) were determined. The three-round systematic SAR exploration led to the discovery of a highly potent novel URAT1 inhibitor, 1h, which was 200- and 8-fold more potent than parent lesinurad and benzbromarone, respectively (IC50 = 0...
January 27, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29309257/the-slc22-transporter-family-a-paradigm-for-the-impact-of-drug-transporters-on-metabolic-pathways-signaling-and-disease
#11
Sanjay K Nigam
The SLC22 transporter family consists of more than two dozen members, which are expressed in the kidney, the liver, and other tissues. Evolutionary analysis indicates that SLC22 transporters fall into at least six subfamilies: OAT (organic anion transporter), OAT-like, OAT-related, OCT (organic cation transporter), OCTN (organic cation/carnitine transporter), and OCT/OCTN-related. Some-including OAT1 [SLC22A6 or NKT (novel kidney transporter)] and OAT3 (SLC22A8), as well as OCT1 (SLC22A1) and OCT2 (SLC22A2)-are widely studied drug transporters...
January 6, 2018: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/29246027/recent-advances-on-uric-acid-transporters
#12
REVIEW
Liuqing Xu, Yingfeng Shi, Shougang Zhuang, Na Liu
Uric acid is the product of purine metabolism and its increased levels result in hyperuricemia. A number of epidemiological reports link hyperuricemia with multiple disorders, such as kidney diseases, cardiovascular diseases and diabetes. Recent studies also showed that expression and functional changes of urate transporters are associated with hyperuricemia. Uric acid transporters are divided into two categories: urate reabsorption transporters, including urate anion transporter 1 (URAT1), organic anion transporter 4 (OAT4) and glucose transporter 9 (GLUT9), and urate excretion transporetrs, including OAT1, OAT3, urate transporter (UAT), multidrug resistance protein 4 (MRP4/ABCC4), ABCG-2 and sodium-dependent phosphate transport protein...
November 21, 2017: Oncotarget
https://www.readbyqxmd.com/read/29233733/effect-and-mechanism-of-dioscin-from-dioscorea-spongiosa-on-uric-acid-excretion-in-animal-model-of-hyperuricemia
#13
Yi Zhang, Lijun Jin, Jinchang Liu, Wei Wang, Haiyang Yu, Jian Li, Qian Chen, Tao Wang
ETHNOPHARMACOLOGY RELEVANCE: Dioscin, a spirostane glycoside, the rhizoma of Dioscorea septemloba (Diocoreacea) is used for diuresis, rheumatism, and joints pain. Given the poor solubility and stability of Dioscin, we proposed a hypothesis that Dioscin's metabolite(s) are the active substance(s) in vivo to contribute to the reducing effects on serum uric acid levels. AIM OF THE STUDY: The aim of this study is to identify the active metabolite(s) of Dioscin in vivo and to explore the mechanism of its antihyperuricemic activity...
March 25, 2018: Journal of Ethnopharmacology
https://www.readbyqxmd.com/read/29145399/point-mutation-in-d8c-domain-of-tamm-horsfall-protein-uromodulin-in-transgenic-mice-causes-progressive-renal-damage-and-hyperuricemia
#14
Lijie Ma, Yan Liu, Nichole K Landry, Tarek M El-Achkar, John C Lieske, Xue-Ru Wu
Hereditary mutations in Tamm-Horsfall protein (THP/uromodulin) gene cause autosomal dominant kidney diseases characterized by juvenile-onset hyperuricemia, gout and progressive kidney failure, although the disease pathogenesis remains unclear. Here we show that targeted expression in transgenic mice of a mutation within the domain of 8 cysteines of THP in kidneys' thick ascending limb (TAL) caused unfolded protein response in younger (1-month old) mice and apoptosis in older (12-month old) mice. While the young mice had urine concentration defects and polyuria, such defects progressively reversed in the older mice to marked oliguria, highly concentrated urine, fibrotic kidneys and reduced creatinine clearance...
2017: PloS One
https://www.readbyqxmd.com/read/29126251/evidence-for-a-role-of-pdz-domain-containing-proteins-to-mediate-hypophosphatemia-in-calcium-stone-formers
#15
Kristin J Bergsland, Fredric L Coe, Joan H Parks, John R Asplin, Elaine M Worcester
Background: Hypophosphatemia (HYP) is common among calcium stone formers (SFs) and in rare cases is associated with mutations in sodium-phosphate cotransporters or in Na+/H+ exchanger regulatory factor 1 (NHERF1), but the majority of cases are unexplained. We hypothesized that reduced sodium-phosphate cotransporter activity mediated via NHERF1 or a similar PDZ domain-containing protein, causes HYP. If so, other transport activities controlled by NHERF1, such as NHE3 and URAT1, might be reduced in HYP...
November 6, 2017: Nephrology, Dialysis, Transplantation
https://www.readbyqxmd.com/read/29103339/lesinurad-for-the-treatment-of-hyperuricaemia-in-people-with-gout
#16
Philip C Robinson, Nicola Dalbeth
Gout is a common form of inflammatory arthritis caused by deposition of monosodium urate crystals. The central strategy for effective long-term management of gout is serum urate lowering. Current urate-lowering drugs include both xanthine oxidase inhibitors and uricosuric agents. Lesinurad is a URAT1 inhibitor that selectively inhibits urate rebsorption at the proximal renal tubule. Lesinurad 200mg daily in combination with a xanthine oxidase is approved for urate-lowering therapy in patients with gout. Areas covered: The published literature was searched using Pubmed and additional information was obtained from publically available regulatory documents...
December 2017: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/29091862/the-anti-hyperuricemic-effect-of-epigallocatechin-3-gallate-egcg-on-hyperuricemic-mice
#17
Chuang Zhu, Yan Xu, Zeng-Hui Liu, Xiao-Chun Wan, Da-Xiang Li, Ling-Ling Tai
Epigallocatechin-3-gallate (EGCG), a major constituent of green tea catechin, has been used for antioxidant. This study aimed to evaluate the antihyperuricemic activity of EGCG on hyperuricemic mice. We demonstrated that serum uric acid (UA) level was decreased significantly with dose-dependence by EGCG treated with 10, 20, and 50mg/kg. Compared with the model, data on blood urea nitrogen (BUN) supported that there was significance with high dose of EGCG (50mg/kg). Levels of serum creatinine (Cr) in each EGCG-treated group were decreased but not significant; the activities of hepatic xanthine oxidase (XOD) and adenosine deaminase (ADA) in high dose groups' EGCG were notably lower than those of model group...
January 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29057475/erding-formula-in-hyperuricaemia-treatment-unfolding-traditional-chinese-herbal-compatibility-using-modern-pharmaceutical-approaches
#18
Jieyu Zuo, Hongming He, Zhengyun Zuo, Nádia Bou-Chacra, Raimar Löbenberg
OBJECTIVES: Traditional Chinese herbal formulas are difficult to be understood because of complex compositions and specific therapeutic principles. To better understand herbal compatibility in Traditional Chinese medicine (TCM), this study was conducted to investigate the effects of a Chinese pharmacopoeia-listed formula, Erding Formula (EF) and its constituent herbs for a new indication, hyperuricaemia. METHODS: A hypoxanthine and potassium oxonate-induced hyperuricemic mouse model, a xylene-induced inflammatory mouse model and an acetic acid-induced pain model were used to test the effects of EF and its constituent herbs...
January 2018: Journal of Pharmacy and Pharmacology
https://www.readbyqxmd.com/read/29035321/a-novel-multi-epitope-vaccine-based-on-urate-transporter-1-alleviates-streptozotocin-induced-diabetes-by-producing-anti-urat1-antibody-and-an-immunomodulatory-effect-in-c57bl-6j-mice
#19
Yanjie Ma, Huimin Cao, Zhixin Li, Jinzhi Fang, Xiaomin Wei, Peng Cheng, Rui Jiao, Xiaoran Liu, Ya Li, Yun Xing, Jiali Tang, Liang Jin, Taiming Li
Hyperuricemia (HUA) is related to diabetes. Uric acid-induced inflammation and oxidative stress are risk factors for diabetes and its complications. Human urate transporter 1 (URAT1) regulates the renal tubular reabsorption of uric acid. IA-2(5)-P2-1, a potent immunogenic carrier designed by our laboratory, can induce high-titer specific antibodies when it carries a B cell epitope, such as B cell epitopes of DPP4 (Dipeptidyl peptidase-4), xanthine oxidase. In this report, we describe a novel multi-epitope vaccine composing a peptide of URAT1, an anti-diabetic B epitope of insulinoma antigen-2(IA-2) and a Th2 epitope (P2:IPALDSLTPANED) of P277 peptide in human heat shock protein 60 (HSP60)...
October 16, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28979780/lesinurad-what-the-nephrologist-should-know
#20
Maria Dolores Sanchez-Niño, Binbin Zheng-Lin, Lara Valiño-Rivas, Ana Belen Sanz, Adrian Mario Ramos, Jose Luño, Marian Goicoechea, Alberto Ortiz
Lesinurad is an oral inhibitor of the monocarboxylic/urate transporter URAT1 encoded by the SLC22A12 gene. Market authorization was granted in February 2016 in Europe and December 2015 in the USA. As a potentially nephrotoxic uricosuric drug acting on the kidney, nephrologists should become familiar with its indications and safety profile. The approved indication is treatment of gout in combination with a xanthine oxidase (XO) inhibitor in adult patients who have not achieved target serum uric acid levels with an XO inhibitor alone...
October 2017: Clinical Kidney Journal
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