云南分心木提取物对小鼠高尿酸血症模型治疗作用研究

为探究云南分心木提取物对高尿酸血症(HUA)小鼠模型的治疗作用,以联合氧嗪酸钾及腺嘌呤灌胃给药复制高尿酸血症小鼠为模型,对云南分心木水提物、醇提物及两种去除无机元素提取物的治疗作用进行考察。经过14天连续给药后,检测血清尿酸(UA)、肌酐(Cr)、尿素氮(BUN)的含量、肝脏组织黄嘌呤氧化酶(XOD)的活力、肾脏组织中IL-1β和TNF-α的水平,观察肾组织病理结构变化,评价不同提取物对HUA小鼠模型的治疗作用。结果显示,与模型组相比,云南分心木4种样品不同程度的降低UA、BUN、Cr的含量,降低XOD的活性,下调IL-1β及TNF-α的水平,减轻病理结构变化,且醇提物的效果最为显著。表明云南分心木提取物,可通过调节肾功能、抑制XOD活性以及抗炎的作用,对HUA小鼠模型产生治疗作用。     

石花菜醇提物对小鼠高尿酸血症的拮抗效应

本实验主要探讨了不同剂量(0.3 g/kg、0.6 g/kg、1.0 g/kg)的石花菜醇提物对小鼠高尿酸血症的拮抗效应。采用氧嗪酸钾盐对小鼠进行急性高尿酸血症造模,测定小鼠血清中尿酸(UA)、肌酐(Cr)和尿素氮(BUN)水平,以及小鼠肝脏匀浆液中黄嘌呤氧化酶(XOD)和腺苷脱氨酶(ADA)活性,HE染色观察其肾脏组织病理学变化。结果表明,与空白组相比,模型组小鼠血清中尿酸、肌酐和尿素氮水平显著升高(P0.01),同时,XOD活性也得到显著升高(P0.01),ADA活性升高(P0.05)。与模型组相比,阳性对照组与各药物治疗组均能显著降低小鼠血清中尿酸、肌酐和尿素氮水平(P0.01),同时,阳性对照组与各药物治疗组XOD活性均显著降低(P0.01),而两组ADA活性则均无统计学差异。光镜下与模型组相比,阳性对照组和药物治疗组小鼠肾脏的肾小球损伤一定程度上恢复正常。总体而言,石花菜醇提物对小鼠高尿酸血症具有很大程度的缓解作用,其机制与体内抑制尿酸生成和促进尿酸排泄有关。     

海带褐藻多糖硫酸酯对腺嘌呤诱导的小鼠高尿酸血症的拮抗作用

本文探讨了海带褐藻多糖硫酸酯(fucoidan from Laminaria japonica,FL)对腺嘌呤诱导的小鼠高尿酸血症的拮抗作用。首先利用腺嘌呤灌胃法建立高尿酸血症动物模型,再以不同剂量(0.100、0.150、0.200 g/kg)的海带褐藻多糖硫酸酯治疗4周,最后对小鼠血清尿酸、肌酐、肝脏匀浆液中腺苷脱氨酶(ADA)和黄嘌呤氧化酶(XOD)的活性及小鼠肾脏组织病理学变化进行检测(HE染色)。结果表明,与空白组相比,腺嘌呤能极显著升高小鼠血清尿酸、肌酐水平、肝脏XOD及ADA活性(P0.01)。与模型组相比,海带褐藻多糖硫酸酯各剂量均能极显著降低小鼠血清尿酸、肌酐水平、肝脏XOD及ADA活性(P0.01)。光镜观察结果显示,与模型组相比,海带褐藻多糖硫酸酯治疗组小鼠的肾损伤有一定程度恢复。综上所述,海带褐藻多糖硫酸酯对腺嘌呤诱导的小鼠高尿酸血症有一定程度的缓解作用。     

L-阿拉伯糖对尿酸的调节作用

该文研究了L-阿拉伯糖对正常及高尿酸血症小鼠尿酸的调节作用。在正常小鼠、氧嗪酸钾和次黄嘌呤联合诱导的高尿酸血症小鼠以及氧嗪酸钾和尿酸联合诱导的高尿酸血症小鼠中,通过灌胃给予L-阿拉伯糖:收集尿液,测定尿酸排泄量;取血,测定血清中尿酸、总胆固醇、甘油三酯、血糖、肌酐、尿素氮等常规生化指标;处死小鼠后,取肝、肾、脾,称重,计算脏器指数;取小肠与肝脏,匀浆后测定黄嘌呤氧化酶活性。结果表明:L-阿拉伯糖对正常小鼠,可以增加尿酸排泄,但不能降低血尿酸水平;对氧嗪酸钾和次黄嘌呤联合诱导的高尿酸血症小鼠,对尿酸排泄没有影响,但能升高血尿酸水平;对氧嗪酸钾和尿酸联合诱导的高尿酸血症小鼠,对尿酸排泄及血尿酸水平都没有影响。该研究结果表明L-阿拉伯糖对正常血尿酸水平没有影响,但能升高特定条件下高尿酸血症小鼠的血尿酸水平。     

鹅肌肽对高尿酸血症大鼠的干预作用研究

目的：探讨鹅肌肽对高尿酸血症大鼠的作用及其机制。方法：选用雄性SD大鼠60只,随机分为6组：空白对照组（CON）、高尿酸血症组（HUA）、别嘌呤醇组［Allo：10 mg/（kg·d）］和鹅肌肽干预组［Ans 1 mg：1 mg/（kg·d）］;［Ans 10 mg：10 mg/（kg·d）］;［Ans 100 mg：100 mg/（kg·d）］,空白对照组喂养普通大鼠饲料,其他5组均喂养高尿酸血症模型饲料,进行相应物质的灌胃,实验周期为6周,实验结束后,收集大鼠24 h尿量,评价大鼠尿酸和肾功能指标,并进行肾脏组织学观察。结果：与CON组相比,HUA组血尿酸水平显著升高（P＜0.05）,血尿素氮、尿量及尿酸排泄指标均有显著性差异（P< 0.05）。与HUA组相比,鹅肌肽干预组中,Ans 10 mg和Ans 100 mg组的血尿酸水平降低（P< 0.05）,尿量及尿酸排泄指标有显著性差异（P< 0.05）,Ans 1 mg的胱抑素C和Ans 100 mg的血清腺苷脱氨酶显著降低（P< 0.05）。组织学分析显示,鹅肌肽各干预组大鼠管腔扩张和肾小管上皮细胞空泡变性明显改善,无纤维化,与空白对照组差异较小,能明显延缓高尿酸血症大鼠的肾脏损伤。结论：鹅肌肽能降低高尿酸血症大鼠尿酸水平,可能是通过促进肾脏尿酸排泄和保护肾功能来实现的。     

3,5,2',4'-四羟基查尔酮对小鼠尿酸及尿酸合成相关酶基因的影响

用氧嗪酸钾诱导高尿酸血症动物模型,对化合物3,5,2',4'-四羟基查尔酮(P40)的降尿酸作用及尿酸合成相关酶基因进行研究。用磷钨酸法测定小鼠血清尿酸水平,用RT-PCR测定脑组织中次黄嘌呤鸟嘌呤磷酸核糖转移酶(HGPRT)、肝脏中的磷酸核糖焦磷酸合成酶(PRPS)和磷酸核糖焦磷酸酰胺转移酶(PRPPAT)mRNA的表达水平。结果表明:灌胃给予高尿酸血症小鼠P40 2、4、8 mg/kg和阳性对照药别嘌醇1 mg/kg,共给药5次,每天2次,均显著降低血清尿酸水平(P0.05,0.01),具有显著的降尿酸作用;但对HGPRT、PRPS、PRPPAT的mRNA表达水平无明显影响。     

土茯苓对高尿酸症小鼠肾损伤的防治作用

目的：观察土茯苓对高尿酸症小鼠肾功及血清尿酸的影响。方法：将昆明种小鼠分为正常对照组、模型对照组、土茯苓治疗组、别嘌呤醇治疗组,造模成功后分别给予土茯苓、别嘌呤醇灌胃,7d后检测各组大鼠血中肌酐（Cr）,尿素氮（Bun）、尿酸（UA）及黄嘌呤氧化酶（XOD）。结果：治疗7d后,与模型组相比,土茯苓治疗组大鼠血肌酐、尿素氮、血UA、XOD明显降低（P〈0．05）。结论：土茯苓对高尿酸症小鼠肾功能有保护作用,对尿酸升高有明显的治疗作用。     

短乳杆菌DM9218对高果糖饮食诱导的 高尿酸血症的缓解作用及机制研究

摘要：目的 探讨短乳杆菌DM9218对高果糖饮食诱导的高尿酸血症的缓解作用及可能机制。方法 4~6周龄SPF级Balb/c雌鼠随机分为3组（每组15只）,分别为正常对照组（Control）、高果糖饮水组（HF）、高果糖饮水+益生菌干预组（Probiotic）。高果糖组和益生菌干预组每天给予15%（w/v）果糖水自由饮用;益生菌干预组在果糖饮用的同时每天以0.2 mL/只（1×109 CFU/kg）短乳杆菌DM9218灌胃,对照组和高果糖组予以0.2 mL/只的PBS灌胃处理。采用酶标仪比色法检测各组血清中血糖（Glu）、甘油三酯（TG）、总胆固醇（TC）、血尿酸（UA）水平;ELISA法检测小鼠肝组织匀浆上清液中内毒素（LPS）、干扰素α（IFN-α）、肌苷（Inosine）水平及黄嘌呤氧化酶（XOD）浓度、活性;Q-PCR法检测XOD mRNA的表达变化。结果 HF组Glu、TG、TC、UA水平均明显高于Control组（P<0.05,P<0.05,P<0.05,P<0.01）,Probiotic组血清UA水平显著低于HF组（P<0.01）;HF组肝脏LPS、IFN-α、Inosine水平及XOD浓度、活性显著高于Control组（P均<0.01）,Probiotic组与HF组相比LPS、IFN-α、Inosine水平及XOD浓度、活性有明显下降趋势,差异具有统计学意义（P<0.05,P<0.01,P<0.01,P<0.05,P<0.05）;HF组XOD mRNA的相对表达量显著高于Control组（P<0.01）,Probiotic组与HF组相比有下降趋势,差异具有统计学意义（P<0.01）。结论 短乳杆菌DM9128一方面可以改善肠屏障功能降低LPS水平,从而缓解XOD的表达及活性;另一方面经由“肝?肠循环”直接降解肌苷,从而影响血清UA的水平。     

肥胖对小鼠十二指肠 DMT1和 FPN1表达的影响

目的：观察肥胖对小鼠十二指肠二价金属离子转运体（divalent metal transporter 1,DMT1）mRNA、膜铁转运蛋白（ferroportin1,FPN1）mRNA及蛋白表达的变化,探讨肥胖影响铁吸收的机制。方法 C57BL／6J小鼠随机分为正常对照组和肥胖模型组,每组6只,通过喂养高脂饲料喂养建立肥胖模型,对照组采用普通饲料饲养,实验干预期14周。建模完成后,采用实时荧光定量PCR方法检测小鼠十二指肠DMT1、FPN1 mRNA 的表达,用Western blot检测小鼠十二指肠FPN1蛋白表达。结果与对照组小鼠相比,肥胖模型组小鼠十二指肠DMT1、FPN1 mRNA表达以及FPN1蛋白表达水平降低,差异具有统计学意义（ P ＜0.05）。结论肥胖会下调机体十二指肠DMT1、FPN1的表达,导致铁吸收不良,为进一步研究肥胖引起铁缺乏机制提供理论和实验依据。     

芹菜素-钐配合物的合成及其抗小鼠高尿酸血症研究北大核心CSCD

秉承中药配位化学理论,以具有一定抗炎、抗痛风活性的芹菜素(AP)为配体,以稀土金属钐(Ⅲ)离子为配位中心,设计合成芹菜素-钐配合物(AP-Sm),以期提高抗高尿酸血症活性。采用紫外(UV)、红外(IR)、氢核磁共振(1H NMR)、电导法、差热-热重分析(TG-DTA)等技术对配合物的化学结构进行表征。考察配合物对酵母浸粉联合氧嗪酸钾诱导的高尿酸血症小鼠模型中尿酸、黄嘌呤氧化酶及超氧阴离子水平的影响。结果表明,芹菜素与钐(Ⅲ)离子配位生成了配合物,配合物组成式为:Sm(C_(15)H_9O_5)_3. 2H_2O。芹菜素A环的5-OH和C环的4位C=O与钐(Ⅲ)离子形成了配合物,且芹菜素与钐(Ⅲ)离子的配位比为3。抗高尿酸血症活性研究发现,芹菜素-钐配合物对高尿酸血症小鼠黄嘌呤氧化酶的抑制作用、清除超氧阴离子能力、降低血清尿酸水平及促进尿酸排泄能力均优于芹菜素。综上说明芹菜素与钐(Ⅲ)离子配位后,所得配合物抗高尿酸血症活性增强。     

Hypouricemic Actions of Exopolysaccharide Produced by Cordyceps militaris in Potassium Oxonate-Induced Hyperuricemic Mice

The hypouricemic actions of exopolysaccharide produced by Cordyceps militaris (EPCM) in potassium oxonate-induced hyperuricemia in mice were examined. Hyperuricemic mice were administered intragastrically with EPCM (200, 400 and 800 mg/kg body weight) or allopurinol (5 mg/kg body weight) once daily. Serum uric acid, blood urea nitrogen and liver xanthine oxidase (XOD) activities of each treatment were measured after administration for 7 days. EPCM showed dose-dependent uric acid-lowering actions. EPCM at a dose of 400 mg/kg body weight and allopurinol showed the same effect in serum uric acid, blood urea nitrogen and liver XOD activities in hyperuricemic mice. An increase in liver XOD activities was observed in hyperuricemic mice due to administration of EPCM at a dose of 200 mg/kg body weight. EPCM at a dose of 800 mg/kg body weight did not show significant effects on serum uric acid and XOD activities. We conclude that EPCM has a hypouricemic effect caused by decreases in urate production and the inhibition of XOD activities in hyperuricemic mice, and this natural product exhibited more potential efficacy than allopurinol in renal protection.     

Comprehensive analysis of mechanism underlying hypouricemic effect of glucosyl hesperidin

Hyperuricemia is caused by hepatic overproduction of uric acid and/or underexcretion of urate from the kidneys and small intestine. Although increased intake of citrus fruits, a fructose-rich food, is associated with increased risk of gout in humans, hesperidin, a flavonoid naturally present in citrus fruits, reportedly reduces serum uric acid (SUA) levels by inhibiting xanthine oxidase (XOD) activity in rats. However, the effects of hesperidin on renal and intestinal urate excretion were previously unknown. In this study, we used glucosyl hesperidin (GH), which has greater bioavailability than hesperidin, to clarify comprehensive mechanisms underlying the hypouricemic effects of hesperidin in vivo. GH dose-dependently decreased SUA levels in mice with hyperuricemia induced by potassium oxonate and a fructose-rich diet, and inhibited XOD activity in the liver. GH decreased renal urate excretion without changes in kidney URAT1, ABCG2 or GLUT9 expressions, suggesting that reducing uric acid pool size by inhibiting XOD decreased renal urate excretion. We also found that GH had no effect on intestinal urate excretion or protein expression of ABCG2. Therefore, we concluded that GH exhibits a hypouricemic effect by inhibiting XOD activity in the liver without increasing renal or intestinal urate excretion. Of note, this is the first study to elucidate the effect of a flavonoid on intestinal urate excretion using a mice model, whose findings should prove useful in future food science research in the area of urate metabolism. Taking these findings together, GH may be useful for preventing hyperuricemia, especially in people with the overproduction type.     

Development of novel NLRP3-XOD dual inhibitors for the treatment of gout

Gout is a crystalline-related arthropathy caused by the deposition of monosodium urate (MSU). Acute gouty arthritis is the most common first symptom of gout. Studies have shown that NOD-like receptor protein 3 (NLRP3) inflammasome as pattern recognition receptors can be activated by uric acid crystallization, triggering immune inflammation and causing acute gouty arthritis symptoms. Currently, the treatment of gout mainly includes two basic methods: reducing uric acid and alleviating inflammation. In this paper, 22 novel benzoxazole and benzimidazole derivatives were synthesized from deoxybenzoin oxime derivatives. These compounds have good inhibitory effects on NLRP3 and XOD screened by our research group in the early stage. The inhibitory activities of XOD and NLRP3 and their derivatives were also screened. Notably, compound 9b is a multi-targeting inhibitor of NLRP3 and XOD with excellent potency in treating hyperuricemia and acute gouty arthritis.     

High uric acid directly inhibits insulin signalling and induces insulin resistance

Background and aim

Accumulating clinical evidence suggests that hyperuricemia is strongly associated with abnormal glucose metabolism and insulin resistance. However, how high uric acid (HUA) level causes insulin resistance remains unclear. We aimed to determine the direct role of HUA in insulin resistance in vitro and in vivo in mice.

Methods

An acute hyperuricemia mouse model was created by potassium oxonate treatment, and the impact of HUA level on insulin resistance was investigated by glucose tolerance test, insulin tolerance test and insulin signalling, including phosphorylation of insulin receptor substrate 1 (IRS1) and Akt. HepG2 cells were exposed to HUA treatment and N-acetylcysteine (NAC), reactive oxygen species scavenger; IRS1 and Akt phosphorylation was detected by Western blot analysis after insulin treatment.

Results

Hyperuricemic mice showed impaired glucose tolerance with insulin resistance. Hyperuricemia inhibited phospho-Akt (Ser473) response to insulin and increased phosphor-IRS1 (Ser307) in liver, muscle and fat tissues. HUA induced oxidative stress, and the antioxidant NAC blocked HUA-induced IRS1 activation and Akt inhibition in HepG2 cells.

Conclusion

This study supplies the first evidence of HUA directly inducing insulin resistance in vivo and in vitro. Increased uric acid level may inhibit IRS1 and Akt insulin signalling and induce insulin resistance. The reactive oxygen species pathway plays a key role in HUA-induced insulin resistance.     

Uric acid induces renal inflammation via activating tubular NF-κB signaling pathway

Inflammation is a pathologic feature of hyperuricemia in clinical settings. However, the underlying mechanism remains unknown. Here, infiltration of T cells and macrophages were significantly increased in hyperuricemia mice kidneys. This infiltration of inflammatory cells was accompanied by an up-regulation of TNF-α, MCP-1 and RANTES expression. Further, infiltration was largely located in tubular interstitial spaces, suggesting a role for tubular cells in hyperuricemia-induced inflammation. In cultured tubular epithelial cells (NRK-52E), uric acid, probably transported via urate transporter, induced TNF-α, MCP-1 and RANTES mRNA as well as RANTES protein expression. Culture media of NRK-52E cells incubated with uric acid showed a chemo-attractive ability to recruit macrophage. Moreover uric acid activated NF-κB signaling. The uric acid-induced up-regulation of RANTES was blocked by SN 50, a specific NF-κB inhibitor. Activation of NF-κB signaling was also observed in tubule of hyperuricemia mice. These results suggest that uric acid induces renal inflammation via activation of NF-κB signaling.     

Antihyperuricemia and antigouty arthritis effects of Persicaria capitata herba in mice

Background: Hyperuricemia (HUA) is an important risk factor for gout, renal dysfunction and cardiovascular diseases. The whole plant of Persicaria capitata (Buch.-Ham. ex D. Don) H. Gross, namely Persicaria capitata herba, is a well-known ethnic herb with potent therapeutic effects on urinary tract infections and urinary calculus, yet previous reports have only focused on its effect on urinary tract infections.Purpose: To evaluate the therapeutic potential of P. capitata herba against gout by investigating its antihyperuricemia and antigouty arthritis effects and possible mechanisms.Methods: The ethanol extract (EP) and water extract (WP) of P. capitata herba were prepared by extracting dried and ground whole plants of P. capitata with 75% ethanol and water, respectively, followed by removal of solvents and characterization by UHPLC-Q-TOF/MS. The antihyperuricemia and antigouty arthritis effects of the two extracts were evaluated in a potassium oxonate- and hypoxanthine-induced hyperuricemia mouse model and a monosodium urate crystal (MSUC)-induced acute gouty arthritis mouse model, respectively. The mechanisms were investigated by testing their effects on the expression of correlated proteins (by Western blot) and mRNAs (by RT–PCR).Results: UHPLC-HRMS fingerprinting and two chemical markers (i.e., quercetin and quercitrin) determination were used for the characterization of the WP and EP extracts. Both WP and EP extracts showed pronounced antihyperuricemia activities, with a remarkable decline in serum uric acid and a marked increase in urine uric acid in hyperuricemic mice. Unlike the clinical xanthine oxidase (XOD) inhibitor allopurinol, WP and EP did not show any distinct renal toxicities. The underlying antihyperuricemia mechanism involves the inhibition of the activity and expression of XOD and the downregulation of the mRNA and protein expression of glucose transporter 9 (GLUT9) and urate transporter 1 (URAT1). The extracts of P. capitata herba also demonstrated remarkable anti-inflammatory activity in MSUC-induced acute gouty arthritis mice. The mechanism might involve inhibitory effects on the expression of proinflammatory factors.Conclusions: The extracts of P. capitata herba possessed pronounced antihyperuricemia and antigouty arthritis effects and were, therefore, promising natural medicines for hyperuricemia-related disorders and gouty arthritis. The use of P. capitata herba for the treatment of urinary calculus may be, at least to some degree, related to its potential as an antihyperuricemia and antigouty arthritis drug.     

Sex hormone-regulated renal transport of perfluorooctanoic acid

The biological half-life (t1/2) of perfluorooctanoic acid (PFOA) in male rats is 70 times longer than that in female rats. The difference is mainly due to the difference in renal clearance (CL(R)), which was significantly reduced by probenecid, suggesting that PFOA is excreted by organic anion transporter(s). Castration of male rats caused a 14-fold increase in the CL(R) of PFOA, which made it comparable with that of female rats. The elevated PFOA CL(R) in castrated males was reduced by treating them with testosterone. Treatment of male rats with estradiol increased the CL(R) of PFOA. In female rats, ovariectomy caused a significant increase in CL(R) of PFOA, which was reduced by estradiol treatment. Treatments of female rats with testosterone reduced the CL(R) of PFOA as observed in castrated male rats. To identify the transporter molecules that are responsible for PFOA transport in rat kidney, renal mRNA levels of organic anion transporter 1 (OAT1), OAT2, OAT3, organic anion transporting polypeptide 1 (oatp1), oatp2 and kidney specific organic anion transporter (OAT-K) were determined in male and female rats under various hormonal states and compared with the CL(R) of PFOA. The level of OAT2 mRNA in male rats was only 13% that in female rats. Castration or estradiol treatment increased the level of OAT2 mRNA whereas treatment of castrated male rats with testosterone reduced it. In contrast to OAT2, mRNA levels of both oatp1 and OAT-K were significantly higher in male rats compared with female rats. Castration or estradiol treatment caused a reduction in the levels of mRNA of oatp1 and OAT-K in male rats. Ovariectomy of female rats significantly increased the level of OAT3 mRNA. Multiple regression analysis suggests that the change in the CL(R) of PFOA is, at least in part, due to altered expression of OAT2 and OAT3.     

OAT2 catalyses efflux of glutamate and uptake of orotic acid

OAT (organic anion transporter) 2 [human gene symbol SLC22A7 (SLC is solute carrier)] is a member of the SLC22 family of transport proteins. In the rat, the principal site of expression of OAT2 is the sinusoidal membrane domain of hepatocytes. The particular physiological function of OAT2 in liver has been unresolved so far. In the present paper, we have used the strategy of LC (liquid chromatography)-MS difference shading to search for specific and cross-species substrates of OAT2. Heterologous expression of human and rat OAT2 in HEK (human embryonic kidney)-293 cells stimulated accumulation of the zwitterion trigonelline; subsequently, orotic acid was identified as an excellent and specific substrate of OAT2 from the rat (clearance=106 μl·min?1·mg of protein?1) and human (46 μl·min?1·mg of protein?1). The force driving uptake of orotic acid was identified as glutamate antiport. Efficient transport of glutamate by OAT2 was directly demonstrated by uptake of [3H]glutamate. However, because of high intracellular glutamate, OAT2 operates as glutamate efflux transporter. Thus expression of OAT2 markedly increased the release of glutamate (measured by LC-MS) from cells, even without extracellular exchange substrate. Orotic acid strongly trans-stimulated efflux of glutamate. We thus propose that OAT2 physiologically functions as glutamate efflux transporter. OAT2 mRNA was detected, after laser capture microdissection of rat liver slices, equally in periportal and pericentral regions; previous reports of hepatic release of glutamate into blood can now be explained by OAT2 activity. A specific OAT2 inhibitor could, by lowering plasma glutamate and thus promoting brain-to-blood efflux of glutamate, alleviate glutamate exotoxicity in acute brain conditions.     

Discovery of novel curcumin derivatives targeting xanthine oxidase and urate transporter 1 as anti-hyperuricemic agents

A series of curcumin derivatives as potent dual inhibitors of xanthine oxidase (XOD) and urate transporter 1 (URAT1) was discovered as anti-hyperuricemic agents. These compounds proved efficient effects on anti-hyperuricemic activity and uricosuric activity in vivo. More importantly, some of them exhibited proved efficient effects on inhibiting XOD activity and suppressing uptake of uric acid via URAT1 in vitro. Especially, the treatment of 4d was demonstrated to improve uric acid over-production and under-excretion in oxonate-induced hyperuricemic mice through regulating XOD activity and URAT1 expression. Docking study was performed to elucidate the potent XOD inhibition of 4d. Compound 4d may serve as a tool compound for further design of anti-hyperuricemic drugs targeting both XOD and URAT1.     

Human Sodium Phosphate Transporter 4 (hNPT4/SLC17A3) as a Common Renal Secretory Pathway for Drugs and Urate

The evolutionary loss of hepatic urate oxidase (uricase) has resulted in humans with elevated serum uric acid (urate). Uricase loss may have been beneficial to early primate survival. However, an elevated serum urate has predisposed man to hyperuricemia, a metabolic disturbance leading to gout, hypertension, and various cardiovascular diseases. Human serum urate levels are largely determined by urate reabsorption and secretion in the kidney. Renal urate reabsorption is controlled via two proximal tubular urate transporters: apical URAT1 (SLC22A12) and basolateral URATv1/GLUT9 (SLC2A9). In contrast, the molecular mechanism(s) for renal urate secretion remain unknown. In this report, we demonstrate that an orphan transporter hNPT4 (human sodium phosphate transporter 4; SLC17A3) was a multispecific organic anion efflux transporter expressed in the kidneys and liver. hNPT4 was localized at the apical side of renal tubules and functioned as a voltage-driven urate transporter. Furthermore, loop diuretics, such as furosemide and bumetanide, substantially interacted with hNPT4. Thus, this protein is likely to act as a common secretion route for both drugs and may play an important role in diuretics-induced hyperuricemia. The in vivo role of hNPT4 was suggested by two hyperuricemia patients with missense mutations in SLC17A3. These mutated versions of hNPT4 exhibited reduced urate efflux when they were expressed in Xenopus oocytes. Our findings will complete a model of urate secretion in the renal tubular cell, where intracellular urate taken up via OAT1 and/or OAT3 from the blood exits from the cell into the lumen via hNPT4.