| 傅安妮,张雷,闫子怡,等.南极磷虾肽改善高尿酸血症机制研究[J].中国海洋药物,2021,40(4):9-17. |
| 南极磷虾肽改善高尿酸血症机制研究 |
| The Antihyperuricemic Mechanism of Peptides from Antarctic krill (Euphausia superba) |
| 投稿时间：2020-10-23 修订日期：2020-11-25 |
| DOI： |
| 中文关键词: 南极磷虾肽 高尿酸血症 黄嘌呤氧化酶 尿酸转运体 |
| English Keywords:Antarctic krill (Euphausia superba) hyperuricemia Xanthine oxidase (XOD) uric acid transporter |
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| 中文摘要: |
| 目的 探究南极磷虾肽(AKP)对于高尿酸血症模型小鼠的降尿酸功效及其作用机制。方法 采用HPLC法体外筛选出具尿酸合成关键限速酶--黄嘌呤氧化酶(Xanthine oxidase, XOD)抑制活性的AKP,体内动物实验验证AKP的降尿酸活性。雄性SPF级Balb/c小鼠采用高嘌呤饲料(25%酵母浸粉)喂养联合腹腔注射尿酸酶抑制剂(氧嗪酸钾,200 mg.kg-1.BW-1)建立高尿酸血症小鼠模型,造模21天后进行AKP干预。小鼠随机分为正常对照组(生理盐水),模型对照组(生理盐水)、阳性药组(非布司他)、AKP低剂量组(450 mg.kg-1.BW-1),AKP高剂量组(900 mg.kg-1.BW-1),干预30天后检测血清尿酸含量(Uric acid, UA),肝脏尿酸合成关键酶酶活,肾脏及肠道尿酸转运蛋白mRNA的转录水平及形态学改变。结果 AKP体外XOD抑制率可达24.4%。动物实验验证表明AKP可显著降低高尿酸模型小鼠的UA,作用机制为通过抑制肝脏尿酸合成关键酶XOD及腺苷脱氨酶(Adenosine Deaminase, ADA)酶活,从而抑制肝脏尿酸生成；上调肾脏及肠道尿酸分泌转运体三磷酸腺苷结合盒转运蛋白(ATP binding cassette superfamily G member 2, ABCG2)、有机阴离子转运体(organic anion transporter 1, OAT1)转录水平,并抑制尿酸重吸收转运体葡萄糖转运体9(glucose transporter 9, GLUT9)、尿酸转运体1(urate transporter 1, URAT1)转录水平,从而促进肾脏及肠道尿酸排泄。AKP可显著降低血清尿素氮(Blood urea nitrogen, BUN)含量,肾脏及肠道切片观察结果进一步表明,AKP可以显著改善高尿酸血症造成的肾脏及肠道损伤,维护肾脏及肠道尿酸排泄功能。结论 AKP可通过抑制肝脏尿酸生成,促进肾脏及肠道尿酸排泄,维护肾脏及肠道形态及功能,从而改善高尿酸血症。 |
| English Summary: |
| Objective To explore the anti-hyperuricemic effect and the mechanism of peptides from Antarctic krill (Euphausia superba) on hyperuricemic mice. Methods The AKP which presented the key rate-limiting enzyme of liver uric acid synthesis--Xanthine oxidase (XOD) was screen out by HPLC method, and then the anti-hyperuricemic activity of AKP was verified in vivo. Male Balb/c mice were fed with high-purine feed (25% yeast extract) combined with intraperitoneal injection of uricase inhibitor (potassium oxazine, 200 mg.kg-1.BW-1) to establish hyperuricemia mouse model, and the AKP gavage was performed after the model was established about 21 days. Then they were randomly assigned into five groups, including normal control group (normal saline), model control group (normal saline), positive drug group (febuxostat), Antarctic krill peptide low-dose group (450 mg.kg-1.BW-1) and Antarctic krill peptide high-dose group (900 mg.kg-1.BW-1). After 30 days treatment, the serum uric acid content (Uric acid, UA), the key enzyme activity of uric acid synthesis in the liver, the morphological changes and the mRNA expressions of uric acid transporter in kidney and intestine tissue were assayed. Results The XOD inhibition rate of AKP in vitro was 24.4%. AKP could significantly reduce UA on hyperuricemic mice by inhibiting the production of uric acid while promoting uric acid excretion. AKP significantly inhibited the XOD and adenosine deaminase (ADA) activity which were key enzymes of liver uric acid synthesis; and up-regulated the renal and intestinal uric acid secretion transporter adenosine triphosphate binding cassette superfamily G member 2 (ABCG2 ), organic anion transporter 1(OAT1) expression; and inhibited the expression of uric acid reabsorption transporter glucose transporter 9 ( GLUT9), urate transporter 1 (URAT1). AKP could significantly reduce blood urea nitrogen (BUN) content. The histological analysis of kidney and intestine further shows that AKP can significantly improve kidney and intestinal damage caused by hyperuricemia, and maintain kidney and intestinal uric acid excretion function. Conclusion AKP could improve hyperuricemia by inhibiting the production of uric acid in the liver, promoting the excretion of uric acid in the kidney and intestine, and maintaining the shape and function of the kidney and intestine. |
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