台灣土肉桂葉精油與其活性成分枷羅木醇及肉桂醛對potassium oxonate和尿酸誘發高血尿酸小鼠之肝、腎保護作用探討

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台湾土肉桂叶精油与其活性成分枷罗木醇及肉桂醛对potassium oxonate和尿酸诱发高血尿酸小鼠之肝、肾保护作用探讨

The effect of the leaf essential oil of Cinnamomum osmophloeum Kanehira and its active ingredients linalool and cinnamaldehyde on liver and renal protection in hyperuricemia mice induced by potassium oxonate and uric acid

麦庭瑜 , 硕士　　导师：刘承慈　　

繁体中文

高尿酸血症； potassium oxonate ；尿酸；土肉桂叶精油；枷罗木醇；肉桂醛；尿酸转运蛋白； TLR2 ； TLR4 ； NLRP3 ；促发炎激素； hyperuricemia ； potassium oxonate ； uric acid ； Cinnamomum osmophloeum Kanehira ； linalool ； cinnamaldehyde ； uric acid transporter ； TLR2 ； TLR4 ； NLRP3 ； proinflammatory cytokine

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摘要 │ 参考文献 (188) │ 国际计量

摘要〈TOP〉

目前常见的高血尿酸动物模式之一是以含有potassium oxonate和尿酸之饮食所诱发，已知此模式会影响实验动物肾脏转运蛋白之表现量，但尚不清楚此模式是否影响肝、肾功能及诱发其发炎性反应，因此，本研究目的为观察此模式下是否对於肝、肾功能指标及其发炎性反应之影响，并进一步探讨此模式灌食枷罗木醇型土肉桂叶精油（TC）及其活性成分枷罗木醇（linalool, Lin）和肉桂醛（cinnamaldehyde, Cin）之作用，并与目前临床药物allopurinol和colchicine相比较。实验以雄性C57BL/6小鼠随机分为十组，其中九组喂食高尿酸饮食，其余一组则喂食一般饮食共56天，在开始诱发高血尿酸後第42天起，每隔一日分别灌食：载剂玉米油（2 ml/kgBW）、土肉桂叶精油（13 mg/kg BW）、枷罗木醇合并肉桂醛（5.2 mg/kg和0.9 mg/kg BW）、低剂量枷罗木醇（2.6 mg/kg BW）、高剂量枷罗木醇（5.2 mg/kg BW）、低剂量肉桂醛（0.45 mg/kg BW）、高剂量肉桂醛（0.9 mg/kg BW）、allopurinol（5 mg/kg BW）、colchicine（1.5 mg/kg BW），正常饮食之控制组则灌食载剂玉米油（2 ml/kgBW），共灌食八次，於最後一次灌食结束後，禁食12小时牺牲收集血液、肾脏与肝脏备用於分析。结果显示，在长期给予含2 %（w/w）potassium oxonate和3 %（w/w）尿酸之饮食的模式下，与正常饮食组小鼠相较，虽未显着影响小鼠肝功能指数ALT、AST，但造成肝脏中nitrate/nitrite含量增加并促进xanthine oxidase活性上升（P<0.05），且也提升小鼠血液BUN值及肾脏中nitrate/nitrite含量（P<0.05）。然而，未发现肝、肾中发炎激素IL-1β和TNF-α的含量或肾中TLR2/TLR4、NLRP3发炎相关讯号路径分子蛋白质表现量受到此模式的影响。另一方面，此模式可抑制肾脏尿酸转运蛋白OAT1 mRNA表现量（P<0.05），与灌食载剂组相较，TC可降低肝脏xanthine oxidase活性且TC及其活性成分Lin与Cin亦可降低肝指数AST，而allopurinol也有降低AST的效果（P<0.05），但colchicine则无。另外也发现Cin可降低高尿酸饮食下之BUN值（P<0.05），且colchicine也有降低BUN的效果（P<0.05），但allopurinol则无。TC及Lin和Cin不但降低肝、肾nitrate/nitrite含量，且也降低肝、肾中发炎激素IL-1β及/或TNF-α之含量，其改善这些数值的幅度与allopurinol及colchicine的效果相当，且与降低肾中TLR2、MYD88、MD2、NLRP3、ASC和caspase-1 p20蛋白质表现量及caspase-1活性有关。在肾脏尿酸转运蛋白表现量方面，Lin和Cin显着降低URAT1和增加OAT1、OAT3转运蛋白mRNA表现量，且显着降低URAT1和增加OAT3蛋白质表现量，显示此两种活性成分有助於尿酸排泄，但TC未影响这些尿酸转运蛋白之表现。总言之，利用此高尿酸饮食模式，本研究显示Lin与Cin提供抗发炎及促进血尿酸排除之作用，适用於预防高血尿酸相关肝、肾病症，而TC亦可用於防治高血尿酸相关之肝、肾发炎性损伤。

并列摘要〈TOP〉

One of the most common hyperuricemic animal models is induced by a diet containing potassium oxonate and uric acid. It is known that this model will affect the expression of urate transporter in kidney of the experimental animals, but it is not clear whether this model affects the function and inflammatory response of liver or kidney. The aim of the present study is to investigate the effects of this model and the intervention with Cinnamomum osmophloeum Kanehira (TC) and its active components, linalool (Lin) and cinnamaldehyde (Cin) on the function and inflammatory response of liver and kidney. Positive control was intervened with either allopurinol or colchicines. Male C57BL/6 mice were randomly assigned to ten groups, of which nine groups were fed the high uric acid (HU) diet containing 2% (w/w) potassium oxonate and 3% (w/w) uric acid, and the rest group was fed a general diet for 56 days. On the day when treated with HU diet for 42 days, mice were intervened with corn oil (2 ml/kgBW), TC (13 mg/kgBW), Lin (5.2 mg/kg) plus Cin 0.9 mg/kg BW), Lin (2.6 or 5.2 mg/kgBW), Cin (0.45 or 0.9 mg/kgBW), allopurinol (5 mg/kgBW) or colchicine (1.5 mg/kgBW) by gavage every other day until day 56. Subsequently, all mice were fasting overnight and then sacrificed by CO2. The result showed that the persistent treatment with the HU diet, compared with the normal diet, significantly increased the content of nitrate/nitrite and the activity of xanthine oxidase in the liver (P<0.05), although not significantly affecting the activity of ALT, AST in peripheral blood (P>0.05). Moreover, HU diet increased BUN value and nitrate/nitrite content in the kidney (P<0.05). However, the expression of IL-1β and TNF-α in the liver and kidney, or the expression of TLR2/TLR4 and NLRP3-related signaling pathways in the kidney were not affected by HU diet. On the other hand, HU diet inhibited the expression of uric acid transporter OAT1 mRNA (P<0.05). Compared with the corn oil group, TC reduced the activity of liver xanthine oxidase. TC and its active components Lin and Cin also reduced peripheral AST activity. Allopurinol reduced peripheral AST activity as well (P<0.05), but colchicine did not. It was found that Cin reversed HU diet induced elevation of BUN (P<0.05), colchicine but not allopurinol showed to be effective on reducing HU diet-induced BUN levels as well (P<0.05). Among mice received HU diet, compared with mice intervened with corn oil, TC, Lin and Cin not only reduced the content of nitrate/nitrite, but also the content of IL-1β and/or TNF-α in liver and kidney and to an extent similar to that by allopurinol and colchicines. This can be attributable to decreased expression of TLR2, MYD88, MD2, NLRP3, ASC and caspase-1 p20 protein and caspase-1 activity in kidney. In terms of uric acid transporter expression in the kidney, Lin and Cin significantly reduced the expression of URAT1 mRNA and protein, while significantly increased the expression of OAT1 and OAT3 mRNA and OAT3 protein, indicating the capability of both active ingredients of TC to promote uric acid excretion. Nevertheless, TC was not found to affect the expression of either mRNA or protein of these uric acid transporters. In conclusion, this study shows that in mice received HU diet, TC and its active components Lin and Cin possess protective effect on liver and kidney through anti-inflammatory effect. In addition, Lin and Cin are also protective through the uricosuric effect.

参考文献 ( 188 ) 〈TOP〉

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引用含有DOI的文献

DOI可强化引用精确性、增强学术圈连结，并给予使用者跨平台的良好使用经验，目前在全世界已有超过五千万个对象申请DOI。 如想对DOI的使用与概念有进一步了解，请参考 （ ） 。

DOI可强化引用精确性、增强学术圈连结，并给予使用者跨平台的良好使用经验，目前在全世界已有超过五千万个对象申请DOI。如想对DOI的使用与概念有进一步了解，请参考（）。