台灣土肉桂葉精油與其活性成分枷羅木醇及肉桂醛對於potassium oxonate和uric acid誘發高血尿酸小鼠血糖及血壓調控因子之影響

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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於potassium oxonate和uric acid诱发高血尿酸小鼠血糖及血压调控因子之影响

The effect of the leaf essential oil of Cinnamomum osmophloeum Kanehira and its active ingredients linalool and cinnamaldehyde on factors affecting glucose and blood pressure homeostasis in potassium oxonate and uric acid induced hyperuricemic mice.

余家莹 , 硕士　　导师：刘承慈　　

繁体中文

台湾土肉桂叶精油；枷罗木醇；肉桂醛；尿酸；胰岛素阻抗；高血压； Cinnamomum osmophloeum Kanehira ； linalool ； cinnamaldehyde ； uric acid ； insulin resistance ； hypertension

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摘要 │ 参考文献 (193) │ 国际计量

摘要〈TOP〉

高血尿酸与第 2 型糖尿病及心血管疾病发展有关,但传统的降尿酸药物之副作用限缩了其临床使用,故需积极寻找替代疗法。已知台湾土肉桂叶精油 (TC) 及其活性成分枷罗木醇 (linalool, Lin) 及肉桂醛(cinnamaldehyde, Cin) 能抑制 xanthine oxidase 活性,且有抗发炎效果。本研究利用十周龄雄性 C57BL/6 小鼠随机分为十组,其中一组给予一般饮食,其余九组给予含有 2% potassium oxonate 及 3% uric acid 之高尿酸饮食,於开始实验後第四十二天以隔日管喂一次的方式给予试剂,共灌食八次。一般饮食组及其中一组高尿酸饮食组灌食载剂玉米油 (2 ml/kg BW),其余八组高尿酸饮食组则分别灌食 TC (13 mg/kg BW)、Lin 合并 Cin (Lin:5.2 mg/kg BW、Cin:0.9 mg/kgBW)、低剂量 Lin (2.6 mg/kg BW)、高剂量 Lin (5.2 mg/kg BW)、低剂量 Cin (0.45 mg/kgBW)、高剂量 Cin (0.9 mg/kg BW)、allopurinol (5 mg/kgBW)、colchicine (1.5 mg/kg BW)。於第六次灌食後执行口服葡萄糖耐受试验及胰岛素耐受试验,在实验开始後第五十六天的早上眼窝采血,备用於血尿酸浓度分析,并於灌食後禁食十五小时再以二氧化碳窒息牺牲,收集血液,备用於尿酸、fructosamime、IL-1β、CXCL1、ICAM、C-peptide、nitrate/nitrite 浓度分析,并收集组织/脏器,备用於nitrate/nitrite、IL-1β、TNF-α 含量分析、caspase-1 活性分析、西方墨点分析及/或组织学观察。结果显示,给予高尿酸饲料或灌食土肉桂精油成分後对於小鼠体重并无显着影响。与控制组相较,此模式显着提高饱食状态下血尿酸浓度,且介入 TC 可显着降低其浓度,但无论是单独或合并给予 Lin、Cin 虽有降低尿酸值之趋势,但不具统计学意义。在血糖调控方面,此模式虽未影响葡萄糖耐受性及周边 fructosamine 浓度,但显着增加血清中 C-peptide 浓度,且经过葡萄糖负荷两小时,血清中 C-peptide 浓度也有增加之趋势,显示此模式虽然尚未影响血糖值及胰岛素分泌能力,但可能有胰岛素阻抗之现象以致需分泌较多胰岛素来维持正常血糖;而介入 TC、单独或合并给予 Lin 或 Cin 均可在不影响血糖的情况下显着降低高尿酸所导致之 C-peptide 升高,显示精油及其成分具有改善胰岛素阻抗之效果,其机制可部分归因於逆转高血尿酸所造成之脂肪组织中 TLR2、MyD88、ASC、caspase-1 p20 的蛋白质表现量增加及 IL-1β 含量增加,及逆转骨骼肌中 nitrate/nitrite 含量减少的情况。在血压及血管内皮功能方面,与控制组相较,此模式造成血管内皮中 eNOS 蛋白质表现量减少,并伴随周边血中 nitrate/nitrite 浓度显着下降,这可能造成血管内皮功能不良,进而导致血压调控异常,而无论是介入 TC、IX合并或单独给予 Lin 及 Cin 均显着提升周边血中 nitrate/nitrite 浓度,并伴随回复血管内皮 eNOS 蛋白质表现量。综合以上结果,TC 及其活性成分Lin 及 Cin 具有减缓高血尿酸所造成之脂肪组织发炎反应活化,并有助於回复骨骼肌及内皮细胞释出 NO,进而改善高尿酸所导致之血糖调控不佳及血压异常。

并列摘要〈TOP〉

Recent studies suggest that hyperuricemia is an independent risk factor for type 2 diabetes mellitus and cardiovascular disease. However, the use of urate-lowering drugs is usually limited by the adverse effects. Hence, there is a need for alternative/complamentary treatments. Previous studies found the leaf essential oil of Cinnamomum osmophloeum Kanehira (TC) and its active ingredients linalool (Lin) and cinnamaldehyde (Cin) have inhibitory effect on xanthine oxidase and possess anti-inflammatory activity. In the present study, male C57BL/6 mice were randomly assigned to ten groups, one of which was given normal diet, and the others were given hyperuricemia-inducing (HU) diet containing 2% potassium oxonate and 3% uric acid and treated for 56 days. On the 42nd day, mice receiving HU diet were gavaged with vehicle (corn oil, 2 ml/kg BW), TC (13 mg/kg BW), Lin (5.2 mg/kg BW) plus Cin (0.9 mg/kg BW), Lin (2.6 or 5.2 mg/kg BW), Cin (0.4 or 0.9mg/kg BW), allopurinol (5 mg/kg BW) or colchicine (1.5 mg/kg BW) every other day until day 56. Mice receiving normal diet were gavaged with vehicle. Oral glucose tolerance test and insulin tolerance test were conducted on the 53th and 54th day, respectively. On the 56th day, blood samples were collected from orbital sinus and used for the determination of serum uric acid concentration. Subsequently, mice were starved overnight before sacrificed with CO2 which was followed by the collection of blood and tissues/organs for analysis. It was found that body weight of the animals was not affected by either the treatment with HU diet or the intervention with TC, Cin, or Lin. Compared with the normal diet-fed mice, HU diet-fed mice showed significantly elevated level of serum uric acid at fed satus but can be reversed by the treatment with TC. Although HU diet did not affect fasting peripheral fructosamine concentration or glucose tolerance, fasting serum C-peptide concentration was found to be significantly increased thus suggest insulin resistance may occur in mice receiving HU diet. In addition, the treatment with TC, Cin, and Lin reversed elevated fasting C-peptide level in mice receiving HU diet without affecting glucose tolerance of these animals, suggesting improved insulin-sensitivity by these agents. The protective effect of these agents is attributable to not only the reduced IL-1β content in  epididymal adipose tissue which was associated with decreased expression of TLR2, MyD88, ASC and caspase-1 p20 in this tissue but also the reversed level of nitrate/nitrite in gastrocnemius muscle of these mice. The present study also found that fed mice with HU diet decreased eNOS expression in vascular endothelial along with significant reduction of serum nitrate/nitrite, suggesting endothelial dysfunction may occur in mice receiving HU diet. The treatment with TC, Cin, and Lin significantly reversed HU diet-induced reduction of serum nitrate/nitrite and showed to be associated with elevated expression of eNOS in vascular endothelial. In conclusion, the results of this study suggest that TC and its active ingredients Lin and Cin have preventive effects on HU diet-induced activation of inflammation in adipose tissue and help to restore physiological level of NO in skeletal muscle and in peripheral blood, thereby would benefit glycemic and blood pressure homeostasis under hyperurecemic condition.

参考文献 ( 193 ) 〈TOP〉

Akira, S., Uematsu, S. & Takeuchi, O. 2006. Pathogen recognition and innate immunity.Cell, 124(4), pp 783-801.
连结：
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连结：
Alvarez-Lario, B. & Macarron-Vicente, J. 2010. Uric acid and evolution. Rheumatology,49(11), pp 2010-2015
连结：
Ames, B. N., Cathcart, R., Schwiers, E. & Hochstein, P. 1981. Uric acid provides anantioxidant defense in humans against oxidant-and radical-caused aging and cancer: ahypothesis. Proceedings of the National Academy of Sciences, 78(11), pp 6858-6862.
连结：
Annemans, L., Spaepen, E., Gaskin, M., Bonnemaire, M., Malier, V., Gilbert, T. & Nuki, G.2008. Gout in the UK and Germany: prevalence, comorbidities and management in general practice 2000-2005. Annals of the rheumatic diseases, 67(7), pp 960-966.
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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（）。