Biotechnology Center, Suzhou Health College, China.
Arch Pharm Res. 2012 May;35(5):877-86. doi: 10.1007/s12272-012-0513-0. Epub 2012 May 29.
Vascular complications are the leading causes of morbidity and mortality in diabetes mellitus (DM). The RAGE (receptor for advanced glycation end products)-NADPH oxidase-NF-κB signal transduction pathway plays an important role in the development of oxidative stress-related vascular complications in DM. Ursolic acid (UA), a pentacyclic triterpenoid derived from plants, has been reported to have multiple pharmacological effects, including a potent antioxidant activity. This study aimed to investigate both the effect of UA on aortic injury in streptozotocin (STZ)-induced diabetic rats and the drug's mechanism of action. STZ-induced diabetic animals were randomized in one of the following 4 groups: no treatment (diabetic model group), aminoguanidine (AG, 100 mg/kg), high-dose UA (50 mg/kg), and low-dose UA (25 mg/kg). A non-diabetic control group was followed concurrently. After 8 weeks, the diabetic model rats exhibited: severe aortic arch injury, histologically elevated serum glucose, fructosamine, and glycosylated hemoglobin; and accumulation of advanced glycation end products (AGEs) in the arota. In addition, the levels of RAGE protein, transcription factor NF-κB p65, and the p22phox subunit of NADPH oxidase were increased, as were the serum levels of malondialdehyde and tumor necrosis factor-alpha (TNF-α; p < 0.01 vs control), suggesting that the mechanisms of oxidative stress contributed to vascular injury in the diabetic model group. In contrast, rats treated with UA (50 mg/kg) had a markedly less vascular injury and significantly improved biochemical parameters. Oxidative balance was also normalized in the UA-treated rats, and a marked reduction in the levels of RAGE and p22phox paralleled the reduced activation of NF-κB p65 and TNF-α (p < 0.01 and p < 0.05, respectively, vs diabetic model). These findings suggest that UA may suppress oxidative stress, thus blunting activation of the RAGE-NADPH oxidase-NF-κB signal transduction pathway, to ameliorate vascular injury in the STZ-induced DM rats.
血管并发症是糖尿病（DM）患者发病率和死亡率的主要原因。晚期糖基化终产物（RAGE）-NADPH 氧化酶-NF-κB 信号转导通路在 DM 中氧化应激相关血管并发症的发展中起重要作用。熊果酸（UA），一种从植物中提取的五环三萜，已被报道具有多种药理作用，包括强大的抗氧化活性。本研究旨在探讨 UA 对链脲佐菌素（STZ）诱导的糖尿病大鼠主动脉损伤的影响及其作用机制。STZ 诱导的糖尿病动物随机分为以下 4 组之一：无治疗（糖尿病模型组）、氨基胍（AG，100mg/kg）、高剂量 UA（50mg/kg）和低剂量 UA（25mg/kg）。同时设立非糖尿病对照组。8 周后，糖尿病模型大鼠出现：严重主动脉弓损伤，血清葡萄糖、果糖胺和糖化血红蛋白水平升高；主动脉中晚期糖基化终产物（AGEs）积聚。此外，RAGE 蛋白、转录因子 NF-κB p65 和 NADPH 氧化酶 p22phox 亚基的水平增加，血清丙二醛和肿瘤坏死因子-α（TNF-α）水平升高（与对照组相比，p<0.01），表明氧化应激机制导致糖尿病模型组血管损伤。相比之下，用 UA（50mg/kg）治疗的大鼠血管损伤明显减轻，生化参数显著改善。UA 治疗组的氧化平衡也恢复正常，RAGE 和 p22phox 水平显著降低，与 NF-κB p65 和 TNF-α的激活减少平行（分别与糖尿病模型组相比，p<0.01 和 p<0.05）。这些发现表明 UA 可能抑制氧化应激，从而减弱 RAGE-NADPH 氧化酶-NF-κB 信号转导通路的激活，从而改善 STZ 诱导的糖尿病大鼠的血管损伤。
