山茱萸环烯醚萜苷改善糖尿病诱导的雄性大鼠睾丸损伤：抑制晚期糖基化终末产物/晚期糖基化终末产物受体/p38丝裂原活化蛋白激酶信号通路的作用

Iridoid glycoside from Cornus officinalis ameliorated diabetes mellitus-induced testicular damage in male rats: Involvement of suppression of the AGEs/RAGE/p38 MAPK signaling pathway.

作者信息

Chen Yuping, Wu Yunhao, Gan Xiaoyang, Liu Kai, Lv Xing, Shen Hongsheng, Dai Guoying, Xu Huiqin

机构信息

Key Laboratory of efficacy and safety evaluation of traditional Chinese medicine in Jiangsu Province, Nanjing 210023, China; School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; Nursing department, Chemistry and Life Science College, Nanjing University Jinling College, Nanjing, Jiangsu 210089, China.

出版信息

J Ethnopharmacol. 2016 Dec 24;194:850-860. doi: 10.1016/j.jep.2016.10.079. Epub 2016 Oct 27.

DOI:10.1016/j.jep.2016.10.079

PMID:27989876

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE

Cornus officinalis (CO) has been widely used as a traditional Chinese medicine for treating diabetes mellitus (DM) and its complications. Iridoid glycoside from C. officinalis (IGCO) can resist apoptosis, hyperglycemia, oxidation and so on. The aim of this study was to investigate the therapeutic effects of IGCO on DM-induced testicular damage through inhibition of the AGEs/RAGE/p38 MAPK signaling pathway.

MATERIALS AND METHODS

A DM model of male Wistar rats was induced with streptozotocin injection (30mg/kg, i.p.) and high-fat diet. The DM rats were administrated with IGCO at low and high doses (15 and 30mg/kg, p.o.) for 12 weeks. Testicular damage was evaluated by estimating relative testicular weights, testicular pathohistology, sperm count, live sperm rate, endogenous sex hormone level and activity of testicular marker enzymes. Besides, general diabetic symptoms, renal function, oxidative stress parameters and testicular apoptosis marker were also determined. Finally, the mechanism was explored based on the AGEs/RAGE/p38 MAPK pathway.

RESULTS

IGCO effectively mitigated the general symptoms of DM rats including weight loss, polydipsia, polyphagia, polyuria, elevated blood glucose level and low serum insulin level. Nourishing the kidney evidently, IGCO reduced serum creatinine, urea nitrogen and urine protein excretion, and also markedly protected against DM-induced testicular damage by increasing testis/body weight ratio and live sperm rate, improving the histomorphology of testes, upregulating testosterone, LH, FSH and GnRH levels and preventing the decrease of testicular marker enzymes LDH, ACP and γ-GT. Moreover, IGCO showed considerable anti-oxidative and anti-apoptotic effects, which downregulated the increase of ROS and MDA levels, restored SOD and CAT activities, and decreased spermatogenic cell apoptosis and Bax/Bcl-2 ratio. In the end, the increased AGEs, RAGE and p-p38 MAPK protein levels in DM rats were also reversed by IGCO significantly.

CONCLUSIONS

The kidney tonic IGCO well protected DM rats from testicular damage, which may be related to suppression of the AGEs-RAGE-p38 MAPK pathway.

摘要

民族药理学相关性

山茱萸（CO）作为一种传统中药，已被广泛用于治疗糖尿病（DM）及其并发症。山茱萸中的环烯醚萜苷（IGCO）具有抗细胞凋亡、高血糖、氧化等作用。本研究旨在通过抑制晚期糖基化终产物/晚期糖基化终产物受体/p38丝裂原活化蛋白激酶信号通路，探讨IGCO对糖尿病诱导的睾丸损伤的治疗作用。

材料与方法

通过腹腔注射链脲佐菌素（30mg/kg）和高脂饮食诱导雄性Wistar大鼠糖尿病模型。糖尿病大鼠分别给予低剂量和高剂量IGCO（15和30mg/kg，口服），持续12周。通过评估相对睾丸重量、睾丸病理组织学、精子计数、活精子率、内源性性激素水平和睾丸标志物酶活性来评估睾丸损伤。此外，还测定了一般糖尿病症状、肾功能、氧化应激参数和睾丸凋亡标志物。最后，基于晚期糖基化终产物/晚期糖基化终产物受体/p38丝裂原活化蛋白激酶通路探讨其作用机制。

结果

IGCO有效减轻了糖尿病大鼠的一般症状，包括体重减轻、多饮、多食、多尿、血糖水平升高和血清胰岛素水平降低。IGCO明显补肾，降低血清肌酐、尿素氮和尿蛋白排泄，还通过增加睾丸/体重比和活精子率、改善睾丸组织形态学、上调睾酮、促黄体生成素、促卵泡生成素和促性腺激素释放激素水平以及防止睾丸标志物酶乳酸脱氢酶、酸性磷酸酶和γ-谷氨酰转移酶水平降低，显著保护糖尿病大鼠免受睾丸损伤。此外，IGCO表现出显著的抗氧化和抗凋亡作用，下调活性氧和丙二醛水平的升高，恢复超氧化物歧化酶和过氧化氢酶活性，降低生精细胞凋亡和Bax/Bcl-2比值。最后，IGCO还显著逆转了糖尿病大鼠中晚期糖基化终产物、晚期糖基化终产物受体和磷酸化p38丝裂原活化蛋白激酶蛋白水平的升高。