Therapeutic efficacy and mechanism of artesunate for mouse model of polycystic ovary syndrome

WANG Xueling; ZHONG Peiling; ZHAO Zhipeng; CHEN Fei; LIU Xin; LIU Sijia; YUAN Lie; FANG Lu; YAO Qianyi; YANG Xiong; LIU Chao; CHENG Jiakun; CAI Yongqing; LI Xiaoli; LI Weihong

doi:10.16016/j.2097-0927.202408003

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Therapeutic efficacy and mechanism of artesunate for mouse model of polycystic ovary syndrome

Basic Medicine | 更新时间：2025-02-26

- Therapeutic efficacy and mechanism of artesunate for mouse model of polycystic ovary syndrome
- Journal of Army Medical University Vol. 47, Issue 3, Pages: 193-204(2025)
- 作者机构：
  
  1.重庆医科大学：附属第一医院生殖医学中心
  2.重庆医科大学：重庆高校生物化学与分子药理学重点实验室
  3.重庆医科大学：药学院药理系，重庆
  4.重庆医科大学：曲靖市第一人民医院病理科，云南曲靖
  5.重庆医科大学：达州市中西医结合医院药学科，四川达州
  6.重庆医科大学：陆军军医大学（第三军医大学）第一附属医院临床研究中心，重庆
  7.重庆医科大学：陆军特色医学中心（第三军医大学大坪医院）药剂科，重庆
- 作者简介：
  
  LI Xiaoli， E-mail： lixiaoli@cqmu.edu.cn
  LI Weihong， E-mail： liweihong1211@163.com
- 基金信息：
  
  the General Program of Natural Science Foundation of Chongqing(CSTB2022NSCQ-MSX0086;CSTB2024NSCQ-MSX1180);the Sichuan Provincial Special Project of Local Science and Technology Development Fund Guided by Central Government （Regional Innovation System Construction-Chengdu-Chongqing Shuangcheng Economic Circle, 2023ZYD0283） and 2024 “Pharmaceutical Innovation Star” Undergraduate Research Literacy Cultivation Program of College of Pharmacy, Chongqing Medical University
- DOI：10.16016/j.2097-0927.202408003
  CLC： R282.71;R285.6;R711.75
- Received：01 August 2024，
  
  Revised：15 August 2024，
  
  Published：15 February 2025
- 稿件说明：
移动端阅览
‍王雪玲，钟佩伶，赵志鹏，等.青蒿琥酯对多囊卵巢综合征模型小鼠的治疗作用及机制研究［J］.陆军军医大学学报，2025，47（03）：193-204.DOI：10.16016/j.2097-0927.202408003.

‍WANG X L，ZHONG P L，ZHAO Z P，et al.Therapeutic efficacy and mechanism of artesunate for mouse model of polycystic ovary syndrome［J］.J Army Med Univ，2025，47（03）：193-204.DOI：10.16016/j.2097-0927.202408003.
‍王雪玲，钟佩伶，赵志鹏，等.青蒿琥酯对多囊卵巢综合征模型小鼠的治疗作用及机制研究［J］.陆军军医大学学报，2025，47（03）：193-204.DOI：10.16016/j.2097-0927.202408003. DOI：

‍WANG X L，ZHONG P L，ZHAO Z P，et al.Therapeutic efficacy and mechanism of artesunate for mouse model of polycystic ovary syndrome［J］.J Army Med Univ，2025，47（03）：193-204.DOI：10.16016/j.2097-0927.202408003. DOI：

摘要

‍

目的

观察青蒿琥酯（artesunate，AS）对多囊卵巢综合征（polycystic ovary syndrome，PCOS）模型小鼠的治疗作用，并对其作用机制进行初步探讨。

方法

25只雌性C57BL/6J小鼠按照随机数字表法分为（

=5）：对照组（Control组）、模型组（PCOS组）、青蒿琥酯低剂量组（AS15组）、青蒿琥酯高剂量组（AS30组）和二甲双胍组（metformin， Met组）。除Control组外，其余各组小鼠皮下注射脱氢表雄酮（dehydroepiandrosterone，DHEA， 60 mg/kg）并给予高脂饲料21 d以构建PCOS模型，AS组腹腔分别注射15和30 mg/kg剂量的青蒿琥酯，Met组灌胃给予200 mg/kg剂量的二甲双胍，每日1次，持续6周。采用ELISA法检测小鼠血清睾酮（testosterone，T）、空腹胰岛素（fasting insulin，FINS）、黄体生成素（luteinizing hormone，LH）、卵泡刺激水平（follicle-stimulating hormone，FSH），并计算LH/FSH比值；采用全自动生化仪检测小鼠空腹血糖（fasting blood glucose，FBG）、甘油三酯（triglyceride，TG）和总胆固醇（total cholesterol，TC）水平，并计算胰岛素抵抗指数（homeostasis model assessment of insulin resistance，HOMA-IR）；采用HE染色观察小鼠动情周期，以及卵巢、子宫组织病理形态改变；采用免疫荧光染色观察小鼠卵巢组织中p-eIF2α、ATF4、CHOP蛋白表达情况。体外，使用100 μmol/L DHEA诱导人颗粒细胞瘤样细胞系KGN细胞模拟PCOS的高雄激素环境，以5和10 μg/mL浓度的AS分别处理24 h后，Western blot检测内质网应激信号通路蛋白表达情况。

结果

与Control组相比，PCOS组小鼠动情周期紊乱，卵巢出现多囊样改变，血清T、LH/FSH比值显著升高（

0.05）；代谢方面，PCOS小鼠HOMA-IR、TC、TG水平明显升高（

0.01）；PCOS小鼠卵巢颗粒细胞和KGN细胞中p-eIF2α、ATF4、CHOP表达增加（

0.05）。而与PCOS组相比，AS各剂量组小鼠卵巢和子宫病理形态改变显著改善，血清T、LH/FSH比值也明显降低（

0.05）；代谢方面，AS各剂量组小鼠HOMA-IR、TC、TG水平明显降低（

0.05）；AS各剂量组小鼠卵巢颗粒细胞和KGN细胞中p-eIF2α、ATF4、CHOP表达降低（

0.05）。

结论

AS可显著改善PCOS小鼠的糖脂代谢异常和生殖功能，其作用机制可能是通过抑制PERK/eIF2α/ATF4/CHOP通路缓解内质网应激。

Abstract

‍Objective‍

To investigate the therapeutic efficacy of artesunate (AS) on polycystic ovary syndrome (PCOS) in mice and explore the potential mechanism primarily.

Methods‍

‍Twenty-five female C57BL/6J mice were randomly divided into Control group

model group (PCOS group)

low- and high-dose AS groups (AS15 and AS30 groups) and metformin group (Met group). In addition to the Control group

the mouse model of PCOS was established by subcutaneous injection of dehydroepiandrosterone (DHEA

60 mg/kg) following by a high-fat diet for 21 d. After modeling

AS of 15 and 30 mg/kg was intraperitoneally injected into the mice of the AS15 and AS30 groups

respectively

and 200 mg/kg Met was given to those of the Met group by gavage

once per day

for 6 weeks. ELISA was used to detect serum testosterone (T)

fasting insulin (FINS)

luteinizing hormone (LH) and follicle-stimulating hormone (FSH)

and the LH/FSH ratio was calculated. The levels of fasting blood glucose (FBG)

triglyceride (TG) and total cholesterol (TC) were detected by automatic biochemical analyzer

and the homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. The estrous cycle was observed

and HE staining was performed for pathological changes in the ovary and uterus. Immunofluorescence assay was employed to measure the expression of p-eIF2α

ATF4 and CHOP in the ovarian tissue. After steroidogenic human granulosa-like tumor cell line KGN were exposed to 100 μmol/L DHEA to simulate the hyperandrogen environment of PCOS

and then treated with 5 and 10 μg/mL AS for 24 h

the protein levels of endoplasmic reticulum stress signaling pathway was detected by Western blotting.

Results

‍Compared with the Control group

the PCOS mice had disturbed estrous cycle

polycystic changes in the ovaries

and significantly increased serum T level and LH/FSH ratio (

0.05)

and obviously elevated HOMA-IR

TC and TG levels in terms of metabolism (

0.01). The expression levels of p-eIF2α

ATF4 and CHOP were notably up-regulated in the ovarian granulosa cells of PCOS mice and KGN cells after DHEA exposure (

0.05). Additionally

AS treatment attenuated the pathological changes of ovary a

nd uterine expression

decreased the serum T level and the LH/FSH ratio (

0.05)

and reduced HOMA-IR

TC and TG levels (

0.05) when compared with the PCOS mice. Moreover

the expression levels of p-eIF2α

ATF4 and CHOP were significantly down-regulated after AS treatment in both ovarian granulosa cells of PCOS mice and KGN cells (

0.05).

Conclusion

‍AS significantly improves glycolipid metabolic disorder and reproductive dysfunction in PCOS mice

which may be associated with its suppressing endoplasmic reticulum stress by inhibiting the PERK/eIF2α/ATF4/CHOP pathway.

关键词

Keywords

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