虾青素通过调节Klotho表达和Wnt/β-Catenin信号通路对多囊卵巢综合征大鼠的改善作用

doi:10.11958/20221727

天津医药 ›› 2023, Vol. 51 ›› Issue (10): 1098-1103.doi: 10.11958/20221727

虾青素通过调节Klotho表达和Wnt/β-Catenin信号通路对多囊卵巢综合征大鼠的改善作用

宋玉(), 朱争艳^△(), 黄桓, 李春, 鲁晶泉, 刘和宇, 胡丽娜

武汉市第三医院妇科（邮编430000）

收稿日期:2022-10-24 修回日期:2023-01-03 出版日期:2023-10-15 发布日期:2023-10-18
通讯作者: ^∆E-mail：kfcwd09@163.com
作者简介:宋玉（1988），女，主治医师，主要从事妇科临床方面研究。E-mail：songyu1988s@163.com
基金资助:
武汉市医学科研项目(WZ21Z01)

The improvement effect of astaxanthin on rats with polycystic ovary syndrome by regulating Klotho expression and Wnt/β-Catenin signaling pathway

SONG Yu(), ZHU Zhengyan^△(), HUANG Huan, LI Chun, LU Jingquan, LIU Heyu, HU Lina

Department of Gynecology, Wuhan Third Hospital, Wuhan 430000, China

Received:2022-10-24 Revised:2023-01-03 Published:2023-10-15 Online:2023-10-18
Contact: ^∆E-mail：kfcwd09@163.com

宋玉, 朱争艳, 黄桓, 李春, 鲁晶泉, 刘和宇, 胡丽娜. 虾青素通过调节Klotho表达和Wnt/β-Catenin信号通路对多囊卵巢综合征大鼠的改善作用[J]. 天津医药, 2023, 51(10): 1098-1103.

SONG Yu, ZHU Zhengyan, HUANG Huan, LI Chun, LU Jingquan, LIU Heyu, HU Lina. The improvement effect of astaxanthin on rats with polycystic ovary syndrome by regulating Klotho expression and Wnt/β-Catenin signaling pathway[J]. Tianjin Medical Journal, 2023, 51(10): 1098-1103.

摘要/Abstract

摘要：

目的研究虾青素调节Klotho表达和Wnt/β-Catenin信号通路对多囊卵巢综合征（PCOS）大鼠的改善作用及机制。方法采用来曲唑溶液灌胃的方法构建30只PCOS模型大鼠，随机分为6组：模型组、虾青素低剂量组（50 mg/kg）、虾青素中剂量组（100 mg/kg）、虾青素高剂量组（200 mg/kg）、虾青素高剂量+空载组、虾青素高剂量+Klotho敲低组，每组5只；另取5只SD大鼠作为对照组。分组处理后测定各组大鼠体质量与卵巢质量。取SD大鼠以同样方法造模并随机分为：模型组、虾青素组（200 mg/kg）、虾青素+Klotho敲低组、虾青素+氯化锂组、虾青素+PD98059（MEK抑制剂）组，每组9只，另取9只SD大鼠作为对照组。分组处理后，测定各组大鼠体质量、卵巢质量与体积、卵巢组织囊状卵泡数量，血清卵泡刺激素（FSH）、黄体生成素（LH）、睾酮（T）水平及炎性因子前列腺素E2（PGE2）、白细胞介素（IL）-17、肿瘤坏死因子-α（TNF-α）、IL-18水平，卵巢组织Klotho蛋白表达和Wnt/β-Catenin、MEK/ERK信号相关蛋白表达。结果与对照组比较，模型组体质量与卵巢质量明显升高（P<0.05）；与模型组比较，虾青素低剂量组、虾青素中剂量组、虾青素高剂量组的体质量与卵巢质量均降低，并呈剂量依赖性（P<0.05）；与虾青素高剂量组比较，虾青素高剂量+Klotho敲低组体质量与卵巢质量升高（P<0.05），虾青素高剂量+空载组各指标无明显变化。与对照组比较，模型组血清FSH水平和卵巢组织Klotho、p-MEK、p-ERK1/2蛋白表达降低（P<0.05），体质量、卵巢质量与体积、囊状卵泡数量、血清LH、T、PGE2、IL-17、TNF-α及IL-18水平、卵巢组织Wnt1与β-Catenin蛋白表达明显升高（P<0.05）；与模型组比较，虾青素组血清FSH水平和卵巢组织Klotho、p-MEK、p-ERK1/2蛋白表达升高（P<0.05），体质量、卵巢质量与体积、囊状卵泡数量、血清LH、T、PGE2、IL-17、TNF-α及IL-18水平、卵巢组织Wnt1与β-Catenin蛋白表达降低（P<0.05）；敲低Klotho、氯化锂、PD98059均可减弱虾青素对PCOS大鼠的改善作用。结论虾青素可通过上调Klotho而下调Wnt/β-Catenin信号及激活MEK/ERK信号，从而阻止炎症反应，改善PCOS大鼠激素水平，减少囊状卵泡数目，最终减轻其多囊卵巢症状。

关键词: 多囊卵巢综合征, Wnt信号通路, MAP激酶信号系统, 虾青素, Klotho

Abstract:

Objective To study the improvement mechanism of astaxanthin in rats with polycystic ovary syndrome (PCOS) by regulating Klotho expression and Wnt/β-Catenin signaling pathway. Methods Thirty PCOS model rats were constructed by intragastric administration of letrozole, and rats were randomly grouped into 6 groups: the model group, the low-dose astaxanthin group (50 mg/kg), the middle-dose astaxanthin groupm (100 mg/kg), the high-dose astaxanthin group (200 mg/kg), the high-dose astaxanthin+no-load group and the high-dose astaxanthin+Klotho knockdown group, with 5 rats in each group. Another 5 SD rats were taken as the control group. After treatment, the body weight and ovarian weight of rats in each group were measured. Forty-five SD rats were modeled in the same way and randomly grouped into: the model group, the astaxanthin group (200 mg/kg), the astaxanthin+Klotho knockdown group, the astaxanthin+lithium chloride group and the astaxanthin+PD98059 (MEK inhibitor) group, with 9 rats in each group. Another 9 SD rats were taken as the control group. After treatment, data of body weight, ovarian weight and volume, the number of cystic follicles in ovarian tissue, levels of serum hormones including follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone (T) and levels of inflammatory factors prostaglandin 2 (PGE2), interleukin (IL)-17, tumor necrosis factor-α (TNF-α), and IL-18, the expression of Klotho protein and the expression of Wnt/β-Catenin and MEK/ERK signal-related proteins in ovarian tissue were detected in rats of each group. Results Compared with the control group, body weight and ovarian weight were obviously increased in the model group (P<0.05). Compared with the model group, body weight and ovarian weight were all decreased in the low-dose astaxanthin group, the middle-dose astaxanthin group and the high-dose astaxanthin group in a dose-dependent manner (P<0.05). Compared with the high-dose astaxanthin group, body mass and ovarian mass of rats were increased in the high-dose astaxanthin+Klotho knockdown group (P<0.05). There was no significant change in each index of rats in the high dose of astaxanthin+empty load group (P>0.05). Compared with the control group, serum level of FSH, and expression levels of Klotho, p-MEK, p-ERK1/2 proteins in ovarian tissue were obviously decreased in the model group (P<0.05). Body weight, ovarian mass and volume, number of cystic follicles, serum levels of LH, T, PGE2, IL-17, TNF-α and IL-18, and expression levels of Wnt1 and β-Catenin proteins in ovarian tissue were obviously increased in the model group (P<0.05). Compared with the model group, the level of FSH, the expression levels of Klotho, p-MEK and p-ERK1/2 proteins in ovarian tissue were increased in the astaxanthin group (P<0.05). Body weight, ovarian mass and volume, number of cystic follicles, serum levels of LH, T, PGE2, IL-17, TNF-α and IL-18, and expression of Wnt1 and β-Catenin proteins in ovarian tissue were decreased in the astaxanthin group (P<0.05). Knockdown of Klotho, lithium chloride and PD98059 can weaken the improvement effect of astaxanthin on PCOS rats. Conclusion Astaxanthin can down-regulate Wnt/β-Catenin signaling and activate MEK/ERK signaling by up-regulating Klotho, thereby preventing inflammation, improving hormone levels in PCOS rats, reducing number of cystic follicles, and ultimately alleviating the symptoms of polycystic ovaries.

Key words: polycystic ovary syndrome, Wnt signaling pathway, MAP kinase signaling system, Astaxanthin

中图分类号:

R711.75

图/表 7

参考文献 20

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组别	体质量/g	卵巢质量/mg
对照组	248.94±7.95	614.80±18.62
模型组	339.65±14.52^a	783.14±32.37^a
虾青素低剂量组	311.12±12.30^b	723.26±21.30^b
虾青素中剂量组	282.83±13.81^bc	670.11±22.51^bc
虾青素高剂量组	254.68±11.23^bcd	621.24±14.36^bcd
虾青素高剂量+空载组	251.30±15.01^bcd	623.38±15.01^bcd
虾青素高剂量+Klotho敲低组	332.57±14.94^e	778.19±18.20^e
F	45.050^＊＊	61.260^＊＊

组别	体质量/g	卵巢质量/mg
对照组	248.94±7.95	614.80±18.62
模型组	339.65±14.52^a	783.14±32.37^a
虾青素低剂量组	311.12±12.30^b	723.26±21.30^b
虾青素中剂量组	282.83±13.81^bc	670.11±22.51^bc
虾青素高剂量组	254.68±11.23^bcd	621.24±14.36^bcd
虾青素高剂量+空载组	251.30±15.01^bcd	623.38±15.01^bcd
虾青素高剂量+Klotho敲低组	332.57±14.94^e	778.19±18.20^e
F	45.050^＊＊	61.260^＊＊

组别	体质量/g	卵巢质量/mg	卵巢体积/mm³
对照组	251.78±16.89	612.95±19.03	12.09±0.61
模型组	342.54±35.21^a	789.42±33.12^a	15.87±2.10^a
虾青素组	262.13±20.35^b	620.21±20.38^b	12.63±0.78^b
虾青素+Klotho敲低组	329.84±30.19^c	770.48±29.54^c	15.41±1.81^c
虾青素+氯化锂组	332.16±27.21^c	775.23±30.33^c	15.28±1.59^c
虾青素+PD98059组	326.98±29.44^c	779.10±31.26^c	15.30±1.73^c
F	19.086^＊＊	81.866^＊＊	10.070^＊＊

组别	体质量/g	卵巢质量/mg	卵巢体积/mm³
对照组	251.78±16.89	612.95±19.03	12.09±0.61
模型组	342.54±35.21^a	789.42±33.12^a	15.87±2.10^a
虾青素组	262.13±20.35^b	620.21±20.38^b	12.63±0.78^b
虾青素+Klotho敲低组	329.84±30.19^c	770.48±29.54^c	15.41±1.81^c
虾青素+氯化锂组	332.16±27.21^c	775.23±30.33^c	15.28±1.59^c
虾青素+PD98059组	326.98±29.44^c	779.10±31.26^c	15.30±1.73^c
F	19.086^＊＊	81.866^＊＊	10.070^＊＊

组别	FSH/（IU/L）	LH/（IU/L）	T/（μg/L）	囊状卵泡数量/（个/视野）
对照组	7.74±0.90	4.18±0.51	1.76±0.25	0.69±0.23
模型组	2.65±0.42^a	14.52±1.42^a	5.39±0.63^a	17.72±4.15^a
虾青素组	7.20±0.85^b	4.64±0.73^b	2.08±0.36^b	1.21±0.40^b
虾青素+Klotho敲低组	2.89±0.37^c	14.14±1.22^c	5.07±0.52^c	16.87±4.22^c
虾青素+氯化锂组	2.96±0.45^c	14.27±1.18^c	5.14±0.70^c	17.04±5.40^c
虾青素+PD98059组	3.03±0.39^c	14.01±1.34^c	4.99±0.78^c	16.53±6.32^c
F	138.843^＊＊	186.048^＊＊	77.394^＊＊	35.819^＊＊

虾青素通过调节Klotho表达和Wnt/β-Catenin信号通路对多囊卵巢综合征大鼠的改善作用

The improvement effect of astaxanthin on rats with polycystic ovary syndrome by regulating Klotho expression and Wnt/β-Catenin signaling pathway

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参考文献 20

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组别	PGE2	IL-17
对照组	21.95±5.02	197.84±41.30
模型组	86.36±20.53^a	856.73±123.25^a
虾青素组	29.72±5.34^b	214.68±40.72^b
虾青素+Klotho敲低组	75.84±21.70^c	821.17±125.42^c
虾青素+氯化锂组	76.95±23.41^c	830.25±131.19^c
虾青素+PD98059组	72.37±18.94^c	819.06±140.63^c
F	21.853^＊＊	79.218^＊＊
组别	TNF-α	IL-18
对照组	30.11±7.02	223.86±64.27
模型组	93.75±18.67^a	961.72±194.32^a
虾青素组	38.03±8.31^b	252.09±70.35^b
虾青素+Klotho敲低组	85.70±20.11^c	925.46±202.51^c
虾青素+氯化锂组	87.12±15.73^c	918.12±180.76^c
虾青素+PD98059组	80.97±17.39^c	904.97±191.83^c
F	29.137^＊＊	43.676^＊＊

组别		Klotho/GAPDH		Wnt1/GAPDH
对照组		0.79±0.09		0.40±0.05
模型组		0.31±0.06^a		0.88±0.12^a
虾青素组		0.73±0.10^b		0.44±0.03^b
虾青素+Klotho敲低组		0.35±0.05^c		0.80±0.11^c
虾青素+氯化锂组		0.75±0.11^b		0.84±0.14^c
虾青素+PD98059组		0.70±0.08^b		0.67±0.07^c
F		58.667^＊＊		42.819^＊＊
组别	β-Catenin/ GAPDH		p-MEK/MEK		p-ERK1/2/ ERK1/2
对照组	0.37±0.04		0.68±0.06		0.61±0.04
模型组	0.90±0.13^a		0.11±0.02^a		0.07±0.01^a
虾青素组	0.42±0.06^b		0.63±0.07^b		0.57±0.05^b
虾青素+Klotho敲低组	0.81±0.09^c		0.19±0.03^c		0.16±0.03^c
虾青素+氯化锂组	0.85±0.12^c		0.28±0.05^c		0.24±0.02^c
虾青素+PD98059组	0.70±0.13^c		0.13±0.04^c		0.10±0.01^c
F	45.334^＊＊		250.757^＊＊		549.032^＊＊

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