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Liuwei Dihuang Pills alleviate the polycystic ovary syndrome with improved insulin sensitivity through PI3K/Akt signaling pathway.
J Ethnopharmacol. 2020 Mar 25; 250:111965.JE

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE

Polycystic ovary syndrome (PCOS) is a complex gynecological endocrine disease commonly occurred in women of childbearing age. The main hallmark of PCOS includes elevated androgen production and insulin resistance (IR). Liuwei Dihuang Pills (LWDH Pills), a commonly prescribed traditional Chinese medicine (TCM) is widely used as a tonic prescription to treat diabetes, female menopause syndrome and other symptoms with'Kidney-Yin' deficiency. It has been reported the effects LWDH pills on PI3K/Akt signaling pathway in T2DM treatment. Recent studies have also indicated that the treatment of menopausal syndrome may be associated with the ovarian sexual hormone levels regulated by LWDH pills to alleviate female infertility. However, its potential benefits on PCOS have not been fully elucidated.

AIM OF THE STUDY

The primary aim of this study was to investigate the alterations of PI3K/Akt pathway in polycystic ovary syndrome-insulin resistance (PCOS-IR) progression induced by letrozole combined with high fat diet (HFD) and then to explore the detailed mechanism of LWDH Pills to alleviate PCOS.

MATERIALS AND METHODS

The female Sprague-Dawley rats were continuously treated with letrozole (p.o administration at 1 mg kg-1·day-1) and HFD for 21 days to establish the PCOS-IR model. Concurrently, metformin (200 mg kg-1·day-1) or LWDH Pills was orally administrated (1.2 or 3.6 g kg-1·day-1) to intervene disease progression. The ovarian pathology was evaluated by HE (hematoxylin-eosin) staining. The serum sexual hormones, follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol, testosterone, progesterone and fasting insulin (FINS) were determined by radioimmunoassay. The protein expressions of IRS-1, PI3Kp85α, Akt and FoxO1a were analyzed by western blotting, while the mRNA levels of follicle-stimulating hormone receptor (FSHR) and Cyp19a1 in ovarian tissue were measured by qPCR.

RESULTS

The upregulated phosphorylation of IRS-1 (S307), down-regulated phosphorylation of PI3Kp85α, Akt, and FoxO1a were significantly reversed by LWDH Pills (3.6 g kg-1·day-1) in PCOS-IR rats with up-regulated mRNA levels of FSHR and Cyp19a1 in ovary. Also, the index of insulin resistance was gradually adjusted to normal by LWDH Pills. The serum levels of FSH, estradiol, progesterone levels were significantly raised while LH, testosterone were reduced. The ovarian polycystic changes were alleviated while the atresia follicles were reduced.

CONCLUSION

LWDH Pills therapy obviously improved the ovarian polycystic pathogenesis and regained the development of follicles via upregulating Cyp19a1, alleviated insulin resistance through acting on PI3K/Akt signaling pathway. These findings have provided scientific evidence for LWDH Pills to treat PCOS.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, PR China.

Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, PR China.

Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, PR China.

Department of Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY, 14214, USA.

Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, PR China.

Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, PR China.

Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, PR China; Nanjing Zhongshan Pharma Co., Ltd, Nanjing, PR China. Electronic address: cj919@sina.com.

Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, PR China. Electronic address: huangfang@cpu.edu.cn.

MeSH

AnimalsAromataseDrugs, Chinese HerbalFemaleGonadal Steroid HormonesInsulinInsulin ResistanceOvaryPhosphatidylinositol 3-KinasesPolycystic Ovary SyndromeProto-Oncogene Proteins c-aktRats, Sprague-DawleySignal TransductionUterus

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31185267

Citation

Qiu, Zhixia, et al. "Liuwei Dihuang Pills Alleviate the Polycystic Ovary Syndrome With Improved Insulin Sensitivity Through PI3K/Akt Signaling Pathway." Journal of Ethnopharmacology, vol. 250, 2020, p. 111965.

Qiu Z, Dong J, Xue C, et al. Liuwei Dihuang Pills alleviate the polycystic ovary syndrome with improved insulin sensitivity through PI3K/Akt signaling pathway. J Ethnopharmacol. 2020;250:111965.

Qiu, Z., Dong, J., Xue, C., Li, X., Liu, K., Liu, B., Cheng, J., & Huang, F. (2020). Liuwei Dihuang Pills alleviate the polycystic ovary syndrome with improved insulin sensitivity through PI3K/Akt signaling pathway. Journal of Ethnopharmacology, 250, 111965. https://doi.org/10.1016/j.jep.2019.111965

Qiu Z, et al. Liuwei Dihuang Pills Alleviate the Polycystic Ovary Syndrome With Improved Insulin Sensitivity Through PI3K/Akt Signaling Pathway. J Ethnopharmacol. 2020 Mar 25;250:111965. PubMed PMID: 31185267.

* Article titles in AMA citation format should be in sentence-case

TY - JOUR T1 - Liuwei Dihuang Pills alleviate the polycystic ovary syndrome with improved insulin sensitivity through PI3K/Akt signaling pathway. AU - Qiu,Zhixia, AU - Dong,Jingjing, AU - Xue,Chu, AU - Li,Xiaonan, AU - Liu,Kang, AU - Liu,Baolin, AU - Cheng,Jun, AU - Huang,Fang, Y1 - 2019/06/08/ PY - 2018/12/10/received PY - 2019/05/08/revised PY - 2019/05/18/accepted PY - 2019/6/12/pubmed PY - 2020/11/5/medline PY - 2019/6/12/entrez KW - Cyp19a1 KW - Insulin resistance KW - Liuwei Dihuang pills KW - PI3K/Akt KW - Polycystic ovary syndrome SP - 111965 EP - 111965 JF - Journal of ethnopharmacology JO - J Ethnopharmacol VL - 250 N2 - ETHNOPHARMACOLOGICAL RELEVANCE: Polycystic ovary syndrome (PCOS) is a complex gynecological endocrine disease commonly occurred in women of childbearing age. The main hallmark of PCOS includes elevated androgen production and insulin resistance (IR). Liuwei Dihuang Pills (LWDH Pills), a commonly prescribed traditional Chinese medicine (TCM) is widely used as a tonic prescription to treat diabetes, female menopause syndrome and other symptoms with'Kidney-Yin' deficiency. It has been reported the effects LWDH pills on PI3K/Akt signaling pathway in T2DM treatment. Recent studies have also indicated that the treatment of menopausal syndrome may be associated with the ovarian sexual hormone levels regulated by LWDH pills to alleviate female infertility. However, its potential benefits on PCOS have not been fully elucidated. AIM OF THE STUDY: The primary aim of this study was to investigate the alterations of PI3K/Akt pathway in polycystic ovary syndrome-insulin resistance (PCOS-IR) progression induced by letrozole combined with high fat diet (HFD) and then to explore the detailed mechanism of LWDH Pills to alleviate PCOS. MATERIALS AND METHODS: The female Sprague-Dawley rats were continuously treated with letrozole (p.o administration at 1 mg kg-1·day-1) and HFD for 21 days to establish the PCOS-IR model. Concurrently, metformin (200 mg kg-1·day-1) or LWDH Pills was orally administrated (1.2 or 3.6 g kg-1·day-1) to intervene disease progression. The ovarian pathology was evaluated by HE (hematoxylin-eosin) staining. The serum sexual hormones, follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol, testosterone, progesterone and fasting insulin (FINS) were determined by radioimmunoassay. The protein expressions of IRS-1, PI3Kp85α, Akt and FoxO1a were analyzed by western blotting, while the mRNA levels of follicle-stimulating hormone receptor (FSHR) and Cyp19a1 in ovarian tissue were measured by qPCR. RESULTS: The upregulated phosphorylation of IRS-1 (S307), down-regulated phosphorylation of PI3Kp85α, Akt, and FoxO1a were significantly reversed by LWDH Pills (3.6 g kg-1·day-1) in PCOS-IR rats with up-regulated mRNA levels of FSHR and Cyp19a1 in ovary. Also, the index of insulin resistance was gradually adjusted to normal by LWDH Pills. The serum levels of FSH, estradiol, progesterone levels were significantly raised while LH, testosterone were reduced. The ovarian polycystic changes were alleviated while the atresia follicles were reduced. CONCLUSION: LWDH Pills therapy obviously improved the ovarian polycystic pathogenesis and regained the development of follicles via upregulating Cyp19a1, alleviated insulin resistance through acting on PI3K/Akt signaling pathway. These findings have provided scientific evidence for LWDH Pills to treat PCOS. SN - 1872-7573 UR - https://www.unboundmedicine.com/medline/citation/31185267/Liuwei_Dihuang_Pills_alleviate_the_polycystic_ovary_syndrome_with_improved_insulin_sensitivity_through_PI3K/Akt_signaling_pathway_ DB - PRIME DP - Unbound Medicine ER -