Mangiferin ameliorates polycystic ovary syndrome in rats by modulating insulin resistance, gut microbiota, and ovarian cell apoptosis

Zhang Yong; Chen Mimi; Li Yingjie; Guo Yichen; Yu Yansu; Zhou Zhi; Lu Hui; Yao Si; Wu Chongming; Zhang Xiaopo; Ma Ning; Lu Weiying

doi:10.3389/fphar.2024.1457467

Mangiferin ameliorates polycystic ovary syndrome in rats by modulating insulin resistance, gut microbiota, and ovarian cell apoptosis

Front Pharmacol. 2024 Sep 23:15:1457467. doi: 10.3389/fphar.2024.1457467. eCollection 2024.

Authors

Zhang Yong^#^{1

2}, Chen Mimi^#^{1

2}, Li Yingjie^#³, Guo Yichen⁴, Yu Yansu¹, Zhou Zhi⁴, Lu Hui⁴, Yao Si¹, Wu Chongming⁵, Zhang Xiaopo⁶, Ma Ning⁴, Lu Weiying⁴

Affiliations

¹ Key Laboratory of Tropical Translational Medicine of Ministry of Education and Department of Pharmacology, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, China.
² Hainan Academy of Medical Sciences, Hainan Medical University, Haikou, China.
³ School of Pharmacy, Harbin University of Commerce, Harbin, China.
⁴ Reproductive Medical Center, Hainan Women and Children's Medical Center, Haikou, China.
⁵ School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
⁶ Haikou Key Laboratory of Li Nationality Medicine, Hainan Key Laboratory for Research and Development of Tropical Herbs, Engineering Research Center of Tropical Medicine lnnovation and Transformation of Ministry of Education and International Joint Research Center of Human-Machine Intelligent Collaborative for Tumor Precision Diagnosis and Treatment of Hainan Province, School of Pharmacy, Hainan Academy of Medical Sciences, Hainan Medical University, Haikou, China.

^# Contributed equally.

Abstract

Polycystic ovary syndrome (PCOS) is a complex endocrine and metabolic disorder characterized by hyperandrogenism, prolonged anovulation and polycystic ovaries. However, there are no effective interventions to treat this disorder. As previously shown, mangiferin modulated the AMPK and NLRP3 signal pathways to alleviate nonalcoholic fatty liver disease (NAFLD). In recent years, mangiferin has emerged as a promising drug candidate for treating metabolic diseases. In this study, we evaluated the effects of mangiferin on a letrozole (LET) combined with high-fat diet (HFD)-induced PCOS rat model through estrous cycle detection, serum/tissue biochemical analysis, and hematoxylin and eosin (HE) staining of ovarian tissue. The mechanisms of mangiferin's effects on PCOS rats were analyzed using 16S rRNA sequencing, RNA-seq, western blotting (WB), and immunohistochemical (IHC) staining. Our results displayed that mangiferin showed a promising effect in PCOS rats. It improved lipid metabolism, glucose tolerance, insulin resistance, hormonal imbalance, ovarian dysfunction, and adipocyte abnormalities. RNA-seq analysis indicated that mangiferin may be involved in several signal pathways, including apoptosis, necrosis, and inflammation. Furthermore, western blot and immunohistochemical staining demonstrated that mangiferin regulates Caspase-3 and Cytc, exhibiting anti-apoptotic activity in the ovaries. Additionally, mangiferin significantly altered the gut microbiota community of PCOS rats, changing the abundance of firmicutes, bacteroidota, proteobacteria, and actinobacteria at the phylum level and the abundance of Blautia, Coprococcus, Roseburia, and Pseudomonas at the genus level. In conclusion, mangiferin is a promising and novel therapeutic agent for PCOS as it ameliorates insulin resistance, gut microbiota and ovarian cell apoptosis.

Keywords: PCOS; female rats; gut microbiota; hormonal imbalance; insulin resistance; mangiferin; ovarian cell apoptosis.

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was financially supported by the Nature Science Foundation of China (82260304, 82204476, and 82060778), the Hainan provincial Key Research and Development Projects (ZDYF2022SHFZ074, ZDYF2024SHFZ113, and ZDYF2022SHFZ037), the Hainan provincial Nature Science Foundation of China (822RC694), the Hainan Province Clinical Medical Center (QWYH202175), and the Excellent Talent Team of Hainan Province (QRCBT202121).