Guilu-Erxian-Glue alleviates Tripterygium wilfordii polyglycoside-induced oligoasthenospermia in rats by resisting ferroptosis via the Keap1/Nrf2/GPX4 signaling pathway

Pharm Biol. 2023 Dec;61(1):213-227. doi: 10.1080/13880209.2023.2165114.

Abstract

Context: Guilu-Erxian-Glue (GLEXG) is a traditional Chinese formula used to improve male reproductive dysfunction.

Objective: To investigate the ferroptosis resistance of GLEXG in the improvement of semen quality in the oligoasthenospermia (OAS) rat model.

Materials and methods: Male Sprague-Dawley (SD) rats were administered Tripterygium wilfordii polyglycoside, a compound extracted from Tripterygium wilfordii Hook F. (Celastraceae), at a dose of 40 mg/kg/day, to establish an OAS model. Fifty-four SD rats were randomly divided into six groups: sham, model, low-dose GLEXG (GLEXGL, 0.25 g/kg/day), moderate-dose GLEXG (GLEXGM, 0.50 g/kg/day), high-dose GLEXG (GLEXGH, 1.00 g/kg/day) and vitamin E (0.01 g/kg/day) group. The semen quality, structure and function of sperm mitochondria, histopathology, levels of oxidative stress and iron, and mRNA levels and protein expression in the Keap1/Nrf2/GPX4 pathway, were analyzed.

Results: Compared with the model group, GLEXGH significantly improved sperm concentration (35.73 ± 15.42 vs. 17.40 ± 4.12, p < 0.05) and motility (58.59 ± 11.06 vs. 28.59 ± 9.42, p < 0.001), and mitigated testicular histopathology. Moreover, GLEXGH markedly reduced the ROS level (5684.28 ± 1345.47 vs. 15500.44 ± 2307.39, p < 0.001) and increased the GPX4 level (48.53 ± 10.78 vs. 23.14 ± 11.04, p < 0.01), decreased the ferrous iron level (36.31 ± 3.66 vs. 48.64 ± 7.74, p < 0.05), and rescued sperm mitochondrial morphology and potential via activating the Keap1/Nrf2/GPX4 pathway.

Discussion and conclusions: Ferroptosis resistance from GLEXG might be driven by activation of the Keap1/Nrf2/GPX4 pathway. Targeting ferroptosis is a novel approach for OAS therapy.

Keywords: Guilu-Erxian-Glue; Keap1/Nrf2/GPX4 signaling pathway; Tripterygium wilfordii polyglycoside; ferroptosis; oligoasthenospermia.

MeSH terms

  • Animals
  • Ferroptosis*
  • Iron / metabolism
  • Kelch-Like ECH-Associated Protein 1 / metabolism
  • Male
  • NF-E2-Related Factor 2 / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Seeds
  • Semen Analysis
  • Signal Transduction
  • Tripterygium

Substances

  • NF-E2-Related Factor 2
  • Kelch-Like ECH-Associated Protein 1
  • Iron
  • KEAP1 protein, rat

Grants and funding

This study was supported by the National Natural Science Foundation of China [Grant Number: 81774324], the Open Fund Project of Integrated Traditional Chinese and Western Medicine of Hunan University of Chinese Medicine [Grant Number: 2020ZXYJH29], the Fundamental Research Project of Medical and Health in Shenzhen Bao’an District [Grant Number: 2020JD505], the Key Discipline Projects of Hunan University of Chinese Medicine [Grant Number: 2021ZXYJH03], and the Dongjian Postgraduate Innovation Project of Hunan University of Chinese Medicine [Grant Number: 2021DJ03].