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

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.

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“…When GPX4 is inhibited, ferroptosis will be triggered as the lethal amount of LPO accumulation. 50 Recently, both ACSL4 and GPX4-regulated ferroptosis has been found to participate in the pathological processes of CNS injuries. For example, in a mouse cerebral ischemia-reperfusion (I/R) injury model, the administration of baicalein inhibited the ferroptosis by the inhibition of ACSL4 and activation of GPX4.…”

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“…The male and female SD rats (10 weeks of age) were ordered from Hunan Slyke Jingda Experimental Animal Co., LTD. The animals were raised in a temperature‐controlled chamber with a light and dark cycle of 12:12 h. [ 26 ] Male and female rats were caged by 2:1. Sperm was detected in the vaginal discharge test on the first day of pregnancy.…”

Emerging roles of ferroptosis in male reproductive diseases

“… Factor/reagent Categories Mechanism Ref. Busulfan Drug Downregulated NRF2ˎGPX4 and FPN expression [ 70 ] Tripterygium wilfordii polyglycoside tablet Drug Inhibit NRF2/xCT/GPX4 axis and FPN espression [ 118 , 119 ] Ischemia-reperfusion Testicular torsion Downregulated NRF2ˎGPX4 and FPN expression [ 71 ] Scrotal hyperthermia High temperature exposure Increase ACSL4 expression [ 107 ] Smoking (nicotine) Habit Downregulated NRF2 and GPX4 expression [ 82 , 108 ] 2.5-micron particulate matter Environmental factor Depletion of GSH and reduce GPX4 expression [ 83 , 110 ] DEHP Environmental factor Increase TFR1 and HO1 expression Reduce GPX4 level [ 27 , 126 , 135 ] BisphenolA Environmental factor Downregulate NRF2/HO1 and xCT/GPX4 pathwayˎActivate ACSL4 expression and ROS accumulation [ 111 , 112 ] Arsenite Heavy mental Downregulate xCT/GPX4 pathwayˎInduce ROS release and increase iron levels [ 84 ] Cdmium Heavy mental Reduce FTHˎFPN and xCT expressionˎDownregulate NRF2/HO1 pathway and enhance lipid peroxidation [ 69 , 115 ] Hexavalent chromium Heavy mental Inhibit xCT/GPX4 and mTOR [ 99 ] Co...…”

“…Tripterygium wilfordii , a traditional Chinese medicine, is used to treat rheumatoid arthritis. However, the reproductive toxicity of Tripterygium wilfordii limits its clinical application, and its mechanism of reproductive toxicity is not fully understood [ 118 ]. Qin et al [ 119 ] combined metabolomics with transcriptomics and found that ferroptosis was associated with Tripterygium wilfordii -induced testicular injury.…”

“… Drugs Subjects Mechanism Ref. Ferrostatin-1 Mice/Rats/Audults Inhibits lipid peroxidation [ 40 , 69 , 70 , 74 , 82 – 84 , 113 ] Liproxstain-1 Mice Inhibits lipid peroxidation [ 71 ] Vitamin E (α-tocopherol) Mice Inhibits lipid peroxidation [ 40 ] Deferoxamine Mice/Rats Iron chelator [ 69 – 71 , 74 , 83 , 136 , 137 ] N-Acetyl cysteine Mice Recover intracellular cysteine [ 71 ] Melatonin Sheep/mice Regulates glucose-6-phosphate dehydrogenase/glutathione -dependent pathway [ 103 ] Sulforaphane Mice Activation of NRF2 [ 70 ] Bone marrow mesenchymal stem cells transplantation Rats Alleviats ferroptosis and downregulates autophagy-associated proteins through the upregulation of AKT and mTOR phosphorylation [ 99 ] Guilu-Erxian-Glue Rats Activats the Keap1/Nrf2/GPX4 signaling pathway to resist ferroptosis [ 118 ] Alpha-lipoic acid Rats Activats NRF2/xCT/GPX4 axis [ 123 ] Glucagon-like peptide-1 Rats antioxidant capacity [ 138 ] RSL3 …”