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Total flavonoids of Epimedium ameliorate testicular damage via keap1-Nrf2/ARE signalling and multi-target regulation
Hongchao Yuan1, Wenhao Tian2, Hao Hao2
1Jinhuifang Traditional Chinese Medicine Technology Co., Ltd, Hanzhong, Shaanxi, 723000, China.
Abstract:
This study investigates the protective effects of total flavonoids of Epimedium (TFE) against obesity-induced testicular damage in mice. The potential pharmacological mechanisms were predicted using network pharmacology, molecular docking and molecular dynamics simulation. In vivo experiments were conducted in mice randomly assigned to five groups: a normal diet group, a high-fat diet (HFD) group, two TFE groups, and a positive control group. Biomarkers including dihydrotestosterone and testosterone were measured to evaluate testicular function, while lipid profiles were assessed. Oxidative stress was determined through glutathione (GSH), superoxide dismutase (SOD), and malondialdehyde (MDA) assays, and protein expression of heme oxygenase-1 (HO-1), NAD(P)H quinone dehydrogenase 1 (NQO1), nuclear factor erythroid 2-related factor 2 (Nrf2), and Kelch-like ECH-associated protein 1 (Keap1) was analysed. Network pharmacology identified 29 flavonoids and 288 key targets. Molecular docking revealed that 22 active components exhibited strong binding activity, with PLCZ1-isoginkgetin/bilobetin showing the most stable conformation. TFE treatment significantly improved testicular function and mitigated obesity-induced male infertility. It enhanced sperm quality, reversed HFD-induced reductions in sperm count and motility, decreased malformation rates, normalized serum testosterone and dihydrotestosterone levels, ameliorated oxidative stress by enhancing antioxidant enzyme activity (GSH) and reducing lipid peroxidation (MDA), and improved lipid profiles by lowering triglycerides (TG) while increasing high-density lipoprotein cholesterol (HDL-C). Mechanistically, TFE upregulated Nrf2 pathway components (HO-1, NQO1) and modulated Keap1 expression. Collectively, these findings establish that the protective effects of TFE against obesity-induced testicular damage are mediated by the coordinated regulation of oxidative stress and key testicular targets.
Insights
Total flavonoids of Epimedium (TFE) protect against obesity-induced testicular damage in mice by improving sperm quality and normalizing hormone levels. TFE mitigates oxidative stress and lipid imbalances, supporting male reproductive health.
Area of Science:
- Reproductive biology and toxicology
- Pharmacology and natural product research
- Metabolic disease research
Background:
- Obesity is linked to male infertility and testicular dysfunction.
- High-fat diets (HFD) induce oxidative stress and alter lipid profiles, negatively impacting testicular health.
- Epimedium flavonoids are investigated for their potential therapeutic benefits.
Purpose of the Study:
- To investigate the protective effects of total flavonoids of Epimedium (TFE) against obesity-induced testicular damage in mice.
- To elucidate the underlying pharmacological mechanisms using network pharmacology, molecular docking, and molecular dynamics simulations.
- To evaluate TFE's impact on testicular function, oxidative stress, and lipid metabolism in an HFD-induced obesity model.
Main Methods:
- Network pharmacology identified key flavonoids and targets.
- Molecular docking and dynamics simulations predicted binding interactions.
- In vivo studies involved HFD-induced obese mice treated with TFE.
- Assays measured reproductive hormones, lipid profiles, oxidative stress markers (GSH, MDA), and protein expression (Nrf2 pathway).
Main Results:
- TFE treatment significantly improved sperm quality (count, motility, morphology) and normalized testosterone/dihydrotestosterone levels.
- TFE ameliorated HFD-induced oxidative stress by enhancing antioxidant capacity (GSH) and reducing lipid peroxidation (MDA).
- Lipid profiles were improved, with reduced triglycerides and increased HDL-C.
- TFE upregulated Nrf2 pathway components (HO-1, NQO1) and modulated Keap1 expression, indicating activation of antioxidant defense mechanisms.
Conclusions:
- Total flavonoids of Epimedium (TFE) demonstrate significant protective effects against obesity-induced testicular damage and male infertility in mice.
- The protective mechanisms involve the coordinated regulation of oxidative stress via the Nrf2 pathway and modulation of key testicular targets.
- TFE represents a potential therapeutic strategy for managing male reproductive dysfunction associated with obesity and metabolic disorders.
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