四物汤通过调控内质网应激PERK/eIF2alpha/ATF4/CHOP通路改善化疗诱导的早发性卵巢功能不全

Abstract

Background Premature ovarian insufficiency (POI) is a clinically refractory reproductive system disorder. Our previous studies demonstrated that the traditional Chinese herbal formula Si-Wu-Tang (SWT) might ameliorate POI in animal models by improving ovarian angiogenesis, yet the underlying mechanisms remained unclear. Purpose To explore the mechanisms of the traditional Chinese medicine (TCM) formula SWT on human umbilical vein endothelial cells (HUVECs) and animal models of POI. By studying its mechanisms, the research hopes to reveal the connotation of ‘nourishing blood and activating blood circulation’ in TCM. Methods Ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) was applied to identify the chemical constituents in SWT. In the cell experiment section, a chemotherapy-induced HUVEC injury model was established using 4-hydroperoxy cyclophosphamide (4-OOH-CY). Endoplasmic reticulum stress (ERS) and apoptosis levels were detected. Agonists and inhibitors were applied to clarify the regulatory role of SWT on the ERS signaling pathway. In the animal experiment section, rat and mouse models were established using cyclophosphamide (CY), respectively. The modeling and treatment efficacy were assessed by monitoring estrous cycles, ovarian index, histopathological sections, and sex hormone levels. Multiple techniques were employed to detect ERS and apoptosis levels in ovarian tissue and local microvessels. Results SWT enhanced HUVEC viability, reduced chemotherapy-induced ERS, oxidative stress, and apoptosis levels. It also protected the migration and tube formation abilities of HUVECs. The underlying mechanisms involved SWT downregulating the activation of the PERK/eIF2α/ATF4/CHOP signaling pathway triggered by 4-OOH-CY. In POI animal models, SWT restored low body weight, sex hormone levels, follicle count, and ovar