Zhang Yu, Shaukat Aftab, Zhang Han, Yang Yao-Feng, Li Hui-Xia, Li Guang-Ya, Liu Ying-Nan, Liang Chen, Kang Jin-Wen, Li Shao-Chuan, Su Ren-Wei
College of Veterinary Medicine, South China Agricultural University, Guangzhou 540642, China.
Key Laboratory of Animal Vaccine Development, Ministry of Agriculture, Guangzhou 510642, China.
Int J Mol Sci. 2024 Dec 7;25(23):13150. doi: 10.3390/ijms252313150.
Endometriosis is a chronic inflammatory, estrogenic disorder caused by endometrial tissue growth places other than uterine lumen, resulting in infertility and severe pelvic pain. Thymol, an extract of , processes diverse biological properties, including anti-inflammatory, local anesthetic, decongestant, and antiseptic effects. However, the efficacy of thymol in treating endometriosis has still not been explored. Herein, this research aimed to investigate the role of thymol in the treatment of endometriosis using a murine model and Ishikawa cells. Thirty C57BL/6 mice were administered 17β-E2 (100 ng/mouse) subcutaneously for three consecutive days to induce synchronous estrus. On the last day of injection, the mice underwent surgical induction of endometriosis. After that, the mice were divided into three groups, i.e., Control (CTRL), Thymol 30 mg/kg and Thymol 60 mg/kg, receiving oral administration of either saline or thymol (30 mg/kg/d or 60 mg/kg/d, as 0.1 mL/kg/d, respectively) for a three-week duration. Each group consisted of ten mice and was evenly divided into estrus and diestrus according to the vaginal cytology on the last day of treatment. Thymol significantly ( < 0.05) reduced the weight and volume of ectopic tissue, hindered cell proliferation, and stimulated apoptosis compared to the CTRL group. Additionally, in the thymol-treated group, the levels of pro-inflammatory cytokines, , , and , as well as the numbers of neutrophils and macrophages, were significantly ( < 0.05) decreased. Moreover, a novel role of thymol in rebalancing estrogen and progesterone (E-P) signaling was explored, and it was distributed in the ectopic endometrium. Next, the role of thymol on Ishikawa cells was determined. The results demonstrated that thymol significantly ( < 0.05) suppressed the E-induced proliferation of Ishikawa cells. Furthermore, molecular docking analyses suggested that thymol potentially binds to ESR1-like estrogens, indicating its antagonistic activity against estrogens. The estrogen receptor 1 (ESR1) and its target gene expression exhibited significant ( < 0.05) downregulation, while progesterone receptor (PGR) and target genes were markedly ( < 0.05) upregulated following thymol treatment in the ectopic endometrium. Most importantly, our data revealed the minimal impact of thymol treatment on the eutopic endometrium and its crucial role in supporting pregnancy, thus indicating the safety of thymol in treating endometriosis. Overall, our study suggests that thymol holds promising therapeutic implications for endometriosis by virtue of its anti-inflammatory properties and ability to antagonize estrogen activity.
子宫内膜异位症是一种慢性炎症性雌激素相关疾病，由子宫内膜组织在子宫腔以外的部位生长所致，会导致不孕和严重的盆腔疼痛。百里香酚是[具体植物名称]的提取物，具有多种生物学特性，包括抗炎、局部麻醉、减充血和防腐作用。然而，百里香酚治疗子宫内膜异位症的疗效尚未得到研究。在此，本研究旨在使用小鼠模型和 Ishikawa 细胞探究百里香酚在治疗子宫内膜异位症中的作用。30 只 C57BL/6 小鼠连续三天皮下注射 17β - E2（100 ng/只）以诱导同步发情。在注射的最后一天，对小鼠进行手术诱导子宫内膜异位症。之后，将小鼠分为三组，即对照组（CTRL）、30 mg/kg 百里香酚组和 60 mg/kg 百里香酚组，分别接受生理盐水或百里香酚（30 mg/kg/d 或 60 mg/kg/d，均为 0.1 mL/kg/d）口服给药，持续三周。每组由 10 只小鼠组成，并根据治疗最后一天的阴道细胞学检查均匀分为发情期和动情后期。与 CTRL 组相比，百里香酚显著（<0.05）减轻了异位组织的重量和体积，抑制了细胞增殖，并促进了细胞凋亡。此外，在百里香酚治疗组中，促炎细胞因子[具体细胞因子名称]以及中性粒细胞和巨噬细胞的数量显著（<0.05）减少。此外，还探究了百里香酚在重新平衡雌激素和孕激素（E - P）信号传导中的新作用，并且它分布在异位子宫内膜中。接下来，确定了百里香酚对 Ishikawa 细胞的作用。结果表明，百里香酚显著（<0.05）抑制了 E 诱导的 Ishikawa 细胞增殖。此外，分子对接分析表明，百里香酚可能与 ESR1 样雌激素结合，表明其对雌激素具有拮抗活性。在异位子宫内膜中，百里香酚处理后雌激素受体 1（ESR1）及其靶基因表达显著（<0.05）下调，而孕激素受体（PGR）及其靶基因则显著（<0.05）上调。最重要的是，我们的数据显示百里香酚治疗对在位子宫内膜的影响最小，且对支持妊娠具有关键作用，从而表明百里香酚治疗子宫内膜异位症的安全性。总体而言，我们的研究表明，百里香酚凭借其抗炎特性和拮抗雌激素活性的能力，对子宫内膜异位症具有有前景的治疗意义。
