Department of Pathology, Baoding First Central Hospital, Baoding, Hebei, China.
College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China.
J Biochem Mol Toxicol. 2021 Jul;35(7):e22779. doi: 10.1002/jbt.22779. Epub 2021 Mar 23.
The aim of the present study is to explore the preventive efficacy of betulin (BE) in 7,12-dimethylbenz(a)anthracene (DMBA)-administered mammary cancer by modulating Ahr/Nrf2 signaling in experimental models. The mammary cancer was stimulated by the addition of DMBA (25 mg/kg/b.Wt) mixed in 1 ml of vehicle solution (sunflower oil and saline 1:1) through subcutaneous injection. The DMBA-exposed mammary tumor models showed low bodyweight, elevated quantities of lipid peroxidation molecules (TBARS and LOOH), and low enzymatic (GPx, SOD, and CAT), and nonenzymatic (GSH, vitamin C, and vitamin E) antioxidant activities in plasma and mammary tissues. Moreover, histopathological studies confirmed that invasive ductal carcinoma was observed in DMBA-induced mammary tissue of the experimental model. Dietary oral supplementation of BE prevents the loss of bodyweight, overproduces lipid peroxidation, and restores the antioxidant activities in DMBA-exposed experimental animals. The nuclear factor erythroid 2-related factor 2 (Nrf2) is a crucial antioxidant protein that involves preventing numerous cancers. Therefore, Nrf2-associated signaling concern is a significant target for preventing mammary cancer. This study observed an increased expression of MAPKs, Keap1, ARNT, AhR, and CYP1A1, whereas decreased expression of HO-1 and Nrf2 in DMBA-induced cancer-bearing experimental animals. The oral supplementation of BE effectively modulates the expression of MAPKs, AhR/Nrf2-associated protein expressions in DMBA-exposed experimental animals. This current study concluded that BE is a strong antioxidant, which triggers the MAPKs-mediated oxidative stress and inhibits proliferative markers by restoring the activity of Nrf2 signaling.
本研究旨在通过调节 Ahr/Nrf2 信号通路，探索桦木酸（BE）在 7,12-二甲基苯并蒽（DMBA）诱发的乳腺癌中的预防作用。采用皮下注射方式，将 DMBA（25mg/kg/b.Wt）与 1ml 溶剂（葵花籽油和生理盐水 1:1）混合，诱发乳腺癌。DMBA 暴露的乳腺肿瘤模型表现为体重减轻、脂质过氧化产物（TBARS 和 LOOH）含量升高、血浆和乳腺组织中酶（GPx、SOD 和 CAT）和非酶（GSH、维生素 C 和维生素 E）抗氧化活性降低。此外，组织病理学研究证实，在 DMBA 诱导的实验动物乳腺组织中观察到浸润性导管癌。BE 的膳食口服补充可防止体重下降、脂质过氧化过度产生，并恢复 DMBA 暴露实验动物的抗氧化活性。核因子红细胞 2 相关因子 2（Nrf2）是一种重要的抗氧化蛋白，可预防多种癌症。因此，Nrf2 相关信号通路是预防乳腺癌的重要靶点。本研究观察到 MAPKs、Keap1、ARNT、AhR 和 CYP1A1 的表达增加，而 DMBA 诱导的荷瘤实验动物中 HO-1 和 Nrf2 的表达减少。BE 的口服补充可有效调节 MAPKs 和 AhR/Nrf2 相关蛋白在 DMBA 暴露实验动物中的表达。本研究表明，BE 是一种有效的抗氧化剂，可通过 MAPKs 介导的氧化应激和恢复 Nrf2 信号活性来抑制增殖标志物。
