Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention, Ministry of Education, China Medical University, Shenyang 110122, China.
Department of Environmental Health, School of Public Health, China Medical University, Shenyang 110122, China.
Int J Mol Sci. 2024 Aug 15;25(16):8878. doi: 10.3390/ijms25168878.
Arsenic (As) has been classified as a carcinogen for humans. There is abundant evidence indicating that arsenic increases the risk of bladder cancer among human populations. However, the underlying mechanisms have yet to be fully understood and elucidated. NADPH oxidases (NOXs) are the main enzymes for ROS production in the body. NADPH Oxidase 2 (NOX2), which is the most distinctive and ubiquitously expressed subunit of NOXs, can promote the formation and development of tumors. The utilization of NOX2 as a therapeutic target has been proposed to modulate diseases resulting from the activation of NOD-like receptor thermal protein domain associated protein 3 (NLRP3). Matrine has been reported to exhibit various pharmacological effects, including anti-inflammatory, antifibrotic, antitumor, and analgesic properties. However, it has not been reported whether matrine can inhibit malignant transformation induced by arsenic in uroepithelial cells through NOX2. We have conducted a series of experiments using both a sub-chronic NaAsO exposure rat model and a long-term NaAsO exposure cell model. Our findings indicate that arsenic significantly increases cell proliferation, migration, and angiogenesis in vivo and in vitro. Arsenic exposure resulted in an upregulation of reactive oxygen species (ROS), NOX2, and NLRP3 inflammasome expression. Remarkably, both in vivo and in vitro, the administration of matrine demonstrated a significant improvement in the detrimental impact of arsenic on bladder epithelial cells. This was evidenced by the downregulation of proliferation, migration, and angiogenesis, as well as the expression of the NOX2 and NLRP3 inflammasomes. Collectively, these findings indicate that matrine possesses the ability to reduce NOX2 levels and inhibit the transformation of bladder epithelial cells.
砷（As）已被归类为人类致癌物。有大量证据表明，砷会增加人类膀胱癌的风险。然而，其潜在机制尚未完全阐明。NADPH 氧化酶（NOXs）是体内 ROS 产生的主要酶。NADPH 氧化酶 2（NOX2）是 NOXs 中最独特和广泛表达的亚基，可促进肿瘤的形成和发展。已经提出利用 NOX2 作为治疗靶点来调节由于 NOD 样受体热蛋白结构域相关蛋白 3（NLRP3）的激活而导致的疾病。苦参碱已被报道具有多种药理作用，包括抗炎、抗纤维化、抗肿瘤和镇痛作用。然而，尚未有报道表明苦参碱是否可以通过 NOX2 抑制砷诱导的尿路上皮细胞恶性转化。我们使用亚慢性 NaAsO 暴露大鼠模型和长期 NaAsO 暴露细胞模型进行了一系列实验。我们的研究结果表明，砷在体内和体外显著增加细胞增殖、迁移和血管生成。砷暴露导致活性氧（ROS）、NOX2 和 NLRP3 炎性小体表达上调。值得注意的是，体内和体外实验均表明，苦参碱给药可显著改善砷对膀胱上皮细胞的不良影响。这表现在增殖、迁移和血管生成的下调，以及 NOX2 和 NLRP3 炎性小体的表达下调。总之，这些发现表明苦参碱具有降低 NOX2 水平并抑制膀胱上皮细胞转化的能力。
