The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang 550025, China.
State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China.
Int J Mol Sci. 2023 Oct 24;24(21):15521. doi: 10.3390/ijms242115521.
Arsenic is a carcinogenic metalloid toxicant widely found in the natural environment. Acute or prolonged exposure to arsenic causes a series of damages to the organs, mainly the liver, such as hepatomegaly, liver fibrosis, cirrhosis, and even hepatocellular carcinoma. Therefore, it is imperative to seek drugs to prevent arsenic-induced liver injury. Quinazolines are a class of nitrogen heterocyclic compounds with biological and pharmacological effects in vivo and in vitro. This study was designed to investigate the ameliorating effects of quinazoline derivatives on arsenic-induced liver injury and its molecular mechanism. We investigated the mechanism of the quinazoline derivative KZL-047 in preventing and ameliorating arsenic-induced liver injury in vitro by cell cycle and apoptosis. We performed real-time fluorescence quantitative polymerase chain reaction (qPCR) and Western blotting combined with molecular docking. In vivo, the experiments were performed to investigate the mechanism of KZL-047 in preventing and ameliorating arsenic-induced liver injury using arsenic-infected mice. Physiological and biochemical indices of liver function in mouse serum were measured, histopathological changes in liver tissue were observed, and immunohistochemical staining was used to detect changes in the expression of RecQ-family helicases in mouse liver tissue. The results of in vitro experiments showed that sodium arsenite (SA) inhibited the proliferation of L-02 cells, induced apoptosis, blocked the cell cycle at the G1 phase, and decreased the expression of RecQ family helicase; after KZL-047 treatment in arsenic-induced L-02 cells, the expression of RecQ family helicase was upregulated, and the apoptosis rate was slowed, leading to the restoration of the cell viability level. KZL-047 inhibited arsenic-induced oxidative stress, alleviated oxidative damage and lipid peroxidation in vivo, and ameliorated arsenic toxicity-induced liver injury. KZL-047 restored the expression of RecQ family helicase proteins, which is consistent with the results of in vitro studies. In summary, KZL-047 can be considered a potential candidate for the treatment of arsenic-induced liver injury.
砷是一种广泛存在于自然环境中的致癌类金属毒物。急性或长期接触砷会对器官造成一系列损害，主要是肝脏，如肝肿大、肝纤维化、肝硬化，甚至肝癌。因此，迫切需要寻找药物来预防砷诱导的肝损伤。喹唑啉类是一类具有体内和体外生物和药理作用的含氮杂环化合物。本研究旨在探讨喹唑啉衍生物对砷诱导的肝损伤的改善作用及其分子机制。我们通过细胞周期和凋亡研究了喹唑啉衍生物 KZL-047 预防和改善砷诱导的肝损伤的体外作用机制。我们进行了实时荧光定量聚合酶链反应 (qPCR) 和 Western blot 结合分子对接。在体内，通过砷感染小鼠实验研究了 KZL-047 预防和改善砷诱导的肝损伤的作用机制。测量了小鼠血清中肝功能的生理生化指标，观察了肝组织的组织病理学变化，并采用免疫组织化学染色检测了小鼠肝组织中 RecQ 家族解旋酶表达的变化。体外实验结果表明，亚砷酸钠 (SA) 抑制 L-02 细胞增殖，诱导细胞凋亡，使细胞周期阻滞在 G1 期，并降低 RecQ 家族解旋酶的表达；KZL-047 处理砷诱导的 L-02 细胞后，RecQ 家族解旋酶的表达上调，细胞凋亡率减慢，细胞活力水平恢复。KZL-047 抑制砷诱导的氧化应激，减轻体内氧化损伤和脂质过氧化，改善砷毒性引起的肝损伤。KZL-047 恢复了 RecQ 家族解旋酶蛋白的表达，这与体外研究的结果一致。综上所述，KZL-047 可被视为治疗砷诱导的肝损伤的潜在候选药物。
