The present study aimed to evaluate the effect of the manool diterpene on genomic integrity. For this purpose, we evaluated the influence of manool on genotoxicity induced by mutagens with different mechanisms of action, as well as on colon carcinogenesis. The results showed that manool (0.5 and 1.0 µg/ml) significantly reduced the frequency of micronuclei induced by doxorubicin (DXR) and hydrogen peroxide in V79 cells but did not influence genotoxicity induced by etoposide. Mice receiving manool (1.25 mg/kg) exhibited a significant reduction (79.5%) in DXR-induced chromosomal damage. The higher doses of manool (5.0 and 20 mg/kg) did not influence the genotoxicity induced by DXR. The anticarcinogenic effect of manool (0.3125, 1.25 and 5.0 mg/kg) was also observed against preneoplastic lesions chemically induced in rat colon. A gradual increase in manool doses did not cause a proportional reduction of preneoplastic lesions, thus demonstrating the absence of a dose–response relationship. The analysis of serum biochemical indicators revealed the absence of hepatotoxicity and nephrotoxicity of treatments. To explore the chemopreventive mechanisms of manool via anti-inflammatory pathways, we evaluated its effect on nitric oxide (NO) production and on the expression of the NF-kB gene. At the highest concentration tested (4 μg/ml), manool significantly increased NO production when compared to the negative control. On the other hand, in the prophylactic treatment model, manool (0.5 and 1.0 μg/ml) was able to significantly reduce NO levels produced by macrophages stimulated with lipopolysaccharide. Analysis of NF-kB in hepatic and renal tissues of mice treated with manool and DXR revealed that the mutagen was unable to stimulate expression of the gene. In conclusion, manool possesses antigenotoxic and anticarcinogenic effects and its anti-inflammatory potential might be related, at least in part, to its chemopreventive activity.

中文翻译：

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Manool 是一种来自鼠尾草的二萜，对染色体损伤和癌前病变具有预防作用

本研究旨在评估manool二萜对基因组完整性的影响。为此，我们评估了manool对具有不同作用机制的诱变剂诱导的遗传毒性以及结肠癌发生的影响。结果表明，manool（0.5 和 1.0 µg/ml）显着降低了 V79 细胞中多柔比星 (DXR) 和过氧化氢诱导的微核频率，但不影响依托泊苷诱导的遗传毒性。接受 manool (1.25 mg/kg) 的小鼠表现出 DXR 诱导的染色体损伤显着减少 (79.5%)。较高剂量的 manool（5.0 和 20 mg/kg）不影响 DXR 诱导的遗传毒性。manool (0.3125, 1.25 和 5.0 mg/kg) 对大鼠结肠化学诱导的癌前病变也有抗癌作用。Manool 剂量的逐渐增加不会导致肿瘤前病变的成比例减少，因此表明不存在剂量-反应关系。血清生化指标分析显示治疗不存在肝毒性和肾毒性。为了通过抗炎途径探索 manool 的化学预防机制，我们评估了它对一氧化氮 (NO) 产生和 NF-kB 基因表达的影响。在测试的最高浓度 (4 μg/ml) 下，与阴性对照相比，manool 显着增加了 NO 的产生。另一方面，在预防性治疗模型中，manool（0.5 和 1.0 μg/ml）能够显着降低由脂多糖刺激的巨噬细胞产生的 NO 水平。用 manool 和 DXR 处理的小鼠肝和肾组织中的 NF-kB 分析表明，诱变剂不能刺激该基因的表达。总之，manool 具有抗原毒性和抗癌作用，其抗炎潜力可能至少部分与其化学预防活性有关。