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Manool, a diterpene from Salvia officinalis, exerts preventive effects on chromosomal damage and preneoplastic
Heloiza Diniz Nicolella1, Gabriela Fernandes1, Saulo Duarte Ozelin1
1Mutagenesis Laboratory, Universidade de Franca, Avenida Dr. Armando Salles de Oliveira, 201 - Parque Universitário, 14404-600 Franca, São Paulo, Brazil.
Abstract:
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.
Insights
Manool, a diterpene, demonstrates antigenotoxic and anticarcinogenic properties by reducing DNA damage and colon tumors. Its anti-inflammatory effects, particularly on nitric oxide production, may contribute to its chemopreventive potential.
Area of Science:
- Pharmacology and Toxicology
- Cancer Research
- Molecular Biology
Background:
- Genomic integrity is crucial for preventing diseases like cancer.
- Diterpenes are natural compounds with potential therapeutic applications.
- Understanding the chemopreventive mechanisms of natural products is vital.
Purpose of the Study:
- To evaluate the antigenotoxic and anticarcinogenic effects of manool.
- To investigate the influence of manool on genotoxicity induced by various mutagens.
- To explore the anti-inflammatory mechanisms underlying manool's chemopreventive activity.
Main Methods:
- In vitro genotoxicity assays using V79 cells exposed to mutagens (doxorubicin, hydrogen peroxide, etoposide).
- In vivo studies in mice to assess chromosomal damage and in rats for colon carcinogenesis.
- Analysis of serum biochemical indicators for hepatotoxicity and nephrotoxicity.
- Evaluation of nitric oxide (NO) production and NF-kB gene expression in response to manool treatment.
Main Results:
- Manool significantly reduced micronuclei formation induced by doxorubicin and hydrogen peroxide in V79 cells.
- A significant reduction in doxorubicin-induced chromosomal damage was observed in mice treated with manool.
- Manool exhibited anticarcinogenic effects against chemically induced preneoplastic lesions in rat colon.
- Manool modulated nitric oxide production and did not show hepatotoxicity or nephrotoxicity.
Conclusions:
- Manool possesses significant antigenotoxic and anticarcinogenic properties.
- The anti-inflammatory potential of manool, particularly its effect on NO, may contribute to its chemopreventive activity.
- Further research into manool's mechanisms could lead to novel cancer prevention strategies.
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