Inhibition of Escherichia coli nitroreductase by the constituents in Syzygium aromaticum / 中国天然药物

Gut bacterial nitroreductases play an important role in reduction of various nitroaromatic compounds to the corresponding N-nitroso compounds, hydroxylamines or aromatic amines, most of which are carcinogenic and mutagenic agents. Inhibition of gut nitroreductases has been recognized as an attractive approach for reducing mutagen metabolites in the colon, so as to prevent colon diseases. In this study, the inhibitory effects of 55 herbal medicines against Escherichia coli(E. coli) nitroreductase (EcNfsA) were examined. Compared with other herbal extracts, Syzygium aromaticum extract showed superior inhibitory potency toward EcNfsA mediated nitrofurazone reduction. Then, the inhibitory effects of 22 major constituents in Syzygium aromaticum against EcNfsA were evaluted. Compared with other tested natural compounds, ellagic acid, corilagin, betulinic acid, oleanic acid, ursolic acid, urolithin M5 and isorhamnetin were found with strong to moderate inhibitory effect against EcNfsA, with IC50 values ranging from 0.67 to 28.98 mol·L-1. Furthermore, the inhibition kinetic analysis and docking simulation demonstrated that ellagic acid and betulinic acid potently inhibited EcNfsA (Ki < 2 μmol·L -1) in a competitively inhibitory manner, which created strong interactions with the catalytic triad of EcNfsA. In summary, our findings provide new scientific basis for explaining the anti-mutagenic activity of Syzygium aromaticum, where some newly identified EcNfsA inhibitors can be used for developing novel agents to reduce the toxicity induced by bacterial nitroreductase.

Antitumoral, mutagenic and (anti)estrogenic activities of tingenone and pristimerin

Cancer constitutes the second main mortality cause in the world, after cardiovascular diseases. In spite of the progresses in the chemotherapeutics treatments, many patients fail chemotherapy, mainly because of side effects or multi-drugs resistance, proving the need and importance of the research for new molecules with anticancer activity, more effective and with smaller adverse effects. Various compounds derived from plant secondary metabolites are commonly used in the chemotherapy against cancer and the natural products play an important role in the research for new molecules. Among several molecules of natural origin evaluated by MTT assay in murine tumor cell lines [breast (LM3) and lung (LP07)] the quinona-methide triterpenes tingenone and pristimerin showed marked cytotoxic activity presenting IC50 around 2 and 5 µM respectively. The structure-activity relationship suggests that rings A and B containing an α, ß-unsaturated carbonyl group are essential for the observed cytotoxic activity. The interaction between these positions and acetylcisteyne residues suggests a probable mechanism of action. The in vitro mutagenic activity was also evaluated by the Salmonella microsome assay (Ames test) for pristimerin and tingenone with and without metabolic activation (S9) in the strains TA98, TA97a, TA100 and TA102, none of which showed mutagenic potential in any strains. Estrogenic and anti-estrogenic activities were also studied by the e-screen assay in MCF-7 cells with negative results. The present data point to the importance of pristimerin and tingenone as representative of an emerging class of potential anticancer chemicals.

Efeitos tóxicos de alfa e ß-asaronas e do óleo de cálamo em camundongos, embriões de galinha e mutagenicidade em Salmonella tryphimurium / Toxic effects of alpha and beta-asarone and of the calamus oil in mices, chick embryos and mutagenicity in Salmonella typhimurium

Foram verificadas as DL50 do óleo de cálamo de variedades diferentes, assim como os seus componentes ativos a e B3-asaronas em camundongos, por via intraperitoneal. A DL50 do óleo de cálamo, variedade indiana, foi de 154,5 mgv'kg, a da ,B-asarona, de 184,0 mg/kg e a da a-asarona, de 226,0 mgv'kg. Para variedade européia e para o extrato oleoso isento de asaro nas, em virtude de suas baixas toxicidades agudas, não foi possível a determinação dos valores de DL50. O estudo da toxicidade em embriões de galinha para verificar eventual atividade teratogênica foi feito também para os óleos de diferentes variedades, assim como os componentes a e B3-asaronas isolados. A mortalidade média variou de 10,0 a 100,0% e não se constataram sinais de malformação nos embriões desenvolvidos. O teste de Ames foi conduzido com o componente B3-asarona nas concentrações de 10, 50, 100, 200 e 500 ,ug/placa. A amostra não apresentou atividade mutagênica em nenhuma das concentrações, frente à cepa de Salmonella typhimurium, com e sem adição de ativador obtido de extrato de fígado de rato após índução com Aroclor 1254 (AU).