RESUMEN
OBJECTIVE: N6-isopentenyladenosine (iPA) is an intermediate of the mevalonate pathway that exhibits various anti-cancer effects. However, studies on its anti-inflammatory activity are scarce and underlying molecular mechanisms are unknown. Therefore, we aimed to investigate the ability of iPA to exert anti-inflammatory effects in the human cystic fibrosis (CF) cell model of exacerbated inflammation. MATERIALS AND METHODS: TNFα-stimulated CF cells CuFi-1 and its normal counterpart NuLi-1 were pre-treated with increasing concentrations of iPA and cell viability and proliferation were assessed by MTT and BrdU assays. The effect of iPA on IL-8 and RANTES secretion was determined by ELISA, and the activation and expression of signaling molecules and selenoproteins were studied by Western blot. To assess the direct effect of iPA on NFκB activity, luciferase assay was performed on TNFα-stimulated HEK293/T cells transfected with a NFκB reporter plasmid. RESULTS: We demonstrated for the first time that iPA prevents IL-8 and RANTES release in TNFα-stimulated CF cells and this effect is mediated by increasing the expression of the direct NFκB inhibitor IκBα and decreasing the levels of STAT3. Consistent with this, we showed that iPA inhibited TNFα-mediated NFκB activation in HEK/293T cells. Finally, we also found that iPA improved the levels of glutathione peroxidase 1 and thioredoxin reductase 1 only in CF cells suggesting its ability to maintain sufficient expression of these anti-oxidant selenoproteins. CONCLUSIONS: Our findings indicate that iPA can exert anti-inflammatory activity especially in the cases of excessive inflammatory response as in CF.
Asunto(s)
Antiinflamatorios/farmacología , Fibrosis Quística/metabolismo , Isopenteniladenosina/farmacología , FN-kappa B/metabolismo , Factor de Transcripción STAT3/metabolismo , Línea Celular , Supervivencia Celular , Quimiocina CCL5/metabolismo , Fibrosis Quística/enzimología , Glutatión Peroxidasa/metabolismo , Células HEK293 , Humanos , Inflamación/metabolismo , Interleucina-8/metabolismo , Isopenteniladenosina/toxicidad , FN-kappa B/antagonistas & inhibidores , Factor de Transcripción STAT3/antagonistas & inhibidores , Transducción de Señal , Reductasa de Tiorredoxina-Disulfuro/metabolismo , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
Due to their widespread distribution and toxic nature, herbicides may have a serious impact on the environment and exert adverse effects on associated organisms. The present study was conducted to determine the acute toxicological effects of some plant growth hormones used as herbicides on four biological subjects and compare the subjects' sensitivity to individual testing substances. The herbicides 4-(indol-3-yl)acetic acid C10H9O2N (IAA), N6-(beta 2-isopentenyl)adenosine (pi-indolylpropionic acid) C11H11O2N (IPA), 2,4-dichlorophenoxyacetic acid C8H6O3Cl2 (2,4-D), 4-chloro-2-methylphenoxyacetic acid C9H9O3Cl (MCPA), and 1,napthylacetic acid C12H10O2 (NAA) were tested and the following biological subjects were used: Daphnia magna, Tubifex tubifex, Scenedesmus quadricauda, and seeds of Sinapis alba. For S. alba, the influence of herbicides on seed germination (G) and root growth inhibition (I) was observed. For T. tubifex, the tests lasted 96 hr, for D. magna 48 hr, for S. quadricauda 20 days, and for S. alba 72 hr. The rank order of toxicity of herbicides used for T. tubifex was NAA > IAA > IPA > 2,4-D > MCPA; for D. magna. NAA > IAA > IPA > MCPA > 2,4-D; for S. quadricauda, IAA > IPA > NAA > MCPA > 2,4-D; for S. alba seed germination, NAA > IPA > 2,4-D > MCPA > IAA; and for root growth inhibition. NAA > 2,4-D > MCPA > IAA > IPA.(ABSTRACT TRUNCATED AT 250 WORDS)