10.1515/aiht-2017-68-2945

Modifikacije ekspresije gena i proteina koji su uključeni u popravak DNA i metabolizam dušikova oksida karbatonidima [derivati dinatrij-2,6-dimetil-1,4-dihidropiridin-3,5-bis(karboniloksiacetata)] u kontrolnih i dijabetičkih štakora

Abstract

Studies on the pathogenesis of diabetes mellitus complications indicate that the compounds reducing free radicals and enhancing DNA repair could be prospective as possible remedies. Carbatonides, the disodium-2,6-dimethyl-1,4-dihydropyridine-3,5-bis(carbonyloxyacetate) derivatives, were tested for these properties. EPR spectroscopy showed that metcarbatone was an effective scavenger of hydroxyl radicals produced in the Fenton reaction, etcarbatone, and propcarbatone were less effective, styrylcarbatone was ineffective. UV/VIS spectroscopy revealed that styrylcarbatone manifested a hyperchromic effect when interacting with DNA, while all other carbatonides showeda hypochromic effect. Rats with streptozotocin induced type 1 DM were treated with metcarbatone, etcarbatone or styrylcarbatone (all compounds at doses 0.05 mg kg-1 or 0.5 mg kg-1) nine days after the DM approval. Gene expression levels in kidneys and blood were evaluated by quantitative RT-PCR; protein expression - immunohistochemically in kidneys, heart, sciatic nerve, and eyes; DNA breakage - by comet assay in nucleated blood cells. Induction of DM induced DNA breaks; metcarbatone and styrylcarbatone (low dose) alleviated this effect. Metcarbatone and etcarbatone up-regulated mRNA and protein of eNOS in kidneys of diabetic animals; etcarbatone also in myocardium. Etcarbatone reduced the expression of increased iNOS protein in myocardium, nerve, and kidneys. iNos gene expression was up-regulated in kidneys by etcarbatone and metcarbatone in diabetic animals. In blood, development of DM increased iNos gene expression; etcarbatone and metcarbatone normalised it. Etcarbatone up-regulated the expression of H2AX in kidneys of diabetic animals but decreased the production of c-PARP1. Taken together, our data indicate that carbatonides might have a potential as drugs intended to treat DM complications.Rezultati ispitivanja patogeneze komplikacija šećerne bolesti (diabetes mellitus – DM) upozoravaju na to da bi tvari koje smanjuju nastanak slobodnih radikala a pospješuju popravak DNA mogle biti obećavajuće u budućem liječenju te bolesti. U ovome su istraživanju ispitana navedena svojstva karbatonida, derivata dinatrij-2,6-dimetil-1,4-dihidropiridin-3,5-bis(karboniloksiacetata). EPR spektroskopija je pokazala da je metkarbaton učinkovit sakupljač hidroksilnih radikala koji nastaju Fentonovom reakcijom. Etkarbaton i propkarbaton su bili malo manje učinkoviti, a stirilkarbaton nije bio učinkovit. UV/VIS spektroskopija pokazala je hiperkromni učinak stirilkarbatona u interakciji s DNA, a svi ostali karbatonidi pokazali su hipokromni učinak. Štakori kod kojih je DM tipa 1 induciran streptozotocinom tretirani su metkarbatonom, etkarbatonom ili stirilkarbatonom (sve tvari su davane u dozi 0,05 mg kg-1 ili 0,5 mg kg-1) tijekom devet dana nakon što je potvrđeno da je izazvan DM. Razine ekspresije gena u bubrezima procijenjene su kvantitativnim RT-PCR-om, ekspresija proteina – imunohistokemijski u bubrezima, srcu, ishijadičnom živcu i očima, a lom DNA – komet-testom bijelim krvnim stanicama. Indukcija DM-a uzrokovala je lomove u DNA; metkarbaton i stirilkarbaton (niska doza) ublažili su ovaj učinak. Metkarbaton i etkarbaton pojačali su mRNA i ekspresiju proteina eNOS-a u bubrezima dijabetičkih životinja; etkarbaton je takav učinak pokazao i u miokardu. Etkarbaton je smanjio ekspresiju iNOS proteina u miokardu, živcu i bubrezima. Ekspresija iNOS-a bila je pojačana u bubrezima primjenom etkarbatona i metkarbatona u dijabetičkih životinja. Razvoj DM povećao je ekspresiju iNOS-a u krvi, a etkarbaton i metkarbaton vratili su ju na normalne vrijednosti. Etkarbaton je pojačao ekspresiju H2AX u bubrezima dijabetičkih životinja, ali je smanjio proizvodnju c-PARP1. Naši podaci upućuju na potencijal karbatonida kao lijekova za liječenje komplikacija uzrokovanih dijabetesom

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