RESUMEN
Mitochondria are an important intracellular source of ROS as well as a sensitive target for oxidative damage under certain pathological conditions such as iron or copper overload. Mitochondrial membranes are rich in the tetraacyl phospholipid cardiolipin. Its integrity is important for efficient oxidative phosphorylation. Mouse liver mitochondria were subjected to oxidative stress by the Cu(2+)(Fe(2+))/H(2)O(2)/ascorbate system. Phosphatidic acid was detected in oxidized mitochondria, but not in unperturbed mitochondria. The Cu(2+)/H(2)O(2)/and (or not) ascorbate system caused the formation of phosphatidic acid and phosphatidylhydroxyacetone in cardiolipin liposomes. These products proceed via an HO*-radical induced fragmentation taking place in the polar moiety of cardiolipin. Mass spectrometry analysis of phosphatidic acid newly formed in mitochondria revealed that it has been derived from fragmentation of cardiolipin. Thus, free-radical fragmentation of cardiolipin in its polar part with the formation of phosphatidic acid is a likely mechanism that damages mitochondria under conditions of oxidative stress.
Asunto(s)
Mitocondrias Hepáticas/metabolismo , Ácidos Fosfatidicos/biosíntesis , Animales , Fenómenos Biofísicos , Cardiolipinas/metabolismo , Cromatografía Líquida de Alta Presión , Femenino , Técnicas In Vitro , Hierro/toxicidad , Liposomas , Metales/toxicidad , Ratones , Ratones Endogámicos C57BL , Mitocondrias Hepáticas/efectos de los fármacos , Estrés Oxidativo , Especies Reactivas de Oxígeno/metabolismo , Espectrometría de Masa por Láser de Matriz Asistida de Ionización DesorciónRESUMEN
Phospholipase D (PLD) activity was found to be higher in etiolated oat seedlings than in green seedlings. White and red (R) light exposure inhibited PLD activity in etiolated seedlings. Far-red light eliminated R-light-induced decrease in PLD activity, indicating phytochrome participation in observed photomodulation. Inhibitor of electron transport in chloroplast 3-(3,4-dichlorophenyl)-1,1-dimethylurea stimulated and glucose suppressed PLD activity in green and etiolated oat seedlings, respectively. These results suggest that PLD activity in oat seedling is regulated by light with involvement of phytochrome photoreceptor, and associated with photosynthesis process.
Asunto(s)
Avena/enzimología , Luz , Fosfolipasa D/efectos de la radiación , Fotosíntesis , Plantones/enzimología , Avena/efectos de los fármacos , Avena/efectos de la radiación , Diurona/farmacología , Glucosa/farmacología , Fosfolipasa D/antagonistas & inhibidores , Fosfolipasa D/fisiología , Proteínas del Complejo del Centro de Reacción Fotosintética/fisiología , Fitocromo/fisiología , Plantones/efectos de los fármacos , Plantones/efectos de la radiaciónRESUMEN
Novel anti-Human immunodeficiency virus (HIV)-1 agents targeting the V3 loop of envelope protein gp120 were designed by computer modeling based on glycosphingolipid ß-galactosylceramide (ß-GalCer), which is an alternative receptor allowing HIV-1 entry into CD4-negative cells of neural and colonic origin. Models of these ß-GalCer analogs bound to the V3 loops from five various HIV-1 variants were generated by molecular docking and their stability was estimated by molecular dynamics (MDs) and binding free energy simulations. Specific binding to the V3 loop was accomplished primarily by non-conventional XH π interactions between CH/OH sugar groups of the glycolipids and the conserved V3 residues with π-conjugated side chains. The designed compounds were found to block the tip and/or the base of the V3 loop, which form invariant structural motifs that contain residues critical for cell tropism. With the MDs calculations, the docked models of the complexes of the ß-GalCer analogs with V3 are energetically stable in all of the cases of interest and exhibit low values of free energy of their formation. Based on the data obtained, these compounds are considered as promising basic structures for the rational design of novel, potent, and broad-spectrum anti-HIV-1 therapeutics.
Asunto(s)
Fármacos Anti-VIH/química , Ceramidas/química , Glicoesfingolípidos/química , Proteína gp120 de Envoltorio del VIH/química , Monosacáridos/química , Receptores del VIH/química , Fármacos Anti-VIH/metabolismo , Fármacos Anti-VIH/farmacología , Unión Competitiva , Ceramidas/metabolismo , Simulación por Computador , Diseño de Fármacos , Glicoesfingolípidos/metabolismo , Proteína gp120 de Envoltorio del VIH/antagonistas & inhibidores , Proteína gp120 de Envoltorio del VIH/metabolismo , VIH-1/efectos de los fármacos , VIH-1/metabolismo , Humanos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Estructura Molecular , Monosacáridos/metabolismo , Unión Proteica , Estructura Terciaria de Proteína , Receptores del VIH/metabolismo , TermodinámicaRESUMEN
Based on the membrane addressing concept, designing and synthesis of 11-(3,5-di-tert-butyl-2-hydroxyphenylcarbamoyl)undecanoic acid have been carried out. Antioxidant properties of the prepared compound were investigated in comparison with its non-amphiphilic analogues.
Asunto(s)
Antioxidantes/síntesis química , Antioxidantes/farmacología , Carbamatos/síntesis química , Carbamatos/farmacología , Ácidos Grasos/síntesis química , Ácidos Grasos/farmacología , Fenómenos Químicos , Química Física , Cromatografía Líquida de Alta Presión , Citidina Difosfato/química , Radicales Libres/química , Indicadores y Reactivos , Peroxidación de Lípido/efectos de los fármacos , Sustancias Reactivas al Ácido Tiobarbitúrico/químicaRESUMEN
A series of novel phenolic antioxidants of amphiphilic structure has been synthesized. Investigations into the influence of aliphatic spacer length and nature of a hydrophilic anchor on the antioxidant activity allowed elucidating certain structure requirements for the membrane-addressed antioxidant designing.