RESUMEN
Biological drugs targeting tumor necrosis factor-α, such as infliximab, are highly effective in psoriasis. The interference with keratinocyte apoptosis has been included among the possible effects of infliximab in psoriasis, although the available data are still controversial. The purpose of our study was to verify the action of infliximab on psoriatic keratinocytes. Keratinocyte apoptosis was evaluated in the lesional psoriatic skin of 11 patients at baseline and a different time point during treatment with infliximab. Infliximab (5 mg/kg) was given intravenously at weeks 0, 2, and 6, followed by maintenance infusions every 8 weeks. Pretreatment with intravenous hydrocortisone was performed prior to each infusion. Keratinocytes with apoptotic features were histologically identified according to the following changes: chromatin condensation at the periphery of the nucleus, cytoplasmic vesiculation, nuclear fragmentation, nuclear pyknosis. Immunohistochemical assessment of p53 and caspase-3 expression was also performed. At baseline, prior to treatment with infliximab, lesional epidermis showed 1.2-3.2% p53-positive apoptotic keratinocytes in the basal zone. The number of p53-positive apoptotic keratinocytes increased after treatment with infliximab, already at day 1-2 after the first infusion, and such cells were localized at basal and suprabasal layers or were through all layers. There was no immunoreactivity for caspase-3 at any time point examined. Our results suggest that induction of p53-related keratinocyte apoptosis might be one of the mechanisms of infliximab action in psoriasis.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Apoptosis/efectos de los fármacos , Queratinocitos/efectos de los fármacos , Psoriasis/tratamiento farmacológico , Piel/efectos de los fármacos , Adulto , Anticuerpos Monoclonales/administración & dosificación , Caspasa 3/biosíntesis , Esquema de Medicación , Femenino , Humanos , Inmunohistoquímica , Infliximab , Inyecciones Intravenosas , Queratinocitos/inmunología , Queratinocitos/patología , Masculino , Persona de Mediana Edad , Psoriasis/inmunología , Psoriasis/patología , Piel/inmunología , Piel/patología , Factor de Necrosis Tumoral alfa/inmunología , Proteína p53 Supresora de Tumor/biosíntesis , Adulto JovenRESUMEN
BACKGROUND: Recent findings suggest the involvement of oxidative stress in the pathogenesis of chronic idiopathic urticaria (CIU). It has been demonstrated that desloratadine has an antioxidant activity in vitro. We evaluated the effects of desloratadine on markers of oxidative stress in patients with CIU. METHODS: Blood samples were obtained from 10 patients with CIU before and after 4 weeks of treatment with desloratadine. Blood samples from 10 healthy volunteers were used as controls. In platelets from both patients and controls, radical oxygen species (ROS) production was measured using spectrofluorimetric detection of dichloro-fluorescein oxidation, and superoxide dismutase (SOD) activity was determined by means of the xanthine-xanthine oxidase system. RESULTS: Radical oxygen species concentrations and SOD activity were significantly elevated in patients with CIU at baseline as compared with control subjects. Treatment with desloratadine caused a relevant reduction of ROS levels and SOD activity (P<0.005). CONCLUSIONS: These preliminary results suggest that desloratadine exerts antioxidant effects also in vivo.
Asunto(s)
Antagonistas de los Receptores Histamínicos H1 no Sedantes/uso terapéutico , Loratadina/análogos & derivados , Estrés Oxidativo/efectos de los fármacos , Urticaria/tratamiento farmacológico , Adulto , Anciano , Biomarcadores/sangre , Enfermedad Crónica , Femenino , Humanos , Loratadina/uso terapéutico , Masculino , Persona de Mediana Edad , Especies Reactivas de Oxígeno/sangre , Índice de Severidad de la Enfermedad , Superóxido Dismutasa/sangre , Urticaria/sangreRESUMEN
The inhibitor protein IF1 is a basic protein of 84 residues which inhibits the ATPase activity of the mitochondrial FoF1-ATP synthase complex without having any effect on ATP synthesis. Results of cross-linking and limited proteolysis experiments are presented showing that in the intact FoF1 complex "in situ," in the inner membrane of bovine heart mitochondria, the central segment of IF1 (residues 42-58) binds to the alpha and beta subunits of F1 in a pH dependent process, and inhibits the ATPase activity. The C-terminal region of IF1 binds, simultaneously, to the OSCP subunit of Fo in a pH-independent process. This binding keeps IF1 anchored to the complex, both under inhibitory conditions, at acidic pH, and noninhibitory conditions at alkaline pH.