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[This corrects the article DOI: 10.1016/j.chmed.2018.12.002.].
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Oxidative stress is an important pathophysiological factor of asthma and chronic obstructive pulmonary disease (COPD). We hypothesized that procaterol and dexamethasone might treat inflammation through inhibiting oxidative stress in vitro. This study evaluated procaterol and dexamethasone in the hydrogen peroxide (H2O2)-induced immortal human bronchial epithelial cell model of oxidative stress and investigated the underlying mechanisms. Results showed that exposure to 125 µM H2O2 for 2 h led to a 50% reduction in the cell viability, significantly increased the percentage of apoptosis, and elevated levels of malondialdehyde and reactive oxygen species. Pretreatment with procaterol (25 - 200 nM) could reduce these effects in a dose-dependent manner. In contrast, pretreatment with dexamethasone (100 nM, 1000 nM) was inefficient. Pretreatment with procaterol plus dexamethasone (100 nM procaterol + 1000 nM dexamethasone) was effective, but the combined effect was not more effective than the sole pretreatment with 100 nM procaterol. The nuclear factor kappa-B (NF-κB) pathway was involved in the pathogenic mechanisms of H2O2. Procaterol may indirectly inhibit H2O2-induced activation of the NF-κB pathway due to its capability of antioxidation. Glucocorticoids may be not recommended to treat asthma or COPD complicated with severe oxidative stress.
Asunto(s)
Antioxidantes/farmacología , Peróxido de Hidrógeno/farmacología , Estrés Oxidativo/efectos de los fármacos , Procaterol/farmacología , Antiinflamatorios , Apoptosis/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Dexametasona/farmacología , Humanos , Malondialdehído/metabolismo , FN-kappa B/metabolismo , FN-kappa B/fisiología , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Airway hyperresponsiveness (AHR) and airway inflammation are key pathophysiological features of many respiratory diseases, such as asthma and chronic obstructive pulmonary disease (COPD). To evaluate the treatment responses of procaterol and CD38 inhibitors in an ozone-induced AHR mice model, we hypothesized that procaterol and two synthetic CD38 inhibitors (Compounds T and H) might have therapeutic effects on the ozone-induced AHR mice model, and the nuclear factor-kappaB (NF-κB) pathway and the CD38 enzymatic activity might be involved in the mechanisms. With the exception of the Control group, ozone exposure was used to establish an AHR model. Male Kunming mice in the Procaterol and CD38 inhibitors groups were treated with an emulsifier of procaterol hydrochloride, Compound T or H. Results indicated that (1) no drug showed severe toxicity in this study; (2) ozone exposure induced airway inflammation and AHR; (3) intragastric treatment with procaterol and Compound T achieved potent therapeutic effects, but Compound H did not show any therapeutic effect; (4) the NF-κB pathway was involved in both the pathogenic mechanisms of ozone and therapeutic mechanisms of procaterol and Compound T; (5) however, the in vivo effect of Compound T was not caused by its inhibitory activity on CD38. Taken together, procaterol and Compound T are potentially good drugs to treat asthma and COPD complicated with ozone exposure.
Asunto(s)
Antiasmáticos/uso terapéutico , Benzoatos/uso terapéutico , Hiperreactividad Bronquial/tratamiento farmacológico , Indoles/uso terapéutico , Procaterol/uso terapéutico , ADP-Ribosil Ciclasa 1/antagonistas & inhibidores , Animales , Antiasmáticos/farmacología , Benzoatos/farmacología , Hiperreactividad Bronquial/inducido químicamente , Hiperreactividad Bronquial/patología , Hiperreactividad Bronquial/fisiopatología , Pruebas de Provocación Bronquial , Líquido del Lavado Bronquioalveolar/citología , Modelos Animales de Enfermedad , Indoles/farmacología , Recuento de Leucocitos , Pulmón/inmunología , Pulmón/patología , Masculino , Glicoproteínas de Membrana/antagonistas & inhibidores , Cloruro de Metacolina , Ratones , FN-kappa B/inmunología , Ozono , Procaterol/farmacologíaRESUMEN
Parkinson disease (PD) is the second most common neurodegenerative disease, and it cannot be completely cured by current medications. In this study, DJ-1 protein was administrated into medial forebrain bundle of PD model rats those had been microinjected with 6-hydroxydopamine (6-OHDA) or MG-132. We found that DJ-1 protein could reduce apomorphine-induced rotations, inhibit reduction of dopamine contents and tyrosine hydroxylase levels in the striatum, and decrease dopaminergic neuron death in the substantia nigra. In 6-OHDA lesioned rats, uncoupling protein-4, uncoupling protein-5 and superoxide dismutase-2 (SOD2) mRNA and SOD2 protein were increased when DJ-1 protein was co-injected. Simultaneously, administration of DJ-1 protein reduced α-synuclein and hypoxia-inducible factor 1α mRNA and α-synuclein protein in MG-132 lesioned rats. Therefore, DJ-1 protein protected dopaminergic neurons in two PD model rats by increasing antioxidant capacity and inhibiting α-synuclein expression.
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Antiparkinsonianos/uso terapéutico , Neuronas Dopaminérgicas/efectos de los fármacos , Péptidos y Proteínas de Señalización Intracelular/uso terapéutico , Leupeptinas/toxicidad , Fármacos Neuroprotectores/uso terapéutico , Proteínas Oncogénicas/uso terapéutico , Oxidopamina/toxicidad , Trastornos Parkinsonianos/prevención & control , Animales , Antiparkinsonianos/administración & dosificación , Apomorfina/antagonistas & inhibidores , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Cuerpo Estriado/patología , Dopamina/análisis , Neuronas Dopaminérgicas/enzimología , Evaluación Preclínica de Medicamentos , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/biosíntesis , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Péptidos y Proteínas de Señalización Intracelular/administración & dosificación , Canales Iónicos/biosíntesis , Canales Iónicos/genética , Masculino , Microinyecciones , Proteínas de Transporte de Membrana Mitocondrial/biosíntesis , Proteínas de Transporte de Membrana Mitocondrial/genética , Proteínas Mitocondriales/biosíntesis , Proteínas Mitocondriales/genética , Proteínas Desacopladoras Mitocondriales , Actividad Motora/efectos de los fármacos , Proteínas del Tejido Nervioso/análisis , Proteínas del Tejido Nervioso/biosíntesis , Proteínas del Tejido Nervioso/genética , Fármacos Neuroprotectores/administración & dosificación , Proteínas Oncogénicas/administración & dosificación , Estrés Oxidativo/efectos de los fármacos , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/tratamiento farmacológico , Proteína Desglicasa DJ-1 , Ratas , Ratas Sprague-Dawley , Sustancia Negra/efectos de los fármacos , Sustancia Negra/metabolismo , Sustancia Negra/patología , Superóxido Dismutasa/biosíntesis , Superóxido Dismutasa/genética , Tirosina 3-Monooxigenasa/análisis , alfa-Sinucleína/biosíntesis , alfa-Sinucleína/genéticaRESUMEN
Human CD38 is a novel multi-functional protein that acts not only as an antigen for B-lymphocyte activation, but also as an enzyme catalyzing the synthesis of a Ca(2+) messenger molecule, cyclic ADP-ribose, from NAD(+). It is well established that this novel Ca(2+) signaling enzyme is responsible for regulating a wide range of physiological functions. Based on the crystal structure of the CD38/NAD(+) complex, we synthesized a series of simplified N-substituted nicotinamide derivatives (Compound 1-14). A number of these compounds exhibited moderate inhibition of the NAD(+) utilizing activity of CD38, with Compound 4 showing the highest potency. The crystal structure of CD38/Compound 4 complex and computer simulation of Compound 7 docking to CD38 show a significant role of the nicotinamide moiety and the distal aromatic group of the compounds for substrate recognition by the active site of CD38. Biologically, we showed that both Compounds 4 and 7 effectively relaxed the agonist-induced contraction of muscle preparations from rats and guinea pigs. This study is a rational design of inhibitors for CD38 that exhibit important physiological effects, and can serve as a model for future drug development.