RESUMO
Inflammatory bowel disease (IBD) is characterized by recurring inflammatory disorders in digestive system, and devoid of effective treatment. Proprotein convertase subtilisin/kexin type 9 (PCSK9), stimulated via inflammation whose inhibition could decrease secretion of inflammatory factors. We then determined whether inhibition of PCSK9 could improve the inflammation. First, rats model of colitis was first established via administration of 2,4,6-trinitrobenzenesulfonic acid (TNBS), and then verified via determination of body weight loss, myeloperoxidase (MPO) activity, and histopathological analysis of colonic damage. Results showed that treatment with TNBS induced a great body weight loss, MPO activity increase, and serious colonic damage, showing an obviously character of IBD. PCSK9 was elevated in TNBS-induced rats, and PCSK9 inhibition delivered by adenovirus vector increased the body weight, decreased MPO activity, and ameliorated histological change of colon. Second, the protective effect of PCSK9 inhibition against TNBS-induced colitis was accompanied by decrease of proinflammatory factors secretion, including tumor necrosis factor-α, interleukin-1ß, interleukin-6, intercellular adhesion molecule 1, and monocyte chemoattractant protein-1. TNBS could activate toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) signaling pathway, while PCSK9 inhibition suppressed activation of TLR4/NF-κB in TNBS-induced rats. In conclusion, PCSK9 inhibition attenuated TNBS-induced rat colitis through anti-inflammatory effect under inactivation of TLR4/NF-κB, suggesting potential therapeutic strategy in IBD.
Assuntos
Colite/prevenção & controle , Colo/metabolismo , NF-kappa B/genética , Pró-Proteína Convertase 9/genética , Receptor 4 Toll-Like/genética , Adenoviridae/genética , Adenoviridae/metabolismo , Animais , Peso Corporal , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Colite/induzido quimicamente , Colite/genética , Colite/patologia , Colo/efeitos dos fármacos , Colo/patologia , Regulação da Expressão Gênica , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Inflamação , Molécula 1 de Adesão Intercelular/genética , Molécula 1 de Adesão Intercelular/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , NF-kappa B/metabolismo , Inibidores de PCSK9 , Peroxidase/genética , Peroxidase/metabolismo , Pró-Proteína Convertase 9/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais , Receptor 4 Toll-Like/metabolismo , Ácido Trinitrobenzenossulfônico/administração & dosagem , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The reduction of hydrogen peroxide on a silver nanoparticle modified boron doped diamond electrode in a neutral solution is shown to proceed through a CE mechanism. Hydrogen peroxide undergoes a disproportionation reaction to form oxygen (and water) on the silver surface, creating a diffusion layer of oxygen, which, at a sufficiently biased electrode, is then reduced to hydrogen peroxide. Voltammetry and a full mechanistic simulation are undertaken to confirm the mechanism, showing at short times a dependence of the reductive signal on waiting time prior to voltammetric analysis reflecting the extent of the disproportionation step which occurs prior to voltammetric analysis.
