RESUMEN
BACKGROUND: Dimethyl fumarate (DMF), a nuclear factor erythroid 2-related factor 2 (Nrf2) activator, has been proven effective for the systemic treatment of multiple sclerosis. The aim of this study is to evaluate the anti-inflammatory effects of Nrf2 activators on human renal mesangial cells (HRMCs) and the development of lupus nephritis (LN) in mice. METHODS: To assess Nrf2 activation in vitro, HRMCs were treated with safe doses of Nrf2 activators and prednisolone. The expression levels of Nrf2 and its target genes were measured using quantitative reverse transcription PCR and enzyme-linked immunosorbent assay. The anti-inflammatory effects of these compounds were assessed by measuring tumor necrosis factor alpha-induced cytokine secretion. Experimental LN was induced in female BALB/c mice by a single intraperitoneal injection of pristane. The urine albumin-to-creatinine ratio was measured at 20 weeks after injection. Pathological changes as well as protein and mRNA expression levels were assessed in the kidney obtained at the experimental end point. Oral administration of DMF or prednisolone to these mice was initiated after pristane injection. RESULTS: Nrf2 activators such as sulforaphane and DMF showed anti-inflammatory effects in HRMCs, whereas glucocorticoid (prednisolone) showed partial effects. Moreover, DMF ameliorated the development of kidney diseases in pristane-induced LN mice, whereas glucocorticoid had no effect. CONCLUSIONS: Nrf2 activators showed stronger anti-inflammatory and organ-protective effects than glucocorticoid in the kidney. Thus, Nrf2 activators are potential therapeutic targets in glucocorticoid-resistant LN in humans.
Asunto(s)
Antiinflamatorios/farmacología , Nefritis Lúpica/patología , Células Mesangiales/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Animales , Dimetilfumarato/farmacología , Modelos Animales de Enfermedad , Resistencia a Medicamentos , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Glucocorticoides/farmacología , Humanos , Isotiocianatos/farmacología , Nefritis Lúpica/metabolismo , Ratones , Ratones Endogámicos BALB C , Factor 2 Relacionado con NF-E2/efectos de los fármacos , Prednisolona/farmacología , Reacción en Cadena en Tiempo Real de la Polimerasa , SulfóxidosRESUMEN
The aim of our study was twofold: to immobilize an organosilicon quaternary ammonium salt (3-(trimethoxysilyl)-propyldimethyl-octadecyl ammonium chloride, Si-QAC) on the surface of pure titanium and to investigate the antimicrobial activity of Si-QAC-immobilized titanium against microbial adherence and biofilm formation. The results of ToF-SIMS analysis of Si-QAC-titanium suggested the possibility of immobilizing Si-QAC on titanium surface through Ti-O-Si coupling, and that Si-QAC treatment significantly reduced both the adherence and colonization of Candida albicans and Streptococcus mutans isolates. The antimicrobial activity was achieved through at least two mechanisms: the first was attributed to the octadecyl alkyl chain which inhibited initial adherence, and the second was attributed to the quaternary ammonium salt which killed initial adherent cells as well as retarded or inhibited subsequent microbial growth. Further, thermocycling did not significantly reduce the antimicrobial activity of Si-QAC-titanium, and no significant cytotoxicity of Si-QAC-titanium was observed in either cell viability test or proinflammatory cytokine production test using human gingival fibroblasts. These results, taken together, favorably suggested that Si-QAC treatment would be a helpful means to inhibit dental plaque or denture plaque formation.
