RESUMO
Kashin-Beck disease (KBD) is a chronic, endemic osteochondropathy. Its etiopathogenesis is still obscure until now. Epidemiological observation has shown that low selenium play a crucial role in the pathogenesis of KBD. Extracellular signal-regulated kinases (ERKs) and C-Jun N-terminal kinase (JNK), members of the mitogen-activated protein kinase (MAPK) superfamily, play an important role in cell proliferation and differentiation. Nuclear factor-ĸB (NF-ĸB), an important signaling mediator for inflammatory and immune responses, is involved in the regulation of osteoclastogenesis. In the present study, we investigated the expression of ERK and JNK signal molecular, as well as nuclear factor-ĸB in the pathogenesis of Kashin-Beck disease, evaluated the effect of selenium on ERK signal pathway. The expression levels of ERK and JNK signal pathway, as well as nuclear factor-ĸB were investigated for 218 patients and 209 controls by immunoblot analysis in whole blood. Evaluated the effect of selenium on ERK signal pathway by Na2SeO3 treatment. The protein levels of pRaf-1, pMek1/2 and pErk1/2 decreased significantly in KBD patients, p-JNK and NF-ĸB increased in KBD patients. Furthermore, Na2SeO3 treatment improved the reduction of proteins in ERK signal pathway. These findings indicated that ERK and JNK signaling pathways, as well as the expression level of NF-κB signaling molecular are important contributor to the pathogenesis of KBD. Selenium stimulates the phosphorylation of the ERK signaling pathway.
Assuntos
Cartilagem Articular/metabolismo , Doença de Kashin-Bek/genética , MAP Quinase Quinase 4/genética , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/genética , NF-kappa B/genética , Selênio/deficiência , Cartilagem Articular/patologia , Estudos de Casos e Controles , Linhagem Celular , Condrócitos/citologia , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Doença de Kashin-Bek/metabolismo , Doença de Kashin-Bek/patologia , MAP Quinase Quinase 1/genética , MAP Quinase Quinase 1/metabolismo , MAP Quinase Quinase 2/genética , MAP Quinase Quinase 2/metabolismo , MAP Quinase Quinase 4/metabolismo , Masculino , Pessoa de Meia-Idade , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , NF-kappa B/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-raf/genética , Proteínas Proto-Oncogênicas c-raf/metabolismo , Transdução de Sinais , Selenito de Sódio/farmacologia , terc-Butil Hidroperóxido/antagonistas & inibidores , terc-Butil Hidroperóxido/farmacologiaRESUMO
The aerial parts of Saururus chinensis (Lour.) Baill are a Chinese herbal medicine used for the treatment of edema and inflammatory diseases. However, the effect of this medicine on enterovirus 71 (EV71) infection has not been explored. Previous studies showed that MEK1-ERK signal pathway was required for efficient replication of EV71 infection and inhibition of this signal pathway has been shown to suppress virus infection. Here we show that the water extract of S. chinensis (Lour.) Baill (SCB) significantly blocks EV71 infection by inhibiting the activation of MEK1-ERK signal pathway with an IC50 of 8.9µg/mL. SCB at 30 and 60 µg/mL blocked EV71-induced cytopathic effect (CPE) and production of infectious virion by 1.9 and 5.1 logs, respectively. Virucidal assay suggested that SCB had no virucidal activity against EV71 and probably exerted its effect by targeting multiple steps in EV71 infection. Knockdown of MEK1 but not MEK2 blocked EV71 replication. And SCB treatment inhibited the activation of MEK1-ERK signal during EV71 infection. Furthermore, we found that rutin at 200 µM, one of the major components of SCB, significantly suppressed EV71 induced CPE and inhibited viral replication in a dose dependent manner. Taken together, SCB inhibited EV71 infection by hijacking MEK1-ERK signal pathway and rutin was the responsible antiviral component of SCB.
Assuntos
Antivirais/farmacologia , Efeito Citopatogênico Viral/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Enterovirus Humano A/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Saururaceae/química , Replicação Viral/efeitos dos fármacos , Animais , Chlorocebus aethiops , Enterovirus Humano A/fisiologia , Células HEK293 , Humanos , MAP Quinase Quinase 1/antagonistas & inibidores , MAP Quinase Quinase 1/genética , MAP Quinase Quinase 1/metabolismo , MAP Quinase Quinase 2/antagonistas & inibidores , MAP Quinase Quinase 2/genética , MAP Quinase Quinase 2/metabolismo , Rutina/farmacologia , Células VeroRESUMO
Tumor cells require increased adenosine triphosphate (ATP) to support anabolism and proliferation. The precise mechanisms regulating this process in tumor cells are unknown. Here, we show that the receptor for advanced glycation endproducts (RAGE) and one of its primary ligands, high-mobility group box 1 (HMGB1), are required for optimal mitochondrial function within tumors. We found that RAGE is present in the mitochondria of cultured tumor cells as well as primary tumors. RAGE and HMGB1 coordinately enhanced tumor cell mitochondrial complex I activity, ATP production, tumor cell proliferation and migration. Lack of RAGE or inhibition of HMGB1 release diminished ATP production and slowed tumor growth in vitro and in vivo. These findings link, for the first time, the HMGB1-RAGE pathway with changes in bioenergetics. Moreover, our observations provide a novel mechanism within the tumor microenvironment by which necrosis and inflammation promote tumor progression.