RESUMEN
AIMS: In this study, we will investigate the therapeutic effects of berberine (BBR) in Helicobacter pylori (H. pylori) induced chronic atrophic gastritis (CAG). Furthermore, potential mechanisms of BBR in regulating IRF8-IFN-γ signaling axis will also be investigated. MATERIALS AND METHODS: H. pylori were utilized to establish CAG model of rats. Therapeutic effects of BBR on serum supernatant indices, and histopathology of stomach were analyzed in vivo. Moreover, GES-1 cells were infected by H. pylori, and intervened with BBR in vitro. Cell viability, morphology, proliferation, and quantitative analysis were detected by high-content screening (HCS) imaging assay. To further investigate the potential mechanisms of BBR, relative mRNA, immunohistochemistry and protein expression in IRF8-IFN-γ signaling axis were measured. KEY FINDINGS: Results showed serum supernatant indices including IL-17, CXCL1, and CXCL9 were downregulated by BBR intervention, while, G-17 increased significantly. Histological injuries of gastric mucosa induced by H. pylori also were alleviated. Moreover, cell viability and morphology changes of GES-1 cells were improved by BBR intervention. In addition, proinflammatory genes and IRF8-IFN-γ signaling axis related genes, including Ifit3, Upp1, USP18, Nlrc5, were suppressed by BBR administration in vitro and in vivo. The proteins expression related to IRF8-IFN-γ signaling axis, including Ifit3, IRF1 and Ifit1 were downregulated by BBR intervention.
Asunto(s)
Antiinflamatorios/farmacología , Berberina/farmacología , Gastritis Atrófica/tratamiento farmacológico , Infecciones por Helicobacter/tratamiento farmacológico , Factores Reguladores del Interferón/genética , Interferón gamma/genética , Animales , Línea Celular , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Quimiocina CXCL1/antagonistas & inhibidores , Quimiocina CXCL1/genética , Quimiocina CXCL1/inmunología , Quimiocina CXCL9/antagonistas & inhibidores , Quimiocina CXCL9/genética , Quimiocina CXCL9/inmunología , Enfermedad Crónica , Modelos Animales de Enfermedad , Células Epiteliales/efectos de los fármacos , Células Epiteliales/inmunología , Células Epiteliales/microbiología , Gastritis Atrófica/genética , Gastritis Atrófica/inmunología , Gastritis Atrófica/microbiología , Regulación de la Expresión Génica , Infecciones por Helicobacter/genética , Infecciones por Helicobacter/inmunología , Infecciones por Helicobacter/microbiología , Helicobacter pylori/efectos de los fármacos , Helicobacter pylori/crecimiento & desarrollo , Helicobacter pylori/patogenicidad , Humanos , Factores Reguladores del Interferón/antagonistas & inhibidores , Factores Reguladores del Interferón/inmunología , Interferón gamma/antagonistas & inhibidores , Interferón gamma/inmunología , Interleucina-17/agonistas , Interleucina-17/genética , Interleucina-17/inmunología , Masculino , Proteínas NLR/antagonistas & inhibidores , Proteínas NLR/genética , Proteínas NLR/inmunología , Ratas , Ratas Sprague-Dawley , Transducción de Señal , Uridina Fosforilasa/antagonistas & inhibidores , Uridina Fosforilasa/genética , Uridina Fosforilasa/inmunologíaRESUMEN
The medicinal mushroom Antrodia cinnamomea has been demonstrated to have anti-inflammatory properties. However, the bioactive compounds in A. cinnamomea need further investigation. The present study aimed to understand the mechanism of action of antcamphin M, an ergostanoid isolated from A. cinnamomea mycelium and to clarify its underlying mechanisms of action. RAW264.7 cells were pretreated with the indicated concentrations of antcamphin M, prior to stimulation with lipopolysaccharide (LPS). Cell viability, production of nitric oxide (NO), prostaglandin E2 (PGE2), cytokines, and chemokines, as well as the inflammation-related signaling pathways were investigated. The study revealed that antcamphin M significantly decreased the LPS-induced production of NO, PGE2, pro-inflammatory cytokines, and keratinocyte chemoattractant CXCL1 (KC), along with the levels of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) proteins without significant cytotoxicity, indicating it had a better anti-inflammatory activity than that of gisenoside Rb1 and Rg1. Additionally, antcamphin M significantly inhibited the activation of MAPKs (p38, ERK, and JNK), NFκB, and components of the NLRP3 inflammasome (NLRP3, ASC, and caspase-1) signaling pathways and also increased the levels of nuclear factor erythroid-2-related factor (Nrf2) and heme oxygenase-1 (HO-1). These findings suggest that antcamphin M possesses potent anti-inflammatory activities and could be a potential candidate for the development of anti-inflammatory drugs.
Asunto(s)
Antiinflamatorios/farmacología , Medicamentos Herbarios Chinos/farmacología , Ergosterol/análogos & derivados , Hemo-Oxigenasa 1/inmunología , Inflamasomas/inmunología , Factor 2 Relacionado con NF-E2/inmunología , Proteína con Dominio Pirina 3 de la Familia NLR/inmunología , Receptor Toll-Like 4/inmunología , Animales , Antrodia/química , Quimiocina CXCL1/genética , Quimiocina CXCL1/inmunología , Dinoprostona/inmunología , Ergosterol/farmacología , Hemo-Oxigenasa 1/genética , Inflamasomas/genética , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Ratones , Factor 2 Relacionado con NF-E2/genética , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Óxido Nítrico/inmunología , Células RAW 264.7 , Transducción de Señal/efectos de los fármacos , Receptor Toll-Like 4/genéticaRESUMEN
We investigated the anti-inflammatory and antibacterial activities of Hc-cath, a cathelicidin peptide derived from the venom of the sea snake, Hydrophis cyanocyntus, using in vivo models of inflammation and infection. Hc-cath function was evaluated in in vitro, in vivo in the wax moth, Galleria mellonella, and in mouse models of intraperitoneal and respiratory Pseudomonas aeruginosa infection. Hc-Cath downregulated LPS-induced pro-inflammatory responses in macrophages and significantly improved the survival of P. aeruginosa infected G. mellonella over a 5-day period. We also demonstrated, for the first time, that Hc-cath can modulate inflammation in a mouse model of LPS-induced lung inflammation by significantly reducing the release of the pro-inflammatory cytokine and neutrophil chemoattractant, KC, resulting in reduced cellular infiltration into the lungs. Moreover, Hc-cath treatment significantly reduced the bacterial load and inflammation in mouse models of P. aeruginosa intraperitoneal and respiratory infection. The effect of Hc-cath in our studies highlights the potential to develop this peptide as a candidate for therapeutic development.