RESUMO
In recent years, immunosuppressants have shown significant success in the treatment of autoimmune diseases. Therefore, there is an urgent need to develop additional immunosuppressants that offer more options for patients. Toosendanin has been shown to have immunosuppressive activity in vitro as well as effects on autoimmune hepatitis (AIH) in vivo. Toosendanin did not induce apoptosis in activated T-cells and affect the survival rate of naive T-cells. Toosendanin did not affect the expression of CD25 or secretion of IL-2 by activated T-cells, and not affect the expression of IL-4 and INF-γ. Toosendanin did not affect the phosphorylation of STAT5, ERK, AKT, P70S6K. However, toosendanin inhibited proliferation of anti-CD3/anti-CD28 mAbs-activated T-cells with IC50 of (10 ± 2.02) nM. Toosendanin arrested the cell cycle in the G0/G1 phase, significantly inhibited IL-6 and IL-17A secretion, promoted IL-10 expression, and inhibited the P38 MAPK pathway. Finally, toosendanin significantly alleviated ConA-induced AIH in mice. In Summary, toosendanin exhibited immunosuppressive activity in vivo and in vitro. Toosendanin inhibits the proliferation of activated T-cells through the P38 MAPK signalling pathway, significantly suppresses the expression of inflammatory factors, enhances the expression of anti-inflammatory factors, and effectively alleviates ConA-induced AIH in mice, suggesting that toosendanin may be a lead compound for the development of novel immunomodulatory agents with improved efficacy and reduced toxicity.
Assuntos
Proliferação de Células , Medicamentos de Ervas Chinesas , Linfócitos T , Triterpenos , Proteínas Quinases p38 Ativadas por Mitógeno , Animais , Proliferação de Células/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Camundongos , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Medicamentos de Ervas Chinesas/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Hepatite Autoimune/tratamento farmacológico , Hepatite Autoimune/imunologia , Hepatite Autoimune/patologia , Citocinas/metabolismo , Imunossupressores/farmacologia , Camundongos Endogâmicos BALB C , FemininoRESUMO
Three previously undescribed and sixteen known alkaloids were bioguidedly isolated from the bulbs of Narcissus tazetta subsp. chinensis (M.Roem.) Masamura & Yanagih. The structures were elucidated by spectroscopic data, including HRESIMS, NMR, and ECD. Eleven of the isolated alkaloids exhibited immunosuppressive activity on the proliferation of human T cells. (+)-Narciclasine (18) showed the most significantly suppressive activity with an IC50 value of 14 ± 5 nM. In vitro, (+)-narciclasine (18) blocked NF-κB signal transduction, but did not affect PI3K/AKT signal transduction. What was more, (+)-narciclasine significantly reduced ALT and AST levels and alleviated liver damage induced by ConA in AIH mouse model.
Assuntos
Alcaloides , Proliferação de Células , Imunossupressores , Narcissus , Narcissus/química , Humanos , Animais , Alcaloides/farmacologia , Alcaloides/química , Alcaloides/isolamento & purificação , Imunossupressores/farmacologia , Imunossupressores/química , Imunossupressores/isolamento & purificação , Camundongos , Proliferação de Células/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Estrutura Molecular , NF-kappa B/metabolismo , NF-kappa B/antagonistas & inibidores , Benzofenantridinas/farmacologia , Benzofenantridinas/química , Benzofenantridinas/isolamento & purificação , Relação Estrutura-Atividade , Relação Dose-Resposta a Droga , Estereoisomerismo , Transdução de Sinais/efeitos dos fármacos , Fenantridinas , Alcaloides de AmaryllidaceaeRESUMO
BACKGROUND: Guillain-Barré syndrome (GBS) is an auto-inflammatory peripheral nerve disease. Dendritic cell-mediated T cell polarization is of pivotal importance in demyelinating lesions of peripheral nerves and nerve roots. However, the regulatory function of VX-509 (Decernotinib)-modified tolerogenic dendritic cells (VX-509-tolDCs) during immune remodeling following GBS remains unclear. Here, we used experimental autoimmune neuritis (EAN) as a model to investigate these aspects of GBS. METHODS: DCs were treated with varying concentrations of VX-509 (0.25, 1, and 4 µM) or served as a control using 10-8 M 1,25-(OH)2D3. Flow cytometry was employed to assess the apoptosis, phenotype, and capacity to induce T cell responses of the treated DCs. In the in vivo experiments, EAN mice received administration of VX-509-tolDCs or 1,25-(OH)2D3-tolDCs via the tail vein at a dose of 1x106 cells/mouse on days 5, 9, 13, and 17. RESULTS: VX-509 inhibited the maturation of DCs and promoted the development of tolDCs. The function of antigen-specific CD4 + T cells ex vivo was influenced by VX-509-tolDCs. Furthermore, the adoptive transfer of VX-509-tolDCs effectively alleviated inflammatory demyelinating lesions in EAN by promoting Th17/Treg (T helper 17 and regulatory T cells) rebalance. CONCLUSION: The adoptive transfer of VX-509-tolDCs alleviated inflammatory demyelinating lesions in a mouse model of GBS, known as the EAN mouse, by partially restoring the balance between Treg and Th17 cells.