RESUMO
Allergic diseases like asthma, allergic rhinitis and dermatitis pose a significant global health burden, driving the search for novel therapies. The NLRP3 inflammasome, a key component of the innate immune system, is implicated in various inflammatory diseases. Upon exposure to allergens, NLRP3 undergoes a two-step activation process (priming and assembly) to form active inflammasomes. These inflammasomes trigger caspase-1 activation, leading to the cleavage of pro-inflammatory cytokines (IL-1ß and IL-18) and GSDMD. This process induces pyroptosis and amplifies inflammation. Recent studies in humans and mice strongly suggest a link between the NLRP3 inflammasome, IL-1ß, and IL-18, and the development of allergic diseases. However, further research is needed to fully understand NLRP3's specific mechanisms in allergies. This review aims to summarize the latest advances in NLRP3 activation and regulation. We will discuss small molecule drugs and natural products targeting NLRP3 as potential therapeutic strategies for allergic diseases.
Assuntos
Hipersensibilidade , Inflamassomos , Inflamação , Proteína 3 que Contém Domínio de Pirina da Família NLR , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Humanos , Inflamassomos/metabolismo , Inflamassomos/imunologia , Animais , Hipersensibilidade/imunologia , Hipersensibilidade/tratamento farmacológico , Hipersensibilidade/metabolismo , Hipersensibilidade/terapia , Inflamação/imunologia , Inflamação/metabolismoRESUMO
BACKGROUND: The role of periodontal ligament stem cells (PDLSCs) in repairing periodontal destruction is crucial, but their functions can be impaired by excessive oxidative stress (OS). Nocardamine (NOCA), a cyclic siderophore, has been shown to possess anti-cancer and anti-bacterial properties. This study aimed to investigate the protective mechanisms of NOCA against OS-induced cellular dysfunction in PDLSCs. METHODS: The cytotoxicity of NOCA on PDLSCs was assessed using a CCK-8 assay. PDLSCs were then treated with hydrogen peroxide (H2O2) to induce OS. ROS levels, cell viability, and antioxidant factor expression were analyzed using relevant kits after treatment. Small molecule inhibitors U0126 and XAV-939 were employed to block ERK signaling and Wnt pathways respectively. Osteogenic differentiation was assessed using alkaline phosphatase (ALP) activity staining and Alizarin Red S (ARS) staining of mineralized nodules. Expression levels of osteogenic gene markers and ERK pathway were determined via real-time quantitative polymerase chain reaction (RT-qPCR) or western blot (WB) analysis. ß-catenin nuclear localization was examined by western blotting and confocal microscopy. RESULTS: NOCA exhibited no significant cytotoxicity at concentrations below 20 µM and effectively inhibited H2O2-induced OS in PDLSCs. NOCA also restored ALP activity, mineralized nodule formation, and the expression of osteogenic markers in H2O2-stimulated PDLSCs. Mechanistically, NOCA increased p-ERK level and promoted ß-catenin translocation into the nucleus; however, blocking ERK pathway disrupted the osteogenic protection provided by NOCA and impaired its ability to induce ß-catenin nuclear translocation under OS conditions in PDLSCs. CONCLUSIONS: NOCA protected PDLSCs against H2O2-induced OS and effectively restored impaired osteogenic differentiation in PDLSCs by modulating the ERK/Wnt signaling pathway.
Assuntos
Diferenciação Celular , Peróxido de Hidrogênio , Osteogênese , Estresse Oxidativo , Ligamento Periodontal , Células-Tronco , Ligamento Periodontal/citologia , Ligamento Periodontal/metabolismo , Ligamento Periodontal/efeitos dos fármacos , Humanos , Estresse Oxidativo/efeitos dos fármacos , Células-Tronco/metabolismo , Células-Tronco/efeitos dos fármacos , Peróxido de Hidrogênio/farmacologia , Peróxido de Hidrogênio/toxicidade , Osteogênese/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , beta Catenina/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Células Cultivadas , Espécies Reativas de Oxigênio/metabolismoRESUMO
Six new sesquiterpene quinone/hydroquinone meroterpenoids, arenarialins A-F (1-6), were isolated from the marine sponge Dysidea arenaria collected from the South China Sea. Their chemical structures and absolute configurations were determined by HRMS and NMR data analyses coupled with DP4+ and ECD calculations. Arenarialin A (1) features an unprecedented tetracyclic 6/6/5/6 carbon skeleton, whereas arenarialins B-D (2-4) possess two rare secomeroterpene scaffolds. Arenarialins A-F showed inhibitory activity on the production of inflammatory cytokines TNF-α and IL-6 in LPS-induced RAW264.7 macrophages with arenarialin D regulating the NF-κB/MAPK signaling pathway.