Asiaticoside exerts neuroprotection through targeting NLRP3 inflammasome activation.

BACKGROUND: Parkinson's disease (PD), a neurodegenerative disorder, is characterized by motor symptoms due to the progressive loss of dopaminergic neurons in the substantia nigra (SN) and striatum (STR), alongside neuroinflammation. Asiaticoside (AS), a primary active component with anti-inflammatory and neuroprotective properties, is derived from Centella asiatica. However, the precise mechanisms through which AS influences PD associated with inflammation are not yet fully understood. PURPOSE: This study aimed to explore the protective mechanism of AS in PD. METHODS: Targets associated with AS and PD were identified from the Swiss Target Prediction, Similarity Ensemble Approach, PharmMapper, and GeneCards database. A protein-protein interaction (PPI) network was constructed to identify potential therapeutic targets. Concurrently, GO and KEGG analyses were performed to predict potential signaling pathways. To validate these mechanisms, the effects of AS on 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD in mice were investigated. Furthermore, neuroinflammation and the activation of the NLRP3 inflammasome were assessed to confirm the anti-inflammatory properties of AS. In vitro experiments in BV2 cells were then performed to investigate the mechanisms of AS in PD. Moreover, CETSA, molecular docking, and molecular dynamics simulations (MDs) were performed for further validation. RESULTS: Network pharmacology analysis identified 17 potential targets affected by AS in PD. GO and KEGG analyses suggested the biological roles of these targets, demonstrating that AS interacts with 149 pathways in PD. Notably, the NOD-like receptor signaling pathway was identified as a key pathway mediating AS's effect on PD. In vivo studies demonstrated that AS alleviated motor dysfunction and reduced the loss of dopaminergic neurons in MPTP-induced PD mice. In vitro experiments demonstrated that AS substantially decreased IL-1ß release in BV2 cells, attributing this to the modulation of the NLRP3 signaling pathway. CETSA and molecular docking studies indicated that AS forms a stable complex with NLRP3. MDs suggested that ARG578 played an important role in the formation of the complex. CONCLUSION: In this study, we first predicted that the potential target and pathway of AS's effect on PD could be NLRP3 protein and NOD-like receptor signaling pathway by network pharmacology analysis. Further, we demonstrated that AS could alleviate symptoms of PD induced by MPTP through its interaction with the NLRP3 protein for the first time by in vivo and in vitro experiments. By binding to NLRP3, AS effectively inhibits the assembly and activation of the inflammasome. These findings suggest that AS is a promising inhibitor for PD driven by NLRP3 overactivation.

Fecal fermentation behavior and immunomodulatory activity of arabinoxylan from wheat bran.

Arabinoxylan (AX) is the predominant non-starch polysaccharide in wheat bran, known for its significant immunomodulatory activity. However, existing literature lacks comprehensive studies on AX fermentation by gut microbiota and its subsequent immunomodulatory mechanisms. In the present study, we aimed to investigate the effects of AX on the composition of gut microbiota and the characteristics of its immunomodulatory activity. For this purpose, an in vitro fermentation system and a cyclophosphamide-induced immunosuppressed mouse model were established to explore both the in vitro and in vivo effects of AX on gut microbiota and immune modulation. The results demonstrated that AX was metabolized by gut microbes and in turn to promoting the production of short-chain fatty acids (SCFAs), which concurrently led to a significant decrease in pH. Furthermore, AX treatment significantly changed the microbial composition, elevated the relative abundance of Actinobacteria while reducing that of Bacteroidetes. In the immunosuppressed mice, AX administration improved the thymus and spleen indices, mitigated spleen injury, and bolstered overall immunity. Moreover, AX altered the gut microbiota structure, increasing the abundance of Bacteroidetes and decreasing that of Firmicutes. These findings suggest that wheat bran-derived AX can modulate intestinal microbial composition, improve gut microecology, and enhance host immunity by targeting gut microbiota.

LncRNA THRIL, transcriptionally activated by AP-1 and stabilized by METTL14-mediated m6A modification, accelerates LPS-evoked acute injury in alveolar epithelial cells.

Acute lung injury (ALI) and its extreme manifestation, acute respiratory distress syndrome (ARDS), are life-threatening diseases in intensive care units. LncRNA THRIL plays a crucial role in regulating the inflammatory response; however, the potential function of THRIL in ALI/ARDS and the associated mechanism remain unclear. In our study, we found that THRIL was upregulated in the serum of ALI/ARDS patients, and its increased expression was positively correlated with the inflammatory cytokines IL-17. In LPS-induced A549 cells, knockdown of THRIL inhibited the release of the proinflammatory cytokines TNF-α, IL-1ß, IL-17, and IL-6, decreased the number of monodansylcadaverine-positive cells and LC3-II with immunofluorescence staining, decreased the expression of autophagy marker ATG7 and Beclin1, and increased expression of p62. Mechanistically, the transcription factor AP-1 bound directly to the THRIL promoter region and activated its transcription by c-Jun upon LPS exposure. Moreover, m6A modification of THRIL was increased in LPS-treated A549 cells, and METTL14 knockdown significantly abolished m6A modification and reduced stabilization of THRIL mRNA. In conclusion, our findings reveal that THRIL, transcriptionally activated by AP-1 and modified by METTL14-mediated m6A modification, induces autophagy in LPS-treated A549 cells, suggesting the potential application of THRIL for ALI/ARDS therapy.

Dammarane-type triterpene saponins from the roots of Panax notoginseng (Burk.) F. H. Chen and their neuroprotective effects.

Three undescribed dammarane-type triterpene saponins, 20(S)-sanchirhinoside A7-A9 (1-3), together with seventeen known ones, were isolated from the roots of Panax notoginseng (Burk.) F. H. Chen. The chemical structures of the new compounds were determined by HR-MS and NMR experiments along with chemical methods. To the best of our knowledge, compound 1 was the firstly reported fucose-containing triterpene saponin from plants in the genus of Panax. Moreover, the in vitro neuroprotective effects of the isolated compounds were evaluated. Compounds 11-12 displayed remarkable protective effects against PC12 cells injured by 6-hydroxydopamine.