RESUMO
Neuropathic pain (NeP) is a condition charactesized by nervous system injury or dysfunction that affects a significant portion of the population. Current treatments are ineffective, highlighting the need for novel therapeutic approaches. Mahuang Fuzi Xixin decoction (MFXD) has shown promise for treating pain conditions in clinical practice; however, its potential against NeP and the underlying mechanisms remain unclear. This study identified 35 compounds in MFXD using ultra-high performance liquid chromatography coupled with high-resolution mass spectrometry (UHPLC-HRMS). The analgesic effects of MFXD on chronic constriction injury (CCI) rats were evaluated through the detection of mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL). The analgesic effects of MFXD in rats with chronic constriction injury (CCI) were evaluated by measuring the mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL). Low-dose MFXD (L-MFXD) group (4.8 g/kg) and high-dose MFXD (H-MFXD) group (9.6 g/kg) exhibited significantly higher MWT and TWL values than the CCI group on days 11 and 15 post-CCI surgery, substantiating the remarkable analgesic efficacy of MFXD. Network pharmacology analysis identified 58 key targets enriched in pathways such as long-term potentiation (LTP) and glutamatergic synapse. The MCODE algorithm further identified core targets with significant enrichment in LTP. Molecular docking revealed that mesaconitine, rosmarinic acid, and delgrandine from MFXD exhibited high binding affinity with NMDAR2B (-11 kcal/mol), CaMKIIα (-14.3 kcal/mol), and ERK (-10.8 kcal/mol). Western blot and immunofluorescence confirmed that H-MFXD significantly suppressed the phosphorylation levels of NMDAR2B, CaMKIIα, ERK, and CREB in the spinal cord tissue of CCI rats. In conclusion, this study demonstrates that MFXD possesses potent analgesic effects on NeP by suppressing the NMDAR2B/CaMKIIα/ERK/CREB signalling pathway. This study unlocks a path toward potentially revolutionising NeP treatment with MFXD, encouraging further research and clinical development.
RESUMO
BACKGROUND: Exclusive enteral nutrition (EEN) is an important alternative strategy for patients with Crohn's disease (CD), and during this process, microbiota alterations have been observed. However, the underlying mechanisms by which EEN reduces intestinal inflammation are currently unclear. METHODS: The therapeutic potential of enteral nutrition (EN) was assessed using various mouse models. Fecal full-length 16S rDNA sequencing analysis and several CD metagenome datasets were used to identify the candidate therapeutic bacteria Faecalibaculum rodentium (F. rodentium). Whole genome sequencing of F. rodentium and widely-targeted metabolome analysis of the supernatant showed that EN-induced F. rodentium accumulation protected against colitis via histidine biosynthesis. FINDINGS: The therapeutic potential of EN therapy was observed in both dextran sulfate sodium (DSS)-induced colitis and Il10-/- spontaneous colitis mouse models. Accumulation of F. rodentium after EN therapy was determined using full-length 16S rDNA sequencing and verified with several metagenome datasets from patients with CD. Colonization of an isolated F. rodentium could reduce colitis in Il10-/- mice. Significant histidine enrichment was observed in the F. rodentium culture supernatant, and a series of histidine biosynthesis genes were observed in the F. rodentium genome. Engineered Escherichia coli Nissle 1917 (EcN), encoding the heterologous hisG of F. rodentium (EcN-hisG), which was a key driver of histidine biosynthesis in F. rodentium, was found to protect against colitis. INTERPRETATION: This study suggests that EN-induced F. rodentium accumulation protects against colitis in mice via gut bacteria-mediated histidine biosynthesis. FUNDING: A full list of funding bodies can be found in the Acknowledgements section.