Shuguang Guan

Natural polysaccharides possess outstanding advantages including low toxicity, favorable biocompatibility, and multi-target regulatory capabilities. They hold broad application prospects in neuroprotective research on Alzheimer’s disease (AD) and depression. Owing to their high molecular weight and strong hydrophilicity, intact polysaccharides cannot readily cross the blood–brain barrier (BBB). Only a minor proportion enters the systemic circulation after oral administration. However, even under conditions of extremely low intracerebral exposure, polysaccharides still exhibit significant central neuroprotective effects. The underlying mechanism is that intact polysaccharides primarily act as fermentation substrates for gut microbiota, which then promote the production of short-chain fatty acids (SCFAs) and modulate tryptophan and bile acid metabolism. These peripheral metabolites, upon entering the circulation, further regulate peripheral immune responses and the activity of the hypothalamic–pituitary–adrenal (HPA) axis, improve neurotrophic signaling and redox homeostasis, and transmit signals to resident immune cells within the central nervous system via central boundary structures. Therefore, natural polysaccharides do not directly enter the brain. Instead, they exert neuroprotective effects via a cascade pathway involving the gut microbiota-peripheral metabolites-immune and humoral network. This article systematically elaborates on its multi-pathway mechanisms of action and summarizes adjunctive brain-targeted delivery approaches, including pathology-dependent modulation of BBB permeability and brain-targeted delivery. Future research should further elucidate the causal relationships among various signaling pathways, strengthen quality control and clinical trials, and facilitate their translational application.

Metabolic dysfunction-associated steatotic liver disease/nonalcoholic fatty liver disease (MASLD/NAFLD) and rheumatoid arthritis (RA) may share inflammatory mechanisms, although their common cellular basis remains unclear. We integrated bulk transcriptomic datasets (GSE66676 and GSE55235), single-cell RNA-sequencing datasets from murine RA synovium (GSE192504) and NASH liver (GSE129516), disease-association analysis, molecular docking, and in vitro experiments in LPS-stimulated RAW264.7 macrophages. Bulk transcriptomic analysis identified 630 shared differentially expressed genes, including 344 concordantly upregulated genes enriched in immune response, cytokine and chemokine signaling, phagosome, Toll-like receptor signaling, and Fc receptor-mediated phagocytosis; a strict dual-dataset intersection further defined 18 core genes significantly upregulated in both diseases. Immune-signature analysis indicated altered myeloid cell-associated inflammatory activity in both diseases, and several shared genes, including S100A8, S100A9, FCER1G, FCGR3A, LYZ, and MS4A7, correlated positively with monocyte/macrophage-related signatures. Single-cell analysis identified macrophage subsets with high S100a9 expression and elevated shared myeloid inflammatory signature scores in both RA synovium and NASH liver. Triptolide showed favorable predicted binding to the S100A8/A9 complex and reduced LPS-induced inflammatory cytokine secretion and expression of the six-gene signature in RAW264.7 cells, supporting the hypothesis that S100A9-associated inflammatory macrophage activation represents a candidate target for further investigation. These findings support a shared S100A9-positive inflammatory macrophage-associated program in MASLD/NAFLD and RA, and support the hypothesis that the S100A8/A9 complex represents a candidate target for further investigation.