Dual Role of IGF2BP2 in Osteoimmunomodulation during Periodontitis.

Periodontitis is a complex disease characterized by distinct inflammatory stages, with a peak of inflammation in the early phase and less prominent inflammation in the advanced phase. The insulin-like growth factor 2-binding proteins 2 (IGF2BP2) has recently been identified as a new m6A reader that protects m6A-modified messenger RNAs (mRNAs) from decay, thus participating in multiple biological processes. However, its role in periodontitis remains unexplored. Here, we investigated the role of IGF2BP2 in inflammation and osteoclast differentiation using a ligature-induced periodontitis model. Our findings revealed that IGF2BP2 responded to bacterial-induced inflammatory stimuli and exhibited differential expression patterns in early and advanced periodontitis stages, suggesting its dual role in regulating this disease. Depletion of Igf2bp2 contributed to increased release of inflammatory cytokines, thereby exacerbating periodontitis after 3 d of ligature while suppressing osteoclast differentiation and ameliorating periodontitis after 14 d of ligature. Mechanistically, we demonstrated that IGF2BP2 directly interacted with Cd5l and Cd36 mRNA via RNA immunoprecipitation assay. Overexpression of CD36 or recombinant CD5L rescued the osteoclast differentiation ability of Igf2bp2-null cells upon lipopolysaccharide stimulus, and thus the downregulation of Cd36 and Cd5l effectively reversed periodontitis in the advanced stage. Altogether, this study deepens our understanding of the potential mechanistic link among the dysregulated m6A reader IGF2BP2, immunomodulation, and osteoclastogenesis during different stages of periodontitis.

Evodiamine inhibits gastrointestinal motility via CCK and CCK1 receptor in water-avoidence stress rat model.

AIM: Evodiamine (EVO) has been reported to play an important role in regulating gastrointestinal motility, but the evidence is insufficient, and the mechanism remains unknown. The aim of this study is to investigate the possible role of EVO in stress-induced colonic hypermotility and the potential mechanisms via both in vivo and in vitro investigations. METHODS: Male Sprague-Dawley rats were exposed to water avoidance stress (WAS) for 1 h or sham WAS daily for 10 consecutive days to construct the rat model. The colonic contractile activity was studied in an organ bath system. The serum CCK-8 level was detected using an enzyme immunoassay kit, and gastrointestinal transit was detected by intragastric administration of India ink. RESULTS: WAS induced gastrointestinal hypermotility in male rats. EVO significantly inhibited the contractile activity of colonic muscle strips; this effect was not blocked by TTX and the CCK1 receptor antagonist devazepide. Chronic WAS induced a slight but nonsignificant increase in the serum CCK-8 level, while EVO elevated the serum CCK-8 level in the WAS rats in a dose-dependent manner. Exogenous CCK-8 significantly inhibited the contractile activity of the colonic muscle strips; this effect was not blocked by TTX but was completely blocked by devazepide. Both EVO and CCK-8 inhibited gastrointestinal transit, and the effect of EVO could be partially blocked by devazepide. SIGNIFICANCE: EVO can reverse stress-induced gastrointestinal hypermotility. This effect may partially occur as a result of promoting the release of CCK and then activating the CCK1 receptor instead of directly activating the CCK1 receptor.