METTL3 promotes microglial inflammation via MEF2C in spinal cord injury.

Spinal cord injury (SCI) is a significant contributor to disability in contemporary society, resulting in substantial psychological and economic burdens for patients and their family. Microglia-mediated inflammation is an important factor affecting the nerve repair of SCI patients. N6-methyladenosine (m6A) is a prevalent epigenetic modification in mammals, which shows a strong association with inflammation. However, the mechanism of m6A modification regulating microglia-mediated inflammation is still unclear. Here, we observed that METTL3, a m6A methylase, was increased in SCI mice and lipopolysaccharide (LPS)-exposed BV2 cells. Knockdown of METTL3 inhibited the increased expression of iNOS and IL-1ß induced by LPS in vitro. Subsequently, MEF2C, myocyte-specific enhancer factor 2C, was decreased in SCI mice and LPS-exposed BV2 cells. Knockdown of MEF2C promoted the expression of iNOS and IL-1ß. Sequence analysis showed that there were multiple highly confident m6A modification sites on the MEF2C mRNA. METTL3 antibody could pull down a higher level of MEF2C mRNA than the IgG in RNA binding protein immunoprecipitation assay. Knockdown of METTL3 promoted MEF2C protein expression and MEF2C mRNA expression, accompanied by a reduced m6A modification level on the MEF2C mRNA. Knockdown of MEF2C inhibited the anti-inflammatory effect of METTL3 siRNA. Our results suggest that METTL3 promotes microglia inflammation via regulating MEF2C mRNA m6A modification induced by SCI and LPS treatment.

Attenuating intervertebral disc degeneration through spermidine-delivery nanoplatform based on polydopamine for persistent regulation of oxidative stress.

As one of the most widespread musculoskeletal diseases worldwide, intervertebral disc degeneration (IVDD) remains an intractable clinical problem. Currently, oxidative stress has been widely considered as a significant risk factor in the IVDD pathological changes, and targeting oxidative stress injury to improve the harsh microenvironment may provide a novel and promising strategy for disc repair. It is evident that spermidine (SPD) has the ability to attenuate oxidative stress across several disease models. However, limited research exists regarding its impact on oxidative stress within the intervertebral disc. Moreover, enhancing the local utilization rate of SPD holds great significance in IVDD management. This study aimed to develop an intelligent biodegradable mesoporous polydopamine (PDA) nanoplatform for sustained release of SPD. The obtained PDA nanoparticles with spherical morphology and mesoporous structure released loaded-therapeutic molecules under low pH and H2O2. Combined treatment with SPD loaded into PDA nanoparticles (SPD/PDA) resulted in better therapeutic potential than those with SPD alone on oxidative stress injury. Furthermore, both SPD and SPD/PDA could induce anti-inflammatory M2 macrophage polarization. Upon injection into degenerative IVDs, the SPD/PDA group achieved a good repair efficacy with a long-term therapeutic effect. These findings indicated that the synergized use of SPD with responsive drug delivery nanocarriers may steadily scavenge reactive oxygen species and provide an effective approach toward the treatment of IVDD.