Chitosan oligosaccharides ameliorates maternal diabetes-induced embryonic neural tube defects via inhibitting excessive pyroptosis of neuroepithelial cells

Maternal diabetes significantly induces embryonic neural tube defects (NTDs). Thus, it is urgent need to further investigate the regulatory mechanism and therapeutic strategy for maternal diabetes-induced embryonic NTDs. Pyroptosis is a novel mode of programmed cell death. The role of pyroptosis on the maternal diabetes-induced embryonic NTDs is still unclear. Chitosan oligosaccharides (COSs) is a kind of natural polysaccharide with anti-inflammatory and anti-oxidant bioactivities, and its role on NTDs formation is poorly understood. Here, we hypothesized that excessive pyroptosis is another important mechanism for diabetes-induced NTDs formation, and COSs can exert its anti-inflammatory and antioxidant activities to alleviate maternal diabetes-mediated embryonic neuroepithelial cells pyroptosis and NTDs formation. Firstly, we confirmed that maternal diabetes significantly induces the embryonic NTDs formation (13.2% of NTDs rate). More interestingly, the mechansim study found that maternal diabetes significantly triggers the elevated pyroptosis level in embryos. And VX765, a pyroptosis inhibitor, significantly ameliorated the diabetes-induced embryonic NTDs (1.9% NTDs). Additionally, COSs treatment significantly reduced the maternal diabetes-associated the embryonic NTDs formation with 2.6% NTDs rate. Mechanistic studies further demonstrated that COSs significantly inhibits maternal diabetes-induced elevated inflammatory response and oxidative stress in embryos, and subsequently ameliorates the pyroptotic level of embryonic neuroepithelial cells through inhibiting TXNIP-NLRP3 complex formation. In a conclusion, pyroptosis is a another key caused event for maternal diabetes-induced embryonic NTDs. COSs exerts its antioxidant effect to inhibit the pyroptosis of neuroepithelial cells and consequently alleviates maternal diabetes-induced embryonic NTDs.