AS-1通过诱导细胞自噬并阻断内质网应激抑制妊娠糖尿病引起的神经管畸形的作用机制

Congenital malformations occur in up to 10% of babies born to diabetic women. Neural tube defects (NTDs) are among the most frequent and severe malformations associated with diabetes. It has been reported that even transient exposure to hyperglcemia can cause NTDs, so it is not controllable by only using hypoglycemic drugs. We have known that maternal diabetes can activate oxidative stress and endoplasmic reticulum (ER) stress which induce apoptosis resulting in NTDs. Multiple lines of evidence demonstrate that autophagy plays a role in diabetic embryopathy, but the mechanism of autophagy in maternal diabetes-induced NTDs is still unclear. Our preliminary study showed that AS-1, a bioactive flavonoid isolated from Alhagi sparsifolia, significantly inhibited maternal diabetes-induced NTDs in mice. We also found that LC3II, as a sensitive index of autophagy, decreased in embyos from diabetic dam, and obviously increased after AS-1 treatment. The current study will further investigate the mechanism of autophagy in maternal diabetes-induced NTDs, and provide a new target for NTDs therapy. Meanwhile, our study will firstly clarify the machanism of AS-1 on preventing maternal diabetes-induced NTDs by activating autophagy and suppressing ER stress, thus, provide evidence for exploring a highly effective and non-toxic natural drug in the prevention and therapy of NTDs.

妊娠糖尿病引起的胎儿畸形率高达出生缺陷的10%, 其中神经管畸形最为常见畸形之一。研究表明，短暂的高糖暴露即可引起胚胎畸形，因此单纯使用降糖药来控制神经管畸形并不可靠。据报道，妊娠糖尿病可引起氧化应激及内质网应激而诱导细胞凋亡，最终导致神经管畸形。我们研究发现，细胞自噬在妊娠糖尿病致小鼠胚胎神经管畸形中发挥着重要的作用，同时发现骆驼刺中的主成分AS-1能显著抑制妊娠糖尿病引起的神经管畸形。妊娠糖尿病小鼠胚胎中LC3II的含量与对照组相比显著降低，而AS-1给药后其含量显著增高。本研究将进一步深入探讨细胞自噬在妊娠糖尿病引起的神经管畸形中的作用机制，构建治疗该疾病的新靶标。同时首次分别从诱导细胞自噬和抑制内质网应激两个角度揭示AS-1抑制神经管畸形的机制，为发现低毒高效的防治神经管畸形的天然药物提供可靠的科学依据，具有较高的临床价值和社会意义。

妊娠糖尿病引起的胎儿畸形率高达出生缺陷的10%, 其中神经管畸形最为常见畸形之一。研究表明，短暂的高糖暴露即可引起胚胎畸形，因此单纯使用降糖药来控制神经管畸形并不可靠。据报道，妊娠糖尿病可引起氧化应激及内质网应激而诱导细胞凋亡，最终导致神经管畸形。我们研究发现，细胞自噬在妊娠糖尿病致小鼠胚胎神经管畸形中发挥着重要的作用，同时发现骆驼刺中的主成分AS-1能显著抑制妊娠糖尿病引起的神经管畸形。妊娠糖尿病小鼠胚胎中LC3II的含量与对照组相比显著降低，而AS-1给药后其含量显著增高。本研究深入探讨了细胞自噬在妊娠糖尿病引起的神经管畸形中的作用机制，构建治疗该疾病的新靶标。同时首次分别从诱导细胞自噬和抑制内质网应激两个角度揭示了AS-1抑制神经管畸形的机制，为发现低毒高效的防治神经管畸形的天然药物提供可靠的科学依据，具有较高的临床价值和社会意义。