国内团队:缺失MyD88或可改善肠道氧化损伤导致的恶病质
  • 百草枯(PQ)可导致肠上皮细胞(IECs)凋亡,并增加MyD88蛋白表达量;
  • 在IECs敲除MyD88可改善PQ诱导的细胞周期阻滞、 DNA损伤、线粒体功能障碍和ROS水平升高;
  • 敲除MyD88通过抑制mTOR信号,磷酸化p53,促进自噬,进而减少PQ诱导的ROS,减少细胞死亡;
  • 在小鼠模型中,使用MyD88特异性抑制剂ST2825通过促进体内自噬,有效改善PQ导致的体重减轻、食物摄入减少、腓肠肌和比目鱼肌减少和肠氧化应激。
主编推荐语
章台柳
肠道氧化应激在恶病质的诱导和进展中起着关键作用,恶病质通常根据体重减轻进行诊断和分类。因此,减少肠道氧化损伤是维护人类和动物健康的一种常见且高效的策略。中国科学院亚热带农业生态研究所的唐宇龙和湖南农业大学的谭碧娥合作在Journal of Cachexia, Sarcopenia and Muscle上发表文章,MyD88通过自噬依赖机制调节肠道氧化应激,这表明降低MyD88水平可能是肠道氧化损伤诱导体重减轻的一个假定的治疗目标。
关键字
延伸阅读本研究的原文信息和链接出处,以及相关解读和评论文章。欢迎读者朋友们推荐!

MyD88 deficiency ameliorates weight loss caused by intestinal oxidative injury in an autophagy-dependent mechanism

缺乏MyD88可通过自噬依赖机制改善肠道氧化损伤引起的体重减轻

10.1002/jcsm.12858

2021-11-22, Article

Abstract & Authors:展开

Abstract:收起
BACKGROUND: Gut health plays a vital role in the overall health and disease control of human and animals. Intestinal oxidative stress is a critical player in the induction and progression of cachexia which is conventionally diagnosed and classified by weight loss. Therefore, reduction of intestinal oxidative injury is a common and highly effective strategy for the maintenance of human and animal health. Here we identify intestinal myeloid differentiation primary response gene 88 (MyD88) as a novel target for intestinal oxidative stress using canonical oxidative stress model induced by paraquat (PQ) in vitro and in vivo.
METHODS: Intestinal oxidative stress was induced by administration of PQ in intestinal epithelial cells (IECs) and mouse model. Cell proliferation, apoptosis, DNA damage, mitochondrial function, oxidative status, and autophagy process were measured in wild-type and MyD88-deficient IECs during PQ exposure. Autophagy inhibitor (3-methyladenine) and activator (rapamycin) were employed to assess the role of autophagy in MyD88-deficient IECs during PQ exposure. MyD88 specific inhibitor, ST2825, was used to verify function of MyD88 during PQ exposure in mouse model.
RESULTS: MyD88 protein levels and apoptotic rate of IECs are increased in response to PQ exposure (P < 0.001). Intestinal deletion of MyD88 blocks PQ-induced apoptosis (~42% reduction) and DNA damage (~86% reduction), and improves mitochondrial fission (~37% reduction) and function including mitochondrial membrane potential (~23% increment) and respiratory metabolism capacity (~26% increment) (P < 0.01). Notably, there is a marked decrease in reactive oxygen species in MyD88-deficient IECs during PQ exposure (~70% reduction), which are consistent with high activity of antioxidative enzymes (~83% increment) (P < 0.001). Intestinal ablation of MyD88 inhibits mTOR signalling, and further phosphorylates p53 proteins during PQ exposure, which eventually promotes intestinal autophagy (~74% increment) (P < 0.01). Activation of autophagy (rapamycin) promotes IECs growth as compared with 3-methyladenine-treatment during PQ exposure (~173% increment), while inhibition of autophagy (3-methyladenine) exacerbates oxidative stress in MyD88-deficient IECs (P < 0.001). In mouse model, inhibition of MyD88 using specific inhibitor ST2825 followed by PQ treatment effectively ameliorates weight loss (~4% increment), decreased food intake (~92% increment), gastrocnemius and soleus loss (~24% and ~20% increment, respectively), and intestinal oxidative stress in an autophagy dependent manner (P < 0.01).
CONCLUSIONS: MyD88 modulates intestinal oxidative stress in an autophagy-dependent mechanism, which suggests that reducing MyD88 level may constitute a putative therapeutic target for intestinal oxidative injury-induced weight loss.

First Authors:
Ming Qi

Correspondence Authors:
Yulong Tang,Bie Tan

All Authors:
Ming Qi,Simeng Liao,Jingjing Wang,Yuankun Deng,Andong Zha,Yirui Shao,Zhijuan Cui,Tongxing Song,Yulong Tang,Bie Tan,Yulong Yin

评论