1693-P: Rapamycin Reduces Maternal Diabetes-Induced Neural Tube Defects by Suppressing Premature Senescence

Diabetes ◽  
2019 ◽  
Vol 68 (Supplement 1) ◽  
pp. 1693-P
Author(s):  
CHENG XU ◽  
PEIXIN YANG
Keyword(s):  
Neural Tube ◽  
Neural Tube Defects ◽  
Maternal Diabetes ◽  
Premature Senescence

scholarly journals Maternal diabetes induces senescence and neural tube defects sensitive to the senomorphic Rapamycin

2020 ◽  
Author(s):  
Cheng Xu ◽  
Wei-Bin Shen ◽  
E. Albert Reece ◽  
Hidetoshi Hasuwa ◽  
Christopher Harman ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Neural Tube ◽  
Neural Tube Defects ◽  
Maternal Diabetes ◽  
Dominant Negative ◽  
Neural Tube Closure ◽  
Premature Senescence ◽  
Cell Cycle Regulators ◽  
Transgenic Expression ◽  
Mechanistic Basis

ABSTRACTNeural tube defects (NTDs) are the second most common structural birth defects. Senescence, a state of permanent cell cyle arrest, only occurs after neural tube closure. Maternal diabetes-induced NTDs, severe diabetic complications leading to infant mortality or lifelong morbidity, may be linked to premature senescence. Here we report that premature senescence occurs in the mouse neuroepithelium and disrupts neurulation, leading to NTDs in diabetic pregnancy. Premature senescence and NTDs were abolished by deleting the transcription factor Foxo3a, the miR-200c gene, the cell cycle inhibitors p21 or p27, or by transgenic expression of the dominant-negative FoxO3a mutant or by the senomorphic rapamycin. Double transgenic expression of p21 and p27 mimicked maternal diabetes in inducing premature neuroepithelium senescence and NTDs. These findings integrate transcription- and epigenome-regulated miRNAs and cell cycle regulators in premature neruoepithelium senescence, and provide a mechanistic basis for targeting premature senescence and NTDs using senomorphs.

scholarly journals Maternal diabetes induces senescence and neural tube defects sensitive to the senomorphic rapamycin

2021 ◽  
Vol 7 (27) ◽  
pp. eabf5089
Author(s):  
Cheng Xu ◽  
Wei-Bin Shen ◽  
E. Albert Reece ◽  
Hidetoshi Hasuwa ◽  
Christopher Harman ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Neural Tube ◽  
Neural Tube Defects ◽  
Maternal Diabetes ◽  
Dominant Negative ◽  
Neural Tube Closure ◽  
Premature Senescence ◽  
Cell Cycle Regulators ◽  
Transgenic Expression ◽  
Mechanistic Basis

Neural tube defects (NTDs) are the second most common structural birth defect. Senescence, a state of permanent cell cycle arrest, occurs only after neural tube closure. Maternal diabetes–induced NTDs are severe diabetic complications that lead to infant mortality or lifelong morbidity and may be linked to premature senescence. Here, we report that premature senescence occurs in the mouse neuroepithelium and disrupts neurulation, leading to NTDs in diabetic pregnancy. Premature senescence and NTDs were abolished by knockout of the transcription factor Foxo3a, the miR-200c gene, and the cell cycle inhibitors p21 and p27; transgenic expression of the dominant-negative FoxO3a mutant; or the senomorphic rapamycin. Double transgenic expression of p21 and p27 mimicked maternal diabetes in inducing premature neuroepithelium senescence and NTDs. These findings integrate transcription- and epigenome-regulated miRNAs and cell cycle regulators in premature neuroepithelium senescence and provide a mechanistic basis for targeting premature senescence and NTDs using senomorphics.

scholarly journals Formation of neurodegenerative aggresome and death-inducing signaling complex in maternal diabetes-induced neural tube defects

2017 ◽  
Vol 114 (17) ◽  
pp. 4489-4494 ◽  
Author(s):  
Zhiyong Zhao ◽  
Lixue Cao ◽  
E. Albert Reece
Keyword(s):  
Cell Death ◽  
Neural Tube ◽  
Neural Tube Defects ◽  
Protein Misfolding ◽  
Maternal Diabetes ◽  
Misfolded Proteins ◽  
Caspase 8 ◽  
Signaling Complex

Diabetes mellitus in early pregnancy increases the risk in infants of birth defects, such as neural tube defects (NTDs), known as diabetic embryopathy. NTDs are associated with hyperglycemia-induced protein misfolding and Caspase-8–induced programmed cell death. The present study shows that misfolded proteins are ubiquitinylated, suggesting that ubiquitin-proteasomal degradation is impaired. Misfolded proteins form aggregates containing ubiquitin-binding protein p62, suggesting that autophagic-lysosomal clearance is insufficient. Additionally, these aggregates contain the neurodegenerative disease-associated proteins α-Synuclein, Parkin, and Huntingtin (Htt). Aggregation of Htt may lead to formation of a death-inducing signaling complex of Hip1, Hippi, and Caspase-8. Treatment with chemical chaperones, such as sodium 4-phenylbutyrate (PBA), reduces protein aggregation in neural stem cells in vitro and in embryos in vivo. Furthermore, treatment with PBA in vivo decreases NTD rate in the embryos of diabetic mice, as well as Caspase-8 activation and cell death. Enhancing protein folding could be a potential interventional approach to preventing embryonic malformations in diabetic pregnancies.

N-3 polyunsaturated fatty acids effectively protect against neural tube defects in diabetic mice induced by streptozotocin

2021 ◽  
Author(s):  
Kelei Li ◽  
Yan Shi ◽  
Suqin Zhu ◽  
Xianfeng Shao ◽  
Huiying Li ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Fatty Acids ◽  
Polyunsaturated Fatty Acids ◽  
Neural Tube ◽  
Neural Tube Defects ◽  
Maternal Diabetes ◽  
Folate Deficiency ◽  
Diabetic Mice ◽  
Maternal Diabetes Mellitus

Folate cannot prevent all neural tube defects (NTD), indicating other pathogenesis still exists except for folate deficiency. Maternal diabetes mellitus during pregnancy can increase the risk of offspring NTD. Our...

scholarly journals Trehalose prevents neural tube defects by correcting maternal diabetes-suppressed autophagy and neurogenesis

2013 ◽  
Vol 305 (5) ◽  
pp. E667-E678 ◽  
Author(s):  
Cheng Xu ◽  
Xuezheng Li ◽  
Fang Wang ◽  
Hongbo Weng ◽  
Peixin Yang
Keyword(s):  
Gene Expression ◽  
Er Stress ◽  
Neural Tube ◽  
Neural Tube Defects ◽  
Maternal Diabetes ◽  
Neural Tubes ◽  
Potential Efficacy ◽  
Neuroepithelial Cells ◽  
Intracellular Process ◽  
Mitochondrial Defects

Preexisting maternal diabetes increases the risk of neural tube defects (NTDs). The mechanism underlying maternal diabetes-induced NTDs is not totally defined, and its prevention remains a challenge. Autophagy, an intracellular process to degrade dysfunction protein and damaged cellular organelles, regulates cell proliferation, differentiation, and apoptosis. Because autophagy impairment causes NTDs reminiscent of those observed in diabetic pregnancies, we hypothesize that maternal diabetes-induced autophagy impairment causes NTD formation by disrupting cellular homeostasis, leading to endoplasmic reticulum (ER) stress and apoptosis, and that restoration of autophagy by trehalose, a natural disaccharide, prevents diabetes-induced NTDs. Embryos from nondiabetic and type 1 diabetic mice fed with or without 2 or 5% trehalose water were used to assess markers of autophagy, ER stress, and neurogenesis, numbers of autophagosomes, gene expression that regulates autophagy, NTD rates, indices of mitochondrial dysfunction, and neuroepithelial cell apoptosis. Maternal diabetes suppressed autophagy by significantly reducing LC3-II expression, autophagosome numbers, and GFP-LC3 punctate foci in neuroepithelial cells and by altering autophagy-related gene expression. Maternal diabetes delayed neurogenesis by blocking Sox1 neural progenitor differentiation. Trehalose treatment reversed autophagy impairment and prevented NTDs in diabetic pregnancies. Trehalose resolved homeostatic imbalance by correcting mitochondrial defects, dysfunctional proteins, ER stress, apoptosis, and delayed neurogenesis in the neural tubes exposed to hyperglycemia. Our study demonstrates for the first time that maternal diabetes suppresses autophagy in neuroepithelial cells of the developing neural tube, leading to NTD formation, and provides evidence for the potential efficacy of trehalose as an intervention against hyperglycemia-induced NTDs.

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