Oxidative Stress–Induced JNK1/2 Activation Triggers Proapoptotic Signaling and Apoptosis That Leads to Diabetic Embryopathy

Li, Xuezheng; Weng, Hongbo; Xu, Cheng; Reece, E. Albert; Yang, Peixin

doi:10.2337/db11-1624

Cited by 78 publications

(120 citation statements)

References 49 publications

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“…Previously, we have identified caspase 8 and caspase 3 as initiator and effector caspases, respectively, in maternal diabetes-induced apoptosis (23,24). In this study, we demonstrated that trehalose treatment abolished maternal diabetes-induced caspase 3 and 8 cleavage (Fig.…”

Section: Maternal Diabetes Suppresses Autophagy In Neuroepithelial Cesupporting

confidence: 64%

“…Our mouse model of diabetic embryopathy was described previously (23,24). Briefly, female mice were intravenously (iv) injected daily with 75 mg/kg streptozotocin (STZ) over 2 days to induce diabetes.…”

Section: Methodsmentioning

confidence: 99%

“…TUNEL assay. TUNEL assay was performed as described previously (23,24). Briefly, 5-m serial coronal sections through the forebrain-midbrain boundary of the anterior neural tube were fixed with 4% PFA in PBS and incubated with TUNEL reaction agents.…”

Section: Methodsmentioning

confidence: 99%

“…Studies from our group (23,24) and others (1,14,22,34,37) reveal that cellular stress, including oxidative stress and endoplasmic reticulum (ER) stress, and enhanced neural progenitor apoptosis play central roles in the induction of NTDs by maternal diabetes. However, the molecular intermediates downstream of hyperglycemia remain elusive.…”

mentioning

confidence: 99%

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

Xu¹,

Li²,

Wang³

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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115

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isting 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. diabetic embryopathy; autophagy; trehalose; neurogenesis; neural tube defects PREGESTATIONAL DIABETES significantly increases the risk of neural tube defects (NTDs), also known as diabetic embryopathy. There are three to 10 times more NTDs in the offspring of diabetic mothers than in those of nondiabetic mothers (3, 9, 36). Because optimal glycemic control is difficult to achieve and maintain, and even transient exposure to diabetes causes NTDs, maternal diabetes-induced NTDs are significant health problems for both the mother and child. The seriousness of these relationships is emphasized by the upsurge in diabetic pregnancies; nearly 3 million American women and 70 million women worldwide of reproductive age (18 -44 yr) have diabetes today, and this number is expected double by 2030. Although diabetic mellitus is a complex metabolic disease, hyperglycemia is the sole mediator of diabetes teratogenicity. Indeed, clinical studies have revealed a strong correlation between the degree of maternal hyperglycemia and the rate and severity of birth defects (15, 29). When whole rodent embryos are cultured in high concentra...

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Section: Maternal Diabetes Suppresses Autophagy In Neuroepithelial Cesupporting

confidence: 64%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

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

Xu¹,

Li²,

Wang³

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

Self Cite

115

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“…Western blotting was performed as described previously (17,57). Briefly, E12.5 embryonic hearts were sonicated in ice-cold RIPA lysis buffer (Millipore, Bedford, MA).…”

Section: Mice and Reagentsmentioning

confidence: 99%

ASK1 mediates the teratogenicity of diabetes in the developing heart by inducing ER stress and inhibiting critical factors essential for cardiac development

Wang¹,

Wu²,

Quon³

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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Modeling anterior development in mice: Diet as modulator of risk for neural tube defects

Kappen¹

2013

American J of Med Genetics Pt C

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Head morphogenesis is a complex process that is controlled by multiple signaling centers. The most common defects of cranial development are craniofacial defects, such as cleft lip and cleft palate, and neural tube defects, such as anencephaly and encephalocoele in humans. More than 400 genes that contribute to proper neural tube closure have been identified in experimental animals, but only very few causative gene mutations have been identified in humans, supporting the notion that environmental influences are critical. The intrauterine environment is influenced by maternal nutrition, and hence, maternal diet can modulate the risk for cranial and neural tube defects. This article reviews recent progress toward a better understanding of nutrients during pregnancy, with particular focus on mouse models for defective neural tube closure. At least four major patterns of nutrient responses are apparent, suggesting that multiple pathways are involved in the response, and likely in the underlying pathogenesis of the defects. Folic acid has been the most widely studied nutrient, and the diverse responses of the mouse models to folic acid supplementation indicate that folic acid is not universally beneficial, but that the effect is dependent on genetic configuration. If this is the case for other nutrients as well, efforts to prevent neural tube defects with nutritional supplementation may need to become more specifically targeted than previously appreciated. Mouse models are indispensable for a better understanding of nutrient–gene interactions in normal pregnancies, as well as in those affected by metabolic diseases, such as diabetes and obesity.

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Oxidative Stress–Induced JNK1/2 Activation Triggers Proapoptotic Signaling and Apoptosis That Leads to Diabetic Embryopathy

Cited by 78 publications

References 49 publications

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

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

ASK1 mediates the teratogenicity of diabetes in the developing heart by inducing ER stress and inhibiting critical factors essential for cardiac development

Modeling anterior development in mice: Diet as modulator of risk for neural tube defects

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