c-Jun NH2-Terminal Kinase 1/2 and Endoplasmic Reticulum Stress as Interdependent and Reciprocal Causation in Diabetic Embryopathy

Li, Xuezheng; Xu, Cheng; Yang, Peixin

doi:10.2337/db12-0026

Cited by 73 publications

(175 citation statements)

References 45 publications

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“…Ask1 deletion abrogates JNK1/2 activation and the activation of three transcription factors downstream of JNK1/2. Our previous evidence supports a reciprocal causative relationship between the JNK1/2 pathway and ER stress (18). Indeed, along with JNK1/2 activation, ER stress is manifested in the developing heart exposed to diabetes.…”

Section: Discussionmentioning

confidence: 86%

“…Both JNK1/2 activation and ER stress lead to apoptosis in diabetic embryopathy (18). In addition, JNK1/2 activation causes ER stress (18).…”

Section: Maternal Diabetes Activates Ask1 In the Developing Heartmentioning

confidence: 99%

“…In addition, JNK1/2 activation causes ER stress (18). To investigate whether maternal diabetes induces ER stress in the developing heart, we measured the levels of ER markers.…”

Section: Maternal Diabetes Activates Ask1 In the Developing Heartmentioning

confidence: 99%

“…Mouse models of maternal diabetes-induced embryonic malformations were described previously (18,57). Briefly, 10-wk-old WT and Ask1 Ϫ/Ϫ female mice were intravenously injected daily with 75 mg/kg STZ over 2 days to induce diabetes.…”

Section: Mice and Reagentsmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 86%

“…Both JNK1/2 activation and ER stress lead to apoptosis in diabetic embryopathy (18). In addition, JNK1/2 activation causes ER stress (18).…”

Section: Maternal Diabetes Activates Ask1 In the Developing Heartmentioning

confidence: 99%

“…In addition, JNK1/2 activation causes ER stress (18). To investigate whether maternal diabetes induces ER stress in the developing heart, we measured the levels of ER markers.…”

Section: Maternal Diabetes Activates Ask1 In the Developing Heartmentioning

confidence: 99%

Section: Mice and Reagentsmentioning

confidence: 99%

See 2 more Smart Citations

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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“…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%

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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114

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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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Cellular stress and apoptosis contribute to the pathogenesis of autism spectrum disorder

et al. 2018

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Autism results in significant morbidity and mortality in children. The functional and molecular changes in the autistic brains are unclear. The present study utilized autistic brain tissues from the National Institute of Child Health and Human Development's Brain Tissue Bank for the analysis of cellular and molecular changes in autistic brains. Three key brain regions, the hippocampus, the cerebellum, and the frontal cortex, in six cases of autistic brains and six cases of non-autistic brains from 6 to 16 years old deceased children, were analyzed. The current study investigated the possible roles of endoplasmic reticulum (ER) stress, oxidative stress, and apoptosis as molecular mechanisms underlying autism. The activation of three signals of ER stress (protein kinase R-like endoplasmic reticulum kinase, activating transcription factor 6, inositol-requiring enzyme 1 alpha) varies in different regions. The occurrence of ER stress leads to apoptosis in autistic brains. ER stress may result from oxidative stress because of elevated levels of the oxidative stress markers: 4-Hydroxynonenal and nitrotyrosine-modified proteins in autistic brains. These findings suggest that cellular stress and apoptosis may contribute to the autistic phenotype. Pharmaceuticals and/or dietary supplements, which can alleviate ER stress, oxidative stress and apoptosis, may be effective in ameliorating adverse phenotypes associated with autism.

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c-Jun NH2-Terminal Kinase 1/2 and Endoplasmic Reticulum Stress as Interdependent and Reciprocal Causation in Diabetic Embryopathy

Cited by 73 publications

References 45 publications

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

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

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

Cellular stress and apoptosis contribute to the pathogenesis of autism spectrum disorder

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