SOD1 overexpression in vivo blocks hyperglycemia-induced specific PKC isoforms: substrate activation and consequent lipid peroxidation in diabetic embryopathy

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

doi:10.1016/j.ajog.2011.02.071

Cited by 49 publications

(57 citation statements)

References 41 publications

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“…This appears to occur by reduction of LPO levels and diminished expression of the cellular lipidperoxidation marker, 4-HNE, and nitrosative stress marker, nitrotyrosine. Our previous studies have indicated that oxidative stress is a causal event in the induction of diabetic embryopathy 3, 18 . This present work confirms previous observations that curcumin inhibits diabetes-induced superoxide production, a major agonist of oxidative stress 13 .…”

Section: Resultsmentioning

confidence: 98%

“…Oxidative stress is a key mechanism underlying maternal diabetes-induced NTD formation 3, 18, 19 . Maternal diabetes-induced ROS react with iNOS-induced nitric oxide to generate RNS, which cause to a severe form of oxidative stress, nitrosative stress 23 .…”

Section: Resultsmentioning

confidence: 99%

“…iNOS expression and its associated nitrosative stress are induced by maternal diabetes, and deletion of the iNos gene alleviates NTD formation in diabetic pregnancies 23 . Maternal diabetes-induced specific PKC isoform activation is a key component of the causal events in NTD formation 18, 24 . It is possible that curcumin can target all critical events that lead to diabetic embryopathy.…”

Section: Introductionmentioning

confidence: 99%

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Curcumin ameliorates high glucose-induced neural tube defects by suppressing cellular stress and apoptosis

Wang

Reece

et al. 2015

American Journal of Obstetrics and Gynecology

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Objectives Curcumin is a naturally occurring polyphenol present in the roots of the Curcuma longa plant (turmeric), which possesses antioxidant, anti-tumorigenic and anti-inflammatory properties. Here, we test whether curcumin treatment reduces high glucose-induced neural tube defects (NTDs), and if this occurs via blocking cellular stress and caspase activation. Study Design Embryonic day 8.5 mouse embryos were collected for use in whole embryo culture under normal glucose (100 mg/dl glucose) or high glucose (300 mg/dl glucose) conditions, with or without curcumin treatment. After 24 h in culture, protein levels of oxidative stress makers, nitrosative stress makers, endoplasmic reticulum (ER) stress makers, cleaved caspase 3 and 8 and the level of lipid peroxides (LPO) were determined in the embryos. After 36 h in culture, embryos were examined for evidence of NTD formation. Results Although 10 μM curcumin did not significantly reduce the rate of NTDs caused by high glucose, 20 μM curcumin significantly ameliorated high glucose-induced NTD formation. Curcumin suppressed oxidative stress in embryos cultured under high glucose conditions. Treatment reduced the levels of the lipid peroxidation marker, 4-hydroxynonenal(4-HNE), nitrotyrosine-modified protein, and LPO. Curcumin also blocked ER stress by inhibiting phosphorylated protein kinase ribonucleic acid (RNA)-like ER kinase (p-PERK), phosphorylated inositol-requiring protein-1α (p-IRE1α), phosphorylated eukaryotic initiation factor 2α (p-eIF2α), C/EBP-homologous protein (CHOP), binding immunoglobulin protein (BiP) and x-box binding protein 1 (XBP1) mRNA splicing. Additionally, curcumin abolished caspase 3 and caspase 8 cleavage in embryos cultured under high glucose conditions. Conclusions Curcumin reduces high glucose-induced NTD formation by blocking cellular stress and caspase activation, suggesting that curcumin supplements could reduce the negative effects of diabetes on the embryo. Further investigation will be needed to determine if the experimental findings can translate into clinical settings.

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Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Curcumin ameliorates high glucose-induced neural tube defects by suppressing cellular stress and apoptosis

Wang

Reece

et al. 2015

American Journal of Obstetrics and Gynecology

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“…Pregnancy with pre-existing maternal diabetes significantly increases the risk of excess apoptosis occurs in target tissues of the developing embryos resulting in diabetes-induced birth defects, such as neural tube defects (NTDs) and congenital heart defects (CHDs) 1-8 . Each year, 10% of babies of diabetic mothers are born with a major congenital malformation 9 .…”

Section: Introductionmentioning

confidence: 99%

“…Each year, 10% of babies of diabetic mothers are born with a major congenital malformation 9 . Mechanistic studies demonstrate that maternal diabetes alters multiple cellular and metabolic factors contributing to diabetic embryopathy 1, 4, 10-13 . We propose that these cellular and metabolic aberrations occur through a single transcriptional mechanism, a transcription factor and its responsive gene, leading to apoptosis in embryonic cells.…”

Section: Introductionmentioning

confidence: 99%

Advances in revealing the molecular targets downstream of oxidative stress–induced proapoptotic kinase signaling in diabetic embryopathy

Wang

Reece

Yang

2015

American Journal of Obstetrics and Gynecology

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Pre-existing maternal diabetes is a high risk factor of diabetic embryopathy, such as neural tube defects (NTDs) and congenital heart defects (CHD). Maternal diabetes significantly increases the production of reactive oxygen species (ROS) resulting in oxidative stress and diabetic embryopathy. Multiple cellular and metabolic factors contribute to these processes. FoxO3a has been demonstrated as a key transcription factor in the signaling transduction pathways responsible for maternal diabetes-induced birth defects. ASK1 activated by oxidative stress stimulates nuclear translocation of FoxO3a, resulting in over-expression of TRADD, which, in turn, leads to caspase 8 activation and apoptosis. Maternal diabetes-activated JNK1/2, downstream effectors of ASK1, can be blocked by SOD1 overexpression, suggesting that oxidative stress is responsible for JNK1/2 signaling activation. Deletion of JNK1/2 significantly suppressed the activity of FoxO3a. These obersvations indicate that maternal diabetes-induced oxidative stress stimulates the activation of ASK1, JNK1/2, FoxO3a, TRADD, caspase 8 cleavage, finally, apoptosis and diabetic embryopathy.

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Maternal hyperglycemia and fetal cardiac development: Clinical impact and underlying mechanisms

Basu

Garg

2018

Birth Defects Research

120

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Congenital heart disease (CHD) is the most common type of birth defect and is both a significant pediatric and adult health problem, in light of a growing population of survivors. The etiology of CHD has been considered to be multifactorial with genetic and environmental factors playing important roles. The combination of advances in cardiac developmental biology, which have resulted in the elucidation of molecular pathways regulating normal cardiac morphogenesis, and genome sequencing technology have allowed the discovery of numerous genetic contributors of CHD ranging from chromosomal abnormalities to single gene variants. On the other hand, mechanistic details of the contribution of environmental factors to CHD remain unknown. Maternal diabetes mellitus (matDM) is a well-established and increasingly prevalent environmental risk factor for CHD, but the underlying etiologic mechanisms by which pre-gestational matDM increases the vulnerability of embryos to cardiac malformations remains largely elusive. Here, we will briefly discuss the multifactorial etiology of CHD with a focus on the epidemiologic link between matDM and CHD. We will describe the animal models used to study the underlying mechanisms between matDM and CHD and review the numerous cellular and molecular pathways affected by maternal hyperglycemia in the developing heart. Lastly, we discuss how this increased understanding may open the door for the development of novel prevention strategies to reduce the incidence of CHD in this high-risk population.

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SOD1 overexpression in vivo blocks hyperglycemia-induced specific PKC isoforms: substrate activation and consequent lipid peroxidation in diabetic embryopathy

Cited by 49 publications

References 41 publications

Curcumin ameliorates high glucose-induced neural tube defects by suppressing cellular stress and apoptosis

Curcumin ameliorates high glucose-induced neural tube defects by suppressing cellular stress and apoptosis

Advances in revealing the molecular targets downstream of oxidative stress–induced proapoptotic kinase signaling in diabetic embryopathy

Maternal hyperglycemia and fetal cardiac development: Clinical impact and underlying mechanisms

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