Hyperglycemia induces inducible nitric oxide synthase gene expression and consequent nitrosative stress via c-Jun N-terminal kinase activation

Yang, Peixin; Cao, Yuan-Ning; Li, Hua

doi:10.1016/j.ajog.2010.05.003

Cited by 59 publications

(62 citation statements)

References 23 publications

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“…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 . To explore whether curcumin treatment blocks high glucose-induced oxidative and nitrosative stress, we assessed the levels of 4-HNE, a lipidperoxidation marker and nitrotyrosine-modified protein.…”

Section: Resultsmentioning

confidence: 99%

“…Oxidative stress-induced kinase signaling triggers ER stress in the developing embryo, leading to NTD formation 19 . 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 .…”

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: 99%

Section: Introductionmentioning

confidence: 99%

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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“…9 Indeed, it has been shown that hyperglycemia stimulates iNOS gene expression and nitrosative stress in diabetic embryopathy and activation of c-Jun N-terminal kinases 1 and 2 (JNK1/2) appears to play a key role in this process. 26 However, further studies are warranted to establish causality between hyperglycemia and leukocyte NOS2 overexpression in GDM women in the context of nitrosative stress. It is of note that several studies have reported iNOS overexpression in metabolic tissues of both dietary and genetic models of obesity.…”

Section: Discussionmentioning

confidence: 99%

Increased expression of immune-related genes in leukocytes of patients with diagnosed gestational diabetes mellitus (GDM)

Wójcik

Zieleniak

Źurawska-Kliś

et al. 2015

Exp Biol Med (Maywood)

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Compelling evidence indicates that the immune system is linked to metabolism in gestational diabetes mellitus (GDM), but factors participating in these processes still are awaiting identification. Inducible nitric oxide synthase, encoded by the NOS2 gene, and surfactant protein D, encoded by the SFTPD gene, have been implicated in diabetes. We investigated NOS2 and SFTPD mRNA levels in leukocytes obtained from 125 pregnant women with (n ¼ 87) or without (control group; n ¼ 38) GDM, and, in turn, correlated their expression with clinical parameters of subjects. Leukocytes were isolated from the blood of pregnant women and NOS2 and SFTPD expression in these cells was determined by quantitative real time PCR (qRT-PCR). Univariate correlation analyses were performed to assess an association between leukocyte NOS2 and SFTPD expression and clinical characteristics of patients. qRT-PCR experiments disclosed significantly increased leukocyte NOS2 and SFTPD mRNA levels in hyperglycemic GDM patients (P < 0.05). In the entire study group, there were significant positive associations of leukocyte NOS2 and SFTPD mRNAs with C-reactive protein. Additionally, transcript level of SFTPD also correlated positively with fasting glycemia and insulin resistance. This study demonstrates that an impaired glucose metabolism in GDM may be predominant predictor of leukocyte NOS2 and SFTPD overexpression in diabetic patients. Furthermore, alterations in the expression of these genes are associated with glucose metabolism dysfunction and/or inflammation during pregnancy. In addition, these findings support the utilization of leukocytes as good experimental model to study a relationship between immune-related genes and metabolic changes in women with GDM, as well as to assess the potential mechanisms underlying these alterations.

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“…Thus, NOS uncoupling and tetrahydrobiopterin deficiency contribute to the inflammatory and abnormal cytokine milieu in the vasculature (71). Furthermore, hyperglycemia significantly elicits the expression of cytokine-inducible NOS (iNOS) both in vitro and in vivo (36,118). Indeed, hyperglycemia induced by streptozotocin in Nos2 gene knockout mice led to diabetic cardiomyopathy, and sepiapterin, an inhibitor of NOS uncoupling, improved systolic FIG.…”

Section: Inflammation and Oxidative Stress In Endothelial Dysfunctionmentioning

confidence: 99%

Differential Metabolic Actions of Specific Statins: Clinical and Therapeutic Considerations

Lim

Sakuma

Quon

et al. 2014

Antioxidants & Redox Signaling

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Significance: Statins, the most widely prescribed drugs in clinical practice, mainly act by reducing the plasma level of low-density lipoprotein (LDL)-cholesterol. A shift in redox homeostasis to an imbalance between reactive oxygen species generation and endogenous antioxidant mechanisms results in oxidative stress that has been implicated in the pathogenesis of various diseases, including those of the cardiovascular system. Beyond their efficacy in lowering LDL cholesterol, statins modulate redox systems that are implicated in the development of atherosclerosis, cardiovascular morbidity, and mortality. Recent Advances: Differences in specific statins or their dosages result in differential metabolic actions arising from off-target or unknown mechanisms of action that can have important implications for overall patient morbidity and mortality. Critical Issues: A recent meta-analysis and a combined analysis have suggested that high doses of statins increase the risk of developing type 2 diabetes mellitus, but reduce the risk of cardiovascular events. Thus, it is important to consider the cardiovascular and metabolic context and natural history of diseases when choosing a specific statin therapy for optimal individual patient health over the long term. Future Directions: More information is needed regarding the metabolism of statins, and the off-target or unknown actions of statins in affecting insulin resistance and metabolic homeostasis. The differential metabolic effects of specific statins should be considered in formulating optimal therapeutic strategies to reduce not just cardiovascular-related but also overall patient morbidity and mortality. Antioxid. Redox Signal. 20, 1286Signal. 20, -1299

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Hyperglycemia induces inducible nitric oxide synthase gene expression and consequent nitrosative stress via c-Jun N-terminal kinase activation

Cited by 59 publications

References 23 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

Increased expression of immune-related genes in leukocytes of patients with diagnosed gestational diabetes mellitus (GDM)

Differential Metabolic Actions of Specific Statins: Clinical and Therapeutic Considerations

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