To Die or Not to Die: the Function of the Transcription Factor NF‐<i>κ</i>B in Embryos Exposed to Stress

Torchinsky, Arkady; Toder, V.

doi:10.1046/j.8755-8920.2003.00134.x

Cited by 36 publications

(35 citation statements)

References 49 publications

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“…Since it has been reported that IFN-γ and TNF-α synergistically increase iNOS expression in macrophages [38], we postulate that the increased expression of IFN-γ enhanced iNOS expression in the embryos of diabetic mice by activation of NFκB. However, it is not yet clear whether iNos mRNA is regulated by NFκB in embryos, since this pathway may act differently in embryos to the way it acts in adults [39]. In addition, it has been shown that IFN-γ and NADPH oxidase components as well as TNF-α are not affected in diabetic embryopathy [40].…”

Section: Discussionmentioning

confidence: 87%

Prevention of neural tube defects by loss of function of inducible nitric oxide synthase in fetuses of a mouse model of streptozotocin-induced diabetes

et al. 2009

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Aims/hypothesis Maternal diabetes during pregnancy increases the risk of congenital malformations such as neural tube defects (NTDs). Although the mechanism of this effect is uncertain, it is known that levels of nitric oxide synthase (NOS) and nitric oxide are elevated in embryos of a mouse model of diabetes. We postulated that overproduction of nitric oxide causes diabetes-induced congenital malformations and that inhibition of inducible NOS (iNOS) might prevent diabetic embryopathy. Methods Mice were rendered hyperglycaemic by intraperitoneal injection of streptozotocin. The incidence of congenital malformations including NTDs was evaluated on gestational day 18.5. We assessed the involvement of iNOS in diabetesinduced malformation by administering ONO-1714, a specific inhibitor of iNOS, to pregnant mice with streptozotocininduced diabetic mice and by screening mice with iNOS deficiency due to genetic knockout (iNos −/− ). Results ONO-1714 markedly reduced the incidence of congenital anomalies, including NTDs, in fetuses of a mouse model of diabetes. It also prevented apoptosis in the head region of fetuses, indicating that iNOS is involved in diabetesrelated congenital malformations. Indeed, no NTDs were observed in fetuses of diabetic iNos −/− mice and the incidence of other malformations was also markedly reduced. Conclusions/interpretation We conclude that increased iNOS activity during organogenesis plays a crucial role in the pathogenesis of diabetes-induced malformations and suggest that inhibitors of iNOS might help prevent malformations, especially NTDs, in diabetic pregnancy.

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Section: Discussionmentioning

confidence: 87%

Prevention of neural tube defects by loss of function of inducible nitric oxide synthase in fetuses of a mouse model of streptozotocin-induced diabetes

et al. 2009

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“…Early in the infective process, T. cruzi activates a number of host cell signaling pathways (6), including PI-3K/Akt (57) and NF-B (22,26,27), both of which can activate prosurvival responses in mammalian cells (24,36,46,53). To determine if either of these T. cruzi-activated pathways contributes to the overall ability of T. cruzi to protect cardiac cells from apoptosis, T. cruzi-infected H9c2 cells were treated with wortmannin or the NF-B inhibitor peptides SN-50 and I kinase-NBD (IKK-I) immediately following infection and prior to induction of apoptosis by addition of TNF-␣.…”

Section: Resultsmentioning

confidence: 99%

Trypanosoma cruziInfection and Nuclear Factor Kappa B Activation Prevent Apoptosis in Cardiac Cells

et al. 2006

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Studies of cardiac pathology and heart failure have implicated cardiomyocyte apoptosis as a critical determinant of disease. Recent evidence indicates that the intracellular protozoan parasite Trypanosoma cruzi, which causes heart disease in chronically infected individuals, impinges on host apoptotic pathways in a cell type-dependent manner. T. cruzi infection of isolated neuronal cells and cardiomyocytes protects against apoptotic cell death, whereas apoptosis is triggered in T cells in T. cruzi-infected animals. In this study, we demonstrate that the ability of T. cruzi to protect cardiac cells in vitro from apoptosis triggered by a combination of tumor necrosis factor alpha and serum reduction correlates with the presence of intracellular parasites and involves activation of host cell NF-B. We further demonstrate that the apoptotic block diminishes activation of caspase 3. The ability of T. cruzi to prevent apoptosis of infected cardiomyocytes is likely to play an important role in establishment of persistent infection in the heart while minimizing potential damage and remodeling that is associated with cardiomyocyte apoptosis in cardiovascular disease.

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“…As to the role of NF-κB localized in the uterus, lack of activity on its part does not seem to impair implantation, as was observed in experimental mice where NF-κB activation has been blocked (references in [52]). At the same time, NF-κB activity in uterine cells is tightly regulated during implantation [53].…”

Section: Is the Tnfα-induced Apoptosis In The Uterus A Mechanism Of Dmentioning

confidence: 82%

TNFalpha in the Pathogenesis of Diabetes-Induced Embryopathies: Functions and Targets

Torchinsky¹,

Toder²

2007

Rev Diabet Stud

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■ AbstractHyperglycemia-induced increase in the production of reactive oxygen species (ROS) is proposed to be an initial step in the pathogenesis of diabetes-induced spontaneous abortions and structural inborn anomalies. However, the subsequent steps in this process are incompletely understood. One of the key molecules involved is tumor necrosis factor-alpha (TNFα): its expression is regulated by ROS and it regulates ROS production in turn. This cytokine has been the focus of many studies addressing the mechanisms of different forms of diabetes-induced embryopathies, such as early pregnancy loss, inborn anomalies, fetal growth retardation as well as some pathologies appearing during adult life. In this review, we analyze the results of these studies and discuss how TNFα may regulate the response of pre-and postimplantation stage embryos to diabetes-induced detrimental stimuli. The data presented in this review suggest that TNFα may play a dual role in the pathogenesis of diabetes-induced embryopathies. It may act both as a mediator of diabetesinduced embryotoxic stimuli leading to the death of periimplantation stage embryos and, possibly, as a suppressor of diabetes-induced apoptosis in post-implantation stage embryos. It also appears that TNFα fulfills these functions via interaction with leukemia inhibitory factor (LIF) and the transcription factor NF-κB. These molecules are presently considered as attractive targets for the treatment of diabetesinduced complications. Therefore, further studies addressing their role in the mechanisms underlying diabetes-induced embryopathies are needed to evaluate the safety of such therapies for diabetic women of childbearing age.

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To Die or Not to Die: the Function of the Transcription Factor NF‐κB in Embryos Exposed to Stress

Abstract: Data presented in this review suggest that NF-kappaB may act as a protector of embryos exposed to embryopathic stresses, possibly, because of the ability of NF-kappaB to prevent the induction of programmed cell death as well as to activate cell proliferation.

Cited by 36 publications

References 49 publications

Prevention of neural tube defects by loss of function of inducible nitric oxide synthase in fetuses of a mouse model of streptozotocin-induced diabetes

Prevention of neural tube defects by loss of function of inducible nitric oxide synthase in fetuses of a mouse model of streptozotocin-induced diabetes

Trypanosoma cruziInfection and Nuclear Factor Kappa B Activation Prevent Apoptosis in Cardiac Cells

TNFalpha in the Pathogenesis of Diabetes-Induced Embryopathies: Functions and Targets

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