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Peixin Yang - One of the best experts on this subject based on the ideXlab platform.
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deficiency of the oxidative stress responsive kinase p70s6k1 restores autophagy and ameliorates neural tube defects in diabetic Embryopathy
American Journal of Obstetrics and Gynecology, 2020Co-Authors: Songying Cao, Albert E Reece, Weibin Shen, Peixin YangAbstract:ABSTRACT BACKGROUND Autophagy is highly active in neuroepithelial cells of the developing neuroepithelium, and impaired autophagy leads to neural tube defects (NTDs). We have demonstrated that maternal diabetes induces NTDs, and that impaired autophagy and consequent cellular imbalance, including the endoplasmic reticulum (ER), where critical events occur leading to the induction of diabetic Embryopathy. Because the mammalian target of rapamycin (mTOR) pathway suppresses autophagy, we hypothesize that p70S6K1 (70 kDa ribosomal protein S6 kinase 1), a major downstream effector of mTOR, mediates the inhibitory effect of maternal diabetes on autophagy in the developing neuroepithelium. OBJECTIVE We investigated whether p70S6K1 mediates the inhibitory effect of maternal diabetes on autophagy during neurulation. We also examined if p70S6K1 deficiency restores autophagy and thus relieves ER stress and inhibits maternal diabetes-induced apoptosis, which leads to reduction in NTD incidence in diabetic Embryopathy. STUDY DESIGN Female p70S6K1 heterogeneous knockout (p70S6K1+/-) mice were bred with male p70S6K1 heterogeneous knockout (p70S6K1+/-) mice to generate wild type (WT), p70S6K1+/- and p70S6K1 knockout (p70S6K1-/-) embryos. Embryos at embryonic day 8.5 (E8.5) were harvested for the assessment of indices of autophagy, ER stress and apoptosis. NTDs incidence was determined in E10.5 embryos. For in vitro studies, siRNA knockdown of p70S6K1 in C17.2 mouse neural stem cells were used to determine the effect of p70S6K1 deficiency on autophagy impairment and ER stress under high glucose conditions. RESULTS Knockout of the Rps6kb1 gene, which encodes for p70S6K1, ameliorated maternal diabetes-induced NTDs and restored autophagosome formation in neuroepithelial cells suppressed by maternal diabetes. Maternal diabetes-suppressed conversion of LC3-I (Microtubule-associated protein 1A/1B-light chain 3) to LC3-II, an index of autophagic activity, in neurulation stage embryos was abrogated in the absence of p70S6K1. p70S6K1 knockdown in neural stem cells also restored autophagosome formation and the conversion of LC3-I to LC3-II. The activation of the major unfolded protein response (UPR), indicated by phosphorylation of IRE1α, PERK and eIF2α, and the increase of the endoplasmic reticulum (ER) stress marker, CHOP, were induced by maternal diabetes in vivo and high glucose in vitro. UPR and ER stress induced by maternal diabetes or high glucose were diminished by Rps6kb1deletionor p70S6K1 knockdown, respectively. Rps6kb1knockoutblocked maternal diabetes-induced caspase cleavage and neuroepithelial cell apoptosis. The SOD memetic Tempol abolished high glucose-induced p70S6K1 activation. CONCLUSION We revealed the critical involvement of p70S6K1 in the pathogenesis of diabetic Embryopathy.
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the increased activity of a transcription factor inhibits autophagy in diabetic Embryopathy
American Journal of Obstetrics and Gynecology, 2019Co-Authors: Xi Chen, Albert E Reece, Peixin YangAbstract:Background Maternal diabetes induces neural tube defects and stimulates the activity of the forkhead box O3 (Fox)O3a in the embryonic neuroepithelium. We previously demonstrated that deleting the FOXO3a gene ameliorates maternal diabetes-induced neural tube defects. Macroautophagy (hereafter referred to as “autophagy”) is essential for neurulation. Rescuing autophagy suppressed by maternal diabetes in the developing neuroepithelium inhibits neural tube defect formation in diabetic pregnancy. This evidence suggests a possible link between FoxO3a and impaired autophagy in diabetic Embryopathy. Objective We aimed to determine whether maternal diabetes suppresses autophagy through FoxO3a, and if the transcriptional activity of FoxO3a is required for the induction of diabetic Embryopathy. Study Design We used a well-established type 1 diabetic Embryopathy mouse model, in which diabetes was induced by streptozotocin, for our in vivo studies. To determine if FoxO3a mediates the inhibitory effect of maternal diabetes on autophagy in the developing neuroepithelium, we induced diabetic Embryopathy in FOXO3a gene knockout mice and FoxO3a dominant negative transgenic mice. Embryos were harvested at embryonic day 8.5 to determine FoxO3a and autophagy activity and at embryonic day 10.5 for the presence of neural tube defects. We also examined the expression of autophagy-related genes. C17.2 neural stem cells were used for in vitro examination of the potential effects of FoxO3a on autophagy. Results Deletion of the FOXO3a gene restored the autophagy markers, lipidation of microtubule-associated protein 1A/1B-light chain 3I to light chain 3II, in neurulation stage embryos. Maternal diabetes decreased light chain 3I-positive puncta number in the neuroepithelium, which was restored by deleting FoxO3a. Maternal diabetes also decreased the expression of positive regulators of autophagy (Unc-51 like autophagy activating kinase 1, Coiled-coil myosin-like BCL2-interacting protein, and autophagy-related gene 5) and the negative regulator of autophagy, p62. FOXO3a gene deletion abrogated the dysregulation of autophagy genes. In vitro data showed that the constitutively active form of FoxO3a mimicked high glucose in repressing autophagy. In cells cultured under high-glucose conditions, overexpression of the dominant negative FoxO3a mutant blocked autophagy impairment. Dominant negative FoxO3a overexpression in the developing neuroepithelium restored autophagy and significantly reduced maternal diabetes-induced apoptosis and neural tube defects. Conclusion Our study revealed that diabetes-induced FoxO3a activation inhibited autophagy in the embryonic neuroepithelium. We also observed that FoxO3a transcriptional activity mediated the teratogenic effect of maternal diabetes because dominant negative FoxO3a prevents maternal diabetes-induced autophagy impairment and neural tube defect formation. Our findings suggest that autophagy activators could be therapeutically effective in treating maternal diabetes-induced neural tube defects.
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c-Jun NH2-Terminal Kinase 1/2 and Endoplasmic Reticulum Stress as Interdependent and Reciprocal Causation in Diabetic Embryopathy
2016Co-Authors: Peixin YangAbstract:Embryos exposed to high glucose exhibit aberrant maturational and cytoarchitectural cellular changes, implicating cellular or-ganelle stress in diabetic Embryopathy. c-Jun-N-terminal kinase 1/2 (JNK1/2) activation is a causal event in maternal diabetes– induced neural tube defects (NTD). However, the relationship between JNK1/2 activation and endoplasmic reticulum (ER) stress in diabetic Embryopathy has never been explored. We found that maternal diabetes significantly increased ER stress markers and induced swollen/enlarged ER lumens in embry-onic neuroepithelial cells during neurulation. Deletion of either jnk1 or jnk2 gene diminished hyperglycemia-increased ER stress markers and ER chaperone gene expression. In embryos cultured under high-glucose conditions (20 mmol/L), the use of 4-phenylbutyric acid (4-PBA), an ER chemical chaperone, dimin-ished ER stress markers and abolished the activation of JNK1/
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advances in revealing the molecular targets downstream of oxidative stress induced proapoptotic kinase signaling in diabetic Embryopathy
American Journal of Obstetrics and Gynecology, 2015Co-Authors: Fang Wang, Albert E Reece, Peixin YangAbstract:Preexisting maternal diabetes is a high-risk factor of diabetic Embryopathy, such as neural tube defects and congenital heart defects. Maternal diabetes significantly increases the production of reactive oxygen species, resulting in oxidative stress and diabetic Embryopathy. Multiple cellular and metabolic factors contribute to these processes. Forkhead box O (FoxO)-3a has been demonstrated as a key transcription factor in the signaling transduction pathways responsible for maternal diabetes-induced birth defects. Apoptosis signal-regulating kinase 1 (ASK1) activated by oxidative stress stimulates nuclear translocation of FoxO3a, resulting in the overexpression of tumor necrosis factor receptor 1-associated death domain protein, which, in turn, leads to caspase-8 activation and apoptosis. Maternal diabetes–activated c-Jun N-terminal kinase (JNK)-1/2, downstream effectors of ASK1, can be blocked by superoxide dismutase-1 overexpression, suggesting that oxidative stress is responsible for JNK1/2 signaling activation. Deletion of JNK1/2 significantly suppressed the activity of FoxO3a. These observations indicate that maternal diabetes–induced oxidative stress stimulates the activation of ASK1, JNK1/2, FoxO3a, tumor necrosis factor receptor 1-associated death domain protein, caspase-8 cleavage, and finally, apoptosis and diabetic Embryopathy.
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cellular stress excessive apoptosis and the effect of metformin in a mouse model of type 2 diabetic Embryopathy
Diabetes, 2015Co-Authors: Fang Wang, Cheng Wang, Michael J Quon, Peixin YangAbstract:Increasing prevalence of type 2 diabetes in women of childbearing age has led to a higher incidence of diabetes-associated birth defects. We established a model of type 2 diabetic Embryopathy by feeding 4-week-old female mice a high-fat diet (HFD) (60% fat). After 15 weeks on HFD, the mice showed characteristics of type 2 diabetes mellitus (DM) and were mated with lean male mice. During pregnancy, control dams fed a normal diet (10% fat) were maintained on either normal diet or HFD, serving as a control group with elevated circulating free fatty acids. DM dams produced offspring at a rate of 11.3% for neural tube defect (NTD) formation, whereas no embryos in the control groups developed NTDs. Elevated markers of oxidative stress, endoplasmic reticulum stress, caspase activation, and neuroepithelial cell apoptosis (causal events in type 1 diabetic Embryopathy) were observed in embryos of DM dams. DM dams treated with 200 mg/kg metformin in drinking water ameliorated fasting hyperglycemia, glucose intolerance, and insulin resistance with consequent reduction of cellular stress, apoptosis, and NTDs in their embryos. We conclude that cellular stress and apoptosis occur and that metformin effectively reduces type 2 diabetic Embryopathy in a useful rodent model.
Albert E Reece - One of the best experts on this subject based on the ideXlab platform.
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deficiency of the oxidative stress responsive kinase p70s6k1 restores autophagy and ameliorates neural tube defects in diabetic Embryopathy
American Journal of Obstetrics and Gynecology, 2020Co-Authors: Songying Cao, Albert E Reece, Weibin Shen, Peixin YangAbstract:ABSTRACT BACKGROUND Autophagy is highly active in neuroepithelial cells of the developing neuroepithelium, and impaired autophagy leads to neural tube defects (NTDs). We have demonstrated that maternal diabetes induces NTDs, and that impaired autophagy and consequent cellular imbalance, including the endoplasmic reticulum (ER), where critical events occur leading to the induction of diabetic Embryopathy. Because the mammalian target of rapamycin (mTOR) pathway suppresses autophagy, we hypothesize that p70S6K1 (70 kDa ribosomal protein S6 kinase 1), a major downstream effector of mTOR, mediates the inhibitory effect of maternal diabetes on autophagy in the developing neuroepithelium. OBJECTIVE We investigated whether p70S6K1 mediates the inhibitory effect of maternal diabetes on autophagy during neurulation. We also examined if p70S6K1 deficiency restores autophagy and thus relieves ER stress and inhibits maternal diabetes-induced apoptosis, which leads to reduction in NTD incidence in diabetic Embryopathy. STUDY DESIGN Female p70S6K1 heterogeneous knockout (p70S6K1+/-) mice were bred with male p70S6K1 heterogeneous knockout (p70S6K1+/-) mice to generate wild type (WT), p70S6K1+/- and p70S6K1 knockout (p70S6K1-/-) embryos. Embryos at embryonic day 8.5 (E8.5) were harvested for the assessment of indices of autophagy, ER stress and apoptosis. NTDs incidence was determined in E10.5 embryos. For in vitro studies, siRNA knockdown of p70S6K1 in C17.2 mouse neural stem cells were used to determine the effect of p70S6K1 deficiency on autophagy impairment and ER stress under high glucose conditions. RESULTS Knockout of the Rps6kb1 gene, which encodes for p70S6K1, ameliorated maternal diabetes-induced NTDs and restored autophagosome formation in neuroepithelial cells suppressed by maternal diabetes. Maternal diabetes-suppressed conversion of LC3-I (Microtubule-associated protein 1A/1B-light chain 3) to LC3-II, an index of autophagic activity, in neurulation stage embryos was abrogated in the absence of p70S6K1. p70S6K1 knockdown in neural stem cells also restored autophagosome formation and the conversion of LC3-I to LC3-II. The activation of the major unfolded protein response (UPR), indicated by phosphorylation of IRE1α, PERK and eIF2α, and the increase of the endoplasmic reticulum (ER) stress marker, CHOP, were induced by maternal diabetes in vivo and high glucose in vitro. UPR and ER stress induced by maternal diabetes or high glucose were diminished by Rps6kb1deletionor p70S6K1 knockdown, respectively. Rps6kb1knockoutblocked maternal diabetes-induced caspase cleavage and neuroepithelial cell apoptosis. The SOD memetic Tempol abolished high glucose-induced p70S6K1 activation. CONCLUSION We revealed the critical involvement of p70S6K1 in the pathogenesis of diabetic Embryopathy.
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the increased activity of a transcription factor inhibits autophagy in diabetic Embryopathy
American Journal of Obstetrics and Gynecology, 2019Co-Authors: Xi Chen, Albert E Reece, Peixin YangAbstract:Background Maternal diabetes induces neural tube defects and stimulates the activity of the forkhead box O3 (Fox)O3a in the embryonic neuroepithelium. We previously demonstrated that deleting the FOXO3a gene ameliorates maternal diabetes-induced neural tube defects. Macroautophagy (hereafter referred to as “autophagy”) is essential for neurulation. Rescuing autophagy suppressed by maternal diabetes in the developing neuroepithelium inhibits neural tube defect formation in diabetic pregnancy. This evidence suggests a possible link between FoxO3a and impaired autophagy in diabetic Embryopathy. Objective We aimed to determine whether maternal diabetes suppresses autophagy through FoxO3a, and if the transcriptional activity of FoxO3a is required for the induction of diabetic Embryopathy. Study Design We used a well-established type 1 diabetic Embryopathy mouse model, in which diabetes was induced by streptozotocin, for our in vivo studies. To determine if FoxO3a mediates the inhibitory effect of maternal diabetes on autophagy in the developing neuroepithelium, we induced diabetic Embryopathy in FOXO3a gene knockout mice and FoxO3a dominant negative transgenic mice. Embryos were harvested at embryonic day 8.5 to determine FoxO3a and autophagy activity and at embryonic day 10.5 for the presence of neural tube defects. We also examined the expression of autophagy-related genes. C17.2 neural stem cells were used for in vitro examination of the potential effects of FoxO3a on autophagy. Results Deletion of the FOXO3a gene restored the autophagy markers, lipidation of microtubule-associated protein 1A/1B-light chain 3I to light chain 3II, in neurulation stage embryos. Maternal diabetes decreased light chain 3I-positive puncta number in the neuroepithelium, which was restored by deleting FoxO3a. Maternal diabetes also decreased the expression of positive regulators of autophagy (Unc-51 like autophagy activating kinase 1, Coiled-coil myosin-like BCL2-interacting protein, and autophagy-related gene 5) and the negative regulator of autophagy, p62. FOXO3a gene deletion abrogated the dysregulation of autophagy genes. In vitro data showed that the constitutively active form of FoxO3a mimicked high glucose in repressing autophagy. In cells cultured under high-glucose conditions, overexpression of the dominant negative FoxO3a mutant blocked autophagy impairment. Dominant negative FoxO3a overexpression in the developing neuroepithelium restored autophagy and significantly reduced maternal diabetes-induced apoptosis and neural tube defects. Conclusion Our study revealed that diabetes-induced FoxO3a activation inhibited autophagy in the embryonic neuroepithelium. We also observed that FoxO3a transcriptional activity mediated the teratogenic effect of maternal diabetes because dominant negative FoxO3a prevents maternal diabetes-induced autophagy impairment and neural tube defect formation. Our findings suggest that autophagy activators could be therapeutically effective in treating maternal diabetes-induced neural tube defects.
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advances in revealing the molecular targets downstream of oxidative stress induced proapoptotic kinase signaling in diabetic Embryopathy
American Journal of Obstetrics and Gynecology, 2015Co-Authors: Fang Wang, Albert E Reece, Peixin YangAbstract:Preexisting maternal diabetes is a high-risk factor of diabetic Embryopathy, such as neural tube defects and congenital heart defects. Maternal diabetes significantly increases the production of reactive oxygen species, resulting in oxidative stress and diabetic Embryopathy. Multiple cellular and metabolic factors contribute to these processes. Forkhead box O (FoxO)-3a has been demonstrated as a key transcription factor in the signaling transduction pathways responsible for maternal diabetes-induced birth defects. Apoptosis signal-regulating kinase 1 (ASK1) activated by oxidative stress stimulates nuclear translocation of FoxO3a, resulting in the overexpression of tumor necrosis factor receptor 1-associated death domain protein, which, in turn, leads to caspase-8 activation and apoptosis. Maternal diabetes–activated c-Jun N-terminal kinase (JNK)-1/2, downstream effectors of ASK1, can be blocked by superoxide dismutase-1 overexpression, suggesting that oxidative stress is responsible for JNK1/2 signaling activation. Deletion of JNK1/2 significantly suppressed the activity of FoxO3a. These observations indicate that maternal diabetes–induced oxidative stress stimulates the activation of ASK1, JNK1/2, FoxO3a, tumor necrosis factor receptor 1-associated death domain protein, caspase-8 cleavage, and finally, apoptosis and diabetic Embryopathy.
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new concepts in diabetic Embryopathy
Clinics in Laboratory Medicine, 2013Co-Authors: Zhiyong Zhao, Albert E ReeceAbstract:Diabetes mellitus is responsible for nearly 10% of fetal anomalies in diabetic pregnancies. Although aggressive perinatal care and glycemic control are available in developed countries, the birth defect rate in diabetic pregnancies remains higher than that in the general population. Major cellular activities (ie, proliferation and apoptosis) and intracellular metabolic conditions (ie, nitrosative, oxidative, and endoplasmic reticulum stress) have been shown to be associated with diabetic Embryopathy using animal models. Translating advances made in animal studies into clinical applications in humans requires collaborative efforts across the basic research, preclinical, and clinical communities.
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oxidative stress induced jnk1 2 activation triggers proapoptotic signaling and apoptosis that leads to diabetic Embryopathy
Diabetes, 2012Co-Authors: Hongbo Weng, Albert E Reece, Peixin YangAbstract:Oxidative stress and apoptosis are implicated in the pathogenesis of diabetic Embryopathy. The proapoptotic c-Jun NH2-terminal kinases (JNK)1/2 activation is associated with diabetic Embryopathy. We sought to determine whether 1) hyperglycemia-induced oxidative stress is responsible for the activation of JNK1/2 signaling, 2) JNK1 contributes to the teratogenicity of hyperglycemia, and 3) both JNK1 and JNK2 activation cause activation of downstream transcription factors, caspase activation, and apoptosis, resulting in neural tube defects (NTDs). Wild-type (WT) embryos from nondiabetic WT dams and WT, superoxide dismutase (SOD)1–overexpressing, jnk1+/−, jnk1−/−, and jnk2−/− embryos exposed to maternal hyperglycemia were used to assess JNK1/2 activation, NTDs, activation of transcription factors downstream of JNK1/2, caspase cascade, and apoptosis. SOD1 overexpression abolished diabetes-induced activation of JNK1/2 and their downstream effectors: phosphorylation of c-Jun, activating transcription factor 2, and E twenty-six–like transcription factor 1 and dephosphorylation of forkhead box class O3a. jnk1−/− embryos had significantly lower incidences of NTDs than those of WT or jnk1+/− embryos. Either jnk1 or jnk2 gene deletion blocked diabetes-induced activation of JNK1/2 signaling, caspases 3 and 8, and apoptosis in Sox1+ neural progenitors of the developing neural tube. Our results show that JNK1 and JNK2 are equally involved in diabetic Embryopathy and that the oxidative stress–JNK1/2–caspase pathway mediates the proapoptotic signals and the teratogenicity of maternal diabetes.
Mary R. Loeken - One of the best experts on this subject based on the ideXlab platform.
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Challenges in Understanding Diabetic Embryopathy
2016Co-Authors: Mary R. LoekenAbstract:Perhaps one of the most devastating diabetescomplications is diabetic Embryopathy, in whichthe offspring of a mother with diabetes predatingpregnancy develops congenital malformations. These malformations can affect multiple organ systems, including the brain and spinal cord, the heart and major vessel, the kidneys, the gut, and skeletal structures (1,2) and result in pre- or postnatal mortality or disability. As malformations are induced during the earliest stages of organogenesis, coinciding with the first recognition of pregnancy (3), it is important to institute rigorous glyce-mic control before the onset of pregnancy. Nevertheless, recent studies (4,5) have shown that even in planned pregnancies with optimal prepregnancy care, the inci-dence of malformations in diabetic pregnancies is still at least twice that in nondiabetic pregnancies. As malforma-tions occur in the offspring of women with either type 1 or type 2 diabetes (or offspring of women who are obes
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amp activated protein kinase mediates effects of oxidative stress on embryo gene expression in a mouse model of diabetic Embryopathy
Diabetologia, 2012Co-Authors: M Viana, Mary R. Loeken, S ThirumangalathuAbstract:Aims/hypothesis Neural tube defects (NTDs) are a common malformation associated with diabetic Embryopathy. Maternal hyperglycaemia-induced oxidative stress inhibits the expression of Pax3, a gene that is essential for neural tube closure, and increases the incidence of NTDs. Because oxidative stress can stimulate AMP-activated kinase (AMPK) activity, and AMPK can regulate gene transcription, we hypothesised that increased AMPK activity would mediate the adverse effects of maternal hyperglycaemia-induced oxidative stress on Pax3 expression and NTDs.
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Challenges in Understanding Diabetic Embryopathy
Diabetes, 2008Co-Authors: Mary R. LoekenAbstract:Perhaps one of the most devastating diabetes complications is diabetic Embryopathy, in which the offspring of a mother with diabetes predating pregnancy develops congenital malformations. These malformations can affect multiple organ systems, including the brain and spinal cord, the heart and major vessel, the kidneys, the gut, and skeletal structures (1,2) and result in pre- or postnatal mortality or disability. As malformations are induced during the earliest stages of organogenesis, coinciding with the first recognition of pregnancy (3), it is important to institute rigorous glycemic control before the onset of pregnancy. Nevertheless, recent studies (4,5) have shown that even in planned pregnancies with optimal prepregnancy care, the incidence of malformations in diabetic pregnancies is still at least twice that in nondiabetic pregnancies. As malformations occur in the offspring of women with either type 1 or type 2 diabetes (or offspring of women who are obese at the beginning of pregnancy and may have undiagnosed type 2 diabetes) (2,6–8), and recent evidence indicates that the incidence of diabetes, particularly type 2 diabetes, predating pregnancy is rapidly increasing (9), the burden of this diabetes complication is likely to increase in coming years unless efforts to prevent diabetic Embryopathy are improved. However, unlike other diabetes complications, in which the development of pharmacologic interventions offer the hope of treatment or prevention, prevention of …
Ulf J. Eriksson - One of the best experts on this subject based on the ideXlab platform.
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the status of diabetic Embryopathy
Upsala Journal of Medical Sciences, 2016Co-Authors: Ulf J. Eriksson, Parri WentzelAbstract:Diabetic Embryopathy is a theoretical enigma and a clinical challenge. Both type 1 and type 2 diabetic pregnancy carry a significant risk for fetal maldevelopment, and the precise reasons for the diabetes-induced teratogenicity are not clearly identified. The experimental work in this field has revealed a partial, however complex, answer to the teratological question, and we will review some of the latest suggestions.
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linkage study of Embryopathy polygenic inheritance of diabetes induced skeletal malformations in the rat
Reproductive Toxicology, 2012Co-Authors: Niklas Nordquist, Holger Luthman, Ulf Pettersson, Ulf J. ErikssonAbstract:We developed an inbred rat model of diabetic Embryopathy, in which the offspring displays skeletal malformations (agnathia or micrognathia) when the mother is diabetic, and no malformations when she is not diabetic. Our aim was to find genes controlling the embryonic maldevelopment in a diabetic environment. We contrasted the fetal outcome in inbred Sprague-Dawley L rats (20% skeletal malformations in diabetic pregnancy) with that of inbred Wistar Furth rats (denoted W, no skeletal malformations in diabetic pregnancy). We used offspring from the backcross F-1 x L to probe for the genetic basis for malformation of the mandible in diabetic pregnancy. A set of 186 fetuses (93 affected, 93 unaffected) was subjected to a whole genome scan with 160 micro satellites. Analysis of genotype distribution indicated 7 loci on chromosome 4, 10 (3 loci), 14, 18, and 19 in the teratogenic process (and 14 other loci on 12 chromosomes with less strong association to the malformations), several of which contained genes implicated in other experimental studies of diabetic Embryopathy. These candidate genes will be scrutinized in further experimentation. We conclude that the genetic involvement in rodent diabetic Embryopathy is polygenic and predisposing for congenital malformations. (C) 2011 Elsevier Inc. All rights reserved. (Less)
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Genetic and environmental influence on diabetic rat Embryopathy
American Journal of Physiology-Endocrinology and Metabolism, 2011Co-Authors: Andreas Ejdesjö, Parri Wentzel, Ulf J. ErikssonAbstract:We assessed genetic and environmental influence on fetal outcome in diabetic rat pregnancy. Crossing normal (N) and manifestly diabetic (MD) Wistar Furth (W) and Sprague-Dawley (L) females with W o...
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combined supplementation of folic acid and vitamin e diminishes diabetes induced embryotoxicity in rats
Birth Defects Research Part A-clinical and Molecular Teratology, 2006Co-Authors: Mattias Gareskog, Ulf J. Eriksson, Parri WentzelAbstract:Maternal diabetes is associated with increased risk of growth disturbances and congenital malformations. The malformations rate in the offspring of diabetic mothers is 2-3 fold higher compared to infants of nondiabetic mothers. In this thesis we have investigated the role of the protein kinase C (PKC) pathway and the apoptotic machinery in Embryopathy. We investigated the involvement of PKC isoforms in the Embryopathy of diabetic rat pregnancy. Embryos of diabetic rats showed altered activity and protein distribution of several PKC isoforms compared with embryos of normal rats. Using whole embryo culture we found increased activity of PKC-delta and PKC-zeta after 24h of culture and increased rate of malformations and growth retardation in embryos cultured in high glucose concentration compared to embryos cultured in low glucose concentration. Addition of α-cyano-4-cinnamic acid and N-acetylcysteine to the culture medium normalized malformations and growth retardations whereas specific PKC-inhibitors abolished malformations and partly restored the growth retardations. All treatment normalized glucose-induced increase of PKC activity. Estimated occurrence of apoptosis in embryos of diabetic rats and in embryonic cells exposed to high glucose concentration showed increased rate of pro-apoptotic markers. The increased apoptosis in the high glucose exposed embryonic cells was normalized by supplementation of N-acetylcysteine or apoptosis inhibitor. Treatment with vitamin E and folic acid to diabetic pregnant rats decreased diabetes-induced malformations and resorptions, concomitant with normalization of apoptotic protein levels. These results suggest that oxidative stress is augmented in embryos of diabetic rats and that it also plays a role in the activation of PKC and apoptosis. We used antioxidative treatment with beneficial effect although we could not completely abolish the embryonic demise; this may indicate that other mechanisms are involved in diabetic Embryopathy. Further studies are needed to develop multi-nutrient dietary supplement to eliminate embryonic abnormalities induced by maternal diabetes.
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teratogenicity of 3 deoxyglucosone and diabetic Embryopathy
Diabetes, 1998Co-Authors: Ulf J. Eriksson, Harpreet Singh Minhas, Parri Wentzel, Paul J ThornalleyAbstract:The increased rate of embryonic dysmorphogenesis in diabetic pregnancy is correlated with the severity and duration of the concurrent hyperglycemia during early gestation. Whole embryo culture was used to investigate a possible association of hyperglycemia-induced disturbances of embryo development with tissue levels of the three alpha-oxoaldehydes: glyoxal, methylglyoxal, and 3-deoxyglucosone (3-DG). Rat embryos exposed to high glucose levels in vitro showed severe dysmorphogenesis and a 17-fold increased concentration of 3-DG compared with control embryos cultured in a low glucose concentration. Exogenous 3-DG (100 micromol/l) added to the medium of control cultures yielded an increased embryonic malformation rate and a 3-DG concentration similar to that of embryos cultured in high glucose. Addition of superoxide dismutase (SOD) to the culture medium decreased the malformation rates of embryos exposed to either high glucose or high 3-DG levels, but it did not decrease the high embryonic 3-DG concentrations caused by either agent. Our results implicate the potent glycating agent 3-DG as a teratogenic factor in diabetic Embryopathy. In addition, the anti-teratogenic effect of SOD administration appears to occur downstream of 3-DG formation, suggesting that 3-DG accumulation leads to superoxide-mediated Embryopathy.
Parri Wentzel - One of the best experts on this subject based on the ideXlab platform.
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the status of diabetic Embryopathy
Upsala Journal of Medical Sciences, 2016Co-Authors: Ulf J. Eriksson, Parri WentzelAbstract:Diabetic Embryopathy is a theoretical enigma and a clinical challenge. Both type 1 and type 2 diabetic pregnancy carry a significant risk for fetal maldevelopment, and the precise reasons for the diabetes-induced teratogenicity are not clearly identified. The experimental work in this field has revealed a partial, however complex, answer to the teratological question, and we will review some of the latest suggestions.
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Genetic and environmental influence on diabetic rat Embryopathy
American Journal of Physiology-Endocrinology and Metabolism, 2011Co-Authors: Andreas Ejdesjö, Parri Wentzel, Ulf J. ErikssonAbstract:We assessed genetic and environmental influence on fetal outcome in diabetic rat pregnancy. Crossing normal (N) and manifestly diabetic (MD) Wistar Furth (W) and Sprague-Dawley (L) females with W o...
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combined supplementation of folic acid and vitamin e diminishes diabetes induced embryotoxicity in rats
Birth Defects Research Part A-clinical and Molecular Teratology, 2006Co-Authors: Mattias Gareskog, Ulf J. Eriksson, Parri WentzelAbstract:Maternal diabetes is associated with increased risk of growth disturbances and congenital malformations. The malformations rate in the offspring of diabetic mothers is 2-3 fold higher compared to infants of nondiabetic mothers. In this thesis we have investigated the role of the protein kinase C (PKC) pathway and the apoptotic machinery in Embryopathy. We investigated the involvement of PKC isoforms in the Embryopathy of diabetic rat pregnancy. Embryos of diabetic rats showed altered activity and protein distribution of several PKC isoforms compared with embryos of normal rats. Using whole embryo culture we found increased activity of PKC-delta and PKC-zeta after 24h of culture and increased rate of malformations and growth retardation in embryos cultured in high glucose concentration compared to embryos cultured in low glucose concentration. Addition of α-cyano-4-cinnamic acid and N-acetylcysteine to the culture medium normalized malformations and growth retardations whereas specific PKC-inhibitors abolished malformations and partly restored the growth retardations. All treatment normalized glucose-induced increase of PKC activity. Estimated occurrence of apoptosis in embryos of diabetic rats and in embryonic cells exposed to high glucose concentration showed increased rate of pro-apoptotic markers. The increased apoptosis in the high glucose exposed embryonic cells was normalized by supplementation of N-acetylcysteine or apoptosis inhibitor. Treatment with vitamin E and folic acid to diabetic pregnant rats decreased diabetes-induced malformations and resorptions, concomitant with normalization of apoptotic protein levels. These results suggest that oxidative stress is augmented in embryos of diabetic rats and that it also plays a role in the activation of PKC and apoptosis. We used antioxidative treatment with beneficial effect although we could not completely abolish the embryonic demise; this may indicate that other mechanisms are involved in diabetic Embryopathy. Further studies are needed to develop multi-nutrient dietary supplement to eliminate embryonic abnormalities induced by maternal diabetes.
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teratogenicity of 3 deoxyglucosone and diabetic Embryopathy
Diabetes, 1998Co-Authors: Ulf J. Eriksson, Harpreet Singh Minhas, Parri Wentzel, Paul J ThornalleyAbstract:The increased rate of embryonic dysmorphogenesis in diabetic pregnancy is correlated with the severity and duration of the concurrent hyperglycemia during early gestation. Whole embryo culture was used to investigate a possible association of hyperglycemia-induced disturbances of embryo development with tissue levels of the three alpha-oxoaldehydes: glyoxal, methylglyoxal, and 3-deoxyglucosone (3-DG). Rat embryos exposed to high glucose levels in vitro showed severe dysmorphogenesis and a 17-fold increased concentration of 3-DG compared with control embryos cultured in a low glucose concentration. Exogenous 3-DG (100 micromol/l) added to the medium of control cultures yielded an increased embryonic malformation rate and a 3-DG concentration similar to that of embryos cultured in high glucose. Addition of superoxide dismutase (SOD) to the culture medium decreased the malformation rates of embryos exposed to either high glucose or high 3-DG levels, but it did not decrease the high embryonic 3-DG concentrations caused by either agent. Our results implicate the potent glycating agent 3-DG as a teratogenic factor in diabetic Embryopathy. In addition, the anti-teratogenic effect of SOD administration appears to occur downstream of 3-DG formation, suggesting that 3-DG accumulation leads to superoxide-mediated Embryopathy.