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Amos Fein - One of the best experts on this subject based on the ideXlab platform.
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ORIGINAL ARTICLE: Effect of Maternal Immunopotentiation on Apoptosis-Associated Molecules Expression in Teratogen-Treated Embryos
American journal of reproductive immunology (New York N.Y. : 1989), 2009Co-Authors: Shoshana Savion, Arkady Torchinsky, Amos Fein, Ilan Aroch, Keren Mammon, Hasida Orenstein, Vladimir ToderAbstract:Problem Potentiation of the maternal immune system was shown by us to affect the embryonic response to teratogenic insults. In order to understand better the mechanisms underlying that phenomenon, we explored the effect of maternal Immunopotentiation by rat splenocytes on the early stages of the embryonic response to cyclophosphamide (CP). Method of study Immunopotentiated CP-treated embryos were analysed for cell cycle changes by flow cytometry, while cell proliferation and apoptosis were assessed by 5′-bromo-2′-deoxyuridine (BrdU) incorporation and terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick-end labeling (TUNEL) respectively. The expression of the p65 subunit of NF-κB, IκBα, Bax, bcl-2 and p53 was assessed by flow cytometry. Results Exposure to CP resulted in significant growth retardation and in the appearance of cellular damage, a reduction in cell proliferation and the appearance of apoptotic cells, which were all found to be delayed in immunopotentiated embryos. In parallel, CP-treated embryos demonstrated a reduction in the percentage of p65- or IκBα-positive cells, while the percentage of bcl-2- or p53-positive cells increased initially and decreased later. Those changes were normalized by maternal Immunopotentiation when tested at 24 hrs after exposure to the teratogen. Conclusion Our data implicate maternal Immunopotentiation to protect the embryo against teratogenic insults, possibly through its effect on the expression of p65, bcl-2 or p53.
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MHC-associated Immunopotentiation affects the embryo response to teratogens
Clinical and experimental immunology, 2008Co-Authors: Arkady Torchinsky, Amos Fein, Howard Carp, Vladimir ToderAbstract:The present study was performed to evaluate whether the effect of environmental teratogens can be modified by maternal immunostimulation. Two chemicals, cyclophosphamide (CP) and 2,3-quinoxalinedimetanol,1,4-dioxide (QD) were used as the reference teratogens (RT). The response to these RT was investigated in two animal models: (i) primigravid C57Bl/6 mice who underwent intrauterine immunization with allogeneic paternal (CBA/J), third-party (BALB/c) or syngeneic male splenocytes 21 days before mating; (ii) C57Bl/6 and CBA/J mice who were treated with RT during the second pregnancy only, after a different mating combination (syngeneic or allogeneic) in the first and the second pregnancy. Different doses of CP and QD were injected on days 12 and 9 of pregnancy, respectively. On day 19 of pregnancy implantation sites, resorptions, live and dead fetuses were recorded and live fetuses were examined for external and internal malformations with methods routinely used in teratological study. It was shown that intrauterine Immunopotentiation with allogeneic paternal splenocytes clearly enhances the tolerance of F1 embryos to RT. Thus, in CP-treated females the resorption rate and the proportion of malformed fetuses were significantly reduced. It was followed by an almost two-fold increase in fetal weight. The protective effect of such immunization in QD-treated females was manifested as a dramatic decrease of the proportion of malformed fetuses and the resorption rate. Syngeneic splenocytes could not significantly influence an embryo's sensitivity to RT. The response to RT was also significantly weaker in the second pregnancy of female mice mated twice allogeneically than that observed in allogeneically mated primigravid mice. These results show that the embryo's response to environmental teratogens may be influenced by fetomaternal immune interactions.
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Maternal Immunopotentiation affects caspase activation and NF-kappaB DNA-binding activity in embryos responding to an embryopathic stress.
American journal of reproductive immunology (New York N.Y. : 1989), 2006Co-Authors: Arkady Torchinsky, Maka Gongadze, Zeev Zaslavsky, Shoshana Savion, Amos Fein, Veadimir ToderAbstract:Problem Increased embryonic resistance to teratogenic stresses as a result of maternal Immunopotentiation is associated with a decrease in the intensity of teratogen-induced apoptosis in target embryonic structures. These findings suggest that this effect of maternal Immunopotentiation might be realized through modification of the expression of molecules regulating the teratogen-induced apoptotic process. To examine this possibility, we evaluated caspases 3, 8 and 9 activation as well as nuclear factor (NF)-κB DNA-binding activity in the embryos of immunopotentiated mice exposed to cyclophosphamide (CP). Methods of study The rate of resorptions and the proportion of malformed fetuses in CP-treated mice were recorded on day 19 of pregnancy. Activity of caspases was tested in cytoplasmic extracts collected from the embryonic brain 24 hr after CP treatment using appropriate fluorometric kits, whereas NF-κB DNA-binding activity was evaluated in nuclear extracts using the electrophoretic mobility shift assay. Results As in our previous studies, immunopotentiated CP-treated females exhibited a lower rate of resorptions or fetuses with open eyes than their non-immunopotentiated counterparts. In parallel, we observed that maternal Immunopotentiation normalized the CP-induced activation of the tested caspases as well as the CP-induced suppression of NF-κB DNA-binding activity. Conclusions As caspases act as inducers of apoptosis, and NF-κB acts in CP-treated embryos as an apoptosis suppressor, the above results suggest that maternal Immunopotentiation might affect embryonic sensitivity to embryopathic stresses via NF-κB- and caspases-associated pathways.
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Potentiation of the maternal immune system may modify the apoptotic process in embryos exposed to developmental toxicants.
American journal of reproductive immunology (New York N.Y. : 1989), 2003Co-Authors: Shoshana Savion, Arkady Torchinsky, Amos Fein, Hasida Orenstein, Howard Carp, Jeanne Shepshelovich, Anna Kamshitsky-feldman, Irena Ivnitsky, Vladimir ToderAbstract:PROBLEM: We have previously shown that teratogen-induced embryonic maldevelopment may result from excessive apoptosis in affected organs, but the mechanisms underlying this process are not well understood. Here we investigate the ability of maternal Immunopotentiation to affect the apoptotic process and its regulatory genes p53 and bcl-2 in embryos exposed to a teratogenic insult. METHOD OF STUDY: Potentiation of the immune system in pregnant females was performed with xenogeneic rat splenocytes or with granulocyte macrophage-colony stimulating factor (GM-CSF). The animals were exposed to cyclophosphamide (CP) and the reproductive performance in the various experimental groups was recorded. The level of apoptosis was assessed in the embryonic head and liver by TdT-mediated dUTP-biotin nick end labeling and fluorescence-activated cell sorter (FACS) analysis, while p53 and bcl-2 expression was evaluated by FACS and immunohistochemistry. RESULTS: In CP-treated females, a decrease in embryonic weight and an increase in the resorption rate and the percentage of embryos exhibiting head malformations were noted. These effects of CP were accompanied by the appearance of apoptotic cells in the head but not in the liver and an increased expression of p53 in embryonic organs, while bcl-2 expression was found to be decreased in the head and increased in the liver. Immunopotentiation with rat splenocytes or GM-CSF was shown to partially normalize the teratogenic effect of CP. It was also found to partially decrease the CP-induced apoptotic process and exhibited a tendency to normalize the expression of p53 and bcl-2 in the embryonic head and liver. CONCLUSION: Our results suggest a possible role for maternal Immunopotentiation in protecting the embryo from teratogenic insults, possibly through regulation of the CP-induced apoptotic process and the expression of p53 and bcl-2.
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Cytokine expression in the uterus of mice with pregnancy loss: effect of maternal Immunopotentiation with GM-CSF
Reproduction (Cambridge England), 2002Co-Authors: Shoshana Savion, Arkady Torchinsky, Hasida Orenstein, Vladimir Toder, Jeanne Shepshelovich, Ella Zeldich, Hja. Carp, Amos FeinAbstract:It is believed that failure of the maternal immune system to actively support embryonic development, through production of the appropriate cytokine network, might be responsible for embryonic death. Thus, the aim of this study was to evaluate the possible involvement of cytokines such as tumour necrosis factor alpha (TNF-alpha) and transforming growth factor beta2 (TGF-beta2), which are crucial for normal embryonic development, in the early stages of mechanisms that mediate induced pregnancy loss. The early stages of the resorption process induced by lipopolysaccharide (LPS) were characterized by blood accumulation in the vicinity of the embryo, preceding any visible embryonic damage. At that time, immunohistochemical analysis revealed an increased expression of TNF-alpha in the primary and secondary decidua, which was reduced as the resorption process was completed. In contrast, TGF-beta2 expression was decreased in the primary and secondary decidua, as well as in the glandular epithelium, at all the times assessed. Maternal Immunopotentiation with granulocyte macrophage-colony stimulating factor (GM-CSF), which controls maternal immune activities supporting normal embryonic development, decreased the resorption rate in LPS-treated mice while normalizing the expression of TNF-alpha and TGF-beta2 in the uterus of these animals throughout the ongoing resorption process. These results indicate a possible role for maternal Immunopotentiation with GM-CSF in the mechanisms mediating the early stages of pregnancy loss, possibly via modulation of TNF-alpha and TGF-beta2 activity.
Vladimir Toder - One of the best experts on this subject based on the ideXlab platform.
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ORIGINAL ARTICLE: Effect of Maternal Immunopotentiation on Apoptosis-Associated Molecules Expression in Teratogen-Treated Embryos
American journal of reproductive immunology (New York N.Y. : 1989), 2009Co-Authors: Shoshana Savion, Arkady Torchinsky, Amos Fein, Ilan Aroch, Keren Mammon, Hasida Orenstein, Vladimir ToderAbstract:Problem Potentiation of the maternal immune system was shown by us to affect the embryonic response to teratogenic insults. In order to understand better the mechanisms underlying that phenomenon, we explored the effect of maternal Immunopotentiation by rat splenocytes on the early stages of the embryonic response to cyclophosphamide (CP). Method of study Immunopotentiated CP-treated embryos were analysed for cell cycle changes by flow cytometry, while cell proliferation and apoptosis were assessed by 5′-bromo-2′-deoxyuridine (BrdU) incorporation and terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick-end labeling (TUNEL) respectively. The expression of the p65 subunit of NF-κB, IκBα, Bax, bcl-2 and p53 was assessed by flow cytometry. Results Exposure to CP resulted in significant growth retardation and in the appearance of cellular damage, a reduction in cell proliferation and the appearance of apoptotic cells, which were all found to be delayed in immunopotentiated embryos. In parallel, CP-treated embryos demonstrated a reduction in the percentage of p65- or IκBα-positive cells, while the percentage of bcl-2- or p53-positive cells increased initially and decreased later. Those changes were normalized by maternal Immunopotentiation when tested at 24 hrs after exposure to the teratogen. Conclusion Our data implicate maternal Immunopotentiation to protect the embryo against teratogenic insults, possibly through its effect on the expression of p65, bcl-2 or p53.
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MHC-associated Immunopotentiation affects the embryo response to teratogens
Clinical and experimental immunology, 2008Co-Authors: Arkady Torchinsky, Amos Fein, Howard Carp, Vladimir ToderAbstract:The present study was performed to evaluate whether the effect of environmental teratogens can be modified by maternal immunostimulation. Two chemicals, cyclophosphamide (CP) and 2,3-quinoxalinedimetanol,1,4-dioxide (QD) were used as the reference teratogens (RT). The response to these RT was investigated in two animal models: (i) primigravid C57Bl/6 mice who underwent intrauterine immunization with allogeneic paternal (CBA/J), third-party (BALB/c) or syngeneic male splenocytes 21 days before mating; (ii) C57Bl/6 and CBA/J mice who were treated with RT during the second pregnancy only, after a different mating combination (syngeneic or allogeneic) in the first and the second pregnancy. Different doses of CP and QD were injected on days 12 and 9 of pregnancy, respectively. On day 19 of pregnancy implantation sites, resorptions, live and dead fetuses were recorded and live fetuses were examined for external and internal malformations with methods routinely used in teratological study. It was shown that intrauterine Immunopotentiation with allogeneic paternal splenocytes clearly enhances the tolerance of F1 embryos to RT. Thus, in CP-treated females the resorption rate and the proportion of malformed fetuses were significantly reduced. It was followed by an almost two-fold increase in fetal weight. The protective effect of such immunization in QD-treated females was manifested as a dramatic decrease of the proportion of malformed fetuses and the resorption rate. Syngeneic splenocytes could not significantly influence an embryo's sensitivity to RT. The response to RT was also significantly weaker in the second pregnancy of female mice mated twice allogeneically than that observed in allogeneically mated primigravid mice. These results show that the embryo's response to environmental teratogens may be influenced by fetomaternal immune interactions.
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Potentiation of the maternal immune system may modify the apoptotic process in embryos exposed to developmental toxicants.
American journal of reproductive immunology (New York N.Y. : 1989), 2003Co-Authors: Shoshana Savion, Arkady Torchinsky, Amos Fein, Hasida Orenstein, Howard Carp, Jeanne Shepshelovich, Anna Kamshitsky-feldman, Irena Ivnitsky, Vladimir ToderAbstract:PROBLEM: We have previously shown that teratogen-induced embryonic maldevelopment may result from excessive apoptosis in affected organs, but the mechanisms underlying this process are not well understood. Here we investigate the ability of maternal Immunopotentiation to affect the apoptotic process and its regulatory genes p53 and bcl-2 in embryos exposed to a teratogenic insult. METHOD OF STUDY: Potentiation of the immune system in pregnant females was performed with xenogeneic rat splenocytes or with granulocyte macrophage-colony stimulating factor (GM-CSF). The animals were exposed to cyclophosphamide (CP) and the reproductive performance in the various experimental groups was recorded. The level of apoptosis was assessed in the embryonic head and liver by TdT-mediated dUTP-biotin nick end labeling and fluorescence-activated cell sorter (FACS) analysis, while p53 and bcl-2 expression was evaluated by FACS and immunohistochemistry. RESULTS: In CP-treated females, a decrease in embryonic weight and an increase in the resorption rate and the percentage of embryos exhibiting head malformations were noted. These effects of CP were accompanied by the appearance of apoptotic cells in the head but not in the liver and an increased expression of p53 in embryonic organs, while bcl-2 expression was found to be decreased in the head and increased in the liver. Immunopotentiation with rat splenocytes or GM-CSF was shown to partially normalize the teratogenic effect of CP. It was also found to partially decrease the CP-induced apoptotic process and exhibited a tendency to normalize the expression of p53 and bcl-2 in the embryonic head and liver. CONCLUSION: Our results suggest a possible role for maternal Immunopotentiation in protecting the embryo from teratogenic insults, possibly through regulation of the CP-induced apoptotic process and the expression of p53 and bcl-2.
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Cytokine expression in the uterus of mice with pregnancy loss: effect of maternal Immunopotentiation with GM-CSF
Reproduction (Cambridge England), 2002Co-Authors: Shoshana Savion, Arkady Torchinsky, Hasida Orenstein, Vladimir Toder, Jeanne Shepshelovich, Ella Zeldich, Hja. Carp, Amos FeinAbstract:It is believed that failure of the maternal immune system to actively support embryonic development, through production of the appropriate cytokine network, might be responsible for embryonic death. Thus, the aim of this study was to evaluate the possible involvement of cytokines such as tumour necrosis factor alpha (TNF-alpha) and transforming growth factor beta2 (TGF-beta2), which are crucial for normal embryonic development, in the early stages of mechanisms that mediate induced pregnancy loss. The early stages of the resorption process induced by lipopolysaccharide (LPS) were characterized by blood accumulation in the vicinity of the embryo, preceding any visible embryonic damage. At that time, immunohistochemical analysis revealed an increased expression of TNF-alpha in the primary and secondary decidua, which was reduced as the resorption process was completed. In contrast, TGF-beta2 expression was decreased in the primary and secondary decidua, as well as in the glandular epithelium, at all the times assessed. Maternal Immunopotentiation with granulocyte macrophage-colony stimulating factor (GM-CSF), which controls maternal immune activities supporting normal embryonic development, decreased the resorption rate in LPS-treated mice while normalizing the expression of TNF-alpha and TGF-beta2 in the uterus of these animals throughout the ongoing resorption process. These results indicate a possible role for maternal Immunopotentiation with GM-CSF in the mechanisms mediating the early stages of pregnancy loss, possibly via modulation of TNF-alpha and TGF-beta2 activity.
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Diabetes teratogenicity in mice is accompanied with distorted expression of TGF‐β2 in the uterus
Teratogenesis carcinogenesis and mutagenesis, 2001Co-Authors: Amos Fein, Arkady Torchinsky, Shoshana Savion, Hasida Orenstein, N. Magid, Jeanne Shepshelovich, A. Ornoy, Vladimir ToderAbstract:Early embryonic deaths as well as malformed newborns are among complications of the diabetic pregnancy. Cytokines and growth factors operating in the embryonic vicinity are found to be among factors that determine the sensitivity of embryos to external and internal detrimental stimuli, including diabetes. Transforming Growth Factor-β2 (TGF-β2) has been shown to be essential for embryonic development and survival. In the present work, we evaluated the pattern of TGF-β2 expression in the uterus of streptozotocin-induced diabetic mice, demonstrating a decreased reproductive performance and elevated percentage of litters with severely malformed fetuses. Since stimulation of the maternal immune system was found to increase the resistance of mouse embryos to the teratogenic effect of diabetes, the effect of Immunopotentiation on the expression of the cytokine was also investigated. TGF-β2 expression was studied at the mRNA level by using the in situ hybridization technique and at the protein level by using the immunohistochemical analysis. A clear decrease in TGF-β2 mRNA expression in the uterus of diabetic mice was observed at examined time points: days 1, 5, and 9 of pregnancy. Also, an evident reduction in TGF-β2, the protein expression in the uterus of diabetic mice, was demonstrated at these time points. Maternal Immunopotentiation that improved the reproductive performance of diabetic mice and reduced the number of the litters with malformed fetuses was also accompanied by a clear increase in the level of TGF-β2 mRNA expression in the pregnant uteri. The above results clearly demonstrate that the embryotoxic effect of diabetes is accompanied by an alteration of TGF-β2 expression. Immunopotentiation that was shown to improve the reproductive performance of the diabetic mice was accompanied by a partial normalization of TGF-β2 expression in embryonic vicinity. Teratogenesis Carcinog. Mutagen. 22:59–71, 2002. © 2002 Wiley-Liss, Inc.
Arkady Torchinsky - One of the best experts on this subject based on the ideXlab platform.
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ORIGINAL ARTICLE: Effect of Maternal Immunopotentiation on Apoptosis-Associated Molecules Expression in Teratogen-Treated Embryos
American journal of reproductive immunology (New York N.Y. : 1989), 2009Co-Authors: Shoshana Savion, Arkady Torchinsky, Amos Fein, Ilan Aroch, Keren Mammon, Hasida Orenstein, Vladimir ToderAbstract:Problem Potentiation of the maternal immune system was shown by us to affect the embryonic response to teratogenic insults. In order to understand better the mechanisms underlying that phenomenon, we explored the effect of maternal Immunopotentiation by rat splenocytes on the early stages of the embryonic response to cyclophosphamide (CP). Method of study Immunopotentiated CP-treated embryos were analysed for cell cycle changes by flow cytometry, while cell proliferation and apoptosis were assessed by 5′-bromo-2′-deoxyuridine (BrdU) incorporation and terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick-end labeling (TUNEL) respectively. The expression of the p65 subunit of NF-κB, IκBα, Bax, bcl-2 and p53 was assessed by flow cytometry. Results Exposure to CP resulted in significant growth retardation and in the appearance of cellular damage, a reduction in cell proliferation and the appearance of apoptotic cells, which were all found to be delayed in immunopotentiated embryos. In parallel, CP-treated embryos demonstrated a reduction in the percentage of p65- or IκBα-positive cells, while the percentage of bcl-2- or p53-positive cells increased initially and decreased later. Those changes were normalized by maternal Immunopotentiation when tested at 24 hrs after exposure to the teratogen. Conclusion Our data implicate maternal Immunopotentiation to protect the embryo against teratogenic insults, possibly through its effect on the expression of p65, bcl-2 or p53.
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MHC-associated Immunopotentiation affects the embryo response to teratogens
Clinical and experimental immunology, 2008Co-Authors: Arkady Torchinsky, Amos Fein, Howard Carp, Vladimir ToderAbstract:The present study was performed to evaluate whether the effect of environmental teratogens can be modified by maternal immunostimulation. Two chemicals, cyclophosphamide (CP) and 2,3-quinoxalinedimetanol,1,4-dioxide (QD) were used as the reference teratogens (RT). The response to these RT was investigated in two animal models: (i) primigravid C57Bl/6 mice who underwent intrauterine immunization with allogeneic paternal (CBA/J), third-party (BALB/c) or syngeneic male splenocytes 21 days before mating; (ii) C57Bl/6 and CBA/J mice who were treated with RT during the second pregnancy only, after a different mating combination (syngeneic or allogeneic) in the first and the second pregnancy. Different doses of CP and QD were injected on days 12 and 9 of pregnancy, respectively. On day 19 of pregnancy implantation sites, resorptions, live and dead fetuses were recorded and live fetuses were examined for external and internal malformations with methods routinely used in teratological study. It was shown that intrauterine Immunopotentiation with allogeneic paternal splenocytes clearly enhances the tolerance of F1 embryos to RT. Thus, in CP-treated females the resorption rate and the proportion of malformed fetuses were significantly reduced. It was followed by an almost two-fold increase in fetal weight. The protective effect of such immunization in QD-treated females was manifested as a dramatic decrease of the proportion of malformed fetuses and the resorption rate. Syngeneic splenocytes could not significantly influence an embryo's sensitivity to RT. The response to RT was also significantly weaker in the second pregnancy of female mice mated twice allogeneically than that observed in allogeneically mated primigravid mice. These results show that the embryo's response to environmental teratogens may be influenced by fetomaternal immune interactions.
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Maternal Immunopotentiation affects caspase activation and NF-kappaB DNA-binding activity in embryos responding to an embryopathic stress.
American journal of reproductive immunology (New York N.Y. : 1989), 2006Co-Authors: Arkady Torchinsky, Maka Gongadze, Zeev Zaslavsky, Shoshana Savion, Amos Fein, Veadimir ToderAbstract:Problem Increased embryonic resistance to teratogenic stresses as a result of maternal Immunopotentiation is associated with a decrease in the intensity of teratogen-induced apoptosis in target embryonic structures. These findings suggest that this effect of maternal Immunopotentiation might be realized through modification of the expression of molecules regulating the teratogen-induced apoptotic process. To examine this possibility, we evaluated caspases 3, 8 and 9 activation as well as nuclear factor (NF)-κB DNA-binding activity in the embryos of immunopotentiated mice exposed to cyclophosphamide (CP). Methods of study The rate of resorptions and the proportion of malformed fetuses in CP-treated mice were recorded on day 19 of pregnancy. Activity of caspases was tested in cytoplasmic extracts collected from the embryonic brain 24 hr after CP treatment using appropriate fluorometric kits, whereas NF-κB DNA-binding activity was evaluated in nuclear extracts using the electrophoretic mobility shift assay. Results As in our previous studies, immunopotentiated CP-treated females exhibited a lower rate of resorptions or fetuses with open eyes than their non-immunopotentiated counterparts. In parallel, we observed that maternal Immunopotentiation normalized the CP-induced activation of the tested caspases as well as the CP-induced suppression of NF-κB DNA-binding activity. Conclusions As caspases act as inducers of apoptosis, and NF-κB acts in CP-treated embryos as an apoptosis suppressor, the above results suggest that maternal Immunopotentiation might affect embryonic sensitivity to embryopathic stresses via NF-κB- and caspases-associated pathways.
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Potentiation of the maternal immune system may modify the apoptotic process in embryos exposed to developmental toxicants.
American journal of reproductive immunology (New York N.Y. : 1989), 2003Co-Authors: Shoshana Savion, Arkady Torchinsky, Amos Fein, Hasida Orenstein, Howard Carp, Jeanne Shepshelovich, Anna Kamshitsky-feldman, Irena Ivnitsky, Vladimir ToderAbstract:PROBLEM: We have previously shown that teratogen-induced embryonic maldevelopment may result from excessive apoptosis in affected organs, but the mechanisms underlying this process are not well understood. Here we investigate the ability of maternal Immunopotentiation to affect the apoptotic process and its regulatory genes p53 and bcl-2 in embryos exposed to a teratogenic insult. METHOD OF STUDY: Potentiation of the immune system in pregnant females was performed with xenogeneic rat splenocytes or with granulocyte macrophage-colony stimulating factor (GM-CSF). The animals were exposed to cyclophosphamide (CP) and the reproductive performance in the various experimental groups was recorded. The level of apoptosis was assessed in the embryonic head and liver by TdT-mediated dUTP-biotin nick end labeling and fluorescence-activated cell sorter (FACS) analysis, while p53 and bcl-2 expression was evaluated by FACS and immunohistochemistry. RESULTS: In CP-treated females, a decrease in embryonic weight and an increase in the resorption rate and the percentage of embryos exhibiting head malformations were noted. These effects of CP were accompanied by the appearance of apoptotic cells in the head but not in the liver and an increased expression of p53 in embryonic organs, while bcl-2 expression was found to be decreased in the head and increased in the liver. Immunopotentiation with rat splenocytes or GM-CSF was shown to partially normalize the teratogenic effect of CP. It was also found to partially decrease the CP-induced apoptotic process and exhibited a tendency to normalize the expression of p53 and bcl-2 in the embryonic head and liver. CONCLUSION: Our results suggest a possible role for maternal Immunopotentiation in protecting the embryo from teratogenic insults, possibly through regulation of the CP-induced apoptotic process and the expression of p53 and bcl-2.
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Cytokine expression in the uterus of mice with pregnancy loss: effect of maternal Immunopotentiation with GM-CSF
Reproduction (Cambridge England), 2002Co-Authors: Shoshana Savion, Arkady Torchinsky, Hasida Orenstein, Vladimir Toder, Jeanne Shepshelovich, Ella Zeldich, Hja. Carp, Amos FeinAbstract:It is believed that failure of the maternal immune system to actively support embryonic development, through production of the appropriate cytokine network, might be responsible for embryonic death. Thus, the aim of this study was to evaluate the possible involvement of cytokines such as tumour necrosis factor alpha (TNF-alpha) and transforming growth factor beta2 (TGF-beta2), which are crucial for normal embryonic development, in the early stages of mechanisms that mediate induced pregnancy loss. The early stages of the resorption process induced by lipopolysaccharide (LPS) were characterized by blood accumulation in the vicinity of the embryo, preceding any visible embryonic damage. At that time, immunohistochemical analysis revealed an increased expression of TNF-alpha in the primary and secondary decidua, which was reduced as the resorption process was completed. In contrast, TGF-beta2 expression was decreased in the primary and secondary decidua, as well as in the glandular epithelium, at all the times assessed. Maternal Immunopotentiation with granulocyte macrophage-colony stimulating factor (GM-CSF), which controls maternal immune activities supporting normal embryonic development, decreased the resorption rate in LPS-treated mice while normalizing the expression of TNF-alpha and TGF-beta2 in the uterus of these animals throughout the ongoing resorption process. These results indicate a possible role for maternal Immunopotentiation with GM-CSF in the mechanisms mediating the early stages of pregnancy loss, possibly via modulation of TNF-alpha and TGF-beta2 activity.
Shoshana Savion - One of the best experts on this subject based on the ideXlab platform.
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ORIGINAL ARTICLE: Effect of Maternal Immunopotentiation on Apoptosis-Associated Molecules Expression in Teratogen-Treated Embryos
American journal of reproductive immunology (New York N.Y. : 1989), 2009Co-Authors: Shoshana Savion, Arkady Torchinsky, Amos Fein, Ilan Aroch, Keren Mammon, Hasida Orenstein, Vladimir ToderAbstract:Problem Potentiation of the maternal immune system was shown by us to affect the embryonic response to teratogenic insults. In order to understand better the mechanisms underlying that phenomenon, we explored the effect of maternal Immunopotentiation by rat splenocytes on the early stages of the embryonic response to cyclophosphamide (CP). Method of study Immunopotentiated CP-treated embryos were analysed for cell cycle changes by flow cytometry, while cell proliferation and apoptosis were assessed by 5′-bromo-2′-deoxyuridine (BrdU) incorporation and terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick-end labeling (TUNEL) respectively. The expression of the p65 subunit of NF-κB, IκBα, Bax, bcl-2 and p53 was assessed by flow cytometry. Results Exposure to CP resulted in significant growth retardation and in the appearance of cellular damage, a reduction in cell proliferation and the appearance of apoptotic cells, which were all found to be delayed in immunopotentiated embryos. In parallel, CP-treated embryos demonstrated a reduction in the percentage of p65- or IκBα-positive cells, while the percentage of bcl-2- or p53-positive cells increased initially and decreased later. Those changes were normalized by maternal Immunopotentiation when tested at 24 hrs after exposure to the teratogen. Conclusion Our data implicate maternal Immunopotentiation to protect the embryo against teratogenic insults, possibly through its effect on the expression of p65, bcl-2 or p53.
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Maternal Immunopotentiation affects caspase activation and NF-kappaB DNA-binding activity in embryos responding to an embryopathic stress.
American journal of reproductive immunology (New York N.Y. : 1989), 2006Co-Authors: Arkady Torchinsky, Maka Gongadze, Zeev Zaslavsky, Shoshana Savion, Amos Fein, Veadimir ToderAbstract:Problem Increased embryonic resistance to teratogenic stresses as a result of maternal Immunopotentiation is associated with a decrease in the intensity of teratogen-induced apoptosis in target embryonic structures. These findings suggest that this effect of maternal Immunopotentiation might be realized through modification of the expression of molecules regulating the teratogen-induced apoptotic process. To examine this possibility, we evaluated caspases 3, 8 and 9 activation as well as nuclear factor (NF)-κB DNA-binding activity in the embryos of immunopotentiated mice exposed to cyclophosphamide (CP). Methods of study The rate of resorptions and the proportion of malformed fetuses in CP-treated mice were recorded on day 19 of pregnancy. Activity of caspases was tested in cytoplasmic extracts collected from the embryonic brain 24 hr after CP treatment using appropriate fluorometric kits, whereas NF-κB DNA-binding activity was evaluated in nuclear extracts using the electrophoretic mobility shift assay. Results As in our previous studies, immunopotentiated CP-treated females exhibited a lower rate of resorptions or fetuses with open eyes than their non-immunopotentiated counterparts. In parallel, we observed that maternal Immunopotentiation normalized the CP-induced activation of the tested caspases as well as the CP-induced suppression of NF-κB DNA-binding activity. Conclusions As caspases act as inducers of apoptosis, and NF-κB acts in CP-treated embryos as an apoptosis suppressor, the above results suggest that maternal Immunopotentiation might affect embryonic sensitivity to embryopathic stresses via NF-κB- and caspases-associated pathways.
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Potentiation of the maternal immune system may modify the apoptotic process in embryos exposed to developmental toxicants.
American journal of reproductive immunology (New York N.Y. : 1989), 2003Co-Authors: Shoshana Savion, Arkady Torchinsky, Amos Fein, Hasida Orenstein, Howard Carp, Jeanne Shepshelovich, Anna Kamshitsky-feldman, Irena Ivnitsky, Vladimir ToderAbstract:PROBLEM: We have previously shown that teratogen-induced embryonic maldevelopment may result from excessive apoptosis in affected organs, but the mechanisms underlying this process are not well understood. Here we investigate the ability of maternal Immunopotentiation to affect the apoptotic process and its regulatory genes p53 and bcl-2 in embryos exposed to a teratogenic insult. METHOD OF STUDY: Potentiation of the immune system in pregnant females was performed with xenogeneic rat splenocytes or with granulocyte macrophage-colony stimulating factor (GM-CSF). The animals were exposed to cyclophosphamide (CP) and the reproductive performance in the various experimental groups was recorded. The level of apoptosis was assessed in the embryonic head and liver by TdT-mediated dUTP-biotin nick end labeling and fluorescence-activated cell sorter (FACS) analysis, while p53 and bcl-2 expression was evaluated by FACS and immunohistochemistry. RESULTS: In CP-treated females, a decrease in embryonic weight and an increase in the resorption rate and the percentage of embryos exhibiting head malformations were noted. These effects of CP were accompanied by the appearance of apoptotic cells in the head but not in the liver and an increased expression of p53 in embryonic organs, while bcl-2 expression was found to be decreased in the head and increased in the liver. Immunopotentiation with rat splenocytes or GM-CSF was shown to partially normalize the teratogenic effect of CP. It was also found to partially decrease the CP-induced apoptotic process and exhibited a tendency to normalize the expression of p53 and bcl-2 in the embryonic head and liver. CONCLUSION: Our results suggest a possible role for maternal Immunopotentiation in protecting the embryo from teratogenic insults, possibly through regulation of the CP-induced apoptotic process and the expression of p53 and bcl-2.
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Cytokine expression in the uterus of mice with pregnancy loss: effect of maternal Immunopotentiation with GM-CSF
Reproduction (Cambridge England), 2002Co-Authors: Shoshana Savion, Arkady Torchinsky, Hasida Orenstein, Vladimir Toder, Jeanne Shepshelovich, Ella Zeldich, Hja. Carp, Amos FeinAbstract:It is believed that failure of the maternal immune system to actively support embryonic development, through production of the appropriate cytokine network, might be responsible for embryonic death. Thus, the aim of this study was to evaluate the possible involvement of cytokines such as tumour necrosis factor alpha (TNF-alpha) and transforming growth factor beta2 (TGF-beta2), which are crucial for normal embryonic development, in the early stages of mechanisms that mediate induced pregnancy loss. The early stages of the resorption process induced by lipopolysaccharide (LPS) were characterized by blood accumulation in the vicinity of the embryo, preceding any visible embryonic damage. At that time, immunohistochemical analysis revealed an increased expression of TNF-alpha in the primary and secondary decidua, which was reduced as the resorption process was completed. In contrast, TGF-beta2 expression was decreased in the primary and secondary decidua, as well as in the glandular epithelium, at all the times assessed. Maternal Immunopotentiation with granulocyte macrophage-colony stimulating factor (GM-CSF), which controls maternal immune activities supporting normal embryonic development, decreased the resorption rate in LPS-treated mice while normalizing the expression of TNF-alpha and TGF-beta2 in the uterus of these animals throughout the ongoing resorption process. These results indicate a possible role for maternal Immunopotentiation with GM-CSF in the mechanisms mediating the early stages of pregnancy loss, possibly via modulation of TNF-alpha and TGF-beta2 activity.
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Diabetes teratogenicity in mice is accompanied with distorted expression of TGF‐β2 in the uterus
Teratogenesis carcinogenesis and mutagenesis, 2001Co-Authors: Amos Fein, Arkady Torchinsky, Shoshana Savion, Hasida Orenstein, N. Magid, Jeanne Shepshelovich, A. Ornoy, Vladimir ToderAbstract:Early embryonic deaths as well as malformed newborns are among complications of the diabetic pregnancy. Cytokines and growth factors operating in the embryonic vicinity are found to be among factors that determine the sensitivity of embryos to external and internal detrimental stimuli, including diabetes. Transforming Growth Factor-β2 (TGF-β2) has been shown to be essential for embryonic development and survival. In the present work, we evaluated the pattern of TGF-β2 expression in the uterus of streptozotocin-induced diabetic mice, demonstrating a decreased reproductive performance and elevated percentage of litters with severely malformed fetuses. Since stimulation of the maternal immune system was found to increase the resistance of mouse embryos to the teratogenic effect of diabetes, the effect of Immunopotentiation on the expression of the cytokine was also investigated. TGF-β2 expression was studied at the mRNA level by using the in situ hybridization technique and at the protein level by using the immunohistochemical analysis. A clear decrease in TGF-β2 mRNA expression in the uterus of diabetic mice was observed at examined time points: days 1, 5, and 9 of pregnancy. Also, an evident reduction in TGF-β2, the protein expression in the uterus of diabetic mice, was demonstrated at these time points. Maternal Immunopotentiation that improved the reproductive performance of diabetic mice and reduced the number of the litters with malformed fetuses was also accompanied by a clear increase in the level of TGF-β2 mRNA expression in the pregnant uteri. The above results clearly demonstrate that the embryotoxic effect of diabetes is accompanied by an alteration of TGF-β2 expression. Immunopotentiation that was shown to improve the reproductive performance of the diabetic mice was accompanied by a partial normalization of TGF-β2 expression in embryonic vicinity. Teratogenesis Carcinog. Mutagen. 22:59–71, 2002. © 2002 Wiley-Liss, Inc.
Jeanne Shepshelovich - One of the best experts on this subject based on the ideXlab platform.
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Potentiation of the maternal immune system may modify the apoptotic process in embryos exposed to developmental toxicants.
American journal of reproductive immunology (New York N.Y. : 1989), 2003Co-Authors: Shoshana Savion, Arkady Torchinsky, Amos Fein, Hasida Orenstein, Howard Carp, Jeanne Shepshelovich, Anna Kamshitsky-feldman, Irena Ivnitsky, Vladimir ToderAbstract:PROBLEM: We have previously shown that teratogen-induced embryonic maldevelopment may result from excessive apoptosis in affected organs, but the mechanisms underlying this process are not well understood. Here we investigate the ability of maternal Immunopotentiation to affect the apoptotic process and its regulatory genes p53 and bcl-2 in embryos exposed to a teratogenic insult. METHOD OF STUDY: Potentiation of the immune system in pregnant females was performed with xenogeneic rat splenocytes or with granulocyte macrophage-colony stimulating factor (GM-CSF). The animals were exposed to cyclophosphamide (CP) and the reproductive performance in the various experimental groups was recorded. The level of apoptosis was assessed in the embryonic head and liver by TdT-mediated dUTP-biotin nick end labeling and fluorescence-activated cell sorter (FACS) analysis, while p53 and bcl-2 expression was evaluated by FACS and immunohistochemistry. RESULTS: In CP-treated females, a decrease in embryonic weight and an increase in the resorption rate and the percentage of embryos exhibiting head malformations were noted. These effects of CP were accompanied by the appearance of apoptotic cells in the head but not in the liver and an increased expression of p53 in embryonic organs, while bcl-2 expression was found to be decreased in the head and increased in the liver. Immunopotentiation with rat splenocytes or GM-CSF was shown to partially normalize the teratogenic effect of CP. It was also found to partially decrease the CP-induced apoptotic process and exhibited a tendency to normalize the expression of p53 and bcl-2 in the embryonic head and liver. CONCLUSION: Our results suggest a possible role for maternal Immunopotentiation in protecting the embryo from teratogenic insults, possibly through regulation of the CP-induced apoptotic process and the expression of p53 and bcl-2.
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Cytokine expression in the uterus of mice with pregnancy loss: effect of maternal Immunopotentiation with GM-CSF
Reproduction (Cambridge England), 2002Co-Authors: Shoshana Savion, Arkady Torchinsky, Hasida Orenstein, Vladimir Toder, Jeanne Shepshelovich, Ella Zeldich, Hja. Carp, Amos FeinAbstract:It is believed that failure of the maternal immune system to actively support embryonic development, through production of the appropriate cytokine network, might be responsible for embryonic death. Thus, the aim of this study was to evaluate the possible involvement of cytokines such as tumour necrosis factor alpha (TNF-alpha) and transforming growth factor beta2 (TGF-beta2), which are crucial for normal embryonic development, in the early stages of mechanisms that mediate induced pregnancy loss. The early stages of the resorption process induced by lipopolysaccharide (LPS) were characterized by blood accumulation in the vicinity of the embryo, preceding any visible embryonic damage. At that time, immunohistochemical analysis revealed an increased expression of TNF-alpha in the primary and secondary decidua, which was reduced as the resorption process was completed. In contrast, TGF-beta2 expression was decreased in the primary and secondary decidua, as well as in the glandular epithelium, at all the times assessed. Maternal Immunopotentiation with granulocyte macrophage-colony stimulating factor (GM-CSF), which controls maternal immune activities supporting normal embryonic development, decreased the resorption rate in LPS-treated mice while normalizing the expression of TNF-alpha and TGF-beta2 in the uterus of these animals throughout the ongoing resorption process. These results indicate a possible role for maternal Immunopotentiation with GM-CSF in the mechanisms mediating the early stages of pregnancy loss, possibly via modulation of TNF-alpha and TGF-beta2 activity.
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Diabetes teratogenicity in mice is accompanied with distorted expression of TGF‐β2 in the uterus
Teratogenesis carcinogenesis and mutagenesis, 2001Co-Authors: Amos Fein, Arkady Torchinsky, Shoshana Savion, Hasida Orenstein, N. Magid, Jeanne Shepshelovich, A. Ornoy, Vladimir ToderAbstract:Early embryonic deaths as well as malformed newborns are among complications of the diabetic pregnancy. Cytokines and growth factors operating in the embryonic vicinity are found to be among factors that determine the sensitivity of embryos to external and internal detrimental stimuli, including diabetes. Transforming Growth Factor-β2 (TGF-β2) has been shown to be essential for embryonic development and survival. In the present work, we evaluated the pattern of TGF-β2 expression in the uterus of streptozotocin-induced diabetic mice, demonstrating a decreased reproductive performance and elevated percentage of litters with severely malformed fetuses. Since stimulation of the maternal immune system was found to increase the resistance of mouse embryos to the teratogenic effect of diabetes, the effect of Immunopotentiation on the expression of the cytokine was also investigated. TGF-β2 expression was studied at the mRNA level by using the in situ hybridization technique and at the protein level by using the immunohistochemical analysis. A clear decrease in TGF-β2 mRNA expression in the uterus of diabetic mice was observed at examined time points: days 1, 5, and 9 of pregnancy. Also, an evident reduction in TGF-β2, the protein expression in the uterus of diabetic mice, was demonstrated at these time points. Maternal Immunopotentiation that improved the reproductive performance of diabetic mice and reduced the number of the litters with malformed fetuses was also accompanied by a clear increase in the level of TGF-β2 mRNA expression in the pregnant uteri. The above results clearly demonstrate that the embryotoxic effect of diabetes is accompanied by an alteration of TGF-β2 expression. Immunopotentiation that was shown to improve the reproductive performance of the diabetic mice was accompanied by a partial normalization of TGF-β2 expression in embryonic vicinity. Teratogenesis Carcinog. Mutagen. 22:59–71, 2002. © 2002 Wiley-Liss, Inc.
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expression of tumor necrosis factor α in the pregnant uterus of diabetic mice effect of maternal Immunopotentiation
American Journal of Reproductive Immunology, 2001Co-Authors: Amos Fein, Arkady Torchinsky, Shoshana Savion, V Toder, Hasida Orenstein, Jeanne Shepshelovich, E. Kostina, A. OrnoyAbstract:PROBLEM Tumor necrosis factor (TNF)-alpha mRNA and protein are expressed in the pregnant uterus of streptozotocin-induced diabetic mice at various stages of pregnancy. We intend to characterize their pattern and to evaluate whether the potentiation of the maternal immune system alters the pattern of the expression of the cytokine. METHOD OF STUDY Diabetes was induced in ICR mice by streptozotocin injection. To modulate maternal immune responses, ICR mice were injected intrauterine with rat splenocytes 3 weeks before mating. The expression of TNF-alpha mRNA and protein was evaluated by in situ hybridization and immunohistochemistry techniques. RESULTS The population of diabetic mice used in this study demonstrated a reduction in pregnancy rate and an increased number of litters with severely malformed fetuses. It has been observed that these disturbances are associated with a clear increase in TNF-alpha mRNA and protein expression in the uterus of these mice. Maternal Immunopotentiation, while improving reproductive performance of these diabetic mice, was found to be accompanied by a reduced expression of TNF-alpha, both at the mRNA and protein level. CONCLUSIONS The results of the present study suggest a possible involvement of TNF-alpha in mechanisms underlying diabetes-associated dismorphogenesis. Normalization of TNF-alpha expression by maternal Immunopotentiation might represent a mechanism mediating its protective effect against diabetes-induced embryotoxic insult.
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Expression of Tumor Necrosis Factor‐α in the Pregnant Uterus of Diabetic Mice: Effect of Maternal Immunopotentiation
American journal of reproductive immunology (New York N.Y. : 1989), 2001Co-Authors: Amos Fein, Arkady Torchinsky, Shoshana Savion, Hasida Orenstein, Vladimir Toder, Jeanne Shepshelovich, E. Kostina, A. OrnoyAbstract:PROBLEM Tumor necrosis factor (TNF)-alpha mRNA and protein are expressed in the pregnant uterus of streptozotocin-induced diabetic mice at various stages of pregnancy. We intend to characterize their pattern and to evaluate whether the potentiation of the maternal immune system alters the pattern of the expression of the cytokine. METHOD OF STUDY Diabetes was induced in ICR mice by streptozotocin injection. To modulate maternal immune responses, ICR mice were injected intrauterine with rat splenocytes 3 weeks before mating. The expression of TNF-alpha mRNA and protein was evaluated by in situ hybridization and immunohistochemistry techniques. RESULTS The population of diabetic mice used in this study demonstrated a reduction in pregnancy rate and an increased number of litters with severely malformed fetuses. It has been observed that these disturbances are associated with a clear increase in TNF-alpha mRNA and protein expression in the uterus of these mice. Maternal Immunopotentiation, while improving reproductive performance of these diabetic mice, was found to be accompanied by a reduced expression of TNF-alpha, both at the mRNA and protein level. CONCLUSIONS The results of the present study suggest a possible involvement of TNF-alpha in mechanisms underlying diabetes-associated dismorphogenesis. Normalization of TNF-alpha expression by maternal Immunopotentiation might represent a mechanism mediating its protective effect against diabetes-induced embryotoxic insult.
