D by Fas or dexamethasone [49,50]. In our previous study, a small yet significantly higher proportion of splenic CD4+CD25+ T cells underwent apoptosis in pregnant mice infected with T. gondii than that in gestational age-matched controls [17]. In this study, after the administration of T. gondii ESA, the significant apoptosis of splenic CD4+CD25+ Tregs could also be observed at G5 ip and G10 ip compared with that of the control group. It is suggested that apoptosis should be contributive to the diminished number and function of Tregs after T. gondii ESA injection at early and intermediate stages of pregnancy. Supposing that the changes in number and function of Tregs were related to apoptosis, we sought to further determine their possible mechanisms. Caspase-3 plays an irreplaceable role in apoptosis. Moreover, a recent study demonstrated that T. gondii might up-regulate the expressions of death receptor ligands; the subsequent binding of FasL to its receptor induces the trimerization of the receptor and formation of a death-inducing complex, which cause FCCP web Caspase-8 activation, then cleaves various proteins and finally results in the activation of caspase cascades [51]. Besides, Bax and Bcl-2, the proteins of Bcl-2 family, serve as distinct regulators of apoptosis at its early stages. An interaction between Bcl-2 and Bax may be necessary for the apoptotic process to proceed [52,53]. In this study, we confirmed that the administration of T. gondii ESA at G5 ip and G10 ip led to the up-regulation of cleaved Caspase-3 expression. Furthermore, wefound the down- regulation of Bcl-2 at G5 ip and G10 ip and the up-regulation at G15 ip after T. gondii ESA administration, suggesting that the apoptosis induced by T. gondii ESA is through down-regulation of Bcl-2 expression. However, as for the expression of Bax, no significant differences were observed among mice with T. gondii ESA administration at G5 ip, G10 ip, G15 ip, although overexpression of Bax induced or enhanced spontaneous cell death without additional factors [54]. In conclusion, the present results demonstrate for the first time, to our knowledge, that T. gondii ESA injection at different gestational periods can differently influence CD4+CD25+ regulatory T cells and then lead to different pregnancy outcomes. The injection of T. gondii ESA at early and intermediate stages of pregnancy could result in the decreased frequency and impaired suppressive capacity of CD4+CD25+ regulatory T cells, while the administration that occurs at late pregnancy fails to impair those cells. In addition, the decreased frequency of CD4+CD25+ regulatory T cells is associated with the apoptosis caused by T. gondii ESA by down-regulating Bcl-2 expression and Bcl-2/Bax ratio. Our further study is focusing on the effects of T.gondii ESA on Tregs under estrogen/progestogen stress during pregnancy. In conclusion, the present study provides new insights into the mechanism that the abortion caused by T. gondii is more likely depending on the timing of pregnancy.AcknowledgmentsWe thank Prof. Ji-Long Shen, Anhui Medical University, Hefei, China, for providing us with the RH Salmon calcitonin strain of T. gondii and 23977191 for his helpful suggestions.Author ContributionsConceived and designed the experiments: YW J-PW J-LC. Performed the experiments: J-LC Y-YG JZ X-YQ. Analyzed the data: J-LC Y-YG JZ JFQ. Contributed reagents/materials/analysis tools: J-LC Y-YG JZ X-YQ. Wrote the paper: J-LC YW J-FQ.
Neuropathic pain is a pathological pain condi.D by Fas or dexamethasone [49,50]. In our previous study, a small yet significantly higher proportion of splenic CD4+CD25+ T cells underwent apoptosis in pregnant mice infected with T. gondii than that in gestational age-matched controls [17]. In this study, after the administration of T. gondii ESA, the significant apoptosis of splenic CD4+CD25+ Tregs could also be observed at G5 ip and G10 ip compared with that of the control group. It is suggested that apoptosis should be contributive to the diminished number and function of Tregs after T. gondii ESA injection at early and intermediate stages of pregnancy. Supposing that the changes in number and function of Tregs were related to apoptosis, we sought to further determine their possible mechanisms. Caspase-3 plays an irreplaceable role in apoptosis. Moreover, a recent study demonstrated that T. gondii might up-regulate the expressions of death receptor ligands; the subsequent binding of FasL to its receptor induces the trimerization of the receptor and formation of a death-inducing complex, which cause Caspase-8 activation, then cleaves various proteins and finally results in the activation of caspase cascades [51]. Besides, Bax and Bcl-2, the proteins of Bcl-2 family, serve as distinct regulators of apoptosis at its early stages. An interaction between Bcl-2 and Bax may be necessary for the apoptotic process to proceed [52,53]. In this study, we confirmed that the administration of T. gondii ESA at G5 ip and G10 ip led to the up-regulation of cleaved Caspase-3 expression. Furthermore, wefound the down- regulation of Bcl-2 at G5 ip and G10 ip and the up-regulation at G15 ip after T. gondii ESA administration, suggesting that the apoptosis induced by T. gondii ESA is through down-regulation of Bcl-2 expression. However, as for the expression of Bax, no significant differences were observed among mice with T. gondii ESA administration at G5 ip, G10 ip, G15 ip, although overexpression of Bax induced or enhanced spontaneous cell death without additional factors [54]. In conclusion, the present results demonstrate for the first time, to our knowledge, that T. gondii ESA injection at different gestational periods can differently influence CD4+CD25+ regulatory T cells and then lead to different pregnancy outcomes. The injection of T. gondii ESA at early and intermediate stages of pregnancy could result in the decreased frequency and impaired suppressive capacity of CD4+CD25+ regulatory T cells, while the administration that occurs at late pregnancy fails to impair those cells. In addition, the decreased frequency of CD4+CD25+ regulatory T cells is associated with the apoptosis caused by T. gondii ESA by down-regulating Bcl-2 expression and Bcl-2/Bax ratio. Our further study is focusing on the effects of T.gondii ESA on Tregs under estrogen/progestogen stress during pregnancy. In conclusion, the present study provides new insights into the mechanism that the abortion caused by T. gondii is more likely depending on the timing of pregnancy.AcknowledgmentsWe thank Prof. Ji-Long Shen, Anhui Medical University, Hefei, China, for providing us with the RH strain of T. gondii and 23977191 for his helpful suggestions.Author ContributionsConceived and designed the experiments: YW J-PW J-LC. Performed the experiments: J-LC Y-YG JZ X-YQ. Analyzed the data: J-LC Y-YG JZ JFQ. Contributed reagents/materials/analysis tools: J-LC Y-YG JZ X-YQ. Wrote the paper: J-LC YW J-FQ.
Neuropathic pain is a pathological pain condi.

D by Fas or dexamethasone [49,50]. In our previous study, a small

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