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Feiyue Xing - One of the best experts on this subject based on the ideXlab platform.
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microrna let 7c is essential for the Anisomycin elicited apoptosis in jurkat t cells by linking jnk1 2 to ap 1 stat1 stat3 signaling
Scientific Reports, 2016Co-Authors: Zhiwei Zhou, Jing Liu, Jin Wang, Jia Xiao, Feiyue XingAbstract:Anisomycin, an antibiotic produced by Streptomyces griseolus, strongly induces apoptosis in various tumor cells in vitro, superior dramatically to adriamycin. The present study aims to elucidate its detailed mechanistic process. The results showed that Anisomycin sufficiently promoted the apoptosis in human leukemic Jurkat T cells at a quite low dose. microRNA let-7c (let-7c) contributed to the Anisomycin-induced apoptosis, which could be abrogated by the inactivation of JNK signaling. The let-7c over-expression and the addition of its mimics facilitated the activation of AP-1, STAT1 and Bim by linking JNK1/2 to AP-1/STAT1, but rather inhibited the activation of STAT3 and Bcl-xL by connecting JNK1/2 to STAT3, followed by the augmented apoptosis in the cells. The let-7c deficiency reduced the AP-1, STAT1 and Bim activities, and enhanced the STAT3 and Bcl-xL, alleviating the Anisomycin-induced apoptosis. The knockdown of the bim gene repressed the Anisomycin-boosted apoptosis through the attenuation of the active Bak and Bax. The findings indicate for the first time that miR let-7c is essential for the Anisomycin-triggered apoptosis by linking JNK1/2 to AP-1/STAT1/STAT3/Bim/Bcl-xL/Bax/Bak signaling. This provides a novel insight into the mechanism by which Anisomycin leads to the tumor cell apoptosis, potentially laying the foundations for its development and clinical application.
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Low-dose Anisomycin is sufficient to alter the bio-behaviors of Jurkat T cells
Open Life Sciences, 2013Co-Authors: Manman Sun, Feiyue Xing, Shan Zeng, Shan Pan, Jing LiuAbstract:Anisomycin is a pyrrolidine antibiotic isolated from Streptomyces griseolus. It has been found that a quite low dose of Anisomycin is sufficient to block proliferation of primary T lymphocytes. The focus of this study is to explore the possibility of Anisomycin to treat human acute leukemia Jurkat T cells in vitro. The results indicated that the low dose of Anisomycin could significantly inhibit the colony formation of Jurkat T cells and elevate the inhibition rate of Jurkat T cell growth along with its increasing concentrations. Jurkat T cell cycle was blocked into S-phase by Anisomycin. Consistent with the increased proportion of sub-G1 phase, Anisomycin promoted Jurkat T cell apoptosis. The CD69 and CD25 expression on the surface of Jurkat T cells was also down-regulated prominently along with the enhancing concentrations of Anisomycin, followed by the decreased production of IL-4, IL-10, IL-17, TGF-β and IFN-γ, and the down-regulated expression of phosphorylated-ERK1/2. The results suggest that the suppressive effect of Anisomycin on Jurkat T cell growth may be related to inhibiting TGF-β production and ERK1/2 activation, arresting the cell cycle at S-phase and promoting the apoptosis of Jurkat T cells.
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In vitro and in vivo evaluation of Anisomycin against Ehrlich ascites carcinoma
Oncology Reports, 2013Co-Authors: Pengtao You, Feiyue Xing, Shan Zeng, Jie Huo, Baoyu Wang, Jing LiuAbstract:Anisomycin eminently inhibits cell proliferation in vitro. The aim of this study was to explore the potential of Anisomycin to treat tumors in vivo and its mechanism(s) of action. The results showed that peritumoral administration of Anisomycin significantly suppressed Ehrlich ascites carcinoma (EAC) growth resulting in the survival of approximately 60% of the mice 90 days after EAC inoculation. Enhancement of infiltrating lymphocytes was noted in the tumor tissue, which was dramatically superior to adriamycin. The growth inhibitory rate of EAC cells was enhanced with increasing concentrations of Anisomycin, following an enhanced apoptotic rate. The total apoptotic rate induced by 160 ng/ml of Anisomycin was higher when compared to that induced by 500 ng/ml of adriamycin. DNA breakage and nanostructure changes were also noted in the EAC cells. The levels of caspase-3 mRNA, caspase-3 and cleaved-caspase-3 proteins in the Anisomycin‑treated EAC cells were augmented in a dose- and time-dependent manner, following the activation of caspase-8 and caspase-9, which finally triggered PARP cleavage. The cleaved-caspase-3, cleaved-caspase-8 and cleaved-caspase-9 proteins were mainly localized in the nuclei of the cells. These results indicate that Anisomycin efficaciously represses in vitro and in vivo growth of EAC cells through caspase signaling, significantly superior to the effects of adriamycin. This suggests the potential of Anisomycin for the treatment of breast cancer.
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Anisomycin suppresses Jurkat T cell growth by the cell cycle-regulating proteins
Pharmacological Reports, 2013Co-Authors: Feiyue Xing, Zhengle Tang, Christian Bronner, Shan Zeng, Jing LiuAbstract:Abstract Background Recent studies have shown that Anisomycin significantly inhibits mammalian cell proliferation, but its mechanism remains unclear. In this study, Jurkat T cells were used to first explore a relationship between effect of Anisomycin on them and alteration of cell cycle-regulating proteins. Methods Cell colony formation, CCK-8 assay, flow cytometry, RT-PCR and western blot were employed to evaluate correlation of ten cell cycle-regulating proteins with suppression of the cell proliferation and arrest of the cell cycle by Anisomycin. Results Our data showed that Anisomycin inhibited the colony-formation and proliferation of Jurkat T cells in a dose-dependent manner, and arrested the cells into S and G2/M phases with the production of sub-diploid cells. The levels of P21, P-P27 and P53/P-P53 reached their peaks 4 h after Anisomycin treatment, presenting a positive correlation with Anisomycin concentration, and P16, P-P21, P27, P57, P73/P-P73 and P-Rb changed little with the prolonged exposure time or increased concentrations of Anisomycin. But the level of Rb protein was increased at 24 h after the treatment of Anisomycin. The expression of an inverted CCAAT box binding protein (ICBP90) in Jurkat T cells came to decrease 12 h after the treatment of Anisomycin, presenting a negative correlation with Anisomycin concentration. Subsequently, the expression of P-CDK2 was also decreased at 24 h, presenting an obviously negative correlation, whereas P-CDK1 showed no differences among the differently treated Jurkat T cells. Furthermore, the level of P21 and P53 mRNA was increased with the enhanced concentrations of Anisomycin. Conclusion The results indicate that Anisomycin may activate the P53/P21/P27 signaling to decrease the expression of ICBP90, inhibit expression of P-CDK2 to block the cells into S and G2/M phases, and finally result in proliferation inhibition of Jurkat T cells.
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In vivo toxicological evaluation of Anisomycin.
Toxicology Letters, 2011Co-Authors: Zhengle Tang, Feiyue Xing, Di Chen, Yu Yu, Chunyan Yu, Jingfang DiAbstract:Abstract Anisomycin is a pyrrolidine antibiotic isolated from Streptomyces griseolus . Recent studies have shown that Anisomycin as a novel immunosuppressive agent is superior to Cyclosporine A (J. Immunother. 31, 858–870, 2008). In order to make toxicological evaluation of Anisomycin, acute and four-week continuously intravenous toxicity studies were performed in mice. IC 50 value tested on peripheral lymphocytes was 25.44 ng/ml. The calculated LD 50 for Anisomycin was 119.64 mg/kg. The mice were intravenously injected through mouse tail vein with a total dose of 5, 15, 30 and 60 mg/kg/mice of Anisomycin every other day for 4 weeks. Just in the high-dose mice, death of three mice happened and body weight of the mice was significantly decreased. Statistically significant changes in organ index included increases in ratios of the spleen, liver, lung and brain to the body weight, and decrease in ratio of the thymus to the body weight. Changes in clinical biochemistry parameters included increases in the aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities, and decreases in the glucose (GLU) activity. The distinct inflammation appeared in the lung, liver and kidney, and the number and size of megakaryocytes in the spleen were significantly increased. Anisomycin did not induce formation of the peripheral blood micronucleus, but increased the number of micronucleated polychromatic erythrocytes in bone marrow and sperm aberrations. However, the above aberrant changes occurred only in the mice treated with the high-dose Anisomycin. These results indicate that although Anisomycin has no significant side effects at effectively therapeutic doses, its over-dosage may lead to toxicity, particularly pulmo-, nephro- and hepato-toxicity.
Tai-liang Guo - One of the best experts on this subject based on the ideXlab platform.
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disruption of nox2 and tnfrp55 p75 eliminates cardioprotection induced by Anisomycin
American Journal of Physiology-heart and Circulatory Physiology, 2012Co-Authors: Ting C Zhao, Ling Zhang, Jun T. Liu, Tai-liang GuoAbstract:Transient activation of p38 through Anisomycin is demonstrated to precondition the heart against myocardial injury. However, it remains unknown whether specific TNF-α receptor (TNFR) p55/p75 and Nox2, a subunit of NADPH oxidase, are involved in this event. We sought to investigate whether the genetic disruption of TNFRp55/p75 and Nox2 eliminated cardioprotection elicited by Anisomycin and whether p38-dependent activation of Nox2 stimulated TNFR to ultimately achieve protective effects. Adult wild-type and TNFR p55/p75−/− and Nox2−/− mice received intraperitoneal injections of Anisomycin (0.1 mg/kg), a potent activator of p38. The hearts were subjected to 30 min myocardial ischemia/30 min reperfusion in the Langendorff perfused heart after 24 h. Left ventricular function was measured, and infarct size was determined. Myocardial TNF-α protein, Nox2, and superoxides releases were detected. Gel kinase assay was employed to detect the effect of p38 on Nox2 phosphorylation. Activation of p38 through Anisomycin produces marked improvements in left ventricular functional recovery, and the reduction of myocardial infarction, which were abrogated by disruption of Nox2 and TNFR p55/p75. Disruption of Nox2 and TNFR p55/p75 abolished the effect of Anisomycin-induced reduction of infarct size. Anisomycin induced the production of TNF-α, which was abrogated in Nox2−/− mice and by treatment with SB203580, but not by disruption of p55/p75. Anisomycin treatment resulted in an increase in Nox2 protein and the phosphorylation of Nox2, which was blocked by inhibition of p38. Taken together, these results indicate that stimulation of the Nox2 and TNFR p55/p75 pathway is a novel approach to Anisomycin-induced cardioprotection.
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Disruption of Nox2 and TNFRp55/p75 eliminates cardioprotection induced by Anisomycin
American Journal of Physiology-Heart and Circulatory Physiology, 2012Co-Authors: Ting C Zhao, Ling Zhang, Jun T. Liu, Tai-liang GuoAbstract:Transient activation of p38 through Anisomycin is demonstrated to precondition the heart against myocardial injury. However, it remains unknown whether specific TNF-α receptor (TNFR) p55/p75 and Nox2, a subunit of NADPH oxidase, are involved in this event. We sought to investigate whether the genetic disruption of TNFRp55/p75 and Nox2 eliminated cardioprotection elicited by Anisomycin and whether p38-dependent activation of Nox2 stimulated TNFR to ultimately achieve protective effects. Adult wild-type and TNFR p55/p75−/− and Nox2−/− mice received intraperitoneal injections of Anisomycin (0.1 mg/kg), a potent activator of p38. The hearts were subjected to 30 min myocardial ischemia/30 min reperfusion in the Langendorff perfused heart after 24 h. Left ventricular function was measured, and infarct size was determined. Myocardial TNF-α protein, Nox2, and superoxides releases were detected. Gel kinase assay was employed to detect the effect of p38 on Nox2 phosphorylation. Activation of p38 through Anisomycin produces marked improvements in left ventricular functional recovery, and the reduction of myocardial infarction, which were abrogated by disruption of Nox2 and TNFR p55/p75. Disruption of Nox2 and TNFR p55/p75 abolished the effect of Anisomycin-induced reduction of infarct size. Anisomycin induced the production of TNF-α, which was abrogated in Nox2−/− mice and by treatment with SB203580, but not by disruption of p55/p75. Anisomycin treatment resulted in an increase in Nox2 protein and the phosphorylation of Nox2, which was blocked by inhibition of p38. Taken together, these results indicate that stimulation of the Nox2 and TNFR p55/p75 pathway is a novel approach to Anisomycin-induced cardioprotection.
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Abstract 146: Disruption of Nox2 and TNFRp55/p75 Eliminates Anisomycin-Induced Preconditioning Effect in the Heart
Circulation Research, 2012Co-Authors: Ting C Zhao, Ling Zhang, Tai-liang GuoAbstract:Background: Transient activation of p38 through Anisomycin is demonstrated to precondition the heart against myocardial injury. However, it remains unknown whether specific TNF-α receptor (TNFR) p55/p75 and Nox2, a subunit of NADPH-oxidase are involved in this event. Objective: We sought to investigate whether the genetic disruption of TNFRp55/p75 and Nox2 eliminates cardioprotection elicited by Anisomycin and whether p38-dependent activation of Nox2 stimulates TNFR to ultimately achieve protective effects. Methods: Adult wild type and p55/p75 -/- and Nox2 -/- mice received intraperitoneal injections of Anisomycin (0.1mg/kg), a potent activator of p38. The hearts were subjected to 30 min myocardial ischemia /30 min reperfusion in the Langendorff perused heart after twenty four hours. Left ventricular function was measured and infarct size was determined by triphenyltetrazolium chloride. Myocardial TNF-α protein, Nox2 and superoxides releases were detected. Gel kinase assay was employed to detect the effect of p38 on Nox2 phosphorylation. Results: Activation of p38 through Anisomycin produces marked improvements in the recovery of left ventricular end diastolic pressure, rate pressure products, and the reduction of myocardial infarction, which were completely abrogated by disruption of Nox2 and TNFR p55/p75. Genetic disruption of Nox2 and TNFR p55/p75 abolished the effect of Anisomycin-induced reduction of infarct size. Ansiomycin induced the production of TNFα, which was abrogated in Nox2 -/- mice. Notably, activation of p38 resulted in the phosphorylation of Nox2. Conclusion: Taken together, these results indicate that stimulation of the Nox2 and TNFR p55/p75 pathway is a novel approach to Anisomycin-induced cardioprotection.
Wenting Hao - One of the best experts on this subject based on the ideXlab platform.
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Anisomycin inhibits the behaviors of t cells and the allogeneic skin transplantation in mice
Journal of Immunotherapy, 2008Co-Authors: Feiyue Xing, Shan Zeng, Jing Liu, Di Chen, Ling Chen, Zhiyuan Fang, Zhongfeng Guo, Shan Pan, Jiongkun Wang, Wenting HaoAbstract:There is still a lack of a high potent and low toxic immunosuppressive drug. We accidentally found that a quite low dose of Anisomycin was sufficient to block proliferation of T cells. In this study, carboxy-fluorescein diacetate-succinimidyl ester staining showed that over 10.0 ng/mL of Anisomycin markedly inhibited the proliferation of T cells induced by ConA. Propidium iodide staining revealed that Anisomycin led to G0/G1 arrest and blocked S phase entry stimulated by ConA or phorbol 12, 13-dibutyrate plus ionomycin. Anisomycin down-regulated remarkably the CD69 and CD25 expression on the surface of T cells. The response of T cells was repressed by treatment of Anisomycin, which was partly restored by adding exogenous interleukin-2, and there was no difference between Anisomycin and dexamethasone, although the used dose of the latter was 100-fold of the former. The inhibition of cytotoxicity of T cells against 7919 cells by Anisomycin was observed without the direct cytotoxicity to T cells or 7919 cells. The level of transforming growth factor-beta1 fell by <80.0 ng/mL in vitro and 30.0 mg/kg of Anisomycin in vivo and enhanced by more than the doses. The treatment of Anisomycin prolonged the survival of the transplanted skin and depressed the delayed type hypersensitivity development and the T-cell response in the skin-transplanted mice. Moreover, the effect of its restraining allograft rejection might be superior to cyclosporine A, with relatively slight toxic signs. These results indicate Anisomycin significantly inhibits the behaviors of T cells and the transplantation rejection, providing important evidence for Anisomycin as a novel immunosuppressant.
Jing Liu - One of the best experts on this subject based on the ideXlab platform.
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microrna let 7c is essential for the Anisomycin elicited apoptosis in jurkat t cells by linking jnk1 2 to ap 1 stat1 stat3 signaling
Scientific Reports, 2016Co-Authors: Zhiwei Zhou, Jing Liu, Jin Wang, Jia Xiao, Feiyue XingAbstract:Anisomycin, an antibiotic produced by Streptomyces griseolus, strongly induces apoptosis in various tumor cells in vitro, superior dramatically to adriamycin. The present study aims to elucidate its detailed mechanistic process. The results showed that Anisomycin sufficiently promoted the apoptosis in human leukemic Jurkat T cells at a quite low dose. microRNA let-7c (let-7c) contributed to the Anisomycin-induced apoptosis, which could be abrogated by the inactivation of JNK signaling. The let-7c over-expression and the addition of its mimics facilitated the activation of AP-1, STAT1 and Bim by linking JNK1/2 to AP-1/STAT1, but rather inhibited the activation of STAT3 and Bcl-xL by connecting JNK1/2 to STAT3, followed by the augmented apoptosis in the cells. The let-7c deficiency reduced the AP-1, STAT1 and Bim activities, and enhanced the STAT3 and Bcl-xL, alleviating the Anisomycin-induced apoptosis. The knockdown of the bim gene repressed the Anisomycin-boosted apoptosis through the attenuation of the active Bak and Bax. The findings indicate for the first time that miR let-7c is essential for the Anisomycin-triggered apoptosis by linking JNK1/2 to AP-1/STAT1/STAT3/Bim/Bcl-xL/Bax/Bak signaling. This provides a novel insight into the mechanism by which Anisomycin leads to the tumor cell apoptosis, potentially laying the foundations for its development and clinical application.
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Low-dose Anisomycin is sufficient to alter the bio-behaviors of Jurkat T cells
Open Life Sciences, 2013Co-Authors: Manman Sun, Feiyue Xing, Shan Zeng, Shan Pan, Jing LiuAbstract:Anisomycin is a pyrrolidine antibiotic isolated from Streptomyces griseolus. It has been found that a quite low dose of Anisomycin is sufficient to block proliferation of primary T lymphocytes. The focus of this study is to explore the possibility of Anisomycin to treat human acute leukemia Jurkat T cells in vitro. The results indicated that the low dose of Anisomycin could significantly inhibit the colony formation of Jurkat T cells and elevate the inhibition rate of Jurkat T cell growth along with its increasing concentrations. Jurkat T cell cycle was blocked into S-phase by Anisomycin. Consistent with the increased proportion of sub-G1 phase, Anisomycin promoted Jurkat T cell apoptosis. The CD69 and CD25 expression on the surface of Jurkat T cells was also down-regulated prominently along with the enhancing concentrations of Anisomycin, followed by the decreased production of IL-4, IL-10, IL-17, TGF-β and IFN-γ, and the down-regulated expression of phosphorylated-ERK1/2. The results suggest that the suppressive effect of Anisomycin on Jurkat T cell growth may be related to inhibiting TGF-β production and ERK1/2 activation, arresting the cell cycle at S-phase and promoting the apoptosis of Jurkat T cells.
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In vitro and in vivo evaluation of Anisomycin against Ehrlich ascites carcinoma
Oncology Reports, 2013Co-Authors: Pengtao You, Feiyue Xing, Shan Zeng, Jie Huo, Baoyu Wang, Jing LiuAbstract:Anisomycin eminently inhibits cell proliferation in vitro. The aim of this study was to explore the potential of Anisomycin to treat tumors in vivo and its mechanism(s) of action. The results showed that peritumoral administration of Anisomycin significantly suppressed Ehrlich ascites carcinoma (EAC) growth resulting in the survival of approximately 60% of the mice 90 days after EAC inoculation. Enhancement of infiltrating lymphocytes was noted in the tumor tissue, which was dramatically superior to adriamycin. The growth inhibitory rate of EAC cells was enhanced with increasing concentrations of Anisomycin, following an enhanced apoptotic rate. The total apoptotic rate induced by 160 ng/ml of Anisomycin was higher when compared to that induced by 500 ng/ml of adriamycin. DNA breakage and nanostructure changes were also noted in the EAC cells. The levels of caspase-3 mRNA, caspase-3 and cleaved-caspase-3 proteins in the Anisomycin‑treated EAC cells were augmented in a dose- and time-dependent manner, following the activation of caspase-8 and caspase-9, which finally triggered PARP cleavage. The cleaved-caspase-3, cleaved-caspase-8 and cleaved-caspase-9 proteins were mainly localized in the nuclei of the cells. These results indicate that Anisomycin efficaciously represses in vitro and in vivo growth of EAC cells through caspase signaling, significantly superior to the effects of adriamycin. This suggests the potential of Anisomycin for the treatment of breast cancer.
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Anisomycin suppresses Jurkat T cell growth by the cell cycle-regulating proteins
Pharmacological Reports, 2013Co-Authors: Feiyue Xing, Zhengle Tang, Christian Bronner, Shan Zeng, Jing LiuAbstract:Abstract Background Recent studies have shown that Anisomycin significantly inhibits mammalian cell proliferation, but its mechanism remains unclear. In this study, Jurkat T cells were used to first explore a relationship between effect of Anisomycin on them and alteration of cell cycle-regulating proteins. Methods Cell colony formation, CCK-8 assay, flow cytometry, RT-PCR and western blot were employed to evaluate correlation of ten cell cycle-regulating proteins with suppression of the cell proliferation and arrest of the cell cycle by Anisomycin. Results Our data showed that Anisomycin inhibited the colony-formation and proliferation of Jurkat T cells in a dose-dependent manner, and arrested the cells into S and G2/M phases with the production of sub-diploid cells. The levels of P21, P-P27 and P53/P-P53 reached their peaks 4 h after Anisomycin treatment, presenting a positive correlation with Anisomycin concentration, and P16, P-P21, P27, P57, P73/P-P73 and P-Rb changed little with the prolonged exposure time or increased concentrations of Anisomycin. But the level of Rb protein was increased at 24 h after the treatment of Anisomycin. The expression of an inverted CCAAT box binding protein (ICBP90) in Jurkat T cells came to decrease 12 h after the treatment of Anisomycin, presenting a negative correlation with Anisomycin concentration. Subsequently, the expression of P-CDK2 was also decreased at 24 h, presenting an obviously negative correlation, whereas P-CDK1 showed no differences among the differently treated Jurkat T cells. Furthermore, the level of P21 and P53 mRNA was increased with the enhanced concentrations of Anisomycin. Conclusion The results indicate that Anisomycin may activate the P53/P21/P27 signaling to decrease the expression of ICBP90, inhibit expression of P-CDK2 to block the cells into S and G2/M phases, and finally result in proliferation inhibition of Jurkat T cells.
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Anisomycin inhibits the behaviors of t cells and the allogeneic skin transplantation in mice
Journal of Immunotherapy, 2008Co-Authors: Feiyue Xing, Shan Zeng, Jing Liu, Di Chen, Ling Chen, Zhiyuan Fang, Zhongfeng Guo, Shan Pan, Jiongkun Wang, Wenting HaoAbstract:There is still a lack of a high potent and low toxic immunosuppressive drug. We accidentally found that a quite low dose of Anisomycin was sufficient to block proliferation of T cells. In this study, carboxy-fluorescein diacetate-succinimidyl ester staining showed that over 10.0 ng/mL of Anisomycin markedly inhibited the proliferation of T cells induced by ConA. Propidium iodide staining revealed that Anisomycin led to G0/G1 arrest and blocked S phase entry stimulated by ConA or phorbol 12, 13-dibutyrate plus ionomycin. Anisomycin down-regulated remarkably the CD69 and CD25 expression on the surface of T cells. The response of T cells was repressed by treatment of Anisomycin, which was partly restored by adding exogenous interleukin-2, and there was no difference between Anisomycin and dexamethasone, although the used dose of the latter was 100-fold of the former. The inhibition of cytotoxicity of T cells against 7919 cells by Anisomycin was observed without the direct cytotoxicity to T cells or 7919 cells. The level of transforming growth factor-beta1 fell by <80.0 ng/mL in vitro and 30.0 mg/kg of Anisomycin in vivo and enhanced by more than the doses. The treatment of Anisomycin prolonged the survival of the transplanted skin and depressed the delayed type hypersensitivity development and the T-cell response in the skin-transplanted mice. Moreover, the effect of its restraining allograft rejection might be superior to cyclosporine A, with relatively slight toxic signs. These results indicate Anisomycin significantly inhibits the behaviors of T cells and the transplantation rejection, providing important evidence for Anisomycin as a novel immunosuppressant.
Ting C Zhao - One of the best experts on this subject based on the ideXlab platform.
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Disruption of Nox2 and TNFRp55/p75 eliminates cardioprotection induced by Anisomycin
American Journal of Physiology-Heart and Circulatory Physiology, 2012Co-Authors: Ting C Zhao, Ling Zhang, Jun T. Liu, Tai-liang GuoAbstract:Transient activation of p38 through Anisomycin is demonstrated to precondition the heart against myocardial injury. However, it remains unknown whether specific TNF-α receptor (TNFR) p55/p75 and Nox2, a subunit of NADPH oxidase, are involved in this event. We sought to investigate whether the genetic disruption of TNFRp55/p75 and Nox2 eliminated cardioprotection elicited by Anisomycin and whether p38-dependent activation of Nox2 stimulated TNFR to ultimately achieve protective effects. Adult wild-type and TNFR p55/p75−/− and Nox2−/− mice received intraperitoneal injections of Anisomycin (0.1 mg/kg), a potent activator of p38. The hearts were subjected to 30 min myocardial ischemia/30 min reperfusion in the Langendorff perfused heart after 24 h. Left ventricular function was measured, and infarct size was determined. Myocardial TNF-α protein, Nox2, and superoxides releases were detected. Gel kinase assay was employed to detect the effect of p38 on Nox2 phosphorylation. Activation of p38 through Anisomycin produces marked improvements in left ventricular functional recovery, and the reduction of myocardial infarction, which were abrogated by disruption of Nox2 and TNFR p55/p75. Disruption of Nox2 and TNFR p55/p75 abolished the effect of Anisomycin-induced reduction of infarct size. Anisomycin induced the production of TNF-α, which was abrogated in Nox2−/− mice and by treatment with SB203580, but not by disruption of p55/p75. Anisomycin treatment resulted in an increase in Nox2 protein and the phosphorylation of Nox2, which was blocked by inhibition of p38. Taken together, these results indicate that stimulation of the Nox2 and TNFR p55/p75 pathway is a novel approach to Anisomycin-induced cardioprotection.
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disruption of nox2 and tnfrp55 p75 eliminates cardioprotection induced by Anisomycin
American Journal of Physiology-heart and Circulatory Physiology, 2012Co-Authors: Ting C Zhao, Ling Zhang, Jun T. Liu, Tai-liang GuoAbstract:Transient activation of p38 through Anisomycin is demonstrated to precondition the heart against myocardial injury. However, it remains unknown whether specific TNF-α receptor (TNFR) p55/p75 and Nox2, a subunit of NADPH oxidase, are involved in this event. We sought to investigate whether the genetic disruption of TNFRp55/p75 and Nox2 eliminated cardioprotection elicited by Anisomycin and whether p38-dependent activation of Nox2 stimulated TNFR to ultimately achieve protective effects. Adult wild-type and TNFR p55/p75−/− and Nox2−/− mice received intraperitoneal injections of Anisomycin (0.1 mg/kg), a potent activator of p38. The hearts were subjected to 30 min myocardial ischemia/30 min reperfusion in the Langendorff perfused heart after 24 h. Left ventricular function was measured, and infarct size was determined. Myocardial TNF-α protein, Nox2, and superoxides releases were detected. Gel kinase assay was employed to detect the effect of p38 on Nox2 phosphorylation. Activation of p38 through Anisomycin produces marked improvements in left ventricular functional recovery, and the reduction of myocardial infarction, which were abrogated by disruption of Nox2 and TNFR p55/p75. Disruption of Nox2 and TNFR p55/p75 abolished the effect of Anisomycin-induced reduction of infarct size. Anisomycin induced the production of TNF-α, which was abrogated in Nox2−/− mice and by treatment with SB203580, but not by disruption of p55/p75. Anisomycin treatment resulted in an increase in Nox2 protein and the phosphorylation of Nox2, which was blocked by inhibition of p38. Taken together, these results indicate that stimulation of the Nox2 and TNFR p55/p75 pathway is a novel approach to Anisomycin-induced cardioprotection.
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Abstract 146: Disruption of Nox2 and TNFRp55/p75 Eliminates Anisomycin-Induced Preconditioning Effect in the Heart
Circulation Research, 2012Co-Authors: Ting C Zhao, Ling Zhang, Tai-liang GuoAbstract:Background: Transient activation of p38 through Anisomycin is demonstrated to precondition the heart against myocardial injury. However, it remains unknown whether specific TNF-α receptor (TNFR) p55/p75 and Nox2, a subunit of NADPH-oxidase are involved in this event. Objective: We sought to investigate whether the genetic disruption of TNFRp55/p75 and Nox2 eliminates cardioprotection elicited by Anisomycin and whether p38-dependent activation of Nox2 stimulates TNFR to ultimately achieve protective effects. Methods: Adult wild type and p55/p75 -/- and Nox2 -/- mice received intraperitoneal injections of Anisomycin (0.1mg/kg), a potent activator of p38. The hearts were subjected to 30 min myocardial ischemia /30 min reperfusion in the Langendorff perused heart after twenty four hours. Left ventricular function was measured and infarct size was determined by triphenyltetrazolium chloride. Myocardial TNF-α protein, Nox2 and superoxides releases were detected. Gel kinase assay was employed to detect the effect of p38 on Nox2 phosphorylation. Results: Activation of p38 through Anisomycin produces marked improvements in the recovery of left ventricular end diastolic pressure, rate pressure products, and the reduction of myocardial infarction, which were completely abrogated by disruption of Nox2 and TNFR p55/p75. Genetic disruption of Nox2 and TNFR p55/p75 abolished the effect of Anisomycin-induced reduction of infarct size. Ansiomycin induced the production of TNFα, which was abrogated in Nox2 -/- mice. Notably, activation of p38 resulted in the phosphorylation of Nox2. Conclusion: Taken together, these results indicate that stimulation of the Nox2 and TNFR p55/p75 pathway is a novel approach to Anisomycin-induced cardioprotection.
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p38 Triggers Late Preconditioning Elicited by Anisomycin in Heart
Circulation Research, 2001Co-Authors: Ting C Zhao, Mohiuddin M. Taher, Kristoffer Valerie, Rakesh C. KukrejaAbstract:We investigated the role of stress-activated p38 MAP kinase (p38/SAPK-2) signaling in delayed preconditioning of the heart. Adult male out-bred ICR mice were treated with p38 activator, Anisomycin (0.1 mg/kg IP), or vehicle (5% DMSO). Twenty-four hours later, hearts were perfused in Langendorff mode and subjected to 30 minutes of ischemia and 30 minutes of reperfusion. Improvement in postischemic recovery of end-diastolic pressure and reduction in infarct size was observed, which was abolished by SB203580, a specific p38 inhibitor, and pyrrolidinediethyldithiocarbamate (PDTC), the NF-κB inhibitor, but not by PD 98059, a specific inhibitor for MEK1 or 2. Transient increase in p38 phosphorylation was observed 15 minutes after Anisomycin treatment which subsided by 30 minutes. Electrophoretic mobility shift assay demonstrated rapid activation of NF-κB DNA binding with Anisomycin, peaking at 30 minutes. Western blot confirmed the accumulation of p50 and p65 in nuclear extracts after Anisomycin treatment. Anisomycin-induced NF-κB DNA binding activity was inhibited by SB203580 and PDTC. Expression of inducible nitric oxide synthase (iNOS) mRNA, protein, and nitric oxide (NO) synthesis were enhanced in Anisomycin-treated mice. SB203580 and PDTC blocked the increased expression of iNOS and increase in synthesis of NO. Selective iNOS inhibitor S -methylisothiourea abolished the protective effect of Anisomycin. Furthermore, postischemic cardioprotective effect of Anisomycin was absent in mice with targeted ablation of iNOS gene but not in the wild-type B6.129 mice. For the first time, these results suggest that direct pharmacological activation of p38 triggers delayed preconditioning by signaling mechanism involving NF-κB activation and synthesis of NO from iNOS.
