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Pingfan Rao - One of the best experts on this subject based on the ideXlab platform.
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gst tat sod cell permeable bifunctional antioxidant enzyme a potential selective radioprotector
Oxidative Medicine and Cellular Longevity, 2016Co-Authors: Jianru Pan, Guangjin Zheng, Shutao Liu, Pingfan RaoAbstract:Superoxide dismutase (SOD) fusion of TAT was proved to be Radioprotective in our previous work. On that basis, a bifunctional recombinant protein which was the fusion of glutathione S-transferase (GST), SOD, and TAT was constructed and named GST-TAT-SOD. Herein we report the investigation of the cytotoxicity, cell-penetrating activity, and in vitro Radioprotective effect of GST-TAT-SOD compared with wild SOD, single-function recombinant protein SOD-TAT, and amifostine. We demonstrated that wild SOD had little Radioprotective effect on irradiated L-02 and Hep G2 cells while amifostine was protective to both cell lines. SOD-TAT or GST-TAT-SOD pretreatment 3 h prior to radiation protects irradiated normal liver cells against radiation damage by eliminating intracellular excrescent superoxide, reducing cellular MDA level, enhancing cellular antioxidant ability and colony formation ability, and reducing apoptosis rate. Compared with SOD-TAT, GST-TAT-SOD was proved to have better protective effect on irradiated normal liver cells and minimal effect on irradiated hepatoma cells. Besides, GST-TAT-SOD was safe for normal cells and effectively transduced into different organs in mice, including the brain. The characteristics of this protein suggest that it may be a potential Radioprotective Agent in cancer therapy better than amifostine. Fusion of two antioxidant enzymes and cell-penetrating peptides is potentially valuable in the development of Radioprotective Agent.
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GST-TAT-SOD: Cell Permeable Bifunctional Antioxidant Enzyme—A Potential Selective Radioprotector
Hindawi Limited, 2016Co-Authors: Jianru Pan, Guangjin Zheng, Shutao Liu, Pingfan RaoAbstract:Superoxide dismutase (SOD) fusion of TAT was proved to be Radioprotective in our previous work. On that basis, a bifunctional recombinant protein which was the fusion of glutathione S-transferase (GST), SOD, and TAT was constructed and named GST-TAT-SOD. Herein we report the investigation of the cytotoxicity, cell-penetrating activity, and in vitro Radioprotective effect of GST-TAT-SOD compared with wild SOD, single-function recombinant protein SOD-TAT, and amifostine. We demonstrated that wild SOD had little Radioprotective effect on irradiated L-02 and Hep G2 cells while amifostine was protective to both cell lines. SOD-TAT or GST-TAT-SOD pretreatment 3 h prior to radiation protects irradiated normal liver cells against radiation damage by eliminating intracellular excrescent superoxide, reducing cellular MDA level, enhancing cellular antioxidant ability and colony formation ability, and reducing apoptosis rate. Compared with SOD-TAT, GST-TAT-SOD was proved to have better protective effect on irradiated normal liver cells and minimal effect on irradiated hepatoma cells. Besides, GST-TAT-SOD was safe for normal cells and effectively transduced into different organs in mice, including the brain. The characteristics of this protein suggest that it may be a potential Radioprotective Agent in cancer therapy better than amifostine. Fusion of two antioxidant enzymes and cell-penetrating peptides is potentially valuable in the development of Radioprotective Agent
Feride Severcan - One of the best experts on this subject based on the ideXlab platform.
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amifostine a radioprotectant Agent protects rat brain tissue lipids against ionizing radiation induced damage an ftir microspectroscopic imaging study
Archives of Biochemistry and Biophysics, 2012Co-Authors: Gulgun Cakmak, Faruk Zorlu, Lisa M Miller, Feride SevercanAbstract:Amifostine is the only approved Radioprotective Agent by FDA for reducing the damaging effects of radiation on healthy tissues. In this study, the protective effect of amifostine against the damaging effects of ionizing radiation on the white matter (WM) and grey matter (GM) regions of the rat brain were investigated at molecular level. Sprague-Dawley rats, which were administered amifostine or not, were whole-body irradiated at a single dose of 800 cGy, decapitated after 24 h and the brain tissues of these rats were analyzed using Fourier transform infrared microspectroscopy (FTIRM). The results revealed that the total lipid content and CH(2) groups of lipids decreased significantly and the carbonyl esters, olefinic=CH and CH(3) groups of lipids increased significantly in the WM and GM after exposure to ionizing radiation, which could be interpreted as a result of lipid peroxidation. These changes were more prominent in the WM of the brain. The administration of amifostine before ionizing radiation inhibited the radiation-induced lipid peroxidation in the brain. In addition, this study indicated that FTIRM provides a novel approach for monitoring ionizing radiation induced-lipid peroxidation and obtaining different molecular ratio images can be used as biomarkers to detect lipid peroxidation in biological systems.
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screening of protective effect of amifostine on radiation induced structural and functional variations in rat liver microsomal membranes by ft ir spectroscopy
Analytical Chemistry, 2011Co-Authors: Gulgun Cakmak, Faruk Zorlu, Mete Severcan, Feride SevercanAbstract:In this study, the protective effect of amifostine, which is the only FDA-approved Radioprotective Agent, was investigated against the deleterious effects of ionizing radiation on rat liver microsomal membranes at molecular level. Sprague−Dawley rats, which were either administered amifostine or not, were whole-body irradiated with a single dose of 800 cGy and decapitated after 24 h. The microsomal membranes isolated from the livers of these rats were investigated using FT-IR spectroscopy. The results revealed that radiation caused a significant decrease in the lipid-to-protein ratio and the degradation of lipids into smaller fragments that contain less CH2 and more carbonyl esters, olefinic═CH and CH3 groups, which could be interpreted as a result of lipid peroxidation. Radiation altered the secondary structure of proteins by inducing a decrease in the β-sheet structures and an increase in the turns and random coil structures. Moreover, a dramatic increase in lipid order and a significant decrease in the...
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amifostine a radioprotectant Agent protects rat hepatic microsomal membranes against ionizing radiation induced damage
Biophysical Journal, 2009Co-Authors: Gulgun Cakmak, Faruk Zorlu, Mete Severcan, Feride SevercanAbstract:In the present study, the protective effect of amifostine (WR-2721), which is the only approved Radioprotective Agent by the Food and Drug Administration (FDA), was investigated against the deleterious effects of ionizing radiation on rat liver microsomal membranes at molecular level. To achieve this, Sprague-Dawley rats, which were administered amifostine or not, were whole-body irradiated using Cobalt-60 irradiator at a single dose of 800 cGy, decapitated after 24 h and the microsomal membranes isolated from the livers of these rats were analyzed using FTIR spectroscopy. The results revealed that ionizing radiation caused a significant increase in the concentration of lipids whereas amifostine treatment restored the lipid content of microsomal membranes to control values. In addition, the significant increase in lipid order and a significant decrease in membrane dynamics resulting from ionizing radiation were prevented by amifostine. While ionizing radiation caused a significant decrease in the lipid to protein ratio, amifostine injection before radiation, maintained this ratio as in the control group. Furthermore, ionizing radiation-induced variations in protein secondary structure were restored by amifostine. In conclusion, the data obtained in this study indicate that amifostine administration to the rats prior to whole body irradiation protects liver microsomal membranes against the radiation induced damages. Supported by TUBITAK, (SBAG-2939) and by the METU (BAP-2006-07-02-0001).
David J. Grdina - One of the best experts on this subject based on the ideXlab platform.
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Protection from radiation-induced apoptosis by the radioprotector amifostine (WR-2721) is radiation dose dependent
Cell Biology and Toxicology, 2014Co-Authors: Rebecca J. Ormsby, Mark D. Lawrence, Benjamin J. Blyth, Katrina Bexis, Eva Bezak, Jeffrey S. Murley, David J. Grdina, Pamela J. SykesAbstract:The Radioprotective Agent amifostine is a free radical scavenger that can protect cells from the damaging effects of ionising radiation when administered prior to radiation exposure. However, amifostine has also been shown to protect cells from chromosomal mutations when administered after radiation exposure. As apoptosis is a common mechanism by which cells with mutations are removed from the cell population, we investigated whether amifostine stimulates apoptosis when administered after radiation exposure. We chose to study a relatively low dose which is the maximum radiation dose for radiation emergency workers (0.25 Gy) and a high dose relevant to radiotherapy exposures (6 Gy). Mice were administered 400 mg/kg amifostine 30 min before, or 3 h after, whole-body irradiation with 0.25 or 6 Gy X-rays and apoptosis was analysed 3 or 7 h later in spleen and bone marrow. We observed a significant increase in radiation-induced apoptosis in the spleen of mice when amifostine was administered before or after 0.25 Gy X-rays. In contrast, when a high dose of radiation was used (6 Gy), amifostine caused a reduction in radiation-induced apoptosis 3 h post-irradiation in spleen and bone marrow similar to previously published studies. This is the first study to investigate the effect of amifostine on radiation-induced apoptosis at a relatively low radiation dose and the first to demonstrate that while amifostine can reduce apoptosis from high doses of radiation, it does not mediate the same effect in response to low-dose exposures. These results suggest that there may be a dose threshold at which amifostine protects from radiation-induced apoptosis and highlight the importance of examining a range of radiation doses and timepoints.
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protection against radiation induced mutagenesis at the hprt locus by spermine and n n dithiodi 2 1 ethanediyl bis 1 3 propanediamine wr 33278
Mutagenesis, 1994Co-Authors: N. Shigematsu, David J. Grdina, Jeffrey L SchwartzAbstract:The polyamine spermine and the disulfide N,N"-(dithiodi-2,1-ethanediyl)bis-1,3-propanediamine (WR-33278) are structurally similar Agents capable of binding to DNA. WR-33278 is the disulfide moiety of the clinically studied Radioprotective Agent S-2-(3-aminopropylamino)ethylphosphorothioic acid (WR-2721). Because of their reported structural and functional similarities, it was of interest to compare their effects on cell survival and mutation induction at the hypoxanthine-guanine phosphoribosyl transferase (hprt) locus in Chinese hamster AA8 cells. WR-33278 and spermine (at concentrations of 0.01 and 0.001 mM) were electroporated into cells. Electroporation, 300 V and 125 microF, was performed either 30 min prior to or 3 h following exposure of cells to 750 cGy of ionizing radiation. Electroporation alone reduced cell survival to 75% but had no effect on hprt mutation frequency. The electroporation of either spermine or WR-33278 at concentrations greater than 0.01 mM was extremely toxic. The exposure of cells to both electroporation and irradiation gave rise to enhanced cell killing and mutation induction, with the sequence of irradiation followed 3 h later by electroporation being the more toxic protocol. Cell survival was only enhanced following electroporation of 0.01 mM of spermine and WR-33278 30 min prior to irradiation. Protection against radiation-induced hprt mutations was observed for both spermine and WR-33278 under all experimental conditions tested. Spermine at exposure concentrations of 0.01 and 0.001 mM administered 30 min before or 3 h after irradiation reduced mutation frequencies by factors of 2.2, 1.2, 1.9 and 2.2, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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Inhibition of topoisomerase IIα activity in CHO K1 cells by 2- [(aminopropyl)amino]ethanethiol (WR-1065)
Radiation research, 1993Co-Authors: David J. Grdina, Andreas I. Constantinou, N. Shigematsu, Jeffrey S. MurleyAbstract:The aminothiol 2-[(aminopropyl)amino]ethanethiol (WR-1065) is the active thiol of the clinically studied Radioprotective Agent S-2-(3-aminopropylamino)ethylphosphorothioic acid (WR-2721). WR-1065 is an effective radiation protector and antimutagenic Agent when it is administered 30 min prior to radiation exposure to Chinese hamster ovary Kl cells at a concentration of 4 mM. Under these exposure conditions, topoisomerase (topo) I and II activities and associated protein contents were measured in the K1 cell line using the DNA relaxation assay, the P4 unknotting assay, and immunoblotting, respectively. WR-1065 was ineffective in modifying topo I activity, but it did reduce topo IIa activity by an average of 50 percent. The magnitude of topo IIa protein content, however, was not affected by these exposure conditions. Cell cycle effects were monitored by the method of flow cytometry. Exposure of cells to 4 mM WR-1065 for a period of up to 6 h resulted in a buildup of cells in the G2 compartment. However, in contrast to topo II inhibitors used in chemotherapy, WR-1065 is an effective radioprotector Agent capable of protecting against both radiation-induced cell lethality and mutagenesis. One of several mechanisms of radiation protection attributed to aminothiol compounds such as WR-1065 has been their ability to affect endogenousmore » enzymatic reactions involved in DNA synthesis, repair, and cell cycle progression. These results are consistent with such a proposed mechanism and demonstrate in particular a modifying effect by 2-[(aminopropyl)amino]ethanethiol on type II topoisomerase, which is involved in DNA synthesis.« less
Jianru Pan - One of the best experts on this subject based on the ideXlab platform.
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gst tat sod cell permeable bifunctional antioxidant enzyme a potential selective radioprotector
Oxidative Medicine and Cellular Longevity, 2016Co-Authors: Jianru Pan, Guangjin Zheng, Shutao Liu, Pingfan RaoAbstract:Superoxide dismutase (SOD) fusion of TAT was proved to be Radioprotective in our previous work. On that basis, a bifunctional recombinant protein which was the fusion of glutathione S-transferase (GST), SOD, and TAT was constructed and named GST-TAT-SOD. Herein we report the investigation of the cytotoxicity, cell-penetrating activity, and in vitro Radioprotective effect of GST-TAT-SOD compared with wild SOD, single-function recombinant protein SOD-TAT, and amifostine. We demonstrated that wild SOD had little Radioprotective effect on irradiated L-02 and Hep G2 cells while amifostine was protective to both cell lines. SOD-TAT or GST-TAT-SOD pretreatment 3 h prior to radiation protects irradiated normal liver cells against radiation damage by eliminating intracellular excrescent superoxide, reducing cellular MDA level, enhancing cellular antioxidant ability and colony formation ability, and reducing apoptosis rate. Compared with SOD-TAT, GST-TAT-SOD was proved to have better protective effect on irradiated normal liver cells and minimal effect on irradiated hepatoma cells. Besides, GST-TAT-SOD was safe for normal cells and effectively transduced into different organs in mice, including the brain. The characteristics of this protein suggest that it may be a potential Radioprotective Agent in cancer therapy better than amifostine. Fusion of two antioxidant enzymes and cell-penetrating peptides is potentially valuable in the development of Radioprotective Agent.
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GST-TAT-SOD: Cell Permeable Bifunctional Antioxidant Enzyme—A Potential Selective Radioprotector
Hindawi Limited, 2016Co-Authors: Jianru Pan, Guangjin Zheng, Shutao Liu, Pingfan RaoAbstract:Superoxide dismutase (SOD) fusion of TAT was proved to be Radioprotective in our previous work. On that basis, a bifunctional recombinant protein which was the fusion of glutathione S-transferase (GST), SOD, and TAT was constructed and named GST-TAT-SOD. Herein we report the investigation of the cytotoxicity, cell-penetrating activity, and in vitro Radioprotective effect of GST-TAT-SOD compared with wild SOD, single-function recombinant protein SOD-TAT, and amifostine. We demonstrated that wild SOD had little Radioprotective effect on irradiated L-02 and Hep G2 cells while amifostine was protective to both cell lines. SOD-TAT or GST-TAT-SOD pretreatment 3 h prior to radiation protects irradiated normal liver cells against radiation damage by eliminating intracellular excrescent superoxide, reducing cellular MDA level, enhancing cellular antioxidant ability and colony formation ability, and reducing apoptosis rate. Compared with SOD-TAT, GST-TAT-SOD was proved to have better protective effect on irradiated normal liver cells and minimal effect on irradiated hepatoma cells. Besides, GST-TAT-SOD was safe for normal cells and effectively transduced into different organs in mice, including the brain. The characteristics of this protein suggest that it may be a potential Radioprotective Agent in cancer therapy better than amifostine. Fusion of two antioxidant enzymes and cell-penetrating peptides is potentially valuable in the development of Radioprotective Agent
Gulgun Cakmak - One of the best experts on this subject based on the ideXlab platform.
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amifostine a radioprotectant Agent protects rat brain tissue lipids against ionizing radiation induced damage an ftir microspectroscopic imaging study
Archives of Biochemistry and Biophysics, 2012Co-Authors: Gulgun Cakmak, Faruk Zorlu, Lisa M Miller, Feride SevercanAbstract:Amifostine is the only approved Radioprotective Agent by FDA for reducing the damaging effects of radiation on healthy tissues. In this study, the protective effect of amifostine against the damaging effects of ionizing radiation on the white matter (WM) and grey matter (GM) regions of the rat brain were investigated at molecular level. Sprague-Dawley rats, which were administered amifostine or not, were whole-body irradiated at a single dose of 800 cGy, decapitated after 24 h and the brain tissues of these rats were analyzed using Fourier transform infrared microspectroscopy (FTIRM). The results revealed that the total lipid content and CH(2) groups of lipids decreased significantly and the carbonyl esters, olefinic=CH and CH(3) groups of lipids increased significantly in the WM and GM after exposure to ionizing radiation, which could be interpreted as a result of lipid peroxidation. These changes were more prominent in the WM of the brain. The administration of amifostine before ionizing radiation inhibited the radiation-induced lipid peroxidation in the brain. In addition, this study indicated that FTIRM provides a novel approach for monitoring ionizing radiation induced-lipid peroxidation and obtaining different molecular ratio images can be used as biomarkers to detect lipid peroxidation in biological systems.
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screening of protective effect of amifostine on radiation induced structural and functional variations in rat liver microsomal membranes by ft ir spectroscopy
Analytical Chemistry, 2011Co-Authors: Gulgun Cakmak, Faruk Zorlu, Mete Severcan, Feride SevercanAbstract:In this study, the protective effect of amifostine, which is the only FDA-approved Radioprotective Agent, was investigated against the deleterious effects of ionizing radiation on rat liver microsomal membranes at molecular level. Sprague−Dawley rats, which were either administered amifostine or not, were whole-body irradiated with a single dose of 800 cGy and decapitated after 24 h. The microsomal membranes isolated from the livers of these rats were investigated using FT-IR spectroscopy. The results revealed that radiation caused a significant decrease in the lipid-to-protein ratio and the degradation of lipids into smaller fragments that contain less CH2 and more carbonyl esters, olefinic═CH and CH3 groups, which could be interpreted as a result of lipid peroxidation. Radiation altered the secondary structure of proteins by inducing a decrease in the β-sheet structures and an increase in the turns and random coil structures. Moreover, a dramatic increase in lipid order and a significant decrease in the...
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amifostine a radioprotectant Agent protects rat hepatic microsomal membranes against ionizing radiation induced damage
Biophysical Journal, 2009Co-Authors: Gulgun Cakmak, Faruk Zorlu, Mete Severcan, Feride SevercanAbstract:In the present study, the protective effect of amifostine (WR-2721), which is the only approved Radioprotective Agent by the Food and Drug Administration (FDA), was investigated against the deleterious effects of ionizing radiation on rat liver microsomal membranes at molecular level. To achieve this, Sprague-Dawley rats, which were administered amifostine or not, were whole-body irradiated using Cobalt-60 irradiator at a single dose of 800 cGy, decapitated after 24 h and the microsomal membranes isolated from the livers of these rats were analyzed using FTIR spectroscopy. The results revealed that ionizing radiation caused a significant increase in the concentration of lipids whereas amifostine treatment restored the lipid content of microsomal membranes to control values. In addition, the significant increase in lipid order and a significant decrease in membrane dynamics resulting from ionizing radiation were prevented by amifostine. While ionizing radiation caused a significant decrease in the lipid to protein ratio, amifostine injection before radiation, maintained this ratio as in the control group. Furthermore, ionizing radiation-induced variations in protein secondary structure were restored by amifostine. In conclusion, the data obtained in this study indicate that amifostine administration to the rats prior to whole body irradiation protects liver microsomal membranes against the radiation induced damages. Supported by TUBITAK, (SBAG-2939) and by the METU (BAP-2006-07-02-0001).
