Ribonucleotide reductase(RNR), the rate-limitingenzyme in DNA synthesis, catalyzes reduction of thedifferent ribonucleotides to their corresponding deoxyri-bonucleotides. The crucial role of RNR in DNA synthesishas ma...Ribonucleotide reductase(RNR), the rate-limitingenzyme in DNA synthesis, catalyzes reduction of thedifferent ribonucleotides to their corresponding deoxyri-bonucleotides. The crucial role of RNR in DNA synthesishas made it an important target for the development ofantiviral and anticancer drugs. Taking account of the re-cent developments in this field of research, this reviewfocuses on the role of thioredoxin and glutaredoxin sys-tems in the redox reactions of the RNR catalysis.展开更多
Objective To investigate the possible effect of artesunate （ART） on schistosome thioredoxin glutathione reductase （TGR） and cytochrome c peroxidase （CcP） in Schistosoma mansoni-infected mice. Methods A total of ...Objective To investigate the possible effect of artesunate （ART） on schistosome thioredoxin glutathione reductase （TGR） and cytochrome c peroxidase （CcP） in Schistosoma mansoni-infected mice. Methods A total of 200 laboratory bred male Swiss albino mice were divided into 4 groups （50 mice in each group）. Group I： infected untreated group （Control group） received a vehicle of 1% sodium carbonyl methylcellulose （CMC-Na）; Group II： infected then treated with artesunate; Group III infected then treated with praziquantel, and group IV： infected then treated with artesunate then praziquantel. Adult S. mansoni worms were collected by Animal Perfusion Method, tissue egg counted, TGR, and CcP mRNA Expression were estimated of in $. mansoni adult worms by semi-quantitative rt-PCR. Results Semi-quantitative rt-PCR values revealed that treatment with artesunate caused significant decrease in expression of schistosome TGR and CcP in comparison to the untreated group. In contrast, the treatment with praziquantel did not cause significant change in expression of these genes. The results showed more reduction in total worm and female worm count in combined ART-PZQ treated group than in monotherapy treated groups by either ART or PZO, Moreover, complete disappearance （100%） of tissue eggs was recorded in ART-PZQ treated group with a respective reduction rate of 95.9% and 68.4% in ART- and PZQ-treated groups. Conclusion The current study elucidated for the first time that anti-schistosomal mechanisms of artesunate is mediated via reduction in expression of schistosome TGR and CcP. Linking these findings, addition of artesunate to praziquantel could achieve complete cure outcome in treatment of schistosomiasis.展开更多
We aimed to investigate the role of thioredoxin reductase （TR） and inducible heat shock protein 70 （iHsp70） and their relationship with sperm quality in varicocele （VAR） patients. Semen samples were obtained fro...We aimed to investigate the role of thioredoxin reductase （TR） and inducible heat shock protein 70 （iHsp70） and their relationship with sperm quality in varicocele （VAR） patients. Semen samples were obtained from 16 subfertile men diagnosed as VAR and 10 fertile men who applied to the Andrology Laboratory of Istanbul Medical Faculty of Istanbul University. The sperm TR and iHsp 70 expression levels were determined using Western blot analysis. The TR activity of the sperm was assayed spectrophometrically. The sperm quality was evaluated both by conventional sperm analysis and by a terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling （TUNEL） technique that assayed DNA-fragmented spermatozoa in semen samples. The percentage of TUNELopositive spermatozoa in the VAR group （16.3%±5.6%） was higher than that in the fertile group （5.5%±1.9%）. Significant inverse correlations were detected between the percentage of TUNEL-positive cells and both the concentration （r=--0.609; P=0.001） and motility （r=--0.550; P=-0.004） of spermatozoa. Both the TR expression and activity were increased significantly in the VAR group （U=22.0; P=0.001 and U=33.5 P=0.012, respectively） as analyzed using the Mann-Whitney UWilcoxon rank sum Wtest. Furthermore, significant positive correlations were found between TR expression and activity （r=-0.406; P=O.040） and between TR expression and the percentage of TUNEL-positive cells （r=0.665; P=-0.001）. Sperm iHsp70 expression did not differ between the VAR and fertile groups. In conclusion, increased sperm TR expression might be a defense mechanism against apoptosis in the spermatozoa of men with VAR.展开更多
Human thioredoxin reductase (TrxR) system is associated with cancer cell growth and anti-apoptosis process. Effects of 1,2-bis(1,2-benzisoselenazolone-3(2H)-ketone)ethane (BBSKE),a novel TrxR inhibitor,were investigat...Human thioredoxin reductase (TrxR) system is associated with cancer cell growth and anti-apoptosis process. Effects of 1,2-bis(1,2-benzisoselenazolone-3(2H)-ketone)ethane (BBSKE),a novel TrxR inhibitor,were investigated on human leu-kemia cell lines HL-60 and K562. BBSKE treatment induced cell growth inhibition and apoptosis in both cell lines. Apoptosis induced by BBSKE is through Bcl-2/Bax and caspase-3 pathways. Ehrlich's ascites carcinoma-bearing mice were used to inves-tigate the anti-tumor effect of BBSKE in vivo. Tumor-bearing mice treated with BBSKE showed an increase of life span with a comparable effect to cyclophosphamide (CTX). These results suggest a potential usage of BBSKE as a therapeutic agent against non-solid tumors.展开更多
Background: Developing a novel, efficient biomarker for detecting malignant tumors is essential for the early diagnosis of cancers. Our aim was to assess the diagnostic value of a potential plasma tumor marker, thiore...Background: Developing a novel, efficient biomarker for detecting malignant tumors is essential for the early diagnosis of cancers. Our aim was to assess the diagnostic value of a potential plasma tumor marker, thioredoxin reductase (TR), which is expressed in many types of malignant tumor, for the non-invasive detection of cancers. Methods: The plasma activities of TR were measured in 1513 patients with common clinical diseases, 59 patients with benign tumors, and 154 patients with cancers and 586 healthy controls. The area under the ROC curve (AUC) of TR and logistic regression results of different groups were compared by sensitivity, specificity and Youden’s index. Diagnostic cut-offs and clinical reference intervals were established via ROC curve analysis. Results: The logistic regression indicated that TR activity can discriminate between cancers and benign tumors or other common diseases very well (p < 0.0001), with an area under the curve from the receiver-operator characteristics between 0.91 and 0.96. The positive critical value was 2.51 and the cancer critical value was 9.90. The diagnostic gray zone (2.51 - 9.90) may be associated with benign tumors and some common clinical diseases. Conclusions: As a novel potential marker of malignant tumors with quantitative evaluation of proliferation, TR activity detection has an excellent diagnostic potential for early-stage malignant tumors. Impact: The convenient, economical, relatively non-invasive, and reproducible detection method of TR activity makes it suitable for routine clinical practice.展开更多
This study investigated the effects of hyperoxia on dynamic changes of thioredoxin-1 （Trx1） and thioredoxin reductase-1 （TrxR1） in alveolar type Ⅱ epithelial cells （AECⅡ） of premature rats. Pregnant Sprague-Da...This study investigated the effects of hyperoxia on dynamic changes of thioredoxin-1 （Trx1） and thioredoxin reductase-1 （TrxR1） in alveolar type Ⅱ epithelial cells （AECⅡ） of premature rats. Pregnant Sprague-Dawley rats were sacrificed on day 19 of gestation. AECⅡ were isolated and purified from the lungs of premature rats. When cultured to 80% confluence, in vitro cells were randomly divided into air group and hyperoxia group. Cells in the hyperoxia group were continuously exposed to 95% O2/5% CO2 and those in the air group to 95% air/5% CO2. After 12, 24 and 48 h, cells in the two groups were harvested to detect their reactive oxygen species （ROS）, apoptosis, TrxR1 activity and the expressions of Trx1 and TrxR1 by corresponding protocols, respectively. The results showed that AECⅡ exposed to hyperoxia generated excessive ROS and the apoptosis percentage in the hyperoxia group was increased significantly at each time points as compared with that in the air group （P0.001）. Moreover, TrxR1 activity was found to be markedly depressed in the hyperoxia group in comparison to that in the air group （P0.001）. RT-PCR showed the expressions of both Trx1 and TrxR1 mRNA were significantly increased in AECⅡ exposed to hyperoxia for 12 and 24 h （P0.01）, respectively. At 48 h, the level of Trx1 mRNA as well as that of TrxR1 mRNA in the hyperoxia group was reduced and showed no significant difference from that in the air group （P0.05）. Western blotting showed the changes of Trx1 protein expressions in the hyperoxia group paralleled those of Trx1 mRNA expressions revealed by RT-PCR. It was concluded that hyperoxia can up-regulate the protective Trx1/TrxR1 expressed by AECⅡ in a certain period, however, also cause dysfunction of the cytoplasmic thioredoxin system by decreasing TrxR1 activity, which may contribute to the progression of oxidative stress and cell apoptosis and finally result in lung injury.展开更多
Overexpression of thioredoxin reductase has been identified in a variety of primary tumors, suggesting the levels of TrxR activity between tumor patients and normal people are potentially different. Here, we performed...Overexpression of thioredoxin reductase has been identified in a variety of primary tumors, suggesting the levels of TrxR activity between tumor patients and normal people are potentially different. Here, we performed a study to investigate the differences of TrxR activity between normal people and breast tumor patients, with the expectation that TrxR activity can be considered as a novel biomarker involved in breast cancer diagnosis and treatment. In this study, we have demonstrated for the first time that TrxR levels in breast cancer patients before therapy were significantly higher than those of normal people （P〈0.05）. No significant difference of TrxR activity was found among the patients at different stages of breast tumor progression. In the patient group of TrxR 〈10 U/mL, evaluation of TrxR activity has shown a high consistency with the results from cancer diagnostic imaging. Overall, these observations suggest TrxR as an effective biomarker to monitor and evaluate the clinical outcome of breast cancer therapeutics, and identify TrxR activity as a novel approach for breast cancer early-stage detection.展开更多
基金Supported by The Swedish Research Council Medicine,No.3529The Swedish Cancer Society,No.961The Wallenberg Foundation
文摘Ribonucleotide reductase(RNR), the rate-limitingenzyme in DNA synthesis, catalyzes reduction of thedifferent ribonucleotides to their corresponding deoxyri-bonucleotides. The crucial role of RNR in DNA synthesishas made it an important target for the development ofantiviral and anticancer drugs. Taking account of the re-cent developments in this field of research, this reviewfocuses on the role of thioredoxin and glutaredoxin sys-tems in the redox reactions of the RNR catalysis.
文摘Objective To investigate the possible effect of artesunate （ART） on schistosome thioredoxin glutathione reductase （TGR） and cytochrome c peroxidase （CcP） in Schistosoma mansoni-infected mice. Methods A total of 200 laboratory bred male Swiss albino mice were divided into 4 groups （50 mice in each group）. Group I： infected untreated group （Control group） received a vehicle of 1% sodium carbonyl methylcellulose （CMC-Na）; Group II： infected then treated with artesunate; Group III infected then treated with praziquantel, and group IV： infected then treated with artesunate then praziquantel. Adult S. mansoni worms were collected by Animal Perfusion Method, tissue egg counted, TGR, and CcP mRNA Expression were estimated of in $. mansoni adult worms by semi-quantitative rt-PCR. Results Semi-quantitative rt-PCR values revealed that treatment with artesunate caused significant decrease in expression of schistosome TGR and CcP in comparison to the untreated group. In contrast, the treatment with praziquantel did not cause significant change in expression of these genes. The results showed more reduction in total worm and female worm count in combined ART-PZQ treated group than in monotherapy treated groups by either ART or PZO, Moreover, complete disappearance （100%） of tissue eggs was recorded in ART-PZQ treated group with a respective reduction rate of 95.9% and 68.4% in ART- and PZQ-treated groups. Conclusion The current study elucidated for the first time that anti-schistosomal mechanisms of artesunate is mediated via reduction in expression of schistosome TGR and CcP. Linking these findings, addition of artesunate to praziquantel could achieve complete cure outcome in treatment of schistosomiasis.
文摘We aimed to investigate the role of thioredoxin reductase （TR） and inducible heat shock protein 70 （iHsp70） and their relationship with sperm quality in varicocele （VAR） patients. Semen samples were obtained from 16 subfertile men diagnosed as VAR and 10 fertile men who applied to the Andrology Laboratory of Istanbul Medical Faculty of Istanbul University. The sperm TR and iHsp 70 expression levels were determined using Western blot analysis. The TR activity of the sperm was assayed spectrophometrically. The sperm quality was evaluated both by conventional sperm analysis and by a terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling （TUNEL） technique that assayed DNA-fragmented spermatozoa in semen samples. The percentage of TUNELopositive spermatozoa in the VAR group （16.3%±5.6%） was higher than that in the fertile group （5.5%±1.9%）. Significant inverse correlations were detected between the percentage of TUNEL-positive cells and both the concentration （r=--0.609; P=0.001） and motility （r=--0.550; P=-0.004） of spermatozoa. Both the TR expression and activity were increased significantly in the VAR group （U=22.0; P=0.001 and U=33.5 P=0.012, respectively） as analyzed using the Mann-Whitney UWilcoxon rank sum Wtest. Furthermore, significant positive correlations were found between TR expression and activity （r=-0.406; P=O.040） and between TR expression and the percentage of TUNEL-positive cells （r=0.665; P=-0.001）. Sperm iHsp70 expression did not differ between the VAR and fertile groups. In conclusion, increased sperm TR expression might be a defense mechanism against apoptosis in the spermatozoa of men with VAR.
基金Project (No.30472036) supported by the National Natural Science Foundation of China
文摘Human thioredoxin reductase (TrxR) system is associated with cancer cell growth and anti-apoptosis process. Effects of 1,2-bis(1,2-benzisoselenazolone-3(2H)-ketone)ethane (BBSKE),a novel TrxR inhibitor,were investigated on human leu-kemia cell lines HL-60 and K562. BBSKE treatment induced cell growth inhibition and apoptosis in both cell lines. Apoptosis induced by BBSKE is through Bcl-2/Bax and caspase-3 pathways. Ehrlich's ascites carcinoma-bearing mice were used to inves-tigate the anti-tumor effect of BBSKE in vivo. Tumor-bearing mice treated with BBSKE showed an increase of life span with a comparable effect to cyclophosphamide (CTX). These results suggest a potential usage of BBSKE as a therapeutic agent against non-solid tumors.
文摘Background: Developing a novel, efficient biomarker for detecting malignant tumors is essential for the early diagnosis of cancers. Our aim was to assess the diagnostic value of a potential plasma tumor marker, thioredoxin reductase (TR), which is expressed in many types of malignant tumor, for the non-invasive detection of cancers. Methods: The plasma activities of TR were measured in 1513 patients with common clinical diseases, 59 patients with benign tumors, and 154 patients with cancers and 586 healthy controls. The area under the ROC curve (AUC) of TR and logistic regression results of different groups were compared by sensitivity, specificity and Youden’s index. Diagnostic cut-offs and clinical reference intervals were established via ROC curve analysis. Results: The logistic regression indicated that TR activity can discriminate between cancers and benign tumors or other common diseases very well (p < 0.0001), with an area under the curve from the receiver-operator characteristics between 0.91 and 0.96. The positive critical value was 2.51 and the cancer critical value was 9.90. The diagnostic gray zone (2.51 - 9.90) may be associated with benign tumors and some common clinical diseases. Conclusions: As a novel potential marker of malignant tumors with quantitative evaluation of proliferation, TR activity detection has an excellent diagnostic potential for early-stage malignant tumors. Impact: The convenient, economical, relatively non-invasive, and reproducible detection method of TR activity makes it suitable for routine clinical practice.
基金supported by a grant from the National Natural Sciences Foundation of China (No. 30770944)
文摘This study investigated the effects of hyperoxia on dynamic changes of thioredoxin-1 （Trx1） and thioredoxin reductase-1 （TrxR1） in alveolar type Ⅱ epithelial cells （AECⅡ） of premature rats. Pregnant Sprague-Dawley rats were sacrificed on day 19 of gestation. AECⅡ were isolated and purified from the lungs of premature rats. When cultured to 80% confluence, in vitro cells were randomly divided into air group and hyperoxia group. Cells in the hyperoxia group were continuously exposed to 95% O2/5% CO2 and those in the air group to 95% air/5% CO2. After 12, 24 and 48 h, cells in the two groups were harvested to detect their reactive oxygen species （ROS）, apoptosis, TrxR1 activity and the expressions of Trx1 and TrxR1 by corresponding protocols, respectively. The results showed that AECⅡ exposed to hyperoxia generated excessive ROS and the apoptosis percentage in the hyperoxia group was increased significantly at each time points as compared with that in the air group （P0.001）. Moreover, TrxR1 activity was found to be markedly depressed in the hyperoxia group in comparison to that in the air group （P0.001）. RT-PCR showed the expressions of both Trx1 and TrxR1 mRNA were significantly increased in AECⅡ exposed to hyperoxia for 12 and 24 h （P0.01）, respectively. At 48 h, the level of Trx1 mRNA as well as that of TrxR1 mRNA in the hyperoxia group was reduced and showed no significant difference from that in the air group （P0.05）. Western blotting showed the changes of Trx1 protein expressions in the hyperoxia group paralleled those of Trx1 mRNA expressions revealed by RT-PCR. It was concluded that hyperoxia can up-regulate the protective Trx1/TrxR1 expressed by AECⅡ in a certain period, however, also cause dysfunction of the cytoplasmic thioredoxin system by decreasing TrxR1 activity, which may contribute to the progression of oxidative stress and cell apoptosis and finally result in lung injury.
基金National Natural Science Foundation of China(Grant No.81372266)Foundation of Tianjin Binhai Science and Technology Plan(Grant No.2010BK160010)
文摘Overexpression of thioredoxin reductase has been identified in a variety of primary tumors, suggesting the levels of TrxR activity between tumor patients and normal people are potentially different. Here, we performed a study to investigate the differences of TrxR activity between normal people and breast tumor patients, with the expectation that TrxR activity can be considered as a novel biomarker involved in breast cancer diagnosis and treatment. In this study, we have demonstrated for the first time that TrxR levels in breast cancer patients before therapy were significantly higher than those of normal people （P〈0.05）. No significant difference of TrxR activity was found among the patients at different stages of breast tumor progression. In the patient group of TrxR 〈10 U/mL, evaluation of TrxR activity has shown a high consistency with the results from cancer diagnostic imaging. Overall, these observations suggest TrxR as an effective biomarker to monitor and evaluate the clinical outcome of breast cancer therapeutics, and identify TrxR activity as a novel approach for breast cancer early-stage detection.
