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
This study observes the therapeutic detoxification of quercetin, a well-known flavonoid, against carbon tetrachlodde （CCI4） induced acute liver injury in vivo and explores its mechanism. QuerceUn decreased CCI4-incr...This study observes the therapeutic detoxification of quercetin, a well-known flavonoid, against carbon tetrachlodde （CCI4） induced acute liver injury in vivo and explores its mechanism. QuerceUn decreased CCI4-increased serum activities of alanine and aspartate aminotransferases （ALT/AST） when orally taken 30 min after CCI4 intoxica- tion. The results of a histological evaluation further evidenced the ability of quercetin to protect against CCI4-induced liver injury. Quercetin decreased the CCI4-increased malondialdehyde （MDA） and reduced the glutathione （GSH） amounts in the liver. It also reduced the enhanced immunohistochemical staining of the 4-hydroxynonenal （4-HNE） in the liver induced by CCI4. Peroxiredoxin （Prx） 1, 2, 3, 5, 6, thioredoxin reductase 1 and 2 （TrxRl/2）, thioredoxin 1 and 2 （Trxl/2）, nuclear factor erythroid 2-related factor 2 （Nrf2）, and heme oxygenase-1 （HO-1） all play critical roles in maintaining cellular redox homeostasis. Real-time polymerase chain reaction （PCR） results demonstrated that quercetin reversed the decreased mRNA expression of all those genes induced by CCI4. In conclusion, our results demonstrate that quercetin ameliorates CCI4-induced acute liver injury in vivo via alleviating oxidative stress injuries when orally taken after CCI4 intoxication. This protection may be caused by the elevation of the antioxidant capacity induced by quercetin.展开更多
Chronic lymphocytic leukaemia （CLL） is a rare blood cancer that always relapses as refractory disease and eventually leads to death. To date, therapeutic options for CLL patients are scarce and there is an urgent ne...Chronic lymphocytic leukaemia （CLL） is a rare blood cancer that always relapses as refractory disease and eventually leads to death. To date, therapeutic options for CLL patients are scarce and there is an urgent need to develop novel chemotherapeutics that are both effective and safe. Gold-containing compounds induce a lethal oxidative and endoplasmic reticulum stress response in cultured and primary CLL cells via inhibition of thioredoxin reductase （TrxR）. However, traditional gold-containing medicines have revealed side effects during clinical applications. Therefore, safer gold-containing drugs are needed to overcome this challenge. In this study, a novel peptide templated gold cluster Au2sSv9 was synthesized and its therapeutic effect on CLL cells was evaluated. This nanocluster could induce cell apoptosis in MEC-1 cells in a dose-dependent manner which correlated with the uptake amount of clusters in cells. As expected, increasing intracellular reactive oxidative species （ROS） in MEC-1 cells was exhibited with the increase of cluster dosage. Further analyses demonstrated the underlying mechanism that the nan- oclusters suppress the activity ofTrxR1, increase the level of intracellular ROS, destroy the mitochondrial membrane potential and finally trigger the mitochondrial apoptotic pathway in MEC-1 cells. Furthermore, the direct interaction between Au2sSv9 clusters and TrxRl was confirmed for the first time by isothermal titration calorimetry. These findings explored the preclinical efficacy and potential mech- anism of gold clusters in CLL therapy and provided a fundamental reference for the development of other novel gold-containing chemotherapeutics to treat CLL.展开更多
One new spirocyclic alkaloid,5-isopentenyl-cryptoechinuline D(1),along with 11 known compounds(2–12),were iso-lated from a marine fungus Aspergillus ruber TX-M4-1.The structures of compounds 1–12 were elucidated by ...One new spirocyclic alkaloid,5-isopentenyl-cryptoechinuline D(1),along with 11 known compounds(2–12),were iso-lated from a marine fungus Aspergillus ruber TX-M4-1.The structures of compounds 1–12 were elucidated by spectroscopic evi-dences.Compound 1 was initially isolated as an enantiomer,and further separation of 1 by chiral HPLC afforded a pair of enantio-mers,including(-)-5-isopentenyl-cryptoechinuline D(1a)and(+)-5-isopentenyl-cryptoechinuline D(1b).Their absolute configura-tions were elucidated by ECD spectroscopic data.Compounds 1a,5 and 10 could inhibit thioredoxin reductase(TrxR)activity with IC50 values of 6.2,36.3 and 18.6μmol L^(-1),respectively.Surface plasmon resonance(SPR)study also demonsrated the interactions between compounds 6,8 and Niemann-Pick C1 Like 1(NPC1L1)respectively,which indicate that compounds 6 and 8 are potential NPC1L1 inhibitors.展开更多
Thioredoxin Reductase(TrxR)plays a pivotal role in defending cells against reactive oxygen species(ROS)and maintaining a reduced intracellular environment.It has been discovered that TrxR is elevated significantly in ...Thioredoxin Reductase(TrxR)plays a pivotal role in defending cells against reactive oxygen species(ROS)and maintaining a reduced intracellular environment.It has been discovered that TrxR is elevated significantly in human cancer,evidenced by its association with the promotion of tumor cell proliferation,inhibiting tumor cell apoptosis,as well as enhancing tumor drug resistance.Hence,finding highly selective inhibitors of TrxR is urgently needed.Herein,we developed a selenium-containing small molecule(EbD),which had two Se–N bonds.Under reduction conditions,the two Se–N bonds reacted with Se–H bond and S–H bond in TrxR to form new Se–Se bond and Se–S bonds,respectively.Subsequently,the newly formed bonds were able to disrupt the thioredoxin(Trx)reduction catalytic cycle,and thus,inhibited the TrxR activity irreversibly,which resulted in the collapse of the antioxidant system.As a consequence,ROS levels elevated that triggered cancer cell apoptosis.This strategy,based on selenium-containing dynamic covalent bonds,provides a new avenue for cancer therapy via targeting TrxR.展开更多
Thioredoxin reductase(TrxR)is an essential enzyme for regulating the redox balance in cells,promoting cell proliferation,and inhibiting cellular apoptosis.The biochemical pathway of TrxR metabolism involves a series o...Thioredoxin reductase(TrxR)is an essential enzyme for regulating the redox balance in cells,promoting cell proliferation,and inhibiting cellular apoptosis.The biochemical pathway of TrxR metabolism involves a series of selenium-sulfur(Se-S)dynamic chemistry.Theoretically,nanomaterials with Se-S dynamic bonds could exhibit TrxRmimetic activities to tune TrxR activity,affecting cellular activities.Herein,we report the fabrication of Se-S-doped carbon dots(Se-S-CDs),synthesized by a facile hydrothermal method.The Se-S-CDs exhibited good stability and solubility in an aqueous solution,with a quantum yield of 13.27%.The doping of Se-S bonds endowed the Se-S-CDs with great capability of enhancing the TrxR activity,and consequently,a remarkable promotion of cell viability.The significance of Se-S bonds,as well as CDs’role as matrices,are discussed.Moreover,the Se-S-CDs could also revive the cells from the damage induced by oxidative stress.The abovementioned properties demonstrated the potential of the Se-S-CDs for cells and tissues culturing,solving the poor cell viability issue,which is desperately needed for organ transplantation and revitalization of prematurely aging cells,especially those exposed to oxidative stress.展开更多
目的探讨硫氧还蛋白(Trx)、硫氧还蛋白还原酶1(TrxR-1)及硫氧还蛋白互作蛋白(TXNIP)在弥漫大B细胞淋巴瘤(diffuse large B-cell lymphoma,DLBCL)中的表达及临床意义。方法采用免疫组化法检测60例DLBCL和20例淋巴结反应性增生组织中Trx、...目的探讨硫氧还蛋白(Trx)、硫氧还蛋白还原酶1(TrxR-1)及硫氧还蛋白互作蛋白(TXNIP)在弥漫大B细胞淋巴瘤(diffuse large B-cell lymphoma,DLBCL)中的表达及临床意义。方法采用免疫组化法检测60例DLBCL和20例淋巴结反应性增生组织中Trx、TrxR-1及TXNIP的表达,并分析三者表达与DLBCL临床病理特征的关系。结果DLBCL中Trx和TrxR-1的阳性率分别为68.33%和76.67%,淋巴结反应性增生组织中Trx和TrxR-1的阳性率分别为25.00%、35.00%,DLBCL中Trx和TrxR-1的阳性率均明显高于淋巴结反应性增生组织,差异有统计学意义(P<0.05);TXNIP在DLBCL中的表达(20.00%,12/60)低于淋巴结反应性增生组织(80.00%,16/20),差异有统计学意义(P<0.05)。DLBCL中Trx、TrxR-1和TXNIP的表达与临床分期、IPI评分有关(P<0.05),与患者性别、年龄、乳酸脱氢酶水平无关(P>0.05)。ROC结果显示,Trx、TrxR-1单项检测曲线下面积(AUC)分别为0.717与0.708,而两者联合检测AUC为0.767,高于单独检测。结论Trx、TrxR-1及TXNIP表达异常可能与DLBCL发生、发展有关,联合检测Trx和TrxR-1表达可为DLBCL的诊断提供参考价值。展开更多
Retinoid X receptor a （RXRα） and its N-terminally trun- cated version tRXRα play important roles in tumorige. nesis, while some RXRg ligands possess potent anti- cancer activities by targeting and modulating the t...Retinoid X receptor a （RXRα） and its N-terminally trun- cated version tRXRα play important roles in tumorige. nesis, while some RXRg ligands possess potent anti- cancer activities by targeting and modulating the tumorigenic effects of RXRo and tRXRa. Here we describe NSC-640358 （N-6）, a thiazolyl-pyrazole derived compound, acts as a selective RXRα ligand to promote TNFα-mediated apoptosis of cancer cell. N-6 binds to RXRa and inhibits the transactivation of RXRα homod- imer and RXRa/TR3 heterodimer. Using mutational analysis and computational study, we determine that Arg316 in RXRa, essential for 9-cis-retinoic acid binding and activating RXRg transactivation, is not required for antagonist effects of N-6, whereas Trp305 and Phe313 are crucial for N-6 binding to RXRα by forming extra w-w stacking interactions with N-6, indicating a distinct RXRα binding mode of N-6. N-6 inhibits TR3-stimulated transactivation of Gal4-DBD-RXRα-LBD by binding to the ligand binding pocket of RXRa-LBD, suggesting a strategy to regulate TR3 activity indirectly by using small molecules to target its interacting partner RXRα. For its physiological activities, we show that N-6 strongly inhibits tumor necrosis factor a （TNFα）-induced AKT activation and stimulates TNFa-mediated apoptosis in cancer cells in an RXRa/tRXRo dependent manner.The inhibition of TNFα-induced tRXRα/p85α complex formation by N-6 implies that N-6 targets tRXRa to inhibit TNFα-induced AKT activation and to induce cancer cell apoptosis. Together, our data illustrate a new RXRa ligand with a unique RXRα binding mode and the abilities to regulate TR3 activity indirectly and to induce TNFa-mediated cancer cell apoptosis by targeting RXRα/tRXRα.展开更多
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.
基金Project supported by the "Shu Guang" Project from Shanghai Municipal Education Commission and Shanghai Education Development Foundation(No.13SG43)the National Natural Science Foundation of China(No.81322053)the Program for New Century Excellent Talents in University(No.NCET-11-1054),China
文摘This study observes the therapeutic detoxification of quercetin, a well-known flavonoid, against carbon tetrachlodde （CCI4） induced acute liver injury in vivo and explores its mechanism. QuerceUn decreased CCI4-increased serum activities of alanine and aspartate aminotransferases （ALT/AST） when orally taken 30 min after CCI4 intoxica- tion. The results of a histological evaluation further evidenced the ability of quercetin to protect against CCI4-induced liver injury. Quercetin decreased the CCI4-increased malondialdehyde （MDA） and reduced the glutathione （GSH） amounts in the liver. It also reduced the enhanced immunohistochemical staining of the 4-hydroxynonenal （4-HNE） in the liver induced by CCI4. Peroxiredoxin （Prx） 1, 2, 3, 5, 6, thioredoxin reductase 1 and 2 （TrxRl/2）, thioredoxin 1 and 2 （Trxl/2）, nuclear factor erythroid 2-related factor 2 （Nrf2）, and heme oxygenase-1 （HO-1） all play critical roles in maintaining cellular redox homeostasis. Real-time polymerase chain reaction （PCR） results demonstrated that quercetin reversed the decreased mRNA expression of all those genes induced by CCI4. In conclusion, our results demonstrate that quercetin ameliorates CCI4-induced acute liver injury in vivo via alleviating oxidative stress injuries when orally taken after CCI4 intoxication. This protection may be caused by the elevation of the antioxidant capacity induced by quercetin.
基金supported by the National Key Basic Research Program of China (2013CB932703)the National Natural Science Foundation of China (21425522, 81472851, 31670976, 21390410, 31571026, 31500815, 51571185, and 21675157)Beijing Natural Science Foundation (7152158)
文摘Chronic lymphocytic leukaemia （CLL） is a rare blood cancer that always relapses as refractory disease and eventually leads to death. To date, therapeutic options for CLL patients are scarce and there is an urgent need to develop novel chemotherapeutics that are both effective and safe. Gold-containing compounds induce a lethal oxidative and endoplasmic reticulum stress response in cultured and primary CLL cells via inhibition of thioredoxin reductase （TrxR）. However, traditional gold-containing medicines have revealed side effects during clinical applications. Therefore, safer gold-containing drugs are needed to overcome this challenge. In this study, a novel peptide templated gold cluster Au2sSv9 was synthesized and its therapeutic effect on CLL cells was evaluated. This nanocluster could induce cell apoptosis in MEC-1 cells in a dose-dependent manner which correlated with the uptake amount of clusters in cells. As expected, increasing intracellular reactive oxidative species （ROS） in MEC-1 cells was exhibited with the increase of cluster dosage. Further analyses demonstrated the underlying mechanism that the nan- oclusters suppress the activity ofTrxR1, increase the level of intracellular ROS, destroy the mitochondrial membrane potential and finally trigger the mitochondrial apoptotic pathway in MEC-1 cells. Furthermore, the direct interaction between Au2sSv9 clusters and TrxRl was confirmed for the first time by isothermal titration calorimetry. These findings explored the preclinical efficacy and potential mech- anism of gold clusters in CLL therapy and provided a fundamental reference for the development of other novel gold-containing chemotherapeutics to treat CLL.
基金supported by the National Natural Science Foundation of China(No.82204276)the Guangxi Natural Science Foundation(No.2021GXNSFBA075036)+4 种基金the Specific Research Project of Guangxi for Research Bases and Talents(Nos.AD22035018,AD20297036)the 2021 University-Level Scientific Research Projects of Guangxi Minzu University(No.2021MDKJ003)the Talent Scientific Research Initiation Project of Guangxi Minzu University(No.2021KJQD09)the Xiangsi Lake Youth Innovation Team Project of Guangxi Minzu University(No.2021 RSCXSHQN01)the Guangxi Scholarship Fund of Guangxi Education Department.
文摘One new spirocyclic alkaloid,5-isopentenyl-cryptoechinuline D(1),along with 11 known compounds(2–12),were iso-lated from a marine fungus Aspergillus ruber TX-M4-1.The structures of compounds 1–12 were elucidated by spectroscopic evi-dences.Compound 1 was initially isolated as an enantiomer,and further separation of 1 by chiral HPLC afforded a pair of enantio-mers,including(-)-5-isopentenyl-cryptoechinuline D(1a)and(+)-5-isopentenyl-cryptoechinuline D(1b).Their absolute configura-tions were elucidated by ECD spectroscopic data.Compounds 1a,5 and 10 could inhibit thioredoxin reductase(TrxR)activity with IC50 values of 6.2,36.3 and 18.6μmol L^(-1),respectively.Surface plasmon resonance(SPR)study also demonsrated the interactions between compounds 6,8 and Niemann-Pick C1 Like 1(NPC1L1)respectively,which indicate that compounds 6 and 8 are potential NPC1L1 inhibitors.
基金supported financially by the National Basic Research Program of China(2018YFA0208900)the National Natural Science Foundation of China(21734006)+1 种基金China National Funds for Distinguished Young Scientists(21425416)the Funds for Creative Research Groups of China of the National Natural Science Foundation of China(21821001).
文摘Thioredoxin Reductase(TrxR)plays a pivotal role in defending cells against reactive oxygen species(ROS)and maintaining a reduced intracellular environment.It has been discovered that TrxR is elevated significantly in human cancer,evidenced by its association with the promotion of tumor cell proliferation,inhibiting tumor cell apoptosis,as well as enhancing tumor drug resistance.Hence,finding highly selective inhibitors of TrxR is urgently needed.Herein,we developed a selenium-containing small molecule(EbD),which had two Se–N bonds.Under reduction conditions,the two Se–N bonds reacted with Se–H bond and S–H bond in TrxR to form new Se–Se bond and Se–S bonds,respectively.Subsequently,the newly formed bonds were able to disrupt the thioredoxin(Trx)reduction catalytic cycle,and thus,inhibited the TrxR activity irreversibly,which resulted in the collapse of the antioxidant system.As a consequence,ROS levels elevated that triggered cancer cell apoptosis.This strategy,based on selenium-containing dynamic covalent bonds,provides a new avenue for cancer therapy via targeting TrxR.
基金supported financially by the National Basic Research Plan of China(no.2018YFA208900)the National Natural Science Foundation of China(no.21734004)the Foundation for Innovative Research Groups of the National Natural Science Foundation of China(no.21821001).
文摘Thioredoxin reductase(TrxR)is an essential enzyme for regulating the redox balance in cells,promoting cell proliferation,and inhibiting cellular apoptosis.The biochemical pathway of TrxR metabolism involves a series of selenium-sulfur(Se-S)dynamic chemistry.Theoretically,nanomaterials with Se-S dynamic bonds could exhibit TrxRmimetic activities to tune TrxR activity,affecting cellular activities.Herein,we report the fabrication of Se-S-doped carbon dots(Se-S-CDs),synthesized by a facile hydrothermal method.The Se-S-CDs exhibited good stability and solubility in an aqueous solution,with a quantum yield of 13.27%.The doping of Se-S bonds endowed the Se-S-CDs with great capability of enhancing the TrxR activity,and consequently,a remarkable promotion of cell viability.The significance of Se-S bonds,as well as CDs’role as matrices,are discussed.Moreover,the Se-S-CDs could also revive the cells from the damage induced by oxidative stress.The abovementioned properties demonstrated the potential of the Se-S-CDs for cells and tissues culturing,solving the poor cell viability issue,which is desperately needed for organ transplantation and revitalization of prematurely aging cells,especially those exposed to oxidative stress.
文摘目的探讨硫氧还蛋白(Trx)、硫氧还蛋白还原酶1(TrxR-1)及硫氧还蛋白互作蛋白(TXNIP)在弥漫大B细胞淋巴瘤(diffuse large B-cell lymphoma,DLBCL)中的表达及临床意义。方法采用免疫组化法检测60例DLBCL和20例淋巴结反应性增生组织中Trx、TrxR-1及TXNIP的表达,并分析三者表达与DLBCL临床病理特征的关系。结果DLBCL中Trx和TrxR-1的阳性率分别为68.33%和76.67%,淋巴结反应性增生组织中Trx和TrxR-1的阳性率分别为25.00%、35.00%,DLBCL中Trx和TrxR-1的阳性率均明显高于淋巴结反应性增生组织,差异有统计学意义(P<0.05);TXNIP在DLBCL中的表达(20.00%,12/60)低于淋巴结反应性增生组织(80.00%,16/20),差异有统计学意义(P<0.05)。DLBCL中Trx、TrxR-1和TXNIP的表达与临床分期、IPI评分有关(P<0.05),与患者性别、年龄、乳酸脱氢酶水平无关(P>0.05)。ROC结果显示,Trx、TrxR-1单项检测曲线下面积(AUC)分别为0.717与0.708,而两者联合检测AUC为0.767,高于单独检测。结论Trx、TrxR-1及TXNIP表达异常可能与DLBCL发生、发展有关,联合检测Trx和TrxR-1表达可为DLBCL的诊断提供参考价值。
文摘Retinoid X receptor a （RXRα） and its N-terminally trun- cated version tRXRα play important roles in tumorige. nesis, while some RXRg ligands possess potent anti- cancer activities by targeting and modulating the tumorigenic effects of RXRo and tRXRa. Here we describe NSC-640358 （N-6）, a thiazolyl-pyrazole derived compound, acts as a selective RXRα ligand to promote TNFα-mediated apoptosis of cancer cell. N-6 binds to RXRa and inhibits the transactivation of RXRα homod- imer and RXRa/TR3 heterodimer. Using mutational analysis and computational study, we determine that Arg316 in RXRa, essential for 9-cis-retinoic acid binding and activating RXRg transactivation, is not required for antagonist effects of N-6, whereas Trp305 and Phe313 are crucial for N-6 binding to RXRα by forming extra w-w stacking interactions with N-6, indicating a distinct RXRα binding mode of N-6. N-6 inhibits TR3-stimulated transactivation of Gal4-DBD-RXRα-LBD by binding to the ligand binding pocket of RXRa-LBD, suggesting a strategy to regulate TR3 activity indirectly by using small molecules to target its interacting partner RXRα. For its physiological activities, we show that N-6 strongly inhibits tumor necrosis factor a （TNFα）-induced AKT activation and stimulates TNFa-mediated apoptosis in cancer cells in an RXRa/tRXRo dependent manner.The inhibition of TNFα-induced tRXRα/p85α complex formation by N-6 implies that N-6 targets tRXRa to inhibit TNFα-induced AKT activation and to induce cancer cell apoptosis. Together, our data illustrate a new RXRa ligand with a unique RXRα binding mode and the abilities to regulate TR3 activity indirectly and to induce TNFa-mediated cancer cell apoptosis by targeting RXRα/tRXRα.
