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
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
The lysosome is transformed from a major degradative site to a dynamic regulator of cellular homeostasis.Cancer cells with altered redox environments could be exploited as potential targets for cancer therapy.The thio...The lysosome is transformed from a major degradative site to a dynamic regulator of cellular homeostasis.Cancer cells with altered redox environments could be exploited as potential targets for cancer therapy.The thioredoxin(Trx)system,which includes thioredoxin reductases(TrxRs),is a promising target for cancer drug development.Here,by identifying the natural product isowalsuranolide(Hdy-7),we showed that lysosomal biogenesis and autophagy are elicited by Hdy-7 via the inhibition of TrxRs.The attenuation of cellular TrxR activity led to the accumulation of ROS,which are indispensable for p53 activation and subsequent lysosomal biogenesis mediated by the transcription factor TFEB/TFE3.Knockdown of TrxR1/2 led to activation of TFEB/TFE3,thereafter increasing lysosomal biogenesis.Treatment with the ROS scavenger NAC or knockdown of p53 or SESN2 led to attenuation of the nuclear translocation of TFEB/TFE3,lysosomal biogenesis,and autophagic flux,suggesting that the TrxR1/2-p53-TFEB/TFE3 axis plays a role in maintaining lysosomal homeostasis under stress conditions other than starvation.Surprisingly,pharmacological inhibition or genetic ablation of autophagy prevented Hdy-7-induced cell death,suggesting that Hdy-7-induced autophagy is detrimental to cancer cells.Our study revealed that Hdy-7 induces ROS-mediated lysosomal biogenesis and retards cell growth by targeting TrxR1/2.This study highlights the lysosome as a regulatory hub for cellular homeostasis and as an attractive therapeutic target for a variety of lysosome-related diseases,including cancer.展开更多
Objective:The objective of the current study was to evaluate the chemosensitizing capacity of auranofin(AF),a gold(I)complex traditionally used in rheumatoid arthritis treatment,in potentiating the cytotoxic effects o...Objective:The objective of the current study was to evaluate the chemosensitizing capacity of auranofin(AF),a gold(I)complex traditionally used in rheumatoid arthritis treatment,in potentiating the cytotoxic effects of doxorubicin(DOX)in melanoma cell models,specifically drug-sensitive(B16F10)and multidrug-resistant(B16F10/ADR)variants.Methods:Experimental measurements,including in vitro cytotoxicity and apoptosis assays,surface plasmon resonance(SPR),immunoblotting assays,as well as theoretical calculations,such as molecular docking and molecular dynamics(MD)simulations,were used to systematically delineate the interaction dynamics between AF and thioredoxin reductase 1(TrxR1).The anti-tumor efficacy of co-treatment with AF and DOX was assessed by examining cell viability and apoptotic rates.Results:Co-treatment with AF and DOX significantly increased anti-tumor efficacy,as evidenced by reduced cell viability and increased apoptotic rates.This synergistic effect was attributed to inhibition of TrxR1 by AF,which compromised tumor cell antioxidant defenses and elevated intracellular reactive oxygen species(ROS),thereby enhancing apoptotic pathways.Notably,AF treatment mitigated the heightened TrxR activity in DOX-resistant cells,intensifying the pro-oxidant effects of DOX,leading to increased ROS production and cell death.The data also showed that AF binds with high affinity to the selenocysteine residue within the catalytic site of TrxR1,which partially overlapped with the binding site of the endogenous substrate,thioredoxin(Trx),but with greater avidity.This unique binding configuration impedes the reduction of Trx by TrxR1,triggering an apoptotic response in cancer cells.Conclusions:This study underscores the chemosensitizing potential of AF in overcoming multidrug resistance in cancer therapy through redox modulation.The molecular mechanism of action underlying AF on TrxR1 demonstrated the unique binding configuration that impedes the reduction of Trx by TrxR1 and instigates an apoptotic response in cancer cells.These findings pave the way for the clinical application of AF as a chemosensitizer,offering a novel approach to augment the efficacy of existing chemotherapy regimens.展开更多
Selenium(Se),an essential micronutrient among the 15 vital elements required for human physiology,exerts its biological functions primarily through its incorporation into selenoproteins.To date,approximately 25 seleno...Selenium(Se),an essential micronutrient among the 15 vital elements required for human physiology,exerts its biological functions primarily through its incorporation into selenoproteins.To date,approximately 25 selenoproteins have been characterized in mammalian systems,including glutathione peroxidase(GPX),thioredoxin reductase(TrxR),and iodothyronine deiodinases(DIOs),all of which exhibit indispensable physiological functions.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
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。
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 Natural Science Foundation of China (82073740, 82293683 (82293680), 32000548)CAMS Innovation Fund for Medical Sciences (CIFMS, 2021-I2M-5-004)+6 种基金CAS “Light of West China” ProgramYunnan Revitalization Talent Support Program “Young Talent” Project (YNQR-QNRC-2019-091)the CAS Pioneer Hundred Talents Programgrant from the State Key Laboratory of Phytochemistry and Plant Resources in West China (P2021-ZZ04)talent program from Kunming Institute of Botany CASNatural Science Foundation of Yunnan Province (202301AT070282)supported by shared resources of the Service Center for Bioactivity Screening, State Key Laboratory of Phytochemistry and Plant Resources in West China
文摘The lysosome is transformed from a major degradative site to a dynamic regulator of cellular homeostasis.Cancer cells with altered redox environments could be exploited as potential targets for cancer therapy.The thioredoxin(Trx)system,which includes thioredoxin reductases(TrxRs),is a promising target for cancer drug development.Here,by identifying the natural product isowalsuranolide(Hdy-7),we showed that lysosomal biogenesis and autophagy are elicited by Hdy-7 via the inhibition of TrxRs.The attenuation of cellular TrxR activity led to the accumulation of ROS,which are indispensable for p53 activation and subsequent lysosomal biogenesis mediated by the transcription factor TFEB/TFE3.Knockdown of TrxR1/2 led to activation of TFEB/TFE3,thereafter increasing lysosomal biogenesis.Treatment with the ROS scavenger NAC or knockdown of p53 or SESN2 led to attenuation of the nuclear translocation of TFEB/TFE3,lysosomal biogenesis,and autophagic flux,suggesting that the TrxR1/2-p53-TFEB/TFE3 axis plays a role in maintaining lysosomal homeostasis under stress conditions other than starvation.Surprisingly,pharmacological inhibition or genetic ablation of autophagy prevented Hdy-7-induced cell death,suggesting that Hdy-7-induced autophagy is detrimental to cancer cells.Our study revealed that Hdy-7 induces ROS-mediated lysosomal biogenesis and retards cell growth by targeting TrxR1/2.This study highlights the lysosome as a regulatory hub for cellular homeostasis and as an attractive therapeutic target for a variety of lysosome-related diseases,including cancer.
基金supported by the National Natural Science Foundation of China(Grant Nos.82261138630,32171390,and 32201154)the Natural Science Foundation of Guangdong Province(Grant Nos.2023B1515020104 and 2024A1515011244).
文摘Objective:The objective of the current study was to evaluate the chemosensitizing capacity of auranofin(AF),a gold(I)complex traditionally used in rheumatoid arthritis treatment,in potentiating the cytotoxic effects of doxorubicin(DOX)in melanoma cell models,specifically drug-sensitive(B16F10)and multidrug-resistant(B16F10/ADR)variants.Methods:Experimental measurements,including in vitro cytotoxicity and apoptosis assays,surface plasmon resonance(SPR),immunoblotting assays,as well as theoretical calculations,such as molecular docking and molecular dynamics(MD)simulations,were used to systematically delineate the interaction dynamics between AF and thioredoxin reductase 1(TrxR1).The anti-tumor efficacy of co-treatment with AF and DOX was assessed by examining cell viability and apoptotic rates.Results:Co-treatment with AF and DOX significantly increased anti-tumor efficacy,as evidenced by reduced cell viability and increased apoptotic rates.This synergistic effect was attributed to inhibition of TrxR1 by AF,which compromised tumor cell antioxidant defenses and elevated intracellular reactive oxygen species(ROS),thereby enhancing apoptotic pathways.Notably,AF treatment mitigated the heightened TrxR activity in DOX-resistant cells,intensifying the pro-oxidant effects of DOX,leading to increased ROS production and cell death.The data also showed that AF binds with high affinity to the selenocysteine residue within the catalytic site of TrxR1,which partially overlapped with the binding site of the endogenous substrate,thioredoxin(Trx),but with greater avidity.This unique binding configuration impedes the reduction of Trx by TrxR1,triggering an apoptotic response in cancer cells.Conclusions:This study underscores the chemosensitizing potential of AF in overcoming multidrug resistance in cancer therapy through redox modulation.The molecular mechanism of action underlying AF on TrxR1 demonstrated the unique binding configuration that impedes the reduction of Trx by TrxR1 and instigates an apoptotic response in cancer cells.These findings pave the way for the clinical application of AF as a chemosensitizer,offering a novel approach to augment the efficacy of existing chemotherapy regimens.
基金Financial support from the Science and Technology Innovation Program of Hunan Province(No.2022RC4044)。
文摘Selenium(Se),an essential micronutrient among the 15 vital elements required for human physiology,exerts its biological functions primarily through its incorporation into selenoproteins.To date,approximately 25 selenoproteins have been characterized in mammalian systems,including glutathione peroxidase(GPX),thioredoxin reductase(TrxR),and iodothyronine deiodinases(DIOs),all of which exhibit indispensable physiological functions.
文摘目的:研究血浆硫氧还蛋白还原酶(thioredoxin reductase,TrxR)在乳腺癌组织中的表达及其临床价值。方法:乳腺癌患者80例设为乳腺癌组,良性乳腺肿瘤患者48例设为良性对照组,50例健康体检人员设为正常对照组。采用酶联免疫吸附试验检测血浆TrxR水平,化学发光法检测血清癌抗原(carcinoma antigen 153,CA153)水平。比较3组血浆TrxR水平,分析TrxR水平与乳腺癌患者临床病理参数的关系,采用Spearman相关性分析血浆TrxR与血清CA153的相关性,受试者工作特征曲线(receiver operating characteristic curve,ROC)评估血浆TrxR、血清CA153对乳腺癌的诊断价值,比较乳腺癌患者治疗前后TrxR水平的变化。结果:乳腺癌组血浆TrxR水平明显高于良性对照组及正常对照组,良性对照组血浆TrxR水平明显高于正常对照组,差异均有统计学意义(P<0.05)。组织学分级Ⅱ~Ⅲ级乳腺癌患者血浆TrxR水平明显高于Ⅰ级患者,发生淋巴结转移患者血浆TrxR水平明显高于无淋巴结转移患者,TNM分期Ⅲ~Ⅳ期患者血浆TrxR水平明显高于Ⅰ~Ⅱ期患者,差异均有统计学意义(P<0.05)。Spearman相关性分析显示,血浆TrxR和血清CA153具有一定的相关性(r=0.3805,P<0.05)。ROC曲线分析显示,TrxR诊断乳腺癌的敏感度为84.0%,特异度为75.0%,曲线下面积(area under the curve,AUC)为0.8470;CA153诊断乳腺癌的敏感度为70.0%,特异度为77.5%,AUC为0.7815。72例Ⅰ~Ⅲ期乳腺癌患者接受手术治疗及术后辅助治疗,治疗后2个月乳腺癌患者TrxR水平较治疗前明显下降,差异有统计学意义(P<0.05)。结论:血浆TrxR可能成为有效的乳腺癌诊断指标,其在评估乳腺癌病情恶化程度、预测未来发展趋势等方面具有重要的临床意义。
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.
