Cisplatin belongs to platinum-based drugs and is widely used in cancer chemotherapy.Ototoxicity is one of the major dose limiting side-effects of cisplatin.For toxicity to occur cisplatin must first be transported fro...Cisplatin belongs to platinum-based drugs and is widely used in cancer chemotherapy.Ototoxicity is one of the major dose limiting side-effects of cisplatin.For toxicity to occur cisplatin must first be transported from the bloodstream into cochlear cells.Three copper transporters are considered pathways for regulating the uptake and translocation of cisplatin into cells:Ctr1,ATP7A and ATP7B.Our recent study with cochlear organotypic cultures shows that cochlear hair cells can be destroyed by cisplatin at low concentrations from 10μm to 100μn.However,high doses of cisplatin cannot damage hair cells,maybe due to intrinsic feedback reactions that increase export of platinum by ATP7B when the platinum concentration is high in extracellular space.Cimitidine is a specific copper transporter inhibitor that can block the entrance of copper and platinum,and may prevent cisplatin-induced cochlear hair cell injury.To evaluate this hypothesis,we treated cochlear organotypic cultures with cisplatin (10 μm or 50 μm) alone,or cisplatin combined with cimitidine at concentrations ranging from 10-2000 μm for 48 hours.cisplatin at 10 μm damaged about 20% hair cells.In contrast,when cimitidine (10 μm,100 μm and 2000 μm) was added to the culture,near 100% cochlear hair cell survived.At higher concentration (50 μm),cisplatin destroyed about 80% of cochlear hair cells.However,100 μmcimitidine rescued about 50% hair cells from cisplatin damage,and 2000μm cimitidine protected about 80% hair cells.The data of western blot showed that CTR1 and ATP7B expressions were increased in cisplatin treated cochlear tissue,but cimitidine significantly reduced CTR1 and ATP7B.In addition,ATP7A expression was depressed a little after cisplatin treatment.Considering that Ctr1 is involved in copper and platinum influx,but the ATP7A and ATP7B are copper export transporters,the results suggest that cimitidine can effectively block the entrance by copper transporters and stop the influx of cisplatin.展开更多
Platinum(Pt)-based antitumor agents are effective in the treatment of many solid malignancies. However, their efficacy is limited by toxicity and drug resistance. Reduced intracellular Pt accumulation has been consist...Platinum(Pt)-based antitumor agents are effective in the treatment of many solid malignancies. However, their efficacy is limited by toxicity and drug resistance. Reduced intracellular Pt accumulation has been consistently shown to correlate with resistance in tumors. Proteins involved in copper homeostasis have been identified as Pt transporters. In particular, copper transporter receptor 1(CTR1), the major copper influx transporter, has been shown to play a significant role in Pt resistance. Clinical studies demonstrated that expression of CTR1 correlated with intratumoral Pt concentration and outcomes following Pt-based therapy. Other CTRs such as CTR2, ATP7 A and ATP7 B, may also play a role in Pt resistance. Recent clinical studies attempting to modulate CTR1 to overcome Pt resistance may provide novel strategies. This review discusses the role of CTR1 as a potential predictive biomarker of Pt sensitivity and a therapeutic target for overcoming Pt resistance.展开更多
AIM: To study the effect of copper transporting P-type ATPase in copper metabolism of hepatocyte and pathogenesis of Wilson disease (WD).METHODS: WD copper transporting properties in some organelles of the cultu...AIM: To study the effect of copper transporting P-type ATPase in copper metabolism of hepatocyte and pathogenesis of Wilson disease (WD).METHODS: WD copper transporting properties in some organelles of the cultured hepatocytes were studied from WD patients and normal controls. These cultured hepatocytes were incubated in the media of copper 15mg.L-1 only, copper 15 mg. L-1 with vincristine (agonist of P-type ArPase) 0.5mg. L-1, or copper 15 mg. L-1 withvanadate (antagonist of P-type ATPase) 18.39 mg. L-1separately. Microsome (endoplasmic reticulum and Golgi apparatus), lysosome, mitochondria, and cytosol were isolated by differential centrifugation. Copper contents in these organelles were measured with atomic absorption spectrophotometer, and the influence in copper transportion of these organelles by vanadate and vincristine were comparatively analyzed between WD patients and controls.WD copper transporting P-type ATPase was detected by SDS-PAGE in conjunction with Western blot in liver samples of WD patients and controls.RESULTS: The specific WD proteins (Mr155 000 lanes) were expressed in human hepatocytes, including the control and WD patients. After incubation with medium containing copper for 2 h or 24 h, the microsome copper concentration in WD patients was obviously lower than that of controls,and the addtion of vanadate or vincristine would change the copper transporting of microsomes obviously. When incubated with vincristine, levels of copper in microsome were significantly increased, while incubated with vanadate,the copper concentrations in microsome were obviously decreased. The results indicated that there were Wdproteins, the copper transportion P-type ATPase in the microsome of hepatocytes. WD patients possessed abnormal copper transporting function of WD protein in the microsome, and the agonist might correct the defect of copper transportion by promoting the activity of copper transportion P-type ATPase.CONCLUSION: Copper transportion P-type ATPase plays an important role in hepatocytic copper metabolism.Dysfunction of hepatocytic WD protein copper transportion might be one of the most important factors for WD.展开更多
The experiment was conducted to as- sess the effects of dietary supplementation of Cu on the growth performance, digestive enzymes, tissue minerals and absorptive transporters in small intestinal mucosa of weanling pi...The experiment was conducted to as- sess the effects of dietary supplementation of Cu on the growth performance, digestive enzymes, tissue minerals and absorptive transporters in small intestinal mucosa of weanling pigs. One hundred crossbred pigs weaned at 28 ＋ 2 d of age were assigned randomly to one of the following diets with 5 replicates：corn-soy- bean basal diet with 10,100,175,250 mg/kg of Cu as CuSO4·5H20. The results showed that 250 mg/kg Cu had a positive effect （ P 〈 0.05） on average daily gain, daily feed intake and ratio of gain/feed. Com- pared to 10 mg/kg Cu, higher Cu had significant effect on the apparent digestibility of protein and fat （P 〈 0.05 ）. The supplementing of Cu improved am- ylase and lipase activity in jejunum content and lipase in pancreas （ P 〈 0.05） and had no effect on intestinalmorphology. The liver Cu elevated approximately 4- fold in pigs fed diet with 250 mg/kg Cu compared with pigs fed diet with 10 mg/kg Cu, no increases were observed in pigs receiving the lower level of Cu （100 and 175 mg/kg）. Both Fe and Zn contents in kidney and liver were not affected by Cu supplemen- tation. There was no positive effect （ P 〉0.05） of Cu supplementation on PepT1 （peptide transporter 1 ） and SGLT1 （sodium/glucose cotransporter） mRNA abundance in intestinal mucosa. However, higher sup- plementing level （250 mg/kg） significantly elevated the DMT1 （divalent metal transporter） mRNA abun- dance in duodenum mucosa. These results suggested that dietary supplementation with 250 mg/kg Cu could improve growth performance, nutrient digestibil- ity and intestinal enzyme activities of weanling pigs.展开更多
Based on the momentum and mass conservation equations,a comprehensive model of heap bioleaching process is developed to investigate the interaction between chemical reactions,solution flow,gas flow,and solute transpor...Based on the momentum and mass conservation equations,a comprehensive model of heap bioleaching process is developed to investigate the interaction between chemical reactions,solution flow,gas flow,and solute transport within the leaching system.The governing equations are solved numerically using the COMSOL Multiphysics software for the coupled reactive flow and solute transport at micro-scale,meso-scale and macro-scale levels.At or near the surface of ore particle,the acid concentration is relatively higher than that in the central area,while the concentration gradient decreases after 72 d of leaching.The flow simulation between ore particles by combining X-ray CT technology shows that the highest velocity in narrow pore reaches 0.375 m/s.The air velocity within the dump shows that the velocity near the top and side surface is relatively high,which leads to the high oxygen concentration in that area.The coupled heat transfer and liquid flow process shows that the solution can act as an effective remover from the heap,dropping the highest temperature from 60 to 38 °C.The reagent transfer coupled with solution flow is also analyzed.The results obtained allow us to obtain a better understanding of the fundamental physical phenomenon of the bioleaching process.展开更多
蚀变分带和成矿机制的准确厘定是建立斑岩成矿模型与找矿预测的关键。本文以新生代金沙江-哀牢山成矿带的玉龙斑岩铜矿为例,通过质量作用定律(LMA)和吉布斯自由能最小化模型(GEM),构建含矿热液与斑岩侵入体的pH-f O 2相图和动态传输模型...蚀变分带和成矿机制的准确厘定是建立斑岩成矿模型与找矿预测的关键。本文以新生代金沙江-哀牢山成矿带的玉龙斑岩铜矿为例,通过质量作用定律(LMA)和吉布斯自由能最小化模型(GEM),构建含矿热液与斑岩侵入体的pH-f O 2相图和动态传输模型,以揭示蚀变分带成因和金属成矿机制。LMA与GEM结果显示初始成矿流体pH值为4.7,logf_(O2)=-23.0(ΔFMQ=+2.7),且溶解Cu含量为1138×10^(-6),Mo为1.2×10^(-6)。研究表明,当该酸性及强氧化性流体流入二长花岗斑岩体时,在温度为450~360℃范围内,代表钾硅酸盐化蚀变的钾长石、黑云母、硬石膏、赤铁矿和磁铁矿的矿物逐渐沉淀,且与钾硅酸盐化蚀变相关流体具有较高pH值(5.0~7.0)和氧逸度(ΔFMQ=+2.9~+3.6)特征;当温度在360~320℃范围时,代表青磐岩化蚀变阶段的典型矿物如绿帘石、铁绿泥石和斜绿泥石等逐渐形成,流体pH值(5.0~6.4)和氧逸度(ΔFMQ=+1.1)均有所下降;当温度进一步从320℃下降到200℃时,流体pH值(5.0~5.7)进一步小幅下降,而氧逸度则(ΔFMQ=+1.7)略有回升,在此期间,绢云母和方解石等开始沉淀并形成典型的绢英岩化蚀变。此外,以HMoO_(4)^(-)和MoO_(4)^(2-)为载体的Mo在狭窄高温区间(450~370℃)内沉淀,而以CuCl(CuCl_(4)^(3-)、CuCl_(2)^(-)、CuCl)为主要载体的Cu则在在中、高温(450~300℃)范围中沉淀。通过利用LMA反演及GEM正演相结合定量化地刻画了玉龙斑岩铜矿水岩反应过程,由此揭示了斑岩矿床蚀变分带是逐渐冷却的单一岩浆热液与斑岩体不断反应的结果,且不同温度窗口对应着钾硅酸盐化(450~360℃)、青磐岩化(360~320℃)和绢英岩化(320~200℃)蚀变矿物的形成,故含矿流体温度的快速下降可能是玉龙铜矿蚀变叠加的重要因素。此外,Cu、Mo络合离子溶解度对温度变化的差异响应,导致了Mo矿化主要发育于靠近斑岩体的高温区域,而Cu则以网脉状-浸染状叠加到Mo矿化之上,并广泛分布于斑岩体周边的高-中温区域。展开更多
Iron and copper have a wealth of functions in biological systems,which makes them essential micronutrients for all living organisms.Defects in iron and copper homeostasis are directly responsible for diseases,and have...Iron and copper have a wealth of functions in biological systems,which makes them essential micronutrients for all living organisms.Defects in iron and copper homeostasis are directly responsible for diseases,and have been linked to impaired development,metabolic syndromes and fungal virulence.Consequently,it is crucial to gain a comprehensive understanding of the molecular bases of iron-and copper-dependent proteins in living systems.Simon Labbémaintains parallel programs on iron and copper homeostasis using the fission yeast Schizosaccharomyces pombe(Schiz.pombe) as a model system.The study of fission yeast transition-metal metabolism has been successful,not only in discerning the genes and pathways functioning in Schiz.pombe,but also the genes and pathways that are active in mammalian systems and for other fungi.展开更多
文摘Cisplatin belongs to platinum-based drugs and is widely used in cancer chemotherapy.Ototoxicity is one of the major dose limiting side-effects of cisplatin.For toxicity to occur cisplatin must first be transported from the bloodstream into cochlear cells.Three copper transporters are considered pathways for regulating the uptake and translocation of cisplatin into cells:Ctr1,ATP7A and ATP7B.Our recent study with cochlear organotypic cultures shows that cochlear hair cells can be destroyed by cisplatin at low concentrations from 10μm to 100μn.However,high doses of cisplatin cannot damage hair cells,maybe due to intrinsic feedback reactions that increase export of platinum by ATP7B when the platinum concentration is high in extracellular space.Cimitidine is a specific copper transporter inhibitor that can block the entrance of copper and platinum,and may prevent cisplatin-induced cochlear hair cell injury.To evaluate this hypothesis,we treated cochlear organotypic cultures with cisplatin (10 μm or 50 μm) alone,or cisplatin combined with cimitidine at concentrations ranging from 10-2000 μm for 48 hours.cisplatin at 10 μm damaged about 20% hair cells.In contrast,when cimitidine (10 μm,100 μm and 2000 μm) was added to the culture,near 100% cochlear hair cell survived.At higher concentration (50 μm),cisplatin destroyed about 80% of cochlear hair cells.However,100 μmcimitidine rescued about 50% hair cells from cisplatin damage,and 2000μm cimitidine protected about 80% hair cells.The data of western blot showed that CTR1 and ATP7B expressions were increased in cisplatin treated cochlear tissue,but cimitidine significantly reduced CTR1 and ATP7B.In addition,ATP7A expression was depressed a little after cisplatin treatment.Considering that Ctr1 is involved in copper and platinum influx,but the ATP7A and ATP7B are copper export transporters,the results suggest that cimitidine can effectively block the entrance by copper transporters and stop the influx of cisplatin.
文摘Platinum(Pt)-based antitumor agents are effective in the treatment of many solid malignancies. However, their efficacy is limited by toxicity and drug resistance. Reduced intracellular Pt accumulation has been consistently shown to correlate with resistance in tumors. Proteins involved in copper homeostasis have been identified as Pt transporters. In particular, copper transporter receptor 1(CTR1), the major copper influx transporter, has been shown to play a significant role in Pt resistance. Clinical studies demonstrated that expression of CTR1 correlated with intratumoral Pt concentration and outcomes following Pt-based therapy. Other CTRs such as CTR2, ATP7 A and ATP7 B, may also play a role in Pt resistance. Recent clinical studies attempting to modulate CTR1 to overcome Pt resistance may provide novel strategies. This review discusses the role of CTR1 as a potential predictive biomarker of Pt sensitivity and a therapeutic target for overcoming Pt resistance.
基金Supported by Key Clinical Program of Ministry of Ministry of Health(No.37091)"211 Project"of SUMS sponsored by Ministry of Health and Guangdong Provincial Natural Science Foundation,No.990064
文摘AIM: To study the effect of copper transporting P-type ATPase in copper metabolism of hepatocyte and pathogenesis of Wilson disease (WD).METHODS: WD copper transporting properties in some organelles of the cultured hepatocytes were studied from WD patients and normal controls. These cultured hepatocytes were incubated in the media of copper 15mg.L-1 only, copper 15 mg. L-1 with vincristine (agonist of P-type ArPase) 0.5mg. L-1, or copper 15 mg. L-1 withvanadate (antagonist of P-type ATPase) 18.39 mg. L-1separately. Microsome (endoplasmic reticulum and Golgi apparatus), lysosome, mitochondria, and cytosol were isolated by differential centrifugation. Copper contents in these organelles were measured with atomic absorption spectrophotometer, and the influence in copper transportion of these organelles by vanadate and vincristine were comparatively analyzed between WD patients and controls.WD copper transporting P-type ATPase was detected by SDS-PAGE in conjunction with Western blot in liver samples of WD patients and controls.RESULTS: The specific WD proteins (Mr155 000 lanes) were expressed in human hepatocytes, including the control and WD patients. After incubation with medium containing copper for 2 h or 24 h, the microsome copper concentration in WD patients was obviously lower than that of controls,and the addtion of vanadate or vincristine would change the copper transporting of microsomes obviously. When incubated with vincristine, levels of copper in microsome were significantly increased, while incubated with vanadate,the copper concentrations in microsome were obviously decreased. The results indicated that there were Wdproteins, the copper transportion P-type ATPase in the microsome of hepatocytes. WD patients possessed abnormal copper transporting function of WD protein in the microsome, and the agonist might correct the defect of copper transportion by promoting the activity of copper transportion P-type ATPase.CONCLUSION: Copper transportion P-type ATPase plays an important role in hepatocytic copper metabolism.Dysfunction of hepatocytic WD protein copper transportion might be one of the most important factors for WD.
基金supported by Program for Changjiang Scholars and In-novative Research Team in University with grant No. IRTO555-5,China Ministry of Education
文摘The experiment was conducted to as- sess the effects of dietary supplementation of Cu on the growth performance, digestive enzymes, tissue minerals and absorptive transporters in small intestinal mucosa of weanling pigs. One hundred crossbred pigs weaned at 28 ＋ 2 d of age were assigned randomly to one of the following diets with 5 replicates：corn-soy- bean basal diet with 10,100,175,250 mg/kg of Cu as CuSO4·5H20. The results showed that 250 mg/kg Cu had a positive effect （ P 〈 0.05） on average daily gain, daily feed intake and ratio of gain/feed. Com- pared to 10 mg/kg Cu, higher Cu had significant effect on the apparent digestibility of protein and fat （P 〈 0.05 ）. The supplementing of Cu improved am- ylase and lipase activity in jejunum content and lipase in pancreas （ P 〈 0.05） and had no effect on intestinalmorphology. The liver Cu elevated approximately 4- fold in pigs fed diet with 250 mg/kg Cu compared with pigs fed diet with 10 mg/kg Cu, no increases were observed in pigs receiving the lower level of Cu （100 and 175 mg/kg）. Both Fe and Zn contents in kidney and liver were not affected by Cu supplemen- tation. There was no positive effect （ P 〉0.05） of Cu supplementation on PepT1 （peptide transporter 1 ） and SGLT1 （sodium/glucose cotransporter） mRNA abundance in intestinal mucosa. However, higher sup- plementing level （250 mg/kg） significantly elevated the DMT1 （divalent metal transporter） mRNA abun- dance in duodenum mucosa. These results suggested that dietary supplementation with 250 mg/kg Cu could improve growth performance, nutrient digestibil- ity and intestinal enzyme activities of weanling pigs.
基金Projects(50934002,51104011) supported by the National Natural Science Foundation of ChinaProject(IRT0950) supported by Program for Changjiang Scholars and Innovative Research Team in Chinese UniversityProject(20100480200) supported by China Postdoctoral Science Foundation
文摘Based on the momentum and mass conservation equations,a comprehensive model of heap bioleaching process is developed to investigate the interaction between chemical reactions,solution flow,gas flow,and solute transport within the leaching system.The governing equations are solved numerically using the COMSOL Multiphysics software for the coupled reactive flow and solute transport at micro-scale,meso-scale and macro-scale levels.At or near the surface of ore particle,the acid concentration is relatively higher than that in the central area,while the concentration gradient decreases after 72 d of leaching.The flow simulation between ore particles by combining X-ray CT technology shows that the highest velocity in narrow pore reaches 0.375 m/s.The air velocity within the dump shows that the velocity near the top and side surface is relatively high,which leads to the high oxygen concentration in that area.The coupled heat transfer and liquid flow process shows that the solution can act as an effective remover from the heap,dropping the highest temperature from 60 to 38 °C.The reagent transfer coupled with solution flow is also analyzed.The results obtained allow us to obtain a better understanding of the fundamental physical phenomenon of the bioleaching process.
文摘蚀变分带和成矿机制的准确厘定是建立斑岩成矿模型与找矿预测的关键。本文以新生代金沙江-哀牢山成矿带的玉龙斑岩铜矿为例,通过质量作用定律(LMA)和吉布斯自由能最小化模型(GEM),构建含矿热液与斑岩侵入体的pH-f O 2相图和动态传输模型,以揭示蚀变分带成因和金属成矿机制。LMA与GEM结果显示初始成矿流体pH值为4.7,logf_(O2)=-23.0(ΔFMQ=+2.7),且溶解Cu含量为1138×10^(-6),Mo为1.2×10^(-6)。研究表明,当该酸性及强氧化性流体流入二长花岗斑岩体时,在温度为450~360℃范围内,代表钾硅酸盐化蚀变的钾长石、黑云母、硬石膏、赤铁矿和磁铁矿的矿物逐渐沉淀,且与钾硅酸盐化蚀变相关流体具有较高pH值(5.0~7.0)和氧逸度(ΔFMQ=+2.9~+3.6)特征;当温度在360~320℃范围时,代表青磐岩化蚀变阶段的典型矿物如绿帘石、铁绿泥石和斜绿泥石等逐渐形成,流体pH值(5.0~6.4)和氧逸度(ΔFMQ=+1.1)均有所下降;当温度进一步从320℃下降到200℃时,流体pH值(5.0~5.7)进一步小幅下降,而氧逸度则(ΔFMQ=+1.7)略有回升,在此期间,绢云母和方解石等开始沉淀并形成典型的绢英岩化蚀变。此外,以HMoO_(4)^(-)和MoO_(4)^(2-)为载体的Mo在狭窄高温区间(450~370℃)内沉淀,而以CuCl(CuCl_(4)^(3-)、CuCl_(2)^(-)、CuCl)为主要载体的Cu则在在中、高温(450~300℃)范围中沉淀。通过利用LMA反演及GEM正演相结合定量化地刻画了玉龙斑岩铜矿水岩反应过程,由此揭示了斑岩矿床蚀变分带是逐渐冷却的单一岩浆热液与斑岩体不断反应的结果,且不同温度窗口对应着钾硅酸盐化(450~360℃)、青磐岩化(360~320℃)和绢英岩化(320~200℃)蚀变矿物的形成,故含矿流体温度的快速下降可能是玉龙铜矿蚀变叠加的重要因素。此外,Cu、Mo络合离子溶解度对温度变化的差异响应,导致了Mo矿化主要发育于靠近斑岩体的高温区域,而Cu则以网脉状-浸染状叠加到Mo矿化之上,并广泛分布于斑岩体周边的高-中温区域。
基金supported by the National Natural Science Foundation of China(Nos.50934002 and 50774011)the program for New Century Excellent Talents in Chinese Universities(NECT-07-0070)+1 种基金the Specialized Research Fund for the Doctoral Program of Higher Education(No.20070008038)the China Postdoctoral Science Foundation(No.20090450014).]
基金Supported by The Canadian Institutes for Health Research (MOP-36450 to LabbéS)Natural Sciences and Engineering Research Council of Canada(MOP-238238-2010 to LabbéS)the Fonds de la Recherche en Santédu Québec(Senior Investigator Scholarship to LabbéS)
文摘Iron and copper have a wealth of functions in biological systems,which makes them essential micronutrients for all living organisms.Defects in iron and copper homeostasis are directly responsible for diseases,and have been linked to impaired development,metabolic syndromes and fungal virulence.Consequently,it is crucial to gain a comprehensive understanding of the molecular bases of iron-and copper-dependent proteins in living systems.Simon Labbémaintains parallel programs on iron and copper homeostasis using the fission yeast Schizosaccharomyces pombe(Schiz.pombe) as a model system.The study of fission yeast transition-metal metabolism has been successful,not only in discerning the genes and pathways functioning in Schiz.pombe,but also the genes and pathways that are active in mammalian systems and for other fungi.
