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
Brain tissue requires high amounts of copper(Cu)for its key physiological processes,such as energy production,neurotransmitter synthesis,maturation of neuropeptides,myelination,synaptic plasticity,and radical scavengi...Brain tissue requires high amounts of copper(Cu)for its key physiological processes,such as energy production,neurotransmitter synthesis,maturation of neuropeptides,myelination,synaptic plasticity,and radical scavenging.The requirements for Cu in the brain vary depending on specific brain regions,cell types,organism age,and nutritional status.Cu imbalances cause or contribute to several life-threatening neurologic disorders including Menkes disease,Wilson disease,Alzheimer’s disease,Parkinson’s disease,and others.Despite the well-established role of Cu homeostasis in brain development and function,the mechanisms that govern Cu delivery to the brain are not well defined.This review summarizes available information on Cu transfer through the brain barriers and discusses issues that require further research.展开更多
Copper-based nanomaterials demonstrate promising potential in cancer therapy.Cu^(+) efficiently triggers a Fenton-like reaction and further consumes the high level of glutathione,initiating chemical dynamic therapy(CD...Copper-based nanomaterials demonstrate promising potential in cancer therapy.Cu^(+) efficiently triggers a Fenton-like reaction and further consumes the high level of glutathione,initiating chemical dynamic therapy(CDT)and ferroptosis.Cuproptosis,a newly identified cell death modality that represents a great prospect in cancer therapy,is activated.However,active homeostatic systems rigorously keep copper levels within cells exceptionally low,which hinders the application of cooper nanomaterials-based therapy.Herein,a novel strategy of CRISPR-Cas9 RNP nanocarrier to deliver cuprous ions and suppress the expression of copper transporter protein ATP7A for maintaining a high level of copper in cytoplasmic fluid is developed.The Cu_(2)O and organosilica shell would degrade under the high level of glutathione and weak acidic environment,further releasing RNP and Cu^(+).The liberated Cut triggered a Fenton-like reaction for CDT and partially transformed to Cu^(2+),consuming intracellular GSH and initiating cuproptosis and ferroptosis efficiently.Meanwhile,the release of RNP effectively reduced the expression of copper transporter ATP7A,subsequently increasing the accumulation of cooper and enhancing the efficacy of CDT,cuproptosis,and ferroptosis.Such tumor microenvironment responsive multimodal nanoplatform opens an ingenious avenue for colorectal cancer therapy based on gene editing enhanced synergistic cuproptosis/CDT/ferroptosis.展开更多
Menkes disease is a rare X-linked recessive .hereditary disorder first described by Menkes et al in 1962.1 including The gene mutation results in clinical features pili torti, unusual facies, mental/growth retardation...Menkes disease is a rare X-linked recessive .hereditary disorder first described by Menkes et al in 1962.1 including The gene mutation results in clinical features pili torti, unusual facies, mental/growth retardation and metabolic dysfunction. The pathogenic gene ATP7A was identified in 1993.2 It is located on chromosome X and encodes a transmembrane Cu^2＋ transporter. Here we reported the clinical manifestations and results of genetic study of a family with Menkes disease. In this family, a deletion mutation in ATP7A gene is responsible for the disease.展开更多
As a copper(Cu)transport ATPase,ATP7A plays an important role in maintaining Cu homeostasis in the body,but the developmental and physiological roles of atp7a in zebrafish embryogenesis are rarely studied.In this stud...As a copper(Cu)transport ATPase,ATP7A plays an important role in maintaining Cu homeostasis in the body,but the developmental and physiological roles of atp7a in zebrafish embryogenesis are rarely studied.In this study,normal morphological phenotypes of atp7a^(−/−)homozygous zebrafish were observed at both embryonic and adult stages,however,atp7a^(−/−)larvae exhibited delayed touch response and obvious transcriptome changes.Compared with the WT(wild type),differentially expressed genes(DEGs)in atp7a^(−/−)larvae showed the enrichment in gene ontology(GO)terms related to several processes including ATPase activity,oxidoreductase activity,active transmembrane transporter activity,ion binding,and the citrate cycle.Furthermore,decreases in both ATP content and Na+/K+-ATPase activity in atp7a^(−/−)embryos and larvae were unveiled.57 overlapping DEGs were found both in WT stressed with Cu and in WT mutated with atp7a,and GO term analysis indicated the enrichment in the genes related to neurexin family protein binding and neuronal cell-cell adhesion.Moreover,42 overlapping DEGs in Cu stressed WT and Cu stressed atp7a^(−/−)were identified.GO term analysis showed an enrichment in the genes related to heme binding,implying that Cu was independent of the integral function of atp7a to affect heme binding.In addition,genes involved in the negative regulation of angiogenesis were down-regulated in atp7a^(−/−)mutants with and without Cu stress,which failed to occur in WT,implying that the integral function of atp7a is required for maintaining the normal expression of angiogenesis genes.The integrative data in this study demonstrated that atp7a is required for ion transport and angiogenesis,and for Cu-induced neurexin family protein binding defects,rather than for Cu-induced heme binding defects,during zebrafish embryogenesis.These findings provide possible clues for human diseases with ATP7A dysfunction and imbalanced Cu homeostasis.展开更多
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 the National Institute of Health grant R01 GM101502(to SL).
文摘Brain tissue requires high amounts of copper(Cu)for its key physiological processes,such as energy production,neurotransmitter synthesis,maturation of neuropeptides,myelination,synaptic plasticity,and radical scavenging.The requirements for Cu in the brain vary depending on specific brain regions,cell types,organism age,and nutritional status.Cu imbalances cause or contribute to several life-threatening neurologic disorders including Menkes disease,Wilson disease,Alzheimer’s disease,Parkinson’s disease,and others.Despite the well-established role of Cu homeostasis in brain development and function,the mechanisms that govern Cu delivery to the brain are not well defined.This review summarizes available information on Cu transfer through the brain barriers and discusses issues that require further research.
基金the National Natural Science Foundation of China(82374287,82174466,81930117)National Key Research and Development Project(2022YFC3500200,China)+3 种基金Key research and development projects of Ningxia(Grant No.2021BEG02040,China)Natural Science Foundation Project of Jiangsu Province(BK20211390,China)Open Projects of the Discipline of Chinese Medicine of Nanjing University of Chinese Medicine Supported by the Subject of Academic priority discipline of Jiangsu Higher Education Institutions,Program for Leading Talents of Traditional Chinese Medicine of Jiangsu Province(SLJ0314)Blue Project of Jiangsu province.
文摘Copper-based nanomaterials demonstrate promising potential in cancer therapy.Cu^(+) efficiently triggers a Fenton-like reaction and further consumes the high level of glutathione,initiating chemical dynamic therapy(CDT)and ferroptosis.Cuproptosis,a newly identified cell death modality that represents a great prospect in cancer therapy,is activated.However,active homeostatic systems rigorously keep copper levels within cells exceptionally low,which hinders the application of cooper nanomaterials-based therapy.Herein,a novel strategy of CRISPR-Cas9 RNP nanocarrier to deliver cuprous ions and suppress the expression of copper transporter protein ATP7A for maintaining a high level of copper in cytoplasmic fluid is developed.The Cu_(2)O and organosilica shell would degrade under the high level of glutathione and weak acidic environment,further releasing RNP and Cu^(+).The liberated Cut triggered a Fenton-like reaction for CDT and partially transformed to Cu^(2+),consuming intracellular GSH and initiating cuproptosis and ferroptosis efficiently.Meanwhile,the release of RNP effectively reduced the expression of copper transporter ATP7A,subsequently increasing the accumulation of cooper and enhancing the efficacy of CDT,cuproptosis,and ferroptosis.Such tumor microenvironment responsive multimodal nanoplatform opens an ingenious avenue for colorectal cancer therapy based on gene editing enhanced synergistic cuproptosis/CDT/ferroptosis.
文摘Menkes disease is a rare X-linked recessive .hereditary disorder first described by Menkes et al in 1962.1 including The gene mutation results in clinical features pili torti, unusual facies, mental/growth retardation and metabolic dysfunction. The pathogenic gene ATP7A was identified in 1993.2 It is located on chromosome X and encodes a transmembrane Cu^2＋ transporter. Here we reported the clinical manifestations and results of genetic study of a family with Menkes disease. In this family, a deletion mutation in ATP7A gene is responsible for the disease.
基金This work was supported by the National Key R&D Program of China(2022YFF1000302)by the project of the Knowledge Innovation Program of Wuhan-Basic Research 2022020801010223by the National Natural Science Foundation of China(Program No.32070807 to J-X.L).
文摘As a copper(Cu)transport ATPase,ATP7A plays an important role in maintaining Cu homeostasis in the body,but the developmental and physiological roles of atp7a in zebrafish embryogenesis are rarely studied.In this study,normal morphological phenotypes of atp7a^(−/−)homozygous zebrafish were observed at both embryonic and adult stages,however,atp7a^(−/−)larvae exhibited delayed touch response and obvious transcriptome changes.Compared with the WT(wild type),differentially expressed genes(DEGs)in atp7a^(−/−)larvae showed the enrichment in gene ontology(GO)terms related to several processes including ATPase activity,oxidoreductase activity,active transmembrane transporter activity,ion binding,and the citrate cycle.Furthermore,decreases in both ATP content and Na+/K+-ATPase activity in atp7a^(−/−)embryos and larvae were unveiled.57 overlapping DEGs were found both in WT stressed with Cu and in WT mutated with atp7a,and GO term analysis indicated the enrichment in the genes related to neurexin family protein binding and neuronal cell-cell adhesion.Moreover,42 overlapping DEGs in Cu stressed WT and Cu stressed atp7a^(−/−)were identified.GO term analysis showed an enrichment in the genes related to heme binding,implying that Cu was independent of the integral function of atp7a to affect heme binding.In addition,genes involved in the negative regulation of angiogenesis were down-regulated in atp7a^(−/−)mutants with and without Cu stress,which failed to occur in WT,implying that the integral function of atp7a is required for maintaining the normal expression of angiogenesis genes.The integrative data in this study demonstrated that atp7a is required for ion transport and angiogenesis,and for Cu-induced neurexin family protein binding defects,rather than for Cu-induced heme binding defects,during zebrafish embryogenesis.These findings provide possible clues for human diseases with ATP7A dysfunction and imbalanced Cu homeostasis.
