scholarly journals Hyaluronate/black phosphorus complexes as a copper chelating agent for Wilson disease treatment

2021 ◽  
Vol 25 (1) ◽  
Author(s):  
Seong-Jong Kim ◽  
Hye Hyeon Han ◽  
Sei Kwang Hahn
Keyword(s):  
Targeted Delivery ◽  
Wilson Disease ◽  
Copper Ions ◽  
Binding Capacity ◽  
Genetic Disorder ◽  
Chelating Agent ◽  
Black Phosphorus ◽  
The Body ◽  
Copper Binding

Abstract Background Wilson disease (WD) is a genetic disorder of copper storage, resulting in pathological accumulation of copper in the body. Because symptoms are generally related to the liver, chelating agents capable of capturing excess copper ions after targeted delivery to the liver are highly required for the treatment of WD. Methods We developed hyaluronate-diaminohexane/black phosphorus (HA-DAH/BP) complexes for capturing copper ions accumulated in the liver for the treatment of WD. Results HA-DAH/BP complexes showed high hepatocyte-specific targeting efficiency, selective copper capturing capacity, excellent biocompatibility, and biodegradability. HA enhanced the stability of BP nanosheets and increased copper binding capacity. In vitro cellular uptake and competitive binding tests verified targeted delivery of HA-DAH/BP complexes to liver cells via HA receptor mediated endocytosis. The cell viability test confirmed the high biocompatibility of HA-DAH/BP complexes. Conclusion HA-DAH/BP complexes would be an efficient copper chelating agent to remove accumulated copper in the liver for the WD treatment.

scholarly journals Hyaluronate – Black Phosphorus Conjugates as a Copper Chelating Agent for Wilson Disease Treatment

2021 ◽  
Author(s):  
Seong-Jong Kim ◽  
Hye Hyeon Han ◽  
Sei Kwang Hahn
Keyword(s):  
Targeted Delivery ◽  
Wilson Disease ◽  
Copper Ions ◽  
Binding Capacity ◽  
Genetic Disorder ◽  
Chelating Agent ◽  
Black Phosphorus ◽  
The Body ◽  
Copper Binding

Abstract Background: Wilson disease (WD) is a genetic disorder of copper storage, resulting in pathological accumulation of copper in the body. Because symptoms are generally related to the liver, chelating agents capable of capturing excess copper ions after targeted delivery to the liver are highly required for the treatment of WD. Methods: We developed hyaluronate - black phosphorus (HA-BP) conjugates for capturing copper ions accumulated in the liver for the treatment of WD.Results: HA-BP conjugates showed high hepatocyte-specific targeting efficiency, selective copper capturing capacity, excellent biocompatibility, and biodegradability. HA enhanced the stability of BP nanosheets and increased copper binding capacity. In vitro cellular uptake and competitive binding tests verified targeted delivery of HA-BP conjugates to liver cells via HA receptor mediated endocytosis. The cell viability test confirmed the high biocompatibility of HA-BP conjugates.Conclusion: HA-BP conjugates would be an efficient copper chelating agent to remove accumulated copper in the liver for the WD treatment.

scholarly journals Silver Ions as a Tool for Understanding Different Aspects of Copper Metabolism

Nutrients ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 1364 ◽  
Author(s):  
Ludmila V. Puchkova ◽  
Massimo Broggini ◽  
Elena V. Polishchuk ◽  
Ekaterina Y. Ilyechova ◽  
Roman S. Polishchuk
Keyword(s):  
Active Sites ◽  
Large Scale ◽  
Copper Ions ◽  
Copper Metabolism ◽  
Silver Ions ◽  
The Body ◽  
Copper Binding ◽  
Safe Delivery ◽  
Protein Motifs ◽  
Wide Range

In humans, copper is an important micronutrient because it is a cofactor of ubiquitous and brain-specific cuproenzymes, as well as a secondary messenger. Failure of the mechanisms supporting copper balance leads to the development of neurodegenerative, oncological, and other severe disorders, whose treatment requires a detailed understanding of copper metabolism. In the body, bioavailable copper exists in two stable oxidation states, Cu(I) and Cu(II), both of which are highly toxic. The toxicity of copper ions is usually overcome by coordinating them with a wide range of ligands. These include the active cuproenzyme centers, copper-binding protein motifs to ensure the safe delivery of copper to its physiological location, and participants in the Cu(I) ↔ Cu(II) redox cycle, in which cellular copper is stored. The use of modern experimental approaches has allowed the overall picture of copper turnover in the cells and the organism to be clarified. However, many aspects of this process remain poorly understood. Some of them can be found out using abiogenic silver ions (Ag(I)), which are isoelectronic to Cu(I). This review covers the physicochemical principles of the ability of Ag(I) to substitute for copper ions in transport proteins and cuproenzyme active sites, the effectiveness of using Ag(I) to study copper routes in the cells and the body, and the limitations associated with Ag(I) remaining stable in only one oxidation state. The use of Ag(I) to restrict copper transport to tumors and the consequences of large-scale use of silver nanoparticles for human health are also discussed.

scholarly journals Contribution of copper binding to the inhibition of lipid oxidation by plasmalogen phospholipids

1999 ◽  
Vol 340 (2) ◽  
pp. 377-383 ◽  
Author(s):  
Daniela HAHNEL ◽  
Thomas HUBER ◽  
Volker KURZE ◽  
Klaus BEYER ◽  
Bernd ENGELMANN
Keyword(s):  
Lipid Oxidation ◽  
Copper Ions ◽  
Aqueous Media ◽  
Oxidative Degradation ◽  
Direct Interaction ◽  
Molar Ratio ◽  
Protective Effects ◽  
Copper Binding ◽  
Enol Ether

The role of plasmalogen phospholipids for copper-induced lipid oxidation was evaluated. Using 1H-NMR we observed that the copper (CuSO4)-promoted oxidative degradation of polyunsaturated fatty acids in micellar solution was dose-dependently attenuated by the plasmalogen lysoplasmenylethanolamine from bovine brain (lysoBP-PtdEtn). This was due to a direct interaction of copper ions with the plasmalogen-specific enol ether double bond. The enol ether methine 1H signal decreased on the addition of copper, saturation being reached at a molar ratio of lysoBP-PtdEtn to copper of 1:1. The original 1H signal was recovered almost completely after the addition of EDTA. Enrichment of micelles and low-density lipoproteins (LDLs) with plasmalogen phospholipids led to a decrease in the Cu(II) concentration in the aqueous media. After loading of LDLs in vitro with BP-PtdEtn, the LDL-dependent formation of Cu(I) was decreased, in particular in particles experimentally supplemented with α-tocopherol. The suppression of copper-promoted lipid oxidation that was observed in the presence of plasmalogen phospholipids plus α-tocopherol was greater than the sum of the protective effects elicited by the two substances alone. In conclusion, the formation of a complex between copper ions and the plasmalogens accounts partly for their inhibition of copper-induced lipid oxidation.

Folding of copper proteins: role of the metal?

2018 ◽  
Vol 51 ◽  
Author(s):  
Candan Ariöz ◽  
Pernilla Wittung-Stafshede
Keyword(s):  
Metal Ion ◽  
Copper Ions ◽  
Structural Parameters ◽  
Copper Transport ◽  
Transport Systems ◽  
Copper Binding ◽  
Copper Proteins ◽  
Exchange Reactions

AbstractCopper is a redox–active transition metal ion required for the function of many essential human proteins. For biosynthesis of proteins coordinating copper, the metal may bind before, during or after folding of the polypeptide. If the metal binds to unfolded or partially folded structures of the protein, such coordination may modulate the folding reaction. The molecular understanding of how copper is incorporated into proteins requires descriptions of chemical, thermodynamic, kinetic and structural parameters involved in the formation of protein–metal complexes. Because free copper ions are toxic, living systems have elaborate copper-transport systems that include particular proteins that facilitate efficient and specific delivery of copper ions to target proteins. Therefore, these pathways become an integral part of copper protein folding in vivo. This review summarizes biophysical-molecular in vitro work assessing the role of copper in folding and stability of copper-binding proteins as well as protein–protein copper exchange reactions between human copper transport proteins. We also describe some recent findings about the participation of copper ions and copper proteins in protein misfolding and aggregation reactions in vitro.

scholarly journals An investigation into copper-binding capacity of the white leg shrimp head (Litopenaeus vannamei) protein hydrolysate

2020 ◽  
pp. 13-18
Author(s):  
Tam Dinh Le Vo Vo
Keyword(s):  
Amino Acid ◽  
G Protein ◽  
Protein Hydrolysate ◽  
Binding Capacity ◽  
Amino Acid Content ◽  
Chelating Agent ◽  
Essential Amino Acids ◽  
Total Amino Acid ◽  
Copper Binding ◽  
Shrimp Head

The aim of this study is to obtain the copper-binding protein hydrolysate from the white leg shrimp head (WLSH) by-product using enzymatic hydrolysis. The outcome indicated that the copper-binding capacity (CBC) of the WLSH protein hydrolysate achieved the maximum value of 19.4±0.5 mg Cu2+/g protein with hydrolysis conditions including Flavourzyme preparation, pH 7.5, 50°C, the enzyme:substrate (E:S) ratio of 80 U/g protein and 5h of hydrolysis. Under the pH treatment in a range of 1-11 or heat treatment at 100°C for up to 180 min, its CBC remained over 80%. The water holding capacity (WHC) and the oil-holding capacity (OHC) of the protein hydrolysate were 4.1±0.1 ml water/g protein hydrolysate powder and 4.5±0.1 ml oil/g protein hydrolysate powder, respectively. The solution also encompassed up to 8 essential amino acids, accounting for 36.1% of the total amino acid content. The protein hydrolysate could serve not only as a copper chelating agent, preventing copper-deficient or superfluous relating diseases, but also as a texturizer and an amino acid supplement fortified in various types of food.

scholarly journals Appearance of the imprinting effect on the specific pattern of intracellular distribution of copper ions in the liver after exposure to high concentrations of copper sulfate

2010 ◽  
Vol 56 (2) ◽  
pp. 195-208 ◽  
Author(s):  
A.I. Bozhkov ◽  
V.I. Sidorov ◽  
V.L. Dlubovskaya ◽  
M.Ya. Shevtsova ◽  
Yu.N. Surov
Keyword(s):  
Rat Liver ◽  
Copper Sulfate ◽  
Liver Cell ◽  
Copper Ions ◽  
Specific Pattern ◽  
Intracellular Distribution ◽  
The Body ◽  
Copper Binding ◽  
Copper Binding Protein ◽  
High Concentrations

Fractions of copper-binding protein (CBP) specifically bound copper ions were extracted from the rat liver cell cytosole. These fractions of 10-14 kDa proteins are involved in specific pattern of intracellular distribution of copper ions. The imprinting effect of specific pattern of copper ions intracellular distribution has been found. The effect was detected 30 days after sequented injections of copper sulfate into the body. It was shown, that after primary injection of copper the ability of CBP to bind copper ions could increase tenfold, regardless of schemes of copper sulfate injection.

scholarly journals Effects of Copper Chelation on BRAFV600E Positive Colon Carcinoma Cells

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 659 ◽  
Author(s):  
Silvia Baldari ◽  
Giuliana Di Rocco ◽  
Marie C. Heffern ◽  
Timothy A. Su ◽  
Christopher J. Chang ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Protein Kinase ◽  
Chelating Agent ◽  
Mitogen Activated Protein Kinase ◽  
Copper Binding ◽  
Brafv600e Mutation ◽  
Copper Chelation ◽  
Specific Subset

High affinity copper binding to mitogen-activated protein kinase kinase 1 (MAP2K1, also known as MEK1) allosterically promotes the kinase activity of MEK1/2 on extracellular signal regulated kinases 1 and 2 (ERK1/2). Consequently, copper-dependent activation of the mitogen-activated (MAP) kinase pathway has a role in promoting tumor growth. Conversely, copper chelation may represent a possible therapeutic approach for a specific subset of tumors characterized by activating mutations in the serine/threonine protein kinase V-Raf Murine Sarcoma Viral Oncogene Homolog B1 (BRAF), such as the V600E, occurring within the kinase domain (BRAFV600E). Tetrathiomolybdate (TM) is a specific copper chelating agent currently used for the treatment of Wilson’s disease and in preclinical studies for the management of metastatic cancers owing to its anti-angiogenic and anti-inflammatory properties. We evaluated in vitro and in vivo the effects of copper depletion achieved by pharmacological treatment with TM in human colorectal cells bearing the BRAFV600E mutation in comparison with BRAF wild type cells. We provide evidence that selective copper chelation differentially affects proliferation, survival and migration of colon cancer cells bearing the BRAFV600E mutation compared to BRAFwt acting via differential phosphorylation levels of ERK1/2. Moreover, tetrathiomolybdate treatment was also effective in reducing the clonogenic potential of colon cancer BRAFV600E cells resistant to BRAF pharmacological inhibition. In conclusion, these results support further assessment of copper chelation therapy as an adjuvant therapy for inhibiting the progression of colon cancers containing the BRAFV600E mutation.

scholarly journals Prenatal Diagnosis of Thalassemia

2019 ◽  
Vol 33 (7-8) ◽  
pp. 191-9
Author(s):  
Sunarto Sunarto
Keyword(s):  
Prenatal Diagnosis ◽  
Dna Analysis ◽  
Genetic Disorder ◽  
Chorionic Villus ◽  
The Body ◽  
Chorionic Villi ◽  
Globin Chains ◽  
Globin Synthesis ◽  
Fetal Blood Sample

Thalassemia is an individual as well as a community health problem in some countries. It causes a lifelong suffering for the affected individuals. There is no treatment other than supportive, i.e. regular transfusions and removal of iron overload from the body. Only by such continuous and expensive treatment thalassemic patients can-generally achieve nearly normal health, but the health burden of such therapy for a large number of thalassemic patients is unaffordable by the affected communities. Prevention of the births of thalassemic babies is the choice for controlling the thalassemia and has been successful in many countries. For this purpose reliable and time accurate prenatal diagnosis is a conditio sine qua non. Blood fetal sampling is safe and can be done after 16 weeks gestation, amniocentesis after 14 weeks, and even chorionic villi sampling as early as 8 weeks gestation. In vitro globin synthesis analysis applied to the fetal blood sample is very reliable to measure the rate of synthesis of the globin chains that make up the hemoglobin. The-DNA analysis of the fibroblasts obtained by amniocentesis or of the chorionic villus sample is very sensitive and specific for the diagnosis of the genetic disorder in thalassemias. By involving the prenatal diagnosis, the birth of B-homozygous thalassemia has decreased by up to 90%.

scholarly journals Retina-Targeted Delivery of 17β-Estradiol by the Topically Applied DHED Prodrug

Pharmaceutics ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 456
Author(s):  
Katalin Prokai-Tatrai ◽  
Vien Nguyen ◽  
Daniel L. De La Cruz ◽  
Rebecca Guerra ◽  
Khadiza Zaman ◽  
...  
Keyword(s):  
Targeted Delivery ◽  
Ex Vivo ◽  
Estrogen Therapy ◽  
Topical Administration ◽  
The Body ◽  
Female Rats ◽  
Full Potential ◽  
Eye Drops ◽  
17Β Estradiol

The purpose of this study was to explore retina-targeted delivery of 17β-estradiol (E2), a powerful neuroprotectant, by its bioprecursor prodrug 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED) administered as eye drops in animal models. Compared to the parent hormone, DHED displayed increased transcorneal flux ex vivo both with and without the presence of 2-hydroxypropyl-β-cyclodextrin used as a penetration-enhancing excipient in rat, rabbit, and pig. In vitro, the prodrug also showed facile bioactivation to E2 in the retina but not in the cornea. After topical administration to rats and rabbits, peak DHED-derived E2 concentrations reached 13 ± 5 ng/g and 18 ± 7 ng/g in the retina of female rats and rabbits, respectively. However, the prodrug remained inert in the rest of the body and, therefore, did not cause increase in circulating hormone concentration, as well as wet uterine and anterior pituitary weights as typical markers of E2′s endocrine impact. Altogether, our studies presented here have demonstrated the premise of topical retina-selective estrogen therapy by the DHED prodrug approach for the first time and provide compelling support for further investigation into the full potential of DHED for an efficacious and safe ocular neurotherapy.

scholarly journals Multiple forms of copper (II) co-ordination occur throughout the disordered N-terminal region of the prion protein at pH 7.4

2006 ◽  
Vol 400 (3) ◽  
pp. 501-510 ◽  
Author(s):  
Mark A. Wells ◽  
Clare Jelinska ◽  
Laszlo L. P. Hosszu ◽  
C. Jeremy Craven ◽  
Anthony R. Clarke ◽  
...  
Keyword(s):  
Prion Protein ◽  
Tandem Repeats ◽  
Copper Ions ◽  
Equilibrium Dialysis ◽  
Terminal Region ◽  
Copper Binding ◽  
Binding Modes ◽  
Self Association

Although the physiological function of the prion protein remains unknown, in vitro experiments suggest that the protein may bind copper (II) ions and play a role in copper transport or homoeostasis in vivo. The unstructured N-terminal region of the prion protein has been shown to bind up to six copper (II) ions, with each of these ions co-ordinated by a single histidine imidazole and nearby backbone amide nitrogen atoms. Individually, these sites have micromolar affinities, which is weaker than would be expected of a true cuproprotein. In the present study, we show that with subsaturating levels of copper, different forms of co-ordination will occur, which have higher affinity. We have investigated the copper-binding properties of two peptides representing the known copper-binding regions of the prion protein: residues 57–91, which contains four tandem repeats of the octapeptide GGGWGQPH, and residues 91–115. Using equilibrium dialysis and spectroscopic methods, we unambiguously demonstrate that the mode of copper co-ordination in both of these peptides depends on the number of copper ions bound and that, at low copper occupancy, copper ions are co-ordinated with sub-micromolar affinity by multiple histidine imidazole groups. At pH 7.4, three different modes of copper co-ordination are accessible within the octapeptide repeats and two within the peptide comprising residues 91–115. The highest affinity copper (II)-binding modes cause self-association of both peptides, suggesting a role for copper (II) in controlling prion protein self-association in vivo.

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