-
1.
Antibacterial Titanium Implants Biofunctionalized by Plasma Electrolytic Oxidation with Silver, Zinc, and Copper: A Systematic Review.
van Hengel, IAJ, Tierolf, MWAM, Fratila-Apachitei, LE, Apachitei, I, Zadpoor, AA
International journal of molecular sciences. 2021;(7)
Abstract
Patients receiving orthopedic implants are at risk of implant-associated infections (IAI). A growing number of antibiotic-resistant bacteria threaten to hamper the treatment of IAI. The focus has, therefore, shifted towards the development of implants with intrinsic antibacterial activity to prevent the occurrence of infection. The use of Ag, Cu, and Zn has gained momentum as these elements display strong antibacterial behavior and target a wide spectrum of bacteria. In order to incorporate these elements into the surface of titanium-based bone implants, plasma electrolytic oxidation (PEO) has been widely investigated as a single-step process that can biofunctionalize these (highly porous) implant surfaces. Here, we present a systematic review of the studies published between 2009 until 2020 on the biomaterial properties, antibacterial behavior, and biocompatibility of titanium implants biofunctionalized by PEO using Ag, Cu, and Zn. We observed that 100% of surfaces bearing Ag (Ag-surfaces), 93% of surfaces bearing Cu (Cu-surfaces), 73% of surfaces bearing Zn (Zn-surfaces), and 100% of surfaces combining Ag, Cu, and Zn resulted in a significant (i.e., >50%) reduction of bacterial load, while 13% of Ag-surfaces, 10% of Cu-surfaces, and none of Zn or combined Ag, Cu, and Zn surfaces reported cytotoxicity against osteoblasts, stem cells, and immune cells. A majority of the studies investigated the antibacterial activity against S. aureus. Important areas for future research include the biofunctionalization of additively manufactured porous implants and surfaces combining Ag, Cu, and Zn. Furthermore, the antibacterial activity of such implants should be determined in assays focused on prevention, rather than the treatment of IAIs. These implants should be tested using appropriate in vivo bone infection models capable of assessing whether titanium implants biofunctionalized by PEO with Ag, Cu, and Zn can contribute to protect patients against IAI.
-
2.
Transferrin Coated d-penicillamine-Au-Cu Nanocluster PLGA Nanocomposite Reverses Hypoxia-Induced EMT and MDR of Triple-Negative Breast Cancers.
Shome, R, Ghosh, SS
ACS applied bio materials. 2021;(6):5033-5048
Abstract
Triple-negative breast cancer (TNBC), the most aggressive subtype of breast cancer, lacks effective targeted therapies due to negative expression of the targetable bioreceptors. Additionally, hypoxic condition in solid tumors contributes to the epithelial to mesenchymal transition (EMT), which aggravates cancer progression, multidrug resistance (MDR), migration, and stemness of the TNBC. A therapeutic module has been established in this regard by coating PLGA nanoparticle with d-penicillamine templated Au-Cu bimetallic nanoclusters. Further, the resultant nanomaterials were coated with recombinant transferrin protein to specifically target transferrin receptor overexpressing TNBC. The synthesized nanocomposites showed strong orange emission band at 630 nm with fluorescence quantum yield of 2%, rendering it suitable for theranostic applications. Experimental results demonstrated efficient cellular internalization and significant innate anti-cell proliferative potential of the nanocomposites. The fabricated nanocomposites were also able to induce cell death in spheroids, which was confirmed by live/dead dual staining results. Furthermore, when EMT-induced TNBC cells were treated with nanocomposites, they generated reactive oxygen species (ROS), depolarized the mitochondrial membrane potential, and induced apoptosis. Gene expression by real-time PCR indicated that treatment of EMT-induced TNBC cells with nanocomposites facilitated mesenchymal to epithelial transition (MET). In MDA-MB-468 cells, treatment with nanocomposites resulted in a 1.35-fold rise in E-cadherin an epithelial marker and a 1.36-fold decrease in vimentin a mesenchymal marker. Similarly, 2.87-fold and 1.76-fold decrease in stemness markers ALDH1A3 and EpCAM were observed in MDA-MB-231. Furthermore, 4.63-fold decrease in expression of ABCC1, a prominent contributor of MDR, was observed in MDA-MB-231. Protein expression studies revealed that nanocomposites reduced p-STAT-3 by 1.61-fold in MDA-MB-231 and by 7.8-fold in MDA-MB-468. Importantly, nanocomposites downregulated the expression of β-catenin by 3-fold in MDA-MB-231 and by 3.11-fold in MDA-MB-468. Downregulation of EMT with concomitant alteration of STAT-3 and β-catenin signaling pathways led to reduced migration ability of the TNBC cells.
-
3.
Synthesis and Structure of Novel Copper(II) Complexes with N,O- or N,N-Donors as Radical Scavengers and a Functional Model of the Active Sites in Metalloenzymes.
Masternak, J, Zienkiewicz-Machnik, M, Łakomska, I, Hodorowicz, M, Kazimierczuk, K, Nosek, M, Majkowska-Młynarczyk, A, Wietrzyk, J, Barszcz, B
International journal of molecular sciences. 2021;(14)
Abstract
To evaluate the antioxidant activity of potential synthetic enzyme mimetics, we prepared new five copper(II) complexes via a self-assembly method and named them [Cu(2-(HOCH2)py)3](ClO4)2 (1), [Cu(2-(HOCH2)py)2(H2O)2]SiF6 (2), [Cu2(2-(HOCH2CH2)py)2(2-(OCH2CH2)py)2](ClO4)2 (3), [Cu(pyBIm)3](BF4)2·1.5H2O (4) and [Cu(py2C(OH)2)2](ClO4)2 (5). The synthetic protocol involved N,O- or N,N-donors: 2-(hydroxymethyl)pyridine (2-(HOCH2)py), 2-(hydroxyethyl)pyridine (2-(HOCH2CH2)py), 2-(2-pyridyl)benzimidazole (pyBIm), di(2-pyridyl)ketone (py2CO). The obtained Cu(II) complexes were fully characterised by elemental analysis, FTIR, EPR, UV-Vis, single-crystal X-ray diffraction and Hirshfeld surface analysis. Crystallographic and spectroscopic analyses confirmed chromophores of both monomeric ({CuN3O3} (1), {CuN2O4} (2), {CuN6} (4), {CuN4O2} (5)) and dimeric complex ({CuN2O3} (3)). Most of the obtained species possessed a distorted octahedral environment, except dimer 3, which consisted of two copper centres with square pyramidal geometries. The water-soluble compounds (1, 3 and 5) were selected for biological testing. The results of the study revealed that complex 1 in solutions displayed better radical scavenging activity than complexes 3, 5 and free ligands. Therefore, complex 1 has been selected for further studies to test its activity as an enzyme mimetic. The chosen compound was tested on the erythrocyte lysate of two groups of patients after undergoing chemotherapy and chemoradiotherapy. The effect of the tested compound (1) on enzyme activity levels (TAS, SOD and CAT) suggests that the selected complex can be treated as a functional mimetic of the enzymes.
-
4.
Calculations for the nuclear reaction cross-sections via α-particle induced reactions on 65Cu to produce impurity free 67Ga for medical applications.
Aslam, MT, Hussain, M
Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine. 2021;:109678
Abstract
Diagnostics field is facilitated with advancements enacted in anatomic imaging (cross-sectional modalities). Radionuclide scans (imaging) escorted by 67Ga are extensively beneficial in bone scintigraphy and recognition of prosthetic joint failure. Present work comprises the data concerning 67Ga production via α-particle induced nuclear reactions, TTY (thick target yield) and impurity analysis. Experimental measurements regarding 67Ga production are analyzed through a comparative study performed with calculations of theoretical model codes (TALYS-1.95, EMPIRE-3.2.3 and ALICE-IPPE). A data set of recommended cross-sections was generated and utilized to deduce TTY. The contribution of radionuclidic impurities is canvassed to suggest an energy region to produce impurity free 67Ga for medical applications.
-
5.
Electrochemically deposition of catechol-chitosan hydrogel coating on coronary stent with robust copper ions immobilization capability and improved interfacial biological activity.
Wang, B, Hua, J, You, R, Yan, K, Ma, L
International journal of biological macromolecules. 2021;:435-443
Abstract
Establishing a facile and versatile strategy to confer coronary stent with improved interfacial biological activity is crucial for novel cardiovascular implants. Developing a coating with NO release ability catalyzed by metal ions, such as copper, will be highly advantageous for the functionalized surface modification of metal stents. However, most available strategies involve drawbacks of low efficiency, complex processes, and toxic chemicals. Therefore, in this study, we report a green and facile electrobiofabrication method to construct the bioactive hydrogel coating by combining chitosan, catechol groups and copper ions on coronary stent and titanium surfaces. Experimental results demonstrated that the chitosan hydrogel coating can be precisely controlled synthesis via electrochemical deposition and serves as a versatile platform for copper ions immobilization. Additionally, mussel-inspired catechol groups could be chemically grafted on chitosan chains to further enhance the film mechanical properties and binding abilities of copper ions. Moreover, in vitro cell biocompatibility and catalyzed NO-generation activity have also been accessed and which suggesting great possibilities for biomedical applications. Therefore, by coupling the electrobiofabrication approach and multi-functionalities of the hybrid film, this report would advance the development of biomimetic hydrogel coating for vascular engineering (e.g., coronary stent) and other biomedical devices.
-
6.
Copper metabolism in Saccharomyces cerevisiae: an update.
Shi, H, Jiang, Y, Yang, Y, Peng, Y, Li, C
Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine. 2021;(1):3-14
Abstract
Copper is an essential element in all forms of life. It acts as a cofactor of some enzymes and is involved in forming proper protein conformations. However, excess copper ions in cells are detrimental as they can generate free radicals or disrupt protein structures. Therefore, all life forms have evolved conserved and exquisite copper metabolic systems to maintain copper homeostasis. The yeast Saccharomyces cerevisiae has been widely used to investigate copper metabolism as it is convenient for this purpose. In this review, we summarize the mechanism of copper metabolism in Saccharomyces cerevisiae according to the latest literature. In brief, bioavailable copper ions are incorporated into yeast cells mainly via the high-affinity transporters Ctr1 and Ctr3. Then, intracellular Cu+ ions are delivered to different organelles or cuproproteins by different chaperones, including Ccs1, Atx1, and Cox17. Excess copper ions bind to glutathione (GSH), metallothioneins, and copper complexes are sequestered into vacuoles to avoid toxicity. Copper-sensing transcription factors Ace1 and Mac1 regulate the expression of genes involved in copper detoxification and uptake/mobilization in response to changes in intracellular copper levels. Though numerous recent breakthroughs in understanding yeast's copper metabolism have been achieved, some issues remain unresolved. Completely elucidating the mechanism of copper metabolism in yeast helps decode the corresponding system in humans and understand how copper-related diseases develop.
-
7.
Metal ion homeostasis with emphasis on zinc and copper: Potential crucial link to explain the non-classical antioxidative properties of vitamin D and melatonin.
Martín Giménez, VM, Bergam, I, Reiter, RJ, Manucha, W
Life sciences. 2021;:119770
Abstract
Metal ion homeostasis is an essential physiological mechanism necessary for achieving an adequate balance of these ions' concentrations in the different cellular compartments. This fact is of great importance because both an excess and a deficiency of cellular metal ion levels are usually equally harmful due to the exacerbated increase in oxidative stress that may occur in both cases. Metal ion homeostasis ensures an equilibrium among multiple functions associated with the body's antioxidative defense network controlled by metallic micronutrients such as zinc and copper, some of the central regulators of redox processes. These micronutrients significantly modulate the activity of some isoforms of superoxide dismutase (SOD) and other enzymes such as metallothioneins (MTs) and ceruloplasmin (CP), which are directly or indirectly involved in the regulation of redox homeostasis. Although it is well known that both melatonin (MEL) and vitamin D have important roles as natural antioxidants, often some of these effects are related to their actions on antioxidative processes dependent on metal ions. Thus, in addition to their classical antioxidative properties usually associated with mitochondrial effects, it is known that MEL and vitamin D modulate the expression and activity of Cu/Zn-dependent SOD isoforms, MTs and CP; function as copper chelators and regulate genomic and non-genomic mechanisms related to the zinc transport. This review summarizes the main findings related to the crucial participation of zinc and copper in physiological antioxidative status and their relationship with the non-classical antioxidant effects of MEL and vitamin D, suggesting a potential synergism among these four micronutrients.
-
8.
Plant-Based Biosynthesis of Copper/Copper Oxide Nanoparticles: An Update on Their Applications in Biomedicine, Mechanisms, and Toxicity.
Letchumanan, D, Sok, SPM, Ibrahim, S, Nagoor, NH, Arshad, NM
Biomolecules. 2021;(4)
Abstract
Plants are rich in phytoconstituent biomolecules that served as a good source of medicine. More recently, they have been employed in synthesizing metal/metal oxide nanoparticles (NPs) due to their capping and reducing properties. This green synthesis approach is environmentally friendly and allows the production of the desired NPs in different sizes and shapes by manipulating parameters during the synthesis process. The most commonly used metals and oxides are gold (Au), silver (Ag), and copper (Cu). Among these, Cu is a relatively low-cost metal that is more cost-effective than Au and Ag. In this review, we present an overview and current update of plant-mediated Cu/copper oxide (CuO) NPs, including their synthesis, medicinal applications, and mechanisms. Furthermore, the toxic effects of these NPs and their efficacy compared to commercial NPs are reviewed. This review provides an insight into the potential of developing plant-based Cu/CuO NPs as a therapeutic agent for various diseases in the future.
-
9.
Enhancement of Nitrous Oxide Emissions in Soil Microbial Consortia via Copper Competition between Proteobacterial Methanotrophs and Denitrifiers.
Chang, J, Kim, DD, Semrau, JD, Lee, JY, Heo, H, Gu, W, Yoon, S
Applied and environmental microbiology. 2021;(5):e0230120
-
-
Free full text
-
Abstract
Unique means of copper scavenging have been identified in proteobacterial methanotrophs, particularly the use of methanobactin, a novel ribosomally synthesized, post-translationally modified polypeptide that binds copper with very high affinity. The possibility that copper sequestration strategies of methanotrophs may interfere with copper uptake of denitrifiers in situ and thereby enhance N2O emissions was examined using a suite of laboratory experiments performed with rice paddy microbial consortia. Addition of purified methanobactin from Methylosinus trichosporium OB3b to denitrifying rice paddy soil microbial consortia resulted in substantially increased N2O production, with more pronounced responses observed for soils with lower copper content. The N2O emission-enhancing effect of the soil's native mbnA-expressing Methylocystaceae methanotrophs on the native denitrifiers was then experimentally verified with a Methylocystaceae-dominant chemostat culture prepared from a rice paddy microbial consortium as the inoculum. Finally, with microcosms amended with various cell numbers of methanobactin-producing Methylosinus trichosporium OB3b before CH4 enrichment, microbiomes with different ratios of methanobactin-producing Methylocystaceae to gammaproteobacterial methanotrophs incapable of methanobactin production were simulated. Significant enhancement of N2O production from denitrification was evident in both Methylocystaceae-dominant and Methylococcaceae-dominant enrichments, albeit to a greater extent in the former, signifying the comparative potency of methanobactin-mediated copper sequestration, while implying the presence of alternative copper abstraction mechanisms for Methylococcaceae. These observations support that copper-mediated methanotrophic enhancement of N2O production from denitrification is plausible where methanotrophs and denitrifiers cohabit. IMPORTANCE Proteobacterial methanotrophs-groups of microorganisms that utilize methane as a source of energy and carbon-have been known to employ unique mechanisms to scavenge copper, namely, utilization of methanobactin, a polypeptide that binds copper with high affinity and specificity. Previously the possibility that copper sequestration by methanotrophs may lead to alteration of cuproenzyme-mediated reactions in denitrifiers and consequently increase emission of potent greenhouse gas N2O has been suggested in axenic and coculture experiments. Here, a suite of experiments with rice paddy soil slurry cultures with complex microbial compositions were performed to corroborate that such copper-mediated interplay may actually take place in environments cohabited by diverse methanotrophs and denitrifiers. As spatial and temporal heterogeneity allows for spatial coexistence of methanotrophy (aerobic) and denitrification (anaerobic) in soils, the results from this study suggest that this previously unidentified mechanism of N2O production may account for a significant proportion of N2O efflux from agricultural soils.
-
10.
Copper (Cu2+) ion-induced misfolding of tau protein R3 peptide revealed by enhanced molecular dynamics simulation.
Jing, J, Tu, G, Yu, H, Huang, R, Ming, X, Zhan, H, Zhan, F, Xue, W
Physical chemistry chemical physics : PCCP. 2021;(20):11717-11726
Abstract
Tau misfolding plays a significant role in some neurodegenerative diseases such as Alzheimer's disease (AD). It is intrinsically disordered and highly soluble under normal physiological conditions. While the protein will aggregate to form paired helical filaments (PHFs) under copper homeostasis at pathological conditions, which is the main substance of neurofibrillary tangles (NFTs) in the brain of AD patients. However, the molecular mechanism underlying the copper (Cu2+) ion-induced tau misfolding is not fully understood. In this study, using the 1/2 third repeat fragment (R3 peptide) of tau protein (residues 318-335: VTSKCGSLGNIHHKPGGG) as a model, a Gaussian accelerated molecular dynamics (GaMD) method followed by efficient trajectory analysis was carried out to investigate the influences of Cu2+ on the tau about the protein fold and the free energy landscape along the simulation. The two-dimensional potential of mean force (PMF) profiles obtained from reweighting of the GaMD simulations as well as clustering analysis revealed the Cu2+ ion induced α-helix fold R3 peptide located at the low-energy wells of free energy map, which is in agreement with the reported experimental result. In contrast, there is no α-helix fold of R3 peptide that appeared during the GaMD simulation without Cu2+ ion existing. Furthermore, the definition of secondary structure of protein (DSSP) analysis indicated that the R3 peptide with Cu2+ ion forms a stable structure of the helix (Lys321-His330 interval of the peptide) at between 400 and 500 ns. Therefore, the structures and free energy profiles from GaMD simulations proposed that Cu2+ triggers the aggregation of R3 peptide into toxic PHFs through a stable α-helix fold form.