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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.
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Copper(II) Phenanthroline-Based Complexes as Potential AntiCancer Drugs: A Walkthrough on the Mechanisms of Action.
Masuri, S, Vaňhara, P, Cabiddu, MG, Moráň, L, Havel, J, Cadoni, E, Pivetta, T
Molecules (Basel, Switzerland). 2021;(1)
Abstract
Copper is an endogenous metal ion that has been studied to prepare a new antitumoral agent with less side-effects. Copper is involved as a cofactor in several enzymes, in ROS production, in the promotion of tumor progression, metastasis, and angiogenesis, and has been found at high levels in serum and tissues of several types of human cancers. Under these circumstances, two strategies are commonly followed in the development of novel anticancer Copper-based drugs: the sequestration of free Copper ions and the synthesis of Copper complexes that trigger cell death. The latter strategy has been followed in the last 40 years and many reviews have covered the anticancer properties of a broad spectrum of Copper complexes, showing that the activity of these compounds is often multi factored. In this work, we would like to focus on the anticancer properties of mixed Cu(II) complexes bearing substituted or unsubstituted 1,10-phenanthroline based ligands and different classes of inorganic and organic auxiliary ligands. For each metal complex, information regarding the tested cell lines and the mechanistic studies will be reported and discussed. The exerted action mechanisms were presented according to the auxiliary ligand/s, the metallic centers, and the increasing complexity of the compound structures.
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3.
Copper, Iron, and Manganese Toxicity in Neuropsychiatric Conditions.
Tarnacka, B, Jopowicz, A, Maślińska, M
International journal of molecular sciences. 2021;(15)
Abstract
Copper, manganese, and iron are vital elements required for the appropriate development and the general preservation of good health. Additionally, these essential metals play key roles in ensuring proper brain development and function. They also play vital roles in the central nervous system as significant cofactors for several enzymes, including the antioxidant enzyme superoxide dismutase (SOD) and other enzymes that take part in the creation and breakdown of neurotransmitters in the brain. An imbalance in the levels of these metals weakens the structural, regulatory, and catalytic roles of different enzymes, proteins, receptors, and transporters and is known to provoke the development of various neurological conditions through different mechanisms, such as via induction of oxidative stress, increased α-synuclein aggregation and fibril formation, and stimulation of microglial cells, thus resulting in inflammation and reduced production of metalloproteins. In the present review, the authors focus on neurological disorders with psychiatric signs associated with copper, iron, and manganese excess and the diagnosis and potential treatment of such disorders. In our review, we described diseases related to these metals, such as aceruloplasminaemia, neuroferritinopathy, pantothenate kinase-associated neurodegeneration (PKAN) and other very rare classical NBIA forms, manganism, attention-deficit/hyperactivity disorder (ADHD), ephedrone encephalopathy, HMNDYT1-SLC30A10 deficiency (HMNDYT1), HMNDYT2-SLC39A14 deficiency, CDG2N-SLC39A8 deficiency, hepatic encephalopathy, prion disease and "prion-like disease", amyotrophic lateral sclerosis, Huntington's disease, Friedreich's ataxia, and depression.
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4.
Potential molecular mechanisms of zinc- and copper-mediated antiviral activity on COVID-19.
Rani, I, Goyal, A, Bhatnagar, M, Manhas, S, Goel, P, Pal, A, Prasad, R
Nutrition research (New York, N.Y.). 2021;:109-128
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Abstract
Novel coronavirus disease 2019 (COVID-19) has spread across the globe; and surprisingly, no potentially protective or therapeutic antiviral molecules are available to treat severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. However, zinc (Zn) and copper (Cu) have been shown to exert protective effects due to their antioxidant, anti-inflammatory, and antiviral properties. Therefore, it is hypothesized that supplementation with Zn and Cu alone or as an adjuvant may be beneficial with promising efficacy and a favorable safety profile to mitigate symptoms, as well as halt progression of the severe form of SARS-CoV-2 infection. The objective of this review is to discuss the proposed underlying molecular mechanisms and their implications for combating SARS-CoV-2 infection in response to Zn and Cu administration. Several clinical trials have also included the use of Zn as an adjuvant therapy with dietary regimens/antiviral drugs against COVID-19 infection. Overall, this review summarizes that nutritional intervention with Zn and Cu may offer an alternative treatment strategy by eliciting their virucidal effects through several fundamental molecular cascades, such as, modulation of immune responses, redox signaling, autophagy, and obstruction of viral entry and genome replication during SARS-CoV-2 infection.
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5.
Getting out what you put in: Copper in mitochondria and its impacts on human disease.
Cobine, PA, Moore, SA, Leary, SC
Biochimica et biophysica acta. Molecular cell research. 2021;(1):118867
Abstract
Mitochondria accumulate copper in their matrix for the eventual maturation of the cuproenzymes cytochrome c oxidase and superoxide dismutase. Transport into the matrix is achieved by mitochondrial carrier family (MCF) proteins. The major copper transporting MCF described to date in yeast is Pic2, which imports the metal ion into the matrix. Pic2 is one of ~30 MCFs that move numerous metabolites, nucleotides and co-factors across the inner membrane for use in the matrix. Genetic and biochemical experiments showed that Pic2 is required for cytochrome c oxidase activity under copper stress, and that it is capable of transporting ionic and complexed forms of copper. The Pic2 ortholog SLC25A3, one of 53 mammalian MCFs, functions as both a copper and a phosphate transporter. Depletion of SLC25A3 results in decreased accumulation of copper in the matrix, a cytochrome c oxidase defect and a modulation of cytosolic superoxide dismutase abundance. The regulatory roles for copper and cuproproteins resident to the mitochondrion continue to expand beyond the organelle. Mitochondrial copper chaperones have been linked to the modulation of cellular copper uptake and export and the facilitation of inter-organ communication. Recently, a role for matrix copper has also been proposed in a novel cell death pathway termed cuproptosis. This review will detail our understanding of the maturation of mitochondrial copper enzymes, the roles of mitochondrial signals in regulating cellular copper content, the proposed mechanisms of copper transport into the organelle and explore the evolutionary origins of copper homeostasis pathways.
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New insights into copper homeostasis in filamentous fungi.
Antsotegi-Uskola, M, Markina-Iñarrairaegui, A, Ugalde, U
International microbiology : the official journal of the Spanish Society for Microbiology. 2020;(1):65-73
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Abstract
Copper is a metal ion that is required as a micronutrient for growth and proliferation. However, copper accumulation generates toxicity by multiple mechanisms, potentially leading to cell death. Due to its toxic nature at high concentrations, different chemical variants of copper have been extensively used as antifungal agents in agriculture and medicine. Most studies on copper homeostasis have been carried out in bacteria, yeast, and mammalian organisms. However, knowledge on filamentous fungi is less well documented. This review summarizes the knowledge gathered in the last few years about copper homeostasis in the filamentous fungi Aspergillus fumigatus and Aspergillus nidulans: The mechanism of action of copper, the uptake and detoxification systems, their regulation at the transcriptional level, and the role of copper homeostasis in fungal pathogenicity are presented.
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Zinc Therapy in Early Alzheimer's Disease: Safety and Potential Therapeutic Efficacy.
Squitti, R, Pal, A, Picozza, M, Avan, A, Ventriglia, M, Rongioletti, MC, Hoogenraad, T
Biomolecules. 2020;(8)
Abstract
Zinc therapy is normally utilized for treatment of Wilson disease (WD), an inherited condition that is characterized by increased levels of non-ceruloplasmin bound ('free') copper in serum and urine. A subset of patients with Alzheimer's disease (AD) or its prodromal form, known as Mild Cognitive Impairment (MCI), fail to maintain a normal copper metabolic balance and exhibit higher than normal values of non-ceruloplasmin copper. Zinc's action mechanism involves the induction of intestinal cell metallothionein, which blocks copper absorption from the intestinal tract, thus restoring physiological levels of non-ceruloplasmin copper in the body. On this basis, it is employed in WD. Zinc therapy has shown potential beneficial effects in preliminary AD clinical trials, even though the studies have missed their primary endpoints, since they have study design and other important weaknesses. Nevertheless, in the studied AD patients, zinc effectively decreased non-ceruloplasmin copper levels and showed potential for improved cognitive performances with no major side effects. This review discusses zinc therapy safety and the potential therapeutic effects that might be expected on a subset of individuals showing both cognitive complaints and signs of copper imbalance.
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From economy to luxury: Copper homeostasis in Chlamydomonas and other algae.
Merchant, SS, Schmollinger, S, Strenkert, D, Moseley, JL, Blaby-Haas, CE
Biochimica et biophysica acta. Molecular cell research. 2020;(11):118822
Abstract
Plastocyanin and cytochrome c6, abundant proteins in photosynthesis, are readouts for cellular copper status in Chlamydomonas and other algae. Their accumulation is controlled by a transcription factor copper response regulator (CRR1). The replacement of copper-containing plastocyanin with heme-containing cytochrome c6 spares copper and permits preferential copper (re)-allocation to cytochrome oxidase. Under copper-replete situations, the quota depends on abundance of various cuproproteins and is tightly regulated, except under zinc-deficiency where acidocalcisomes over-accumulate Cu(I). CRR1 has a transcriptional activation domain, a Zn-dependent DNA binding SBP-domain with a nuclear localization signal, and a C-terminal Cys-rich region that represses the zinc regulon. CRR1 activates >60 genes in Chlamydomonas through GTAC-containing CuREs; transcriptome differences are recapitulated in the proteome. The differentially-expressed genes encode assimilatory copper transporters of the CTR/SLC31 family including a novel soluble molecule, redox enzymes in the tetrapyrrole pathway that promote chlorophyll biosynthesis and photosystem 1 accumulation, and other oxygen-dependent enzymes, which may influence thylakoid membrane lipids, specifically polyunsaturated galactolipids and γ-tocopherol. CRR1 also down-regulates 2 proteins in Chlamydomonas: for plastocyanin, by activation of proteolysis, while for the di‑iron subunit of the cyclase in chlorophyll biosynthesis, through activation of an upstream promoter that generates a poorly-translated 5' extended transcript containing multiple short ORFs that inhibit translation. The functions of many CRR1-target genes are unknown, and the copper protein inventory in Chlamydomonas includes several whose functions are unexplored. The comprehensive picture of cuproproteins and copper homeostasis in this system is well-suited for reverse genetic analyses of these under-investigated components in copper biology.
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Nucleophilic Synthesis of 6-l-[18F]FDOPA. Is Copper-Mediated Radiofluorination the Answer?
Krasikova, RN
Molecules (Basel, Switzerland). 2020;(19)
Abstract
Positron emission tomography employing 6-l-[18F]fluoro-3,4-dihydroxyphenylalanine (6-l-[18F]FDOPA) is currently a highly relevant clinical tool for detection of gliomas, neuroendocrine tumors and evaluation of Parkinson's disease progression. Yet, the deficiencies of electrophilic synthesis of 6-l-[18F]FDOPA hold back its wider use. To fulfill growing clinical demands for this radiotracer, novel synthetic strategies via direct nucleophilic 18F-radiloabeling starting from multi-Curie amounts of [18F]fluoride, have been recently introduced. In particular, Cu-mediated radiofluorination of arylpinacol boronates and arylstannanes show significant promise for introduction into clinical practice. In this short review these current developments will be discussed with a focus on their applicability to automation.
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Low copper-2 intake in Switzerland does not result in lower incidence of Alzheimer's disease and contradicts the Copper-2 Hypothesis.
Solioz, M
Experimental biology and medicine (Maywood, N.J.). 2020;(3):177-179
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Abstract
UNLABELLED In recent years, the “Copper-2 Hypothesis” has been put forth in an attempt to explain the epidemic of Alzheimer’s disease (AD) in the Western world. According to this hypothesis, “free” copper (copper-2) in drinking water, dietary supplements, and meat is the chief cause of the increased incidence of AD in recent decades. In contrast to the US, copper plumbing for drinking water is not used in Switzerland and tap water is very low in copper. Other “risk” factors including dietary supplements and meat consumption are also lower in Switzerland than in the US. Yet, the incidence of AD is closely similar in the two countries. This contradicts the Copper-2 Hypothesis. IMPACT STATEMENT The Western world is faced with an Alzheimer’s epidemic. Identifying the life style and anthropogenic factors involved has become a priority. This is a formidable challenge due to the complexity and the slow progression of the disease. A hypothesis put forth by George Brewer postulates divalent copper (copper-2), chiefly present in drinking water from copper pipes, to be a major risk factor for Alzheimer’s disease. In Switzerland, copper pipes are not used for drinking water, but the frequency of Alzheimer’s disease is similar to that of other Western countries. This contradicts Brewer’s hypothesis and suggests that other factors are responsible for today’s Alzheimer’s epidemic.