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1.
Wilson disease.
Aggarwal, A, Bhatt, M
Current opinion in neurology. 2020;(4):534-542
Abstract
PURPOSE OF REVIEW The aim of this article is to review recent developments in the areas of the disease features and treatment of Wilson disease, and survey disorders that share its pathophysiology or clinical symptoms. RECENT FINDINGS Knowledge of the clinical spectrum of Wilson disease has expanded with recognition of patients who present in atypical age groups - patients with very early onset (<5 years) and those in whom symptoms present in mid-to-late adulthood. A disease phenotype with dominant psychiatric features and increased risk of cardiac problems and various sleep disorders have been identified.In addition to a better understanding of the phenotype of Wilson disease itself, features of some related disorders ('Wilson disease-mimics') have been described leading to a better understanding of copper homeostasis in humans. These disorders include diseases of copper disposition, such as mental retardation, enteropathy, deafness, neuropathy, ichthyosis, keratoderma syndrome, Niemann-Pick type C, and certain congenital disorders of glycosylation, as well as analogous disorders of iron and manganese metabolism.Outcomes for existing treatments, including in certain patient subpopulations of interest, are better known. Novel treatment strategies being studied include testing of bis-choline tetrathiomolybdate in phase 2 clinical trial as well as various preclinical explorations of new copper chelators and ways to restore ATP7B function or repair the causative gene. SUMMARY Recent studies have expanded the phenotype of Wilson disease, identified rare inherited metal-related disorders that resemble Wilson disease, and studied long-term outcomes of existing treatments. These developments can be expected to have an immediate as well as a long-term impact on the clinical management of the disease, and point to promising avenues for future research.
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2.
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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From coins to cancer therapy: Gold, silver and copper complexes targeting human topoisomerases.
Ceramella, J, Mariconda, A, Iacopetta, D, Saturnino, C, Barbarossa, A, Caruso, A, Rosano, C, Sinicropi, MS, Longo, P
Bioorganic & medicinal chemistry letters. 2020;(3):126905
Abstract
Cancer is a complex issue and, even though the prevention basics and therapy have been implemented, it is still the second leading death cause worldwide. With the hope to discover new powerful and safer molecules to fight cancer, many researchers focused their attention on metal-based compounds, starting from the most famous and successfully employed anticancer drug, i.e. cisplatin. The current article aims to report the most recent discoveries about the use of gold, silver and copper complexes as antitumor agents, highlighting their influences on important enzymes, namely human topoisomerases. The latter are fundamental for the cell life and, if overexpressed, strongly implicated in cancer onset and progression. The identification of lead complexes targeting human topoisomerases and gifted with the appropriate chemical and pharmacological properties represents a fecund starting point to obtain new and more effective anticancer molecules.
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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.
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The Role of Fe, Zn, and Cu in Pregnancy.
Grzeszczak, K, Kwiatkowski, S, Kosik-Bogacka, D
Biomolecules. 2020;(8)
Abstract
Iron (Fe), copper (Cu), and zinc (Zn) are microelements essential for the proper functioning of living organisms. These elements participatein many processes, including cellular metabolism and antioxidant and anti-inflammatory defenses, and also influence enzyme activity, regulate gene expression, and take part in protein synthesis. Fe, Cu, and Zn have a significant impact on the health of pregnant women and in the development of the fetus, as well as on the health of the newborn. A proper concentration of these elements in the body of women during pregnancy reduces the risk of complications such as anemia, induced hypertension, low birth weight, preeclampsia, and postnatal complications. The interactions between Fe, Cu, and Zn influence their availability due to their similar physicochemical properties. This most often occurs during intestinal absorption, where metal ions compete for binding sites with transport compounds. Additionally, the relationships between these ions have a great influence on the course of reactions in the tissues, as well as on their excretion, which can be stimulated or delayed. This review aims to summarize reports on the influence of Fe, Cu, and Zn on the course of single and multiple pregnancies, and to discuss the interdependencies and mechanisms occurring between Fe, Cu, and Zn.
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The use of copper to help prevent transmission of SARS-coronavirus and influenza viruses. A general review.
Cortes, AA, Zuñiga, JM
Diagnostic microbiology and infectious disease. 2020;(4):115176
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Abstract
The SARS-CoV-2 is the causative agent of the COVID-19 disease, a severe acute respiratory syndrome-coronavirus (SARS-CoV). Its main transmission pathway is through large respiratory droplets, as well as direct and indirect contact. Copper in different formats has been used in research and clinical settings to reduce the risk of bacterial and viral contamination. Therefore, this review aims to search for evidence about the biocidal properties of copper over the Coronaviridae family. A literature review was performed using PubMed and Ovid servers without date or language restrictions. The search was carried out on March 7, 2020, using the following search terms: [Copper] Coronavirus OR CoV OR SARS OR MERS OR Influenza. Copper destroys the replication and propagation abilities of SARS-CoV, influenza, and other respiratory viruses, having high potential disinfection in hospitals, communities, and households. Copper can eliminate pathogenic organisms such as coronavirus bacterial strains, influenza virus, HIV, and fungi after a short period of exposure. Copper seems to be an effective and low-cost complementary strategy to help reduce the transmission of several infectious diseases by limiting nosocomial infectious transmission. Copper oxide or nanocompounds may be used as filters, face masks, clothing, and hospital common surfaces to reduce viruses and bacterial incubation.
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Antitumor Activity of Pt(II), Ru(III) and Cu(II) Complexes.
Gałczyńska, K, Drulis-Kawa, Z, Arabski, M
Molecules (Basel, Switzerland). 2020;(15)
Abstract
Metal complexes are currently potential therapeutic compounds. The acquisition of resistance by cancer cells or the effective elimination of cancer-affected cells necessitates a constant search for chemical compounds with specific biological activities. One alternative option is the transition metal complexes having potential as antitumor agents. Here, we present the current knowledge about the application of transition metal complexes bearing nickel(II), cobalt(II), copper(II), ruthenium(III), and ruthenium(IV). The cytotoxic properties of the above complexes causing apoptosis, autophagy, DNA damage, and cell cycle inhibition are described in this review.