Search Results (20)

RNA editing is a significant mechanism underlying genetic variation and protein molecule alteration; C-to-U RNA editing, specifically, is important in the regulation of mammalian genetic diversity. The ability to define and limit accesses of enzymatic machinery to avoid the modification of unintended targets is key to the success of RNA editing. Identification of the core component of the apoB RNA editing holoenzyme, APOBEC, and investigation into new candidate genes encoding other elements of the complex could reveal further details regarding APOBEC-mediated mRNA editing. Menkes disease is a recessive X-chromosome-linked hereditary syndrome in humans, caused by defective copper metabolism due to mutations in the ATP7A gene, which encodes a copper transport protein. Here, we generated plasmids encoding the MS2 system and the APOBEC1 deaminase domain and used a guide RNA with flanking MS2 sites to restore mutated Atp7a in fibroblasts from a macular mouse model of Menkes disease withs T>C mutation. Around 35% of the mutated C nucleotide (nt) was restored to U, demonstrating that our RNA editing system is reliable and has potential for therapeutic clinical application. RNA base editing via human RNA-guided cytidine deaminases is a potentially attractive approach for in vivo therapeutic application and provides opportunities for new developments in this field. Full article

Minerals constitute only 5% of the typical human diet but are vital for health and functionality. Copper, a trace element, is absorbed by the human gut at 30–40% from diets typical of industrialized countries. The liver produces metallothioneins, which store copper. Copper is crucial for mitochondrial respiration, pigmentation, iron transport, antioxidant defense, hormone production, and extracellular matrix biosynthesis. Copper deficiency, often caused by mutations in the ATP7A gene, results in Menkes disease, an X-linked recessive disorder. On the contrary, Wilson disease is characterized by toxic copper accumulation. Cuproptosis, a unique form of cell death regulated by copper, is a subtype of necrosis induced by enhanced mitochondrial metabolism and intracellular copper accumulation. This process can reduce the malignant potential of tumor cells by inhibiting glucose metabolism. Therapeutically, copper and its complexes have shown efficacy in malignancy treatments. The disruption of copper homeostasis and excessive cuproplasia are significant in colorectal cancer development and metastasis. Therefore, manipulating copper status presents a potential therapeutic target for colorectal cancer, using copper chelators to inhibit copper formation or copper ion carriers to promote cuproptosis. This review highlights the role of copper in human physiology and pathology, emphasizing its impact on colorectal cancer and potential therapeutic strategies. Future AI-based approaches are anticipated to accelerate the development of new compounds targeting cuproptosis and copper disruption in colorectal cancer. Full article

Copper is an essential heavy metal for diverse biological functions but toxic in excess. Consequently, a tightly regulated protein system is required to ensure adequate intracellular levels. In recent decades, several studies have explored the role of Cu⁺-ATPases in copper transport and homeostasis, revealing that these proteins are subject to kinase-mediated phosphorylation that significantly impacts their function. Techniques such as phosphoproteomic screening, site-directed mutagenesis, and artificial neural network tools demonstrated the regulatory effect of phosphorylation on these ATPases. Different protein kinases regulate Cu⁺-ATPases, modulating the active copper transport by affecting specific steps of the catalytic cycle, long-range intramolecular crosstalks, protein trafficking, gene expression, and protein stability. Therefore, the regulatory phosphorylation of Cu⁺-ATPases by kinases ultimately influences the intracellular copper distribution. This study aims to present a review of the scientific literature on the regulation of Cu⁺-ATPases by kinase-mediated phosphorylation as a crucial mechanism for copper homeostasis. This regulation offers new perspectives for developing therapies for disorders related to copper metabolism, such as Wilson and Menkes diseases, as well as cancer, diabetes mellitus, Parkinson’s, and Alzheimer’s diseases. These findings emphasize the need to further comprehend the signaling pathways involving protein kinases in the context of copper regulation. Full article

Peptides, both natural and synthetic, are well suited for a wide range of purposes and offer versatile applications in different fields such as biocatalysts, injectable hydrogels, tumor treatment, and drug delivery. The research of the better part of the cited papers was conducted using various database platforms such as MetalPDB. The rising prominence of therapeutic peptides encompasses anticancer, antiviral, antimicrobial, and anti-neurodegenerative properties. The metals Na, K, Mg, Ca, Fe, Mn, Co, Cu, Zn, and Mo are ten of the twenty elements that are considered essential for life. Crucial for understanding the biological role of metals is the exploration of metal-bound proteins and peptides. Aside from essential metals, there are other non-essential metals that also interact biologically, exhibiting either therapeutic or toxic effects. Irregularities in metal binding contribute to diseases like Alzheimer’s, neurodegenerative disorders, Wilson’s, and Menkes disease. Certain metal complexes have potential applications as radiopharmaceuticals. The examination of these complexes was achieved by preforming UV–Vis, IR, EPR, NMR spectroscopy, and X-ray analysis. This summary, although unable to cover all of the studies in the field, offers a review of the ongoing experimentation and is a basis for new ideas, as well as strategies to explore and gain knowledge from the extensive realm of peptide-chelated metals and biotechnologies. Full article

Copper, an essential element for various biological processes, demands precise regulation to avert detrimental health effects and potential cell toxicity. This paper explores the mechanisms of copper-induced cell death, known as cuproptosis, and its potential health and disease implications, including cancer therapy. Copper ionophores, such as elesclomol and disulfiram, increase intracellular copper levels. This elevation triggers oxidative stress and subsequent cell death, offering potential implications in cancer therapy. Additionally, copper ionophores disrupt mitochondrial respiration and protein lipoylation, further contributing to copper toxicity and cell death. Potential targets and biomarkers are identified, as copper can be targeted to those proteins to trigger cuproptosis. The role of copper in different cancers is discussed to understand targeted cancer therapies using copper nanomaterials, copper ionophores, and copper chelators. Furthermore, the role of copper is explored through diseases such as Wilson and Menkes disease to understand the physiological mechanisms of copper. Exploring cuproptosis presents an opportunity to improve treatments for copper-related disorders and various cancers, with the potential to bring significant advancements to modern medicine. Full article

Copper plays an important role in metabolic processes. Both deficiency and excess of this element have a negative effect and lead to pathological conditions. Copper is a cofactor of many enzymatic reactions. Its concentration depends on the delivery in the diet, the absorption in enterocytes, transport with the participation of ATP7A/ATP7B protein, and proper excretion. Copper homeostasis disorders lead to serious medical conditions such as Menkes disease (MD) and Wilson’s disease (WD). A mutation in the ATP7A gene is the cause of Menkes disease, it prevents the supply of copper ions to enzymes dependent on them, such as dopamine β-hydroxylase and lysyl oxidase. This leads to progressive changes in the central nervous system and disorders of the connective tissue. In turn, Wilson’s disease is an inherited autosomal recessive disease. It is caused by a mutation of the ATP7B gene encoding the ATP7B protein which means excess copper cannot be removed from the body, leading to the pathological accumulation of this element in the liver and brain. The clinical picture is dominated by the liver, neurological, and/or psychiatric symptoms. Early inclusion of zinc preparations and chelating drugs significantly improves the prognosis in this group of patients. The aim of the study is to analyse, based on the latest literature, the following factors: the etiopathogenesis, clinical picture, diagnostic tests, treatment, prognosis, and complications of disease entities associated with copper disturbances: Menkes disease and Wilson’s disease. In addition, it is necessary for general practitioners, neurologists, and gastroenterologists to pay attention to these disease entities because they are recognized too late and too rarely, especially in the paediatric population. Full article

Copper (Cu) is an essential micronutrient for the correct development of eukaryotic organisms. This metal plays a key role in many cellular and physiological activities, including enzymatic activity, oxygen transport, and cell signaling. Although the redox activity of Cu is crucial for enzymatic reactions, this property also makes it potentially toxic when found at high levels. Due to this dual action of Cu, highly regulated mechanisms are necessary to prevent both the deficiency and the accumulation of this metal since its dyshomeostasis may favor the development of multiple diseases, such as Menkes’ and Wilson’s diseases, neurodegenerative diseases, diabetes mellitus, and cancer. As the relationship between Cu and cancer has been the most studied, we analyze how this metal can affect three fundamental processes for tumor progression: cell proliferation, angiogenesis, and metastasis. Gynecological diseases are characterized by high prevalence, morbidity, and mortality, depending on the case, and mainly include benign and malignant tumors. The cellular processes that promote their progression are affected by Cu, and the mechanisms that occur may be similar. We analyze the crosstalk between Cu deregulation and gynecological diseases, focusing on therapeutic strategies derived from this metal. Full article

Menkes’ disease (MD) and Wilson’s disease (WD) are two major copper (Cu) metabolism-related disorders caused by mutations of the ATP7A and ATP7B ATPase gene, respectively. While Cu is involved in DNA strand breaks signaling and repair, the response of cells from both diseases to ionizing radiation, a common DNA strand breaks inducer, has not been investigated yet. To this aim, three MD and two WD skin fibroblasts lines were irradiated at two Gy X-rays and clonogenic cell survival, micronuclei, anti-γH2AX, -pATM, and -MRE11 immunofluorescence assays were applied to evaluate the DNA double-strand breaks (DSB) recognition and repair. MD and WD cells appeared moderately radiosensitive with a delay in the radiation-induced ATM nucleo-shuttling (RIANS) associated with impairments in the DSB recognition. Such delayed RIANS was notably caused in both MD and WD cells by a highly expressed ATP7B protein that forms complexes with ATM monomers in cytoplasm. Interestingly, a Cu pre-treatment of cells may influence the activity of the MRE11 nuclease and modulate the radiobiological phenotype. Lastly, some high-passage MD cells cultured in routine may transform spontaneously becoming immortalized. Altogether, our findings suggest that exposure to ionizing radiation may impact on clinical features of MD and WD, which requires cautiousness when affected patients are submitted to radiodiagnosis and, eventually, radiotherapy. Full article

Background: Menkes disease (MD; OMIM #309400) is a progressive neurodegeneration that results from abnormalities in the copper metabolism which are already present before birth. It is an extremely rare condition. The study was conducted to assess the quality of life of children with MD syndrome and the impact of the disease on family functioning. Methods: A cross-sectional questionnaire survey was used. The subjects were 16 parents of children with MD. The method used was the Paediatric Quality of Life Inventory and the PedsQL Family Impact Module and the author’s own questionnaire. Results: Quality of life (QOL) was 29.14 (SD = 14.73), with the lowest for physical functioning (M = 10.55; SD = 10.26) and highest for emotional functioning (M = 48.13; SD = 29.43). The highest score was on the family relationships domain (M = 56.25, SD = 20.38) and the cognitive functioning domain (M = 50.00, SD = 19.24) and the lowest was on the daily activities’ domain (M = 32.29, SD = 20.38) and the physical functioning domain (M = 39.84, SD = 14.90). The analysis did not show statistically significant relationships between age (p = 0.193) and the number of epileptic seizures a week (p = 0.641) and the overall QOL of the children studied. No statistically significant relationships were found between treatment with copper histidine and the overall QOL of the children (p = 0.914) and in physical functioning (p = 0.927), emotional functioning (p = 0.706), and social functioning (p = 0.751). The presence of comorbidities did not have an influence on the overall QOL. Conclusions: MD has a moderate impact on the functioning of the families of the affected children. The age of the child, number of epileptic seizures a week, feeding method (oral feeding or feeding via a PEG tube), and treatment with copper histidine do not have a significant impact on the QOL of children with MD. Full article

Kidneys play an especial role in copper redistribution in the organism. The epithelial cells of proximal tubules perform the functions of both copper uptake from the primary urine and release to the blood. These cells are equipped on their apical and basal membrane with copper transporters CTR1 and ATP7A. Mosaic mutant mice displaying a functional dysfunction of ATP7A are an established model of Menkes disease. These mice exhibit systemic copper deficiency despite renal copper overload, enhanced by copper therapy, which is indispensable for their life span extension. The aim of this study was to analyze the expression of Slc31a1 and Slc31a2 genes (encoding CTR1/CTR2 proteins) and the cellular localization of the CTR1 protein in suckling, young and adult mosaic mutants. Our results indicate that in the kidney of both intact and copper-injected 14-day-old mutants showing high renal copper content, CTR1 mRNA level is not up-regulated compared to wild-type mice given a copper injection. The expression of the Slc31a1 gene in 45-day-old mice is even reduced compared with intact wild-type animals. In suckling and young copper-injected mutants, the CTR1 protein is relocalized from the apical membrane to the cytoplasm of epithelial cells of proximal tubules, the process which prevents copper transport from the primary urine and, thus, protects cells against copper toxicity. Full article

Pili torti is a rare condition characterized by the presence of the hair shaft, which is flattened at irregular intervals and twisted 180° along its long axis. It is a form of hair shaft disorder with increased fragility. The condition is classified into inherited and acquired. Inherited forms may be either isolated or associated with numerous genetic diseases or syndromes (e.g., Menkes disease, Björnstad syndrome, Netherton syndrome, and Bazex-Dupré-Christol syndrome). Moreover, pili torti may be a feature of various ectodermal dysplasias (such as Rapp-Hodgkin syndrome and Ankyloblepharon-ectodermal defects-cleft lip/palate syndrome). Acquired pili torti was described in numerous forms of alopecia (e.g., lichen planopilaris, discoid lupus erythematosus, dissecting cellulitis, folliculitis decalvans, alopecia areata) as well as neoplastic and systemic diseases (such as cutaneous T-cell lymphoma, scalp metastasis of breast cancer, anorexia nervosa, malnutrition, cataracts, and chronic graft-vs.-host disease). The condition may also be induced by several drugs (epidermal growth factor receptor inhibitors, oral retinoids, sodium valproate, and carbamide perhydrate). The diagnosis of pili torti is based on trichoscopic or microscopic examination. As pili torti is a marker of numerous congenital and acquired disorders, in every case, the search for the signs of underlying conditions is recommended. Full article

Menkes disease (MD) is a rare and often lethal X-linked recessive syndrome, characterized by generalized alterations in copper transport and metabolism, linked to mutations in the ATPase copper transporting α (ATP7A) gene. Our objective was to identify genomic alterations and circulating proteomic profiles related to MD assessing their potential roles in the clinical features of the disease. We describe the case of a male patient of 8 months of age with silvery hair, tan skin color, hypotonia, alterations in neurodevelopment, presence of seizures, and low values of plasma ceruloplasmin. Trio-whole-exome sequencing (Trio-WES) analysis, plasma proteome screening, and blood cell migration assays were carried out. Trio-WES revealed a hemizygous change c.4190C > T (p.S1397F) in exon 22 of the ATP7A gene. Compared with his parents and with child controls, 11 plasma proteins were upregulated and 59 downregulated in the patient. According to their biological processes, 42 (71.2%) of downregulated proteins had a participation in cellular transport. The immune system process was represented by 35 (59.3%) downregulated proteins (p = 9.44 × 10⁻¹¹). Additional studies are necessary to validate these findings as hallmarks of MD. Full article

Copper is vital for numerous cellular functions affecting all tissues and organ systems in the body. The copper pump, ATP7A is critical for whole-body, cellular, and subcellular copper homeostasis, and dysfunction due to genetic defects results in Menkes disease. ATP7A dysfunction leads to copper deficiency in nervous tissue, liver, and blood but accumulation in other tissues. Site-specific cellular deficiencies of copper lead to loss of function of copper-dependent enzymes in all tissues, and the range of Menkes disease pathologies observed can now be explained in full by lack of specific copper enzymes. New pathways involving copper activated lysosomal and steroid sulfatases link patient symptoms usually related to other inborn errors of metabolism to Menkes disease. Additionally, new roles for lysyl oxidase in activation of molecules necessary for the innate immune system, and novel adapter molecules that play roles in ERGIC trafficking of brain receptors and other proteins, are emerging. We here summarize the current knowledge of the roles of copper enzyme function in Menkes disease, with a focus on ATP7A-mediated enzyme metalation in the secretory pathway. By establishing mechanistic relationships between copper-dependent cellular processes and Menkes disease symptoms in patients will not only increase understanding of copper biology but will also allow for the identification of an expanding range of copper-dependent enzymes and pathways. This will raise awareness of rare patient symptoms, and thus aid in early diagnosis of Menkes disease patients. Full article

Ion homeostasis is crucial for organism functioning, and its alterations may cause diseases. For example, copper insufficiency and overload are associated with Menkes and Wilson’s diseases, respectively, and iron imbalance is observed in Parkinson’s and Alzheimer’s diseases. To better understand human diseases, Saccharomyces cerevisiae yeast are used as a model organism. In our studies, we used the vps13Δ yeast strain as a model of rare neurological diseases caused by mutations in VPS13A–D genes. In this work, we show that overexpression of genes encoding copper transporters, CTR1, CTR3, and CCC2, or the addition of copper salt to the medium, improved functioning of the vps13Δ mutant. We show that their mechanism of action, at least partially, depends on increasing iron content in the cells by the copper-dependent iron uptake system. Finally, we present that treatment with copper ionophores, disulfiram, elesclomol, and sodium pyrithione, also resulted in alleviation of the defects observed in vps13Δ cells. Our study points at copper and iron homeostasis as a potential therapeutic target for further investigation in higher eukaryotic models of VPS13-related diseases. Full article

Kaempferol is a flavonoid that occurs in tea and in many vegetables and fruits, including broccoli, cabbage, beans, grapes, apples, and strawberries. The efficacy of Kaempferol has been demonstrated in the treatment of breast, esophageal, cervical, ovarian, and liver cancers and leukemia, which very likely arises from its prooxidant properties and the activation of pro-apoptotic pathways. Indeed, this matter has already been the focus of a number of published studies and reviews. The aim of the present study was to elucidate the antioxidant vs. prooxidant properties of flavonoids in the presence of the redox-active metal, copper (II) ion, by means of the Fenton reaction. The specific motivation of this work is that, since an increased level of Cu(II) ions is known to be associated with many disease states such as neurological conditions (Alzheimer’s disease) and cancer, any interaction between these ions and flavonoids might affect the outcome of therapeutic uses of the latter. The structure of the Cu-kaempferol complex in DMSO was investigated by means of low temperature EPR spectroscopy, which confirmed the existence of at least two distinct coordination environments around the copper (II) ion. UV vis-spectra of kaempferol and its Cu(II) complex in DMSO revealed an interaction between the 5-OH (A ring) group and the 4-CO (C ring) group of kaempferol with Cu(II) ions. An ABTS assay confirmed that kaempferol acted as an effective radical scavenger, and that this effect was further enhanced in the form of the Cu(II)-kaempferol complex. Quantitative EPR spin trapping experiments, using DMPO as the spin trap, confirmed suppression of the formation of a mixture of hydroxyl, superoxide, and methyl radicals, in a Fenton reaction system, upon coordination of kaempferol to the redox-active Cu(II) ions, by 80% with respect to the free Cu(II) ions. A viscometric study revealed a better DNA-intercalating ability of the Cu-kaempferol complex than for free kaempferol, essential for conferring anticancer activity of these substances. The results of the viscometric measurements were compared with those from a DNA damage study of Cu-kaempferol complexes in a Fenton reaction system, using gel electrophoresis. At low concentrations of kaempferol (Cu–kaempferol ratios of 1:1 and 1:2), a very weak protective effect on DNA was noted, whereas when kaempferol was present in excess, a significant DNA-protective effect was found. This can be explained if the weakly intercalated kaempferol molecules present at the surface of DNA provide protection against attack by ROS that originate from the Fenton reaction involving intercalated Cu(II)-kaempferol complexes. Following the application of ROS scavengers, L-histidine, DMSO, and SOD, gel electrophoresis confirmed the formation of singlet oxygen, hydroxyl radicals, and superoxide radical anions, respectively. We propose that the prooxidant properties of Cu-kaempferol complexes may provide anticancer activity of these substances. When present in excess, kaempferol displays antioxidant properties under Cu-Fenton conditions. This suggests that kaempferol might prove a suitable candidate for the prevention or treatment of oxidative stress related medical conditions that involve a disturbed metabolism of redox metals such as copper, for example, Menkes disease, and neurological disorders, including Alzheimer’s disease. For the potential use of kaempferol in clinical practice, it will be necessary to optimize the dose size and critical age of the patient so that this flavonoid may be beneficial as a preventive drug against cancer and neurological disorders. Full article