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1.
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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Relation of Serum Copper Status to Survival in COVID-19.
Hackler, J, Heller, RA, Sun, Q, Schwarzer, M, Diegmann, J, Bachmann, M, Moghaddam, A, Schomburg, L
Nutrients. 2021;(6)
Abstract
The trace element copper (Cu) is part of our nutrition and essentially needed for several cuproenzymes that control redox status and support the immune system. In blood, the ferroxidase ceruloplasmin (CP) accounts for the majority of circulating Cu and serves as transport protein. Both Cu and CP behave as positive, whereas serum selenium (Se) and its transporter selenoprotein P (SELENOP) behave as negative acute phase reactants. In view that coronavirus disease (COVID-19) causes systemic inflammation, we hypothesized that biomarkers of Cu and Se status are regulated inversely, in relation to disease severity and mortality risk. Serum samples from COVID-19 patients were analysed for Cu by total reflection X-ray fluorescence and CP was quantified by a validated sandwich ELISA. The two Cu biomarkers correlated positively in serum from patients with COVID-19 (R = 0.42, p < 0.001). Surviving patients showed higher mean serum Cu and CP concentrations in comparison to non-survivors ([mean+/-SEM], Cu; 1475.9+/-22.7 vs. 1317.9+/-43.9 µg/L; p < 0.001, CP; 547.2.5 +/- 19.5 vs. 438.8+/-32.9 mg/L, p = 0.086). In contrast to expectations, total serum Cu and Se concentrations displayed a positive linear correlation in the patient samples analysed (R = 0.23, p = 0.003). Serum CP and SELENOP levels were not interrelated. Applying receiver operating characteristics (ROC) curve analysis, the combination of Cu and SELENOP with age outperformed other combinations of parameters for predicting risk of death, yielding an AUC of 95.0%. We conclude that the alterations in serum biomarkers of Cu and Se status in COVID-19 are not compatible with a simple acute phase response, and that serum Cu and SELENOP levels contribute to a good prediction of survival. Adjuvant supplementation in patients with diagnostically proven deficits in Cu or Se may positively influence disease course, as both increase in survivors and are of crucial importance for the immune response and antioxidative defence systems.
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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.
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Hydrogen sulfide regulates the activity of antioxidant enzymes through persulfidation and improves the resistance of tomato seedling to Copper Oxide nanoparticles (CuO NPs)-induced oxidative stress.
Li, J, Shi, C, Wang, X, Liu, C, Ding, X, Ma, P, Wang, X, Jia, H
Plant physiology and biochemistry : PPB. 2020;:257-266
Abstract
Hydrogen sulfide (H2S), a small gaseous signaling molecule, regulates antioxidase activity and improves plant tolerance to oxidative stress. The phytotoxic effect of Copper Oxide (II) nanoparticles (CuO NPs) is due to oxidative stress. Here, we show that H2S-mediated persulfidation of antioxidase is essential for an effective stress response of tomato exposed to CuO NPs. The CuO NP-induced increase in hydrogen peroxide (H2O2) and malondialdehyde (MDA) levels was significantly reduced by treatment with the H2S donor NaHS. In vivo, NaHS increased superoxide dismutase (SOD), ascorbate peroxidase (APX) and peroxidase (POD) activities under CuO NP stress. In vitro, NaHS increased APX and POD activities but decreased catalase (CAT) activity. Persulfidation existed in recombinant SlCAT1, SlcAPX1 and SlPOD5 proteins. The persulfidatied cysteine (Cys) residues were verified by liquid chromatography-tandem mass spectrometry (LC-MS/MS), revealing their position on the protein surface. Cys234 of SlCAT1 is located in the immune-responsive domain and close to the enzyme activity domain. Cys234 of SlcAPX1 and Cys 61 SlPOD5 are located in the enzyme activity domain. Persulfidation increased SlcAPX1 and SlPOD5 activities but decreased SlCAT1 activity. These data indicate that H2S-mediated persulfidation posttranslationally regulates the activities of CAT, APX and POD, thereby enhancing the plant's response to oxidative stress. Additionally, this work provides an experimental approach for the study of persulfidation in plants.
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5.
Handling of nutrient copper in the bacterial envelope.
Stewart, LJ, Thaqi, D, Kobe, B, McEwan, AG, Waldron, KJ, Djoko, KY
Metallomics : integrated biometal science. 2019;(1):50-63
Abstract
In bacteria, copper (Cu) is often recognised for its potential toxicity and its antibacterial activity is now considered a key component of the mammalian innate immune system. Cu ions bound in weak sites can catalyse harmful redox reactions while Cu ions in strong but adventitious sites can disrupt protein or enzyme function. For these reasons, the outward transport of Cu from bacteria has received significant attention. Yet, Cu is also a bacterial nutrient, required as a cofactor by enzymes that catalyse electron transfer processes, for instance in aerobic and anaerobic respiration. To date, the inward flow of this metal ion as a nutrient and its insertion into target cuproenzymes remain poorly defined. Here we revisit the available evidence related to bacterial nutrient Cu trafficking and identify gaps in knowledge. Particularly intriguing is the evidence that bacterial cuproenzymes do not always require auxiliary metallochaperones to insert nutrient Cu into their active sites. This review outlines our effort to consolidate the available experimental data using an established energy-driven model for metalation.
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The Role of Copper Homeostasis at the Host-Pathogen Axis: From Bacteria to Fungi.
Li, C, Li, Y, Ding, C
International journal of molecular sciences. 2019;(1)
Abstract
Copper is an essential trace element participating in many vital biological processes, however it becomes a toxic agent when in excess. Thus, precise and tight regulation of copper homeostasis processes, including transport, delivery, storage, detoxification, and efflux machineries, is important, ensuring that only the amount needed to sustain basic biological functions and simultaneously prevent copper toxicity in the cell is maintained. Numerous exciting studies have revealed that copper plays an indispensable role at the microbial pathogen-host axis for entities ranging from pathogenic bacteria to deadly fungal species. Analyses of copper homeostases in bacteria and fungi extensively demonstrate that copper is utilized by the host immune system as an anti-microbial agent. The expression of copper efflux and detoxification from microbial pathogens is induced to counteract the host's copper bombardment, which in turn disrupts these machineries, resulting in the attenuation of microbial survival in host tissue. We hereby review the latest work in copper homeostases in pathogenic bacteria and fungi and focus on the maintenance of a copper balance at the pathogen-host interaction axis.
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7.
Copper Deficiency: Causes, Manifestations, and Treatment.
Altarelli, M, Ben-Hamouda, N, Schneider, A, Berger, MM
Nutrition in clinical practice : official publication of the American Society for Parenteral and Enteral Nutrition. 2019;(4):504-513
Abstract
BACKGROUND The metabolism of the essential trace element copper remains incompletely understood and, until recently, nearly ignored in acute medicine. Menkes disease was for long the only known copper deficiency condition, but several case reports and investigations conducted over the last 2 decades have shown that deficiency is more frequent than previously suspected, with devastating individual consequences and potential public health consequences. The copper needs in healthy individuals are 0.9 mg/d, which translates to 0.3 mg/d intravenously in parenteral nutrition; the present review aims at gathering actual knowledge. METHOD AND RESULTS A review of literature was conducted in PubMed and Cochrane systematic reviews to identify the most recent information about copper deficiency and generate a narrative review. Copper deficiency has hereditary and acquired origins, the latter being the most frequent. Clinical manifestations are nonspecific but affect all organs and systems, particularly the hematologic (anemia) and the neurologic (myeloneuropathy) systems. Deficiency also affects the cardiovascular, cutaneous, and immune systems. Severe copper deficiency due to reduced absorption after bariatric bypass surgery has become frequent. CONCLUSION Deficiency is more frequent than previously recognized, probably because of changing nutrition patterns but also because of some treatments that have become very common such as bypass bariatric surgery and, in acute medicine, prolonged continuous renal replacement therapy. The patients may present with severe hematologic and neurologic complications that go untreated because copper deficiency was not considered in the differential diagnosis: These complications often need active intravenous repletion with doses 4-8 times the usual nutrition recommendations.
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Dietary copper and human health: Current evidence and unresolved issues.
Bost, M, Houdart, S, Oberli, M, Kalonji, E, Huneau, JF, Margaritis, I
Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS). 2016;:107-15
Abstract
Although copper (Cu) is recognized as an essential trace element, uncertainties remain regarding Cu reference values for humans, as illustrated by discrepancies between recommendations issued by different national authorities. This review examines human studies published since 1990 on relationships between Cu intake, Cu balance, biomarkers of Cu status, and health. It points out several gaps and unresolved issues which make it difficult to assess Cu requirements. Results from balance studies suggest that daily intakes below 0.8 mg/day lead to net Cu losses, while net gains are consistently observed above 2.4 mg/day. However, because of an incomplete collection of losses in all studies, a precise estimation of Cu requirements cannot be derived from available data. Data regarding the relationship between Cu intake and potential biomarkers are either too preliminary or inconclusive because of low specificity or low sensitivity to change in dietary Cu over a wide range of intakes. Results from observation and intervention studies do not support a link between Cu and a risk of cardiovascular disease, cognitive decline, arthritis or cancer for intakes ranging from 0.6 to 3mg/day, and limited evidence exists for impaired immune function in healthy subjects with a very low (0.38 mg/day) Cu intake. However, data from observation studies should be regarded with caution because of uncertainties regarding Cu concentration in various foods and water. Further studies that accurately evaluate Cu exposure based on reliable biomarkers of Cu status are needed.
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Meta-analysis of Zn, Cu and Fe in the hair of Chinese children with recurrent respiratory tract infection.
Mao, S, Zhang, A, Huang, S
Scandinavian journal of clinical and laboratory investigation. 2014;(7):561-7
Abstract
Trace elements play an important role in maintaining the normal metabolic and immune function. The onset of recurrent respiratory tract infection (RRI) is associated with the immune function, genetic factors and nutritional status. However, the association between the levels of trace elements and RRI remains inconclusive. We aimed to investigate the alterations of hair levels of zinc (Zn), copper (Cu) and iron (Fe) in Chinese children with RRI by performing a meta-analysis. A predefined electronic databases search was performed to identify eligible studies for the analysis of hair Zn, Cu or Fe levels in Chinese children with RRI. Thirteen studies were included. RRI patients displayed significantly lower levels of hair Zn (13 studies, random effects SMD: - 1.215, 95% CI: - 1.704 to - 0.725, p < 0.0001), Cu (11 studies, random effects SMD: - 0.384, 95% CI: - 0.717 to - 0.052, p = 0.023) and Fe (12 studies, random effects SMD: - 0.569, 95% CI: - 0.827 to - 0.312, p < 0.0001) compared with controls. No evidence of publication bias was observed. Sensitivity analysis did not change the results significantly. In conclusion, the deficiency of Zn, Cu and Fe may be contributing factors for the susceptibility of RRI in Chinese children. However, more studies in different ethnicities should be performed in the future.
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10.
Thymic size correlates with cord blood zinc levels in low-birth-weight newborns.
Kumar, A, Pandey, M, Basu, S, Shukla, RC, Asthana, RK
European journal of pediatrics. 2014;(8):1083-7
Abstract
UNLABELLED Thymus is essential for immunity as it provides environment for T cell differentiation and maturation. There is limited information on various factors which determine thymic size at birth. We studied the influence of cord blood zinc and copper levels and maternal and neonatal nutritional status on thymic size in term low-birth-weight (LBW) newborns. A prospective observational study on 44 term LBW (<2,500 g) newborns (cases) and 71 gestational age-matched newborns weighing ≥2,500 g (controls). Sonographically determined thymic index was correlated to cord blood zinc and copper levels and maternal and neonatal nutritional status. Thymic index measured 3.74 ± 1.57 cm(3) in LBW newborns compared to 4.90 ± 2.33 cm(3) in normal-birth-weight newborns. Thymic index was significantly correlated to cord blood zinc levels but not to cord blood copper levels and had linear relationship to the maternal body mass index and midarm circumference and neonatal anthropometric parameters. CONCLUSION Thymic index is linearly related to cord blood zinc levels and maternal and neonatal nutritional status. Compared to thymic size in the Western newborns, the thymus is less than half in size in Indian newborns of normal birth weight. Reduced thymic size in Indian newborns in general and LBW infants in particular may have consequences for their immune competence and the risk of infections. Improving nutrition of pregnant women, particularly zinc nutriture might favorably influence thymic size in their offspring.