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1.
Zinc and respiratory tract infections: Perspectives for COVID‑19 (Review).
Skalny, AV, Rink, L, Ajsuvakova, OP, Aschner, M, Gritsenko, VA, Alekseenko, SI, Svistunov, AA, Petrakis, D, Spandidos, DA, Aaseth, J, et al
International journal of molecular medicine. 2020;(1):17-26
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Abstract
In view of the emerging COVID‑19 pandemic caused by SARS‑CoV‑2 virus, the search for potential protective and therapeutic antiviral strategies is of particular and urgent interest. Zinc is known to modulate antiviral and antibacterial immunity and regulate inflammatory response. Despite the lack of clinical data, certain indications suggest that modulation of zinc status may be beneficial in COVID‑19. In vitro experiments demonstrate that Zn2+ possesses antiviral activity through inhibition of SARS‑CoV RNA polymerase. This effect may underlie therapeutic efficiency of chloroquine known to act as zinc ionophore. Indirect evidence also indicates that Zn2+ may decrease the activity of angiotensin‑converting enzyme 2 (ACE2), known to be the receptor for SARS‑CoV‑2. Improved antiviral immunity by zinc may also occur through up‑regulation of interferon α production and increasing its antiviral activity. Zinc possesses anti‑inflammatory activity by inhibiting NF‑κB signaling and modulation of regulatory T‑cell functions that may limit the cytokine storm in COVID‑19. Improved Zn status may also reduce the risk of bacterial co‑infection by improving mucociliary clearance and barrier function of the respiratory epithelium, as well as direct antibacterial effects against S. pneumoniae. Zinc status is also tightly associated with risk factors for severe COVID‑19 including ageing, immune deficiency, obesity, diabetes, and atherosclerosis, since these are known risk groups for zinc deficiency. Therefore, Zn may possess protective effect as preventive and adjuvant therapy of COVID‑19 through reducing inflammation, improvement of mucociliary clearance, prevention of ventilator‑induced lung injury, modulation of antiviral and antibacterial immunity. However, further clinical and experimental studies are required.
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Inadequacy of Immune Health Nutrients: Intakes in US Adults, the 2005-2016 NHANES.
Reider, CA, Chung, RY, Devarshi, PP, Grant, RW, Hazels Mitmesser, S
Nutrients. 2020;(6)
Abstract
A well-functioning immune system is essential for human health and well-being. Micronutrients such as vitamins A, C, D, E, and zinc have several functions throughout the immune system, yet inadequate nutrient intakes are pervasive in the US population. A large body of research shows that nutrient inadequacies can impair immune function and weaken the immune response. Here, we present a new analysis of micronutrient usual intake estimates based on nationally representative data in 26,282 adults (>19 years) from the 2005-2016 National Health and Nutrition Examination Surveys (NHANES). Overall, the prevalence of inadequacy (% of population below estimated average requirement [EAR]) in four out of five key immune nutrients is substantial. Specifically, 45% of the U.S. population had a prevalence of inadequacy for vitamin A, 46% for vitamin C, 95% for vitamin D, 84% for vitamin E, and 15% for zinc. Dietary supplements can help address nutrient inadequacy for these immune-support nutrients, demonstrated by a lower prevalence of individuals below the EAR. Given the long-term presence and widening of nutrient gaps in the U.S.-specifically in critical nutrients that support immune health-public health measures should adopt guidelines to ensure an adequate intake of these micronutrients. Future research is needed to better understand the interactions and complexities of multiple nutrient shortfalls on immune health and assess and identify optimal levels of intake in at-risk populations.
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[Selenium and zinc: "antioxidants" for healthy aging?].
Steinbrenner, H, Klotz, LO
Zeitschrift fur Gerontologie und Geriatrie. 2020;(4):295-302
Abstract
Selenium and zinc are essential trace elements and an inadequate dietary intake has been implicated in the decline of immune and cognitive functions in aged persons and in the pathogenesis of age-related disorders. Both micronutrients are often marketed as "antioxidants" in mineral supplements; however, neither selenium nor zinc are antioxidants per se but they may exert beneficial effects as components of enzymes and other proteins that catalyze redox reactions and/or are involved in the maintenance of redox homeostasis. According to epidemiological data older individuals have an increased risk of developing deficiencies in the selenium and zinc status; however, such statistical correlations in epidemiological studies do not imply a causal association. Intervention trials are scarce and have yielded inconsistent and sometimes even adverse results. It should also be noted that the observed deficiencies in micronutrients may not necessarily be attributable to inadequate dietary intake as the absorption and distribution within the body might also be influenced by factors such as medications or interaction with other food ingredients. Thus, any dietary supplementation should be implemented with caution and persons who wish to take mineral supplements should first seek medical advice. This article discusses the role of selenium and zinc in biological antioxidant systems, summarizes findings on the supply and supplementation of aged persons with these trace elements and on the influence they may exert on aging-related health issues, such as cognitive decline and type 2 diabetes mellitus.
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Zinc Deficiency-An Independent Risk Factor in the Pathogenesis of Haemorrhagic Stroke?
Grüngreiff, K, Gottstein, T, Reinhold, D
Nutrients. 2020;(11)
Abstract
Zinc is an essential trace element for human health and plays a fundamental role in metabolic, immunological and many other biological processes. The effects of zinc are based on the intra- and extracellular regulatory function of the zinc ion (Zn2+) and its interactions with proteins. The regulation of cellular zinc homeostasis takes place via a complex network of metal transporters and buffering systems that react to changes in the availability of zinc in nutrition, chronic diseases, infections and many other processes. Zinc deficiency is associated with impairment of numerous metabolic processes, reduced resistance to infections due to impaired immune functions, changes in skin and its appendages and disorders of wound healing and haemostasis. While ischemic heart attacks (myocardial infarction) occur more frequently with meat-based normal diets, haemorrhagic strokes are more frequently observed with vegetarian/vegan diets. The causes are discussed as deficiencies of various micronutrients, such as vitamin B12, vitamin D, various amino acids and also zinc. In the present review, after a description of the functions of zinc and its resorption, a discussion of daily food intake will follow, with a special focus on the importance of food composition and preparation for the zinc balance. The close interrelationships between proteins, especially albumin and zinc will be discussed. Finally, the possible causes and consequences of a zinc deficiency on the blood vessels and blood coagulation are considered.
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ZnT2 is an electroneutral proton-coupled vesicular antiporter displaying an apparent stoichiometry of two protons per zinc ion.
Golan, Y, Alhadeff, R, Warshel, A, Assaraf, YG
PLoS computational biology. 2019;(3):e1006882
Abstract
Zinc is a vital trace element crucial for the proper function of some 3,000 cellular proteins. Specifically, zinc is essential for key physiological processes including nucleic acid metabolism, regulation of gene expression, signal transduction, cell division, immune- and nervous system functions, wound healing, and apoptosis. Consequently, impairment of zinc homeostasis disrupts key cellular functions resulting in various human pathologies. Mammalian zinc transport proceeds via two transporter families ZnT and ZIP. However, the detailed mechanism of action of ZnT2, which is responsible for vesicular zinc accumulation and zinc secretion into breast milk during lactation, is currently unknown. Moreover, although the putative coupling of zinc transport to the proton gradient in acidic vesicles has been suggested, it has not been conclusively established. Herein we modeled the mechanism of action of ZnT2 and demonstrated both computationally and experimentally, using functional zinc transport assays, that ZnT2 is indeed a proton-coupled zinc antiporter. Bafilomycin A1, a specific inhibitor of vacuolar-type proton ATPase (V-ATPase) which alkalizes acidic vesicles, abolished ZnT2-dependent zinc transport into intracellular vesicles. Moreover, using LysoTracker Red and Lyso-pHluorin, we further showed that upon transient ZnT2 overexpression in intracellular vesicles and addition of exogenous zinc, the vesicular pH underwent alkalization, presumably due to a proton-zinc antiport; this phenomenon was reversed in the presence of TPEN, a specific zinc chelator. Finally, based on computational energy calculations, we propose that ZnT2 functions as an antiporter with a stoichiometry of 2H+/Zn2+ ion. Hence, ZnT2 is a proton motive force-driven, electroneutral vesicular zinc exchanger, concentrating zinc in acidic vesicles on the expense of proton extrusion to the cytoplasm.
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Association Between Cortisol, Insulin Resistance and Zinc in Obesity: a Mini-Review.
Morais, JBS, Severo, JS, Beserra, JB, de Oiveira, ARS, Cruz, KJC, de Sousa Melo, SR, do Nascimento, GVR, de Macedo, GFS, do Nascimento Marreiro, D
Biological trace element research. 2019;(2):323-330
Abstract
Adipose tissue is considered an endocrine organ and its excess compromises the immune response and the metabolism of hormones and nutrients. Furthermore, visceral fat accumulation contributes to increased cortisol synthesis, which in turn induces metallothionein and Zip14 expression, which are proteins that contribute to reducing plasma zinc levels. Zinc plays a critical role in the secretion and signaling of insulin. Changes in the biochemical parameters of zinc, as observed in individuals who are obese, contribute to the manifestation of related disorders such as insulin resistance. Thus, the purpose of this review is to provide an update on the current information on the relationship between cortisol, zinc, and insulin resistance in obesity. The data in the literature provide evidence that cortisol affects zinc metabolism, and indicate possible repercussions on insulin signaling that might contribute to the development of resistance to the actions of insulin in obesity.
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Metallothionein: a Potential Link in the Regulation of Zinc in Nutritional Immunity.
Rahman, MT, Karim, MM
Biological trace element research. 2018;(1):1-13
Abstract
Nutritional immunity describes mechanisms for withholding essential transition metals as well as directing the toxicity of these metals against infectious agents. Zinc is one of these transition elements that are essential for both humans and microbial pathogens. At the same time, Zn can be toxic both for man and microbes if its concentration is higher than the tolerance limit. Therefore a "delicate" balance of Zn must be maintained to keep the immune cells surveilling while making the level of Zn either to starve or to intoxicate the pathogens. On the other hand, the invading pathogens will exploit the host Zn pool for its survival and replication. Apparently, different sets of protein in human and bacteria are involved to maintain their Zn need. Metallothionein (MT)-a group of low molecular weight proteins, is well known for its Zn-binding ability and is expected to play an important role in that Zn balance at the time of active infection. However, the differences in structural, functional, and molecular control of biosynthesis between human and bacterial MT might play an important role to determine the proper use of Zn and the winning side. The current review explains the possible involvement of human and bacterial MT at the time of infection to control and exploit Zn for their need.
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The effect of probiotics and zinc supplementation on the immune response to oral rotavirus vaccine: A randomized, factorial design, placebo-controlled study among Indian infants.
Lazarus, RP, John, J, Shanmugasundaram, E, Rajan, AK, Thiagarajan, S, Giri, S, Babji, S, Sarkar, R, Kaliappan, PS, Venugopal, S, et al
Vaccine. 2018;(2):273-279
Abstract
BACKGROUND Strategies are needed to improve oral rotavirus vaccine (RV), which provides suboptimal protection in developing countries. Probiotics and zinc supplementation could improve RV immunogenicity by altering the intestinal microbiota and immune function. METHODS Infants 5weeks old living in urban Vellore, India were enrolled in a randomized, double-blind, placebo-controlled trial with a 4-arm factorial design to assess the effects of daily zinc (5mg), probiotic (1010Lactobacillus rhamnosus GG) or placebo on the immunogenicity of two doses of RV (Rotarix®, GlaxoSmithKline Biologicals) given at 6 and 10weeks of age. Infants were eligible for participation if healthy, available for the study duration and without prior receipt of RV or oral poliovirus vaccine other than the birth dose. The primary outcome was seroconversion to rotavirus at 14weeks of age based on detection of VP6-specific IgA at ≥20U/ml in previously seronegative infants or a fourfold rise in concentration. RESULTS The study took place during July 2012 to February 2013. 620 infants were randomized equally between study arms and 551 (88.9%) completed per protocol. Seroconversion was recorded in 54/137 (39.4%), 42/136 (30.9%), 40/143 (28.0%), and 37/135 (27.4%) infants receiving (1) probiotic and zinc, (2) probiotic and placebo, (3) placebo and zinc, (4) two placebos. Seroconversion showed a modest improvement among infants receiving probiotic (difference between groups 1, 2 and 3, 4 was 7.5% (97.5% Confidence Interval (CI): -1.4%, 16.2%), p=0.066) but not zinc (difference between groups 1, 3 and 2, 4 was 4.4% (97.5% CI: -4.4%, 13.2%), p=0.272). 16 serious adverse events were recorded, none related to study interventions. CONCLUSIONS Zinc or probiotic supplementation did not significantly improve the low immunogenicity of rotavirus vaccine given to infants in a poor urban community in India. A modest effect of combined supplementation deserves further investigation. TRIAL REGISTRATION The trial was registered in India (CTRI/2012/05/002677).
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Renal effects of metallothionein induction by zinc in vitro and in vivo.
Schanz, M, Schaaf, L, Dippon, J, Biegger, D, Fritz, P, Alscher, MD, Kimmel, M
BMC nephrology. 2017;(1):91
Abstract
BACKGROUND Metallothionein (MTT) is an endogenous antioxidant that can be induced by both zinc (Zn) and ischemia. In kidneys, increased MTT expression exerts a putative protective role in diabetes and hypoxia. Our goal was to further investigate the behavior of MTT under the influence of Zn and hypoxia in vitro and in vivo. METHODS MTT expression was measured in vitro in cell cultures of proximal tubular cells (LCC-PK1) by immune-histochemistry and real-time PCR after incubation with increasing concentrations of Zn under hypoxic and non-hypoxic conditions. In addition, in vivo studies were carried out in 54 patients to study MTT induction through Zn. This is a sub-study of a prospective, randomized, double-blind trial on prevention of contrast-media-induced nephropathy using Placebo, Zn and N-Acetylcysteine. Blood samples were obtained before and after 2 days p.o. treatment with or without Zn (60 mg). ELISA-based MTT level measurements were done to evaluate the effects of Zn administration. For in vivo analysis, we considered the ratio of MTT to baseline MTT (MTT1/MTT0) and the ratio of eGFR (eGFR1/eGFR0), correspondingly. RESULTS In vitro quantitative immuno-histochemical analysis (IHC) and real-time PCR showed that at increasing levels of Zn (5, 10, and 15 μg/ml) led to a progressive increase of MTTs: Median (IQR) expression of IHC also increased progressively from 0.10 (0.09-0.12), 0.15 (0.12-0.18), 0.25 (0.25-0.27), 0.59 (0.48-0.70) (p < 0.0001). Median (IQR) expression of PCR: 0.59 (0.51-1.72), 1.62 (1.38-4.70), 3.58 (3.06-10.42) and 10.81 (9.24-31.47) (p < 0.0001). In contrast, hypoxia did not change MTT-levels in vitro (p > 0.05). In vivo no significant differences (p = 0.96) occurred in MTT-levels after 2 days of Zn administration compared with no Zn intake. Nevertheless, there was a significant correlation between MTT (MTT1/MTT0) and eGFR (eGFR1/eGFR0) in case of Zn administration (rho = -0.49; 95%-CI: -0.78 to -0.03; p = 0.04). CONCLUSIONS We found that Zn did induce MTTs in vitro, whereas hypoxia had no significant impact. In contrast, no significant increase of MTTs was detected after in vivo administration of Zn. However, there was a significant negative correlation between MTT and eGFR in vivo in case of Zn administration, this could indicate a protective role of MTTs in a setting of reduced kidney function, which is possibly influenced by Zn. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT00399256 . Retrospectively registered 11/13/2006.
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Zinc'ing it out: zinc homeostasis mechanisms and their impact on the pathogenesis of human pathogen group A streptococcus.
Makthal, N, Kumaraswami, M
Metallomics : integrated biometal science. 2017;(12):1693-1702
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Abstract
Group A Streptococccus (GAS) is a major human pathogen that causes significant morbidity and mortality. Zinc is an essential trace element required for GAS growth, however, zinc can be toxic at excess concentrations. The bacterial strategies to maintain zinc sufficiency without incurring zinc toxicity play a crucial role in host-GAS interactions and have a significant impact on GAS pathogenesis. The host deploys nutritional immune mechanisms to retard GAS growth by causing either zinc deprivation or zinc poisoning. However, GAS overcomes the zinc-dependent host defenses and survives in the hostile environment by employing complex adaptive strategies. In this review, we describe the different host immune strategies that employ either zinc limitation or zinc toxicity in different host environments to control GAS infection. We also discuss the molecular mechanisms and machineries used by GAS to evade host nutritional defenses and establish successful infection. Emerging evidence suggests that the metal transporters are major GAS virulence factors as they compete against host nutritional immune mechanisms to acquire or expel metals and promote bacterial survival in the host. Thus, identification of GAS molecules and elucidation of the mechanisms by which GAS combats host-mediated alterations in zinc availability may lead to novel interference strategies targeting GAS metal acquisition systems.