Zinc ionophores: chemistry and biological applications.

Zinc can play a pathophysiological role in several diseases and can interfere in key processes of microbial growth. This evidence justifies the efforts in applying Zinc ionophores to restore Zinc homeostasis and treat bacterial/viral infections such as coronavirus diseases. Zinc ionophores increase the intracellular concentration of Zinc ions causing significant biological effects. This review provides, for the first time, an overview of the applications of the main Zinc ionophores in Zinc deficiency, infectious diseases, and in cancer, discussing the pharmacological and coordination properties of the Zinc ionophores.

Zinc as a Drug for Wilson's Disease, Non-Alcoholic Liver Disease and COVID-19-Related Liver Injury.

Zinc is the second most abundant trace element in the human body, and it plays a fundamental role in human physiology, being an integral component of hundreds of enzymes and transcription factors. The discovery that zinc atoms may compete with copper for their absorption in the gastrointestinal tract let to introduce zinc in the therapy of Wilson's disease, a congenital disorder of copper metabolism characterized by a systemic copper storage. Nowadays, zinc salts are considered one of the best therapeutic approach in patients affected by Wilson's disease. On the basis of the similarities, at histological level, between Wilson's disease and non-alcoholic liver disease, zinc has been successfully introduced in the therapy of non-alcoholic liver disease, with positive effects both on insulin resistance and oxidative stress. Recently, zinc deficiency has been indicated as a possible factor responsible for the susceptibility of elderly patients to undergo infection by SARS-CoV-2, the coronavirus responsible for the COVID-19 pandemic. Here, we present the data correlating zinc deficiency with the insurgence and progression of Covid-19 with low zinc levels associated with severe disease states. Finally, the relevance of zinc supplementation in aged people at risk for SARS-CoV-2 is underlined, with the aim that the zinc-based drug, classically used in the treatment of copper overload, might be recorded as one of the tools reducing the mortality of COVID-19, particularly in elderly people.

Association between COVID-19 and angiotensin-converting enzyme inhibitors with the spotlight on zinc: an opinion.

In the setting of the raging COVID-19 pandemic, the search for innovative therapeutics is desperately sought after. As we learn more about the characteristics and metabolic health of patients and as our understanding of COVID-19 pathophysiology and treatment progresses, so is our understanding of medication effects that might increase disease severity. As of late, ACE inhibitors have been under investigation for a potential increase in illness severity due to ACE2 upregulation. Given our knowledge of other nutrient-pharmaceutical interactions, could the ACE inhibitor impact on COVID be due to something else? In this paper, we discuss the possibility that ACE inhibitors might be affecting COVID-19 patients by causing zinc insufficiency.KEY MESSAGESZinc deficiency caused by chronic ACE inhibitor usage may exacerbate the pathogenicity of COVID-19 in susceptible patients.A multi-center study is needed to assess the zinc levels of patients with COVID-19 who are taking ACE inhibitors and other medications that may result in low zinc levels.

Clinical Significance of Micronutrient Supplementation in Critically Ill COVID-19 Patients with Severe ARDS.

The interplay between inflammation and oxidative stress is a vicious circle, potentially resulting in organ damage. Essential micronutrients such as selenium (Se) and zinc (Zn) support anti-oxidative defense systems and are commonly depleted in severe disease. This single-center retrospective study investigated micronutrient levels under Se and Zn supplementation in critically ill patients with COVID-19 induced acute respiratory distress syndrome (ARDS) and explored potential relationships with immunological and clinical parameters. According to intensive care unit (ICU) standard operating procedures, patients received 1.0 mg of intravenous Se daily on top of artificial nutrition, which contained various amounts of Se and Zn. Micronutrients, inflammatory cytokines, lymphocyte subsets and clinical data were extracted from the patient data management system on admission and after 10 to 14 days of treatment. Forty-six patients were screened for eligibility and 22 patients were included in the study. Twenty-one patients (95%) suffered from severe ARDS and 14 patients (64%) survived to ICU discharge. On admission, the majority of patients had low Se status biomarkers and Zn levels, along with elevated inflammatory parameters. Se supplementation significantly elevated Se (p = 0.027) and selenoprotein P levels (SELENOP; p = 0.016) to normal range. Accordingly, glutathione peroxidase 3 (GPx3) activity increased over time (p = 0.021). Se biomarkers, most notably SELENOP, were inversely correlated with CRP (rs = -0.495), PCT (rs = -0.413), IL-6 (rs = -0.429), IL-1ß (rs = -0.440) and IL-10 (rs = -0.461). Positive associations were found for CD8+ T cells (rs = 0.636), NK cells (rs = 0.772), total IgG (rs = 0.493) and PaO2/FiO2 ratios (rs = 0.504). In addition, survivors tended to have higher Se levels after 10 to 14 days compared to non-survivors (p = 0.075). Sufficient Se and Zn levels may potentially be of clinical significance for an adequate immune response in critically ill patients with severe COVID-19 ARDS.

Assessment of the role of zinc in the prevention of COVID-19 infections and mortality: A retrospective study in the Asian and European population.

Several studies have demonstrated an association between individual zinc status and viral respiratory infections; however, evidence regarding COVID-19 is still missing or insufficient. This study aimed to evaluate the correlation between the prevalence of zinc deficiency and COVID-19 cases and deaths per million population in the Asian and European countries. The COVID-19 data from two different time points, that is, May 30 and June 30, 2020 for the Asian population and May 15 and June 15, 2020 for the European population, were analyzed to determine the correlation with the estimated zinc deficiency for these two continents. The prevalence of zinc deficiency was about two times higher in the Asian population (mean 17.5%) than in the European population (mean 8.9%). A significant positive correlation (p < .05) was observed between the prevalence of zinc deficiency and COVID-19 cases at both time periods for the Asian population. However, the correlation between zinc deficiency prevalence and COVID-19 deaths was not significant in the Asian population. In contrast, a significant but negative correlation (p < .05 for all cases) was observed for zinc deficiency with both COVID-19 cases and deaths per million population at both time periods in the European countries. Considering the direct antiviral properties of zinc, it can be suggested that zinc supplementation may be beneficial for most of the population, especially older people and those who are at risk of COVID-19 infections. In conclusion, there is not enough evidence on the association between individual zinc status and COVID-19 infections and mortality. Therefore, cohort studies and randomized controlled trials are required to test this hypothesis.

Hipótesis sobre las conexiones entre COVID-19 severo en niños y nutrición: una revisión narrativa.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). Compared with adults, children with SARS-CoV-2 infection may have fewer and less severe symptoms. Gastrointestinal symptoms are commonly reported in children, sometimes as the only manifestation of the disease, and most often manifest as anorexia, diarrhea, nausea and vomiting, or abdominal pain. Although most children have asymptomatic or mild disease, 10 % of those infected may experience serious or critical disease, or even death. Multisystem inflammatory syndrome is a rare but serious condition recently reported in children with COVID-19. Studies indicate that children with obesity are at higher risk of developing severe COVID-19, and inflammation associated with obesity could be one of the factors that worsens COVID-19 symptoms due to an increased inflammatory response involving molecules such as interleukin 6, tumor necrosis factor alpha, and monocyte chemoattractant protein. On the other hand, evidence has been reported of a higher protein expression of ACE2 in the visceral adipose tissue of obese and malnourished humans, and this could be associated with complications and severity of COVID-19. Therefore, regulation of the intake of macronutrients or micronutrients could be used as a strategy to reduce the consequences of COVID-19. Diet in general and bioactive compounds could play an important role in the prevention of the inflammatory cascade. The micronutrients with the most evidence suggesting a role in immune support are vitamins C and D, zinc, and polyphenols.

INTRODUCCIÓN: La enfermedad por coronavirus 2019 (COVID-19) está causada por el virus "síndrome respiratorio agudo severo-coronavirus 2" (SARS-CoV-2). En comparación con los adultos, los niños con infección por SARS-CoV-2 pueden tener menos síntomas y estos pueden ser menos graves. Los síntomas gastrointestinales se informan comúnmente en los niños, a veces como única manifestación de la enfermedad. Los más comunes son anorexia, diarrea, náuseas y vómitos, y dolor abdominal. Aunque la mayoría de los niños tienen un cuadro leve o asintomático, el 10 % de los infectados pueden experimentar un cuadro grave o crítico, e incluso la muerte. El síndrome inflamatorio multisistémico es una afección poco común, pero grave, que se documentó recientemente en niños con COVID-19. Los estudios indican que los niños con obesidad tienen mayor riesgo de desarrollar COVID-19 grave, y la inflamación asociada con la obesidad podría ser uno de los factores que empeoran los síntomas de la COVID-19 debido a una respuesta inflamatoria aumentada en donde se ven involucradas moléculas como la interleucina 6, el factor de necrosis tumoral alfa y la proteína quimioatrayente de monocitos. Por otro lado, se ha encontrado evidencia de una mayor expresión proteica de ACE2 en el tejido adiposo visceral de los seres humanos obesos y desnutridos, y esto podría estar asociado a las complicaciones y la severidad de la COVID-19. Por tanto, la regulación de la ingesta de macronutrientes o micronutrientes podría utilizarse como estrategia para reducir las consecuencias de la enfermedad. La dieta en general y los compuestos bioactivos podrían desempeñar un papel importante en la prevención de la cascada inflamatoria. Los micronutrientes con mayor evidencia indicativa de que desempeñan un papel en el apoyo inmunológico son las vitaminas C y D, el zinc y los polifenoles.

Zinc.

Since the discovery of manifest Zn deficiency in 1961, the increasing number of studies demonstrated the association between altered Zn status and multiple diseases. In this chapter, we provide a review of the most recent advances on the role of Zn in health and disease (2010-20), with a special focus on the role of Zn in neurodegenerative and neurodevelopmental disorders, diabetes and obesity, male and female reproduction, as well as COVID-19. In parallel with the revealed tight association between ASD risk and severity and Zn status, the particular mechanisms linking Zn2+ and ASD pathogenesis like modulation of synaptic plasticity through ProSAP/Shank scaffold, neurotransmitter metabolism, and gut microbiota, have been elucidated. The increasing body of data indicate the potential involvement of Zn2+ metabolism in neurodegeneration. Systemic Zn levels in Alzheimer's and Parkinson's disease were found to be reduced, whereas its sequestration in brain may result in modulation of amyloid ß and α-synuclein processing with subsequent toxic effects. Zn2+ was shown to possess adipotropic effects through the role of zinc transporters, zinc finger proteins, and Zn-α2-glycoprotein in adipose tissue physiology, underlying its particular role in pathogenesis of obesity and diabetes mellitus type 2. Recent findings also contribute to further understanding of the role of Zn2+ in spermatogenesis and sperm functioning, as well as oocyte development and fertilization. Finally, Zn2+ was shown to be the potential adjuvant therapy in management of novel coronavirus infection (COVID-19), underlining the perspectives of zinc in management of old and new threats.

Zinc deficiency as a possible risk factor for increased susceptibility and severe progression of Corona Virus Disease 19.

The importance of Zn for human health becomes obvious during Zn deficiency. Even mild insufficiencies of Zn cause alterations in haematopoiesis and immune functions, resulting in a proinflammatory phenotype and a disturbed redox metabolism. Although immune system malfunction has the most obvious effect, the functions of several tissue cell types are disturbed if Zn supply is limiting. Adhesion molecules and tight junction proteins decrease, while cell death increases, generating barrier dysfunction and possibly organ failure. Taken together, Zn deficiency both weakens the resistance of the human body towards pathogens and at the same time increases the danger of an overactive immune response that may cause tissue damage. The case numbers of Corona Virus Disease 19 (COVID-19) are still increasing, which is causing enormous problems for health systems and economies. There is an urgent need to reduce both the number of severe cases and the resulting deaths. While therapeutic options are still under investigation, and first vaccines have been approved, cost-effective ways to reduce the likelihood of or even prevent infection, and the transition from mild symptoms to more serious detrimental disease, are highly desirable. Nutritional supplementation might be an effective option to achieve these aims. In this review, we discuss known Zn deficiency effects in the context of an infection with Severe Acute Respiratory Syndrome-Coronavirus-2 and its currently known pathogenic mechanisms and elaborate on how severe pre-existing Zn deficiency may pre-dispose patients to a severe progression of COVID-19. First published clinical data on the association of Zn homoeostasis with COVID-19 and registered studies in progress are listed.

Association Between Low Zinc Levels and Severity of Acute Respiratory Distress Syndrome by New Coronavirus SARS-CoV-2.

BACKGROUND: We verify the prevalence of low zinc levels among critically ill patients infected by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in the intensive care unit (ICU) who required invasive mechanical ventilation, as well as its association with severity of acute respiratory distress syndrome (ARDS). METHODS: This is an observational study composed of patients admitted to the ICU. Demographics, anthropometric data for calculating body mass index (BMI), and laboratory data were obtained at admission: blood count, ferritin, arterial blood gas, serum zinc levels, and C-reactive protein. Also, arterial oxygen tension (PaO2 ) divided by fractional inspired oxygen (FiO2 ) was calculated by the first arterial blood gas after intubation. A diagnosis of severe ARDS was determined if the PaO2 /FiO2 ratio was ≤100 mm Hg. Low zinc levels were established if zinc levels were <70 µg/dL. RESULTS: A total of 269 patients met inclusion criteria; 51.3% were men; median age was 74 (66-81) years; 91.1% (245 of 269) were elderly. The median BMI was 30.1 (24.7-32.1) kg/m2 , with 59.9% (161 of 269) of patients having overweight and obesity. The prevalence of low zinc levels was 79.6% (214 of 269) and severe ARDS was 56.5% (152 of 269). There was an association of low zinc levels and severe ARDS (odds ratio [OR], 14.4; 95% CI, 6.2-33.5; P < .001), even after adjusting for baseline variables (OR, 15.4; 95% CI, 6.5-36.3; P < .001). CONCLUSION: Critically ill patients infected by SARS-CoV-2 with severe ARDS have a high prevalence of low serum zinc levels.

Zinc against COVID-19? Symptom surveillance and deficiency risk groups.

A wide variety of symptoms is associated with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, and these symptoms can overlap with other conditions and diseases. Knowing the distribution of symptoms across diseases and individuals can support clinical actions on timelines shorter than those for drug and vaccine development. Here, we focus on zinc deficiency symptoms, symptom overlap with other conditions, as well as zinc effects on immune health and mechanistic zinc deficiency risk groups. There are well-studied beneficial effects of zinc on the immune system including a decreased susceptibility to and improved clinical outcomes for infectious pathogens including multiple viruses. Zinc is also an anti-inflammatory and anti-oxidative stress agent, relevant to some severe Coronavirus Disease 2019 (COVID-19) symptoms. Unfortunately, zinc deficiency is common worldwide and not exclusive to the developing world. Lifestyle choices and preexisting conditions alone can result in zinc deficiency, and we compile zinc risk groups based on a review of the literature. It is also important to distinguish chronic zinc deficiency from deficiency acquired upon viral infection and immune response and their different supplementation strategies. Zinc is being considered as prophylactic or adjunct therapy for COVID-19, with 12 clinical trials underway, highlighting the relevance of this trace element for global pandemics. Using the example of zinc, we show that there is a critical need for a deeper understanding of essential trace elements in human health, and the resulting deficiency symptoms and their overlap with other conditions. This knowledge will directly support human immune health for decreasing susceptibility, shortening illness duration, and preventing progression to severe cases in the current and future pandemics.

COVID-19: Poor outcomes in patients with zinc deficiency.

BACKGROUND: Zinc is a trace element with potent immunoregulatory and antiviral properties, and is utilized in the treatment of coronavirus disease 2019 (COVID-19). However, we do not know the clinical significance of serum Zinc levels in COVID-19 patients. The aim of this study was to determine the clinical significance of serum zinc in COVID-19 patients and to establish a correlation with disease severity. METHODS: This was a prospective study of fasting zinc levels in COVID-19 patients at the time of hospitalization. An initial comparative analysis was conducted between COVID-19 patients and healthy controls. COVID-19 patients with zinc deficiency were compared to those with normal zinc levels. RESULTS: COVID-19 patients (n = 47) showed significantly lower zinc levels when compared to healthy controls (n = 45): median 74.5 (interquartile range 53.4-94.6) µg/dl vs 105.8 (interquartile range 95.65-120.90) µg/dl (p < 0.001). Amongst the COVID-19 patients, 27 (57.4%) were found to be zinc deficient. These patients were found to have higher rates of complications (p = 0.009), acute respiratory distress syndrome (18.5% vs 0%, p = 0.06), corticosteroid therapy (p = 0.02), prolonged hospital stay (p = 0.05), and increased mortality (18.5% vs 0%, p = 0.06). The odds ratio (OR) of developing complications was 5.54 for zinc deficient COVID-19 patients. CONCLUSIONS: The study data clearly show that a significant number of COVID-19 patients were zinc deficient. These zinc deficient patients developed more complications, and the deficiency was associated with a prolonged hospital stay and increased mortality.

The Potential Impact of Zinc Supplementation on COVID-19 Pathogenesis.

During the current corona pandemic, new therapeutic options against this viral disease are urgently desired. Due to the rapid spread and immense number of affected individuals worldwide, cost-effective, globally available, and safe options with minimal side effects and simple application are extremely warranted. This review will therefore discuss the potential of zinc as preventive and therapeutic agent alone or in combination with other strategies, as zinc meets all the above described criteria. While a variety of data on the association of the individual zinc status with viral and respiratory tract infections are available, study evidence regarding COVID-19 is so far missing but can be assumed as was indicated by others and is detailed in this perspective, focusing on re-balancing of the immune response by zinc supplementation. Especially, the role of zinc in viral-induced vascular complications has barely been discussed, so far. Interestingly, most of the risk groups described for COVID-19 are at the same time groups that were associated with zinc deficiency. As zinc is essential to preserve natural tissue barriers such as the respiratory epithelium, preventing pathogen entry, for a balanced function of the immune system and the redox system, zinc deficiency can probably be added to the factors predisposing individuals to infection and detrimental progression of COVID-19. Finally, due to its direct antiviral properties, it can be assumed that zinc administration is beneficial for most of the population, especially those with suboptimal zinc status.

COVID-19 Pandemic: Can Maintaining Optimal Zinc Balance Enhance Host Resistance?

The novel coronavirus disease 2019 (COVID-19) is now officially declared as a pandemic by the World Health Organization (WHO), and most parts of the world are taking drastic measures to restrict human movements to contain the infection. Millions around the world are wondering, if there is anything that could be done, other than maintaining high personal hygiene, and be vigilant of the symptoms, to reduce the spread of the disease and chances of getting infected, or at least to lessen the burden of the disease, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The National and International health agencies, including the National Institutes of Health (NIH), the Centers for Disease Control and Prevention (CDC), and the WHO have provided clear guidelines for both preventive and treatment suggestions. In this article, I will briefly discuss, why keeping adequate zinc balance might enhance the host response and be protective of viral infections.