Role of zinc in health and disease.

This review provides a concise overview of the cellular and clinical aspects of the role of zinc, an essential micronutrient, in human physiology and discusses zinc-related pathological states. Zinc cannot be stored in significant amounts, so regular dietary intake is essential. ZIP4 and/or ZnT5B transport dietary zinc ions from the duodenum into the enterocyte, ZnT1 transports zinc ions from the enterocyte into the circulation, and ZnT5B (bidirectional zinc transporter) facilitates endogenous zinc secretion into the intestinal lumen. Putative promoters of zinc absorption that increase its bioavailability include amino acids released from protein digestion and citrate, whereas dietary phytates, casein and calcium can reduce zinc bioavailability. In circulation, 70% of zinc is bound to albumin, and the majority in the body is found in skeletal muscle and bone. Zinc excretion is via faeces (predominantly), urine, sweat, menstrual flow and semen. Excessive zinc intake can inhibit the absorption of copper and iron, leading to copper deficiency and anaemia, respectively. Zinc toxicity can adversely affect the lipid profile and immune system, and its treatment depends on the mode of zinc acquisition. Acquired zinc deficiency usually presents later in life alongside risk factors like malabsorption syndromes, but medications like diuretics and angiotensin-receptor blockers can also cause zinc deficiency. Inherited zinc deficiency condition acrodermatitis enteropathica, which occurs due to mutation in the SLC39A4 gene (encoding ZIP4), presents from birth. Treatment involves zinc supplementation via zinc gluconate, zinc sulphate or zinc chloride. Notably, oral zinc supplementation may decrease the absorption of drugs like ciprofloxacin, doxycycline and risedronate.

Demographic and clinical characteristics of patients with zinc deficiency: analysis of a nationwide Japanese medical claims database.

Zinc deficiency, affecting more than 2 billion people globally, poses a significant public health burden due to its numerous unfavorable effects, such as impaired immune function, taste and smell disorders, pneumonia, growth retardation, visual impairment, and skin disorders. Despite its critical role, extensive large-scale studies investigating the correlation between patient characteristics and zinc deficiency still need to be completed. We conducted a retrospective, cross-sectional observational study using a nationwide Japanese claims database from January 2019 to December 2021. The study population included 13,100 patients with available serum zinc concentration data, excluding individuals under 20 and those assessed for zinc concentrations after being prescribed zinc-containing medication. Significant associations with zinc deficiency were noted among older adults, males, and inpatients. Multivariate analysis, adjusting for age and sex, indicated significant associations with comorbidities, including pneumonitis due to solids and liquids with an adjusted Odds Ratio (aOR) of 2.959; decubitus ulcer and pressure area (aOR 2.403), sarcopenia (aOR 2.217), COVID-19 (aOR 1.889), and chronic kidney disease (aOR 1.835). Significant association with medications, including spironolactone (aOR 2.523), systemic antibacterials (aOR 2.419), furosemide (aOR 2.138), antianemic preparations (aOR 2.027), and thyroid hormones (aOR 1.864) were also found. These results may aid clinicians in identifying patients at risk of zinc deficiency, potentially improving care outcomes.

Dietary zinc inadequacy affects neurotrophic factors and proteostasis in the rat brain.

Zinc (Zn) deficiency has many adverse effects, including growth retardation, loss of appetite, vascular diseases, cognitive and memory impairment, and neurodegenerative diseases. In the current study, we investigated the hypothesis that dietary Zn inadequacy affects neurotrophic factors and proteostasis in the brain. Three-week-old Wistar/Kyoto male rats were fed either a Zn-deficient diet (D; < 1 mg Zn/kg diet; n = 18) or pair-fed with the control diet (C; 48 mg Zn/kg diet; n = 9) for 4 weeks. Subsequently, the rats in the D group were subdivided into two groups (n = 9), in which one group continued to receive a Zn-deficient diet, whereas the other received a Zn-supplemented diet (R; 48 mg Zn/kg diet) for 3 more weeks, after which the rats were sacrificed to collect their brain tissue. Markers of endoplasmic reticulum stress, ubiquitin-proteasome system, autophagy, and apoptosis, along with neurotrophic factors, were investigated by immunoblotting. Proteasomal activity was analyzed by the spectrofluorometric method. The results showed an altered ubiquitin-proteasome system and autophagy components and increased gliosis, endoplasmic reticulum stress, and apoptosis markers in Zn-deficient rats compared with the control group. Zinc repletion for 3 weeks could partially restore these alterations, indicating a necessity for an extended duration of Zn supplementation. In conclusion, a decline in Zn concentrations below a critical threshold may trigger multiple pathways, leading to brain-cell apoptosis.

Study on the Zinc Nutritional Status and Risk Factors of Chinese 6-18-Year-Old Children.

Zinc is an essential micronutrient that is involved in several metabolic processes, especially children's growth and development. Although many previous studies have evaluated the zinc nutritional status of children, there are very few reports on children aged 6-18 years old. Furthermore, there are few reports on children's zinc nutrition status based on the Chinese population. According to WHO data, the prevalence of zinc deficiency in Asian countries is rather high and has resulted in high child mortality. In this study, we aimed to comprehensively assess zinc nutritional status and the prevalence of zinc deficiency among children aged 6-18 years in China based on nationally representative cross-sectional data. Subgroup comparisons were made under possible influencing factors. The potential risk factors of zinc deficiency were also discussed. A total of 64,850 children, equally male and female, were recruited from 150 monitoring sites in 31 provinces through stratified random sampling from China National Nutrition and Health Survey of Children and Lactating Mothers (CNNHS 2016-2017). Median and interquartile intervals were used to represent the overall zinc concentration levels and different subgroups. A Chi-square test was used to compare serum zinc levels and the prevalence of zinc deficiency in children under different group variables. In order to study the influencing factors of zinc deficiency, multiple logistic regression was utilized. It was found that the median concentration of serum Zn was 88.39 µg/dL and the prevalence of Zn deficiency was 9.62%. The possible influence factors for Zn deficiency were sex, anemia, nutritional status, city type and income. By conducting a subgroup analysis of the factors, it was found that males; those with anemia, stunting and low income; and children living in rural areas have a higher risk of Zn deficiency. This study offers a comprehensive analysis of Zn nutritional status among Chinese children, which provides reliable data for policy formulation to improve the zinc nutrition status of children.

A Potential Association of Zinc Deficiency and Tyrosine Kinase Inhibitor-Induced Hand-Foot Skin Reaction.

Hand-foot skin reaction (HFSR) is a common skin-related adverse event induced by multikinase inhibitors targeting both platelet-derived growth factor receptor and vascular endothelial growth factor receptor, possibly due to inadequate repair following frictional trauma. Zinc is a trace element and essential nutrient in humans that plays critical roles in the development and differentiation of skin cells. Zinc transporters (Zrt- and Irt-like proteins and Zn transporters) and metallothioneins are involved in zinc efflux, uptake, and homeostasis and have been reported to be involved in skin differentiation. The underlying mechanism of HFSR remains unclear, and the association between HFSR and zinc has not been previously studied. However, some case reports and case series provide potential evidence to suggest that zinc deficiency may be involved in HFSR development and zinc supplementation may relieve HFSR symptoms. However, no large-scale clinical studies have been conducted to examine this role. Therefore, this review summarizes the evidence supporting a possible link between HFSR development and zinc and proposes potential mechanisms underlying this association based on current evidence.

Dietary zinc deficient condition increases the Bisphenol A toxicity in diabetic rat testes.

Bisphenol A (BPA) is a widely used endocrine disrupter that causes male reproductive dysfunction in humans and rodents. Diabetes-induced hyperglycemia alters spermatogenesis and antioxidant status, which negatively impacts male fertility in adults. Zinc (Zn) deficiency is a global health concern maintaining the testicular structure and functions in developing gonads. The present experiment was designed to investigate the role of Zn deficiency on BPA-induced germ cell and male gonadal toxicity in diabetic conditions. Rats were randomly divided into eight different groups - control (normal feed and water), BPA (10 mg/kg/day), ZDD (fed with a Zn-deficient diet), DIA (diabetic), BPA+ZDD, BPA+DIA, ZDD+DIA and BPA+ZDD+DIA for four weeks. Animals' body and organ weight, sperm count, motility and sperm morphology were examined; testes and epididymis histopathology were investigated. Testicular DNA damage and sperm apoptosis were evaluated by halo and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays respectively. Testicular catalase and octamer-binding transcription factor 4 (OCT4) expressions were evaluated by western blot analysis. The present results demonstrated that dietary Zn-deficient condition significantly increased the BPA-induced testicular, epididymal and sperm toxicity in diabetic rats due to hypogonadism, increased sperm abnormalities, epididymis, testicular structure and DNA damages, sperm apoptosis as well as decreased testicular catalase and OCT4 expressions. The present results revealed that dietary Zn-deficient condition exacerbated the BPA-induced testicular and epididymal toxicity as well as perturbed the general male reproductive health in diabetic rats.

Zinc deficiency and associated factors among pregnant women's attending antenatal clinics in public health facilities of Konso Zone, Southern Ethiopia.

BACKGROUND: Zinc is an essential mineral known to be important for the normal physiological functions of the immune system. It is one of the basic nutrients required during pregnancy for the normal development and growth of the fetus. However, Zinc deficiency during pregnancy causes irreversible effects on the newborn such as growth impairment, spontaneous abortion, congenital malformations and poor birth outcomes. Even though, the effect of Zinc deficiency is devastating during pregnancy, there is scarcity of evidence on Zinc deficiency and related factors among pregnant women in the current study area. OBJECTIVE: To assess Zinc deficiency and associated factors among pregnant women attending antenatal clinics in public health facilities of Konso Zone, Southern Ethiopia. METHODS: Institution based cross-sectional study was conducted among randomly selected 424 pregnant mothers. Data were collected using pre tested questionnaire (for interview part), and 5 blood sample was drawn for serum zinc level determination. Data were entered to Epi-Data version 3.1 software and exported to SPSS version 25 for analysis. Binary logistic regression analysis was computed and independent variables with a p-value ≤ 0.25 were included in multivariable analysis. Serum zinc level was determined using atomic absorption spectroscopy by applying clean and standard procedures in the laboratory. Finally adjusted odds ratio with 95% confidence level, P-value < 0.05 was used to identify significant factors for Zinc deficiency. RESULT: The prevalence of Zinc deficiency was found to be 128 (30.26%) with the mean serum zinc level of 0.56±0.12 g/dl. Age, 25-34 years [AOR 2.14 (1.19,3.82)], and 35-49 years [AOR 2.59 (1.15, 5.85)], type of occupation, farming [AOR 6.17 (1.36, 28.06)], lack of antenatal follow up during pregnancy [AOR 3.57 (1.05,12.14)], lack of freedom to purchase food items from market [AOR 3.61 (1.27, 10.27)], and inadequate knowledge on nutrition [AOR 3.10(1.58, 6.08)] were factors associated with Zinc deficiency. CONCLUSION: Zinc deficiency is a public health problem among pregnant mothers in the current study area. Improving maternal nutritional knowledge, motivating to have frequent antenatal follow up, and empowering to have financial freedom to purchase food items from market were the modifiable factors to reduce Zinc deficiency. Nutritional intervention that focused on improving nutritional knowledge and insuring access to Zinc sources food items should be delivered for pregnant mothers.

Impact of Zinc Transport Mechanisms on Embryonic and Brain Development.

The trace element zinc (Zn) binds to over ten percent of proteins in eukaryotic cells. Zn flexible chemistry allows it to regulate the activity of hundreds of enzymes and influence scores of metabolic processes in cells throughout the body. Deficiency of Zn in humans has a profound effect on development and in adults later in life, particularly in the brain, where Zn deficiency is linked to several neurological disorders. In this review, we will summarize the importance of Zn during development through a description of the outcomes of both genetic and early dietary Zn deficiency, focusing on the pathological consequences on the whole body and brain. The epidemiology and the symptomology of Zn deficiency in humans will be described, including the most studied inherited Zn deficiency disease, Acrodermatitis enteropathica. In addition, we will give an overview of the different forms and animal models of Zn deficiency, as well as the 24 Zn transporters, distributed into two families: the ZIPs and the ZnTs, which control the balance of Zn throughout the body. Lastly, we will describe the TRPM7 ion channel, which was recently shown to contribute to intestinal Zn absorption and has its own significant impact on early embryonic development.

Heterologous Expression of Full-Length and Truncated Human ZIP4 Zinc Transporter in Saccharomyces cerevisiae.

The human (h) transporter hZIP4 is the primary Zn2+ importer in the intestine. hZIP4 is also expressed in a variety of organs such as the pancreas and brain. Dysfunction of hZIP4 can result in the Zn2+ deficiency disease acrodermatitis enteropathica (AE). AE can disrupt digestive and immune system homeostasis. A limited number of hZIP4 expression strategies have hindered increasing knowledge about this essential transmembrane protein. Here, we report the heterologous expression of hZIP4 in Saccharomyces cerevisiae. Both a wild-type and a mutant S. cerevisiae strain, in which the endogenous Zn2+ transporters were deleted, were used to test the expression and localization of an hZIP4-GFP fusion protein. A full-length hZIP4-GFP and a truncated membrane-domain-only (mhZIP4-GFP) protein were observed to be present in the plasma membrane in yeast.

Zinc is an essential element for the maintenance of redox homeostasis and cell cycle in murine auditory hair cells.

A nutrition deficiency is one of the various causes of hearing loss. Zinc is an essential element for cell proliferation, antioxidant reactions, and the maintenance of hearing ability. Our previous studies have reported that the auditory brainstem response (ABR) threshold is increased in mice fed with zinc-deficient diets. However, the molecular mechanism of zinc involved in auditory system remains to be elucidated. In the present study, we examined the detrimental effects of zinc deficiency on cell cycle progression in murine auditory cells (HEI-OC1). The treatment of HEI-OC1 cells with 0.5 µM TPEN (N,N,N',N'-Tetrakis (2-pyridylmethyl) ethylenediamine) for 24 h inhibited cell proliferation, accumulation of reactive oxygen species (ROS), and induction of apoptosis. The cell proliferation block was caused by a G1/S phase arrest. Supplementation of the cell growth medium with 5 µM ZnCl2 after exposure to TPEN attenuated ROS accumulation and the arrest caused by the zinc deficiency. The ABR threshold was elevated in mice fed with a zinc-deficient diet. Additionally, we observed an increased expression of p21 and decreased expression of cyclin E and pRb in the spiral ganglion (SG), the organ of Corti (OC), Limbus (L), and stria vascularis (SV) in the zinc-deficient mouse cochlea. These results indicated that zinc is an essential nutrient for proliferation via the cell cycle and that a dysregulation of the cell cycle may cause hearing loss.

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 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.

Aberrance of Zinc Metalloenzymes-Induced Human Diseases and Its Potential Mechanisms.

Zinc, an essential micronutrient in the human body, is a component in over 300 enzymes and participates in regulating enzymatic activity. Zinc metalloenzymes play a crucial role in physiological processes including antioxidant, anti-inflammatory, and immune responses, as well as apoptosis. Aberrant enzyme activity can lead to various human diseases. In this review, we summarize zinc homeostasis, the roles of zinc in zinc metalloenzymes, the physiological processes of zinc metalloenzymes, and aberrant zinc metalloenzymes in human diseases. In addition, potential mechanisms of action are also discussed. This comprehensive understanding of the mechanisms of action of the regulatory functions of zinc in enzyme activity could inform novel zinc-micronutrient-supply strategies for the treatment of diseases.

Zinc is a key regulator of gastrointestinal development, microbiota composition and inflammation with relevance for autism spectrum disorders.

Gastrointestinal (GI) problems and microbiota alterations have been frequently reported in autism spectrum disorders (ASD). In addition, abnormal perinatal trace metal levels have been found in ASD. Accordingly, mice exposed to prenatal zinc deficiency display features of ASD-like behavior. Here, we model GI development using 3D intestinal organoids grown under zinc-restricted conditions. We found significant morphological alterations. Using proteomic approaches, we identified biological processes affected by zinc deficiency that regulate barrier permeability and pro-inflammatory pathways. We confirmed our results in vivo through proteomics studies and investigating GI development in zinc-deficient mice. These show altered GI physiology and pro-inflammatory signaling, resulting in chronic systemic and neuroinflammation, and gut microbiota composition similar to that reported in human ASD cases. Thus, low zinc status during development is sufficient to compromise intestinal barrier integrity and activate pro-inflammatory signaling, resulting in changes in microbiota composition that may aggravate inflammation, altogether mimicking the co-morbidities frequently observed in ASD.

Prevalence of Zinc Deficiency in Healthy 1-3-Year-Old Children from Three Western European Countries.

Zinc deficiency (ZnD) has adverse health consequences such as stunted growth. Since young children have an increased risk of developing ZnD, it is important to determine its prevalence and associated factors in this population. However, only a few studies have reported on ZnD prevalence in young children from Western high-income countries. This study evaluated ZnD prevalence and associated factors, including dietary Zn intake, in healthy 1-3-year-old children from Western European, high-income countries. ZnD was defined as serum Zn concentration <9.9 µmol/L. A total of 278 children were included with a median age of 1.7 years (Q1-Q3: 1.2-2.3). The median Zn concentration was 11.0 µmol/L (Q1-Q3: 9.0-12.2), and ZnD prevalence was 31.3%. No significant differences were observed in the socio-economic characteristics between children with and without ZnD. Dietary Zn intake was not associated with ZnD. ZnD is common in healthy 1-3-year-old children from Western European countries. However, the use of currently available cut-off values defining ZnD in young children has its limitations since these are largely based on reference values in older children. Moreover, these values were not evaluated in relation to health consequences, warranting further research.

Albumin Substitution in Decompensated Liver Cirrhosis: Don't Forget Zinc.

Decompensated liver cirrhosis has a dismal prognosis, with patients surviving on average for 2-4 years after the first diagnosis of ascites. Albumin is an important tool in the therapy of cirrhotic ascites. By virtue of its oncotic properties, it reduces the risk of cardiovascular dysfunction after paracentesis. Treatment with albumin also counteracts the development of hepatorenal syndrome and spontaneous bacterial peritonitis. More recently, the positive impact of long-term albumin supplementation in liver disease, based on its pleiotropic non-oncotic activities, has been recognized. These include transport of endo- and exogenous substances, anti-inflammatory, antioxidant and immunomodulatory activities, and stabilizing effects on the endothelium. Besides the growing recognition that effective albumin therapy requires adjustment of the plasma level to normal physiological values, the search for substances with adjuvant activities is becoming increasingly important. More than 75% of patients with decompensated liver cirrhosis do not only present with hypoalbuminemia but also with zinc deficiency. There is a close relationship between albumin and the essential trace element zinc. First and foremost, albumin is the main carrier of zinc in plasma, and is hence critical for systemic distribution of zinc. In this review, we discuss important functions of albumin in the context of metabolic, immunological, oxidative, transport, and distribution processes, alongside crucial functions and effects of zinc and their mutual dependencies. In particular, we focus on the major role of chronic inflammatory processes in pathogenesis and progression of liver cirrhosis and how albumin therapy and zinc supplementation may affect these processes.