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Zinc in human health: effect of zinc on immune cells
Prasad AS.Wayne State University School of Medicine, Detroit, Michigan 48201, United States of America
Mol Med. 2008 May-Jun
Although the essentiality of zinc for plants and animals has been known for many decades, the essentiality of zinc for humans was recognized only 40 years ago in the Middle East. The zinc-deficient patients had severe immune dysfunctions, inasmuch as they died of intercurrent infections by the time they were 25 years of age. In our studies in an experimental human model of zinc deficiency, we documented decreased serum testosterone level, oligospermia, severe immune dysfunctions mainly affecting T helper cells, hyperammonemia, neurosensory disorders, and decreased lean body mass. It appears that zinc deficiency is prevalent in the developing world and as many as two billion subjects may be growth retarded due to zinc deficiency. Besides growth retardation and immune dysfunctions, cognitive impairment due to zinc deficiency also has been reported recently. Our studies in the cell culture models showed that the activation of many zinc-dependent enzymes and transcription factors were adversely affected due to zinc deficiency. In HUT-78 (T helper 0 [Th(0)] cell line), we showed that a decrease in gene expression of interleukin-2 (IL-2) and IL-2 receptor alpha(IL-2Ralpha) were due to decreased activation of nuclear factor-kappaB (NF-kappaB) in zinc deficient cells. Decreased NF-kappaB activation in HUT-78 due to zinc deficiency was due to decreased binding of NF-kappaB to DNA, decreased level of NF-kappaB p105 (the precursor of NF-kappaB p50) mRNA, decreased kappaB inhibitory protein (IkappaB) phosphorylation, and decreased Ikappa kappa. These effects of zinc were cell specific. Zinc also is an antioxidant and has anti-inflammatory actions. The therapeutic roles of zinc in acute infantile diarrhea, acrodermatitis enteropathica, prevention of blindness in patients with age-related macular degeneration, and treatment of common cold with zinc have been reported. In HL-60 cells (promyelocytic leukemia cell line), zinc enhances the up-regulation of A20 mRNA, which, via TRAF pathway, decreases NF-kappaB activation, leading to decreased gene expression and generation of tumor necrosis factor-alpha (TNF-alpha), IL-1beta, and IL-8. We have reported recently that in both young adults and elderly subjects, zinc supplementation decreased oxidative stress markers and generation of inflammatory cytokines.
Zinc: mechanisms of host defense
Prasad AS.
Department of Internal Medicine, Division of Hematology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan
J Nutr. 2007 May
Zinc deficiency in humans decreases the activity of serum thymulin (a thymic hormone), which is required for maturation of T-helper cells. T-helper 1 (Th(1)) cytokines are decreased but T-helper 2 (Th(2)) cytokines are not affected by zinc deficiency in humans. This shift of Th (1) to Th (2) function results in cell-mediated immune dysfunction. Because IL-2 production (Th (1) cytokine) is decreased, this leads to decreased activities of natural-killer cell and T cytolytic cells, which are involved in killing viruses, bacteria, and tumor cells. In humans, zinc deficiency may decrease the generation of new CD4+ T cells from the thymus. In cell culture studies (HUT-78, a Th(0) human malignant lymphoblastoid cell line), as a result of zinc deficiency, nuclear factor-kappaB (NF-kappaB) activation, phosphorylation of IkappaB, and binding of NF-kappaB to DNA are decreased and this results in decreased Th(1) cytokine production. In another study, zinc supplementation to humans decreased the gene expression and production of pro-inflammatory cytokines and decreased oxidative stress markers. In HL-60 cells (a human pro-myelocytic leukemia cell line), zinc deficiency increased the levels of TNF-alpha, IL-1beta, and IL-8 cytokines and mRNA. In these cells, zinc induced A20, a zinc finger protein that inhibited NF-kappaB activation via tumor necrosis factor receptor associated factor pathway, and this decreased gene expression of pro-inflammatory cytokines and oxidative stress markers. We conclude that zinc has an important role in cell-mediated immune functions and also functions as antiinflammatory and antioxidant agent.
Acute and persistent diarrhea
Queensland Paediatric Infectious Diseases Laboratory, Queensland Children's Medical Research Institute, Royal Children's Hospital, Herston Road, Herston, Brisbane, Queensland 4029, Australia.
Pediatr Clin North Am. 2009
Socially disadvantaged Indigenous infants and children living in western industrialized countries experience high rates of infectious diarrhea, no more so than Aboriginal children from remote and rural regions of Northern Australia. Diarrheal disease, poor nutrition, and intestinal enteropathy reflect household crowding, inadequate water and poor sanitation and hygiene. Acute episodes of watery diarrhea are often best managed by oral glucose-electrolyte solutions with continuation of breastfeeding and early reintroduction of feeding. Selective use of lactose-free milk formula, short-term zinc supplementation and antibiotics may be necessary for ill children with poor nutrition, persistent symptoms, or dysentery. Education, high standards of environmental hygiene, breastfeeding, and immunization with newly licensed rotavirus vaccines are all needed to reduce the unacceptably high burden of diarrheal disease encountered in young children from Indigenous communities.
Effect of prenatal zinc supplementation on birth weight
Saaka M, Oosthuizen J, Beatty S. School of Exercise, Biomedical and Health Sciences, Edith Cowan University,
J Health Popul Nutr. 2009 Oct
Although iron and zinc deficiencies are known to occur together and also appear to be high in Ghana, a few supplementation studies addressed this concurrently in pregnancy. In a double-blind, randomized controlled trial, 600 pregnant women in Ghana were randomly assigned to receive either a combined supplement of 40 mg of zinc as zinc gluconate and 40 mg of iron as ferrous sulphate or 40 mg of elemental iron as ferrous sulphate. Overall, there was no detectable difference in the mean birthweight between the study groups, although the effect of iron-zinc supplementation on the mean birthweight was masked by a strong interaction between the type of supplement and the iron status of participants [F (1,179) = 5.614, p = 0.019]. Prenatal iron-zinc supplementation was effective in increasing the mean birthweight among anaemic and iron-deficient women but not among women with elevated iron stores in early pregnancy.
Oxidative stress, diabetes, and diabetic complications
Wei W, Liu Q, Tan Y, Liu L, Li X, Cai L.
The Second Hospital, Jilin University, Changchun, China.
Hemoglobin. 2009
Oxidative stress is considered to be the main cause for several chronic diseases including diabetes. Through hyperglycemia, hyperlipidemia, hypertension and possible iron dyshomeostasis, diabetes induces oxidative stress that causes damage to multiple organs, leading to various complications. Therefore, antioxidant therapy may be an interesting approach to prevent diabetes and diabetic complications. Metallothionein as a potent antioxidant was found to significantly protect heart and kidney against diabetes-induced pathophysiological changes. Zinc as an important trace element and a metallothionein inducer was found to have same protective function. Since diabetes would impair defensive system, including growth factor reduction, exogenous supplementation of fibroblast growth factor (FGF) significantly prevented diabetes-induced cardiac oxidative damage and wound healing impairment. These studies suggest that protective agents such as metallothionein, zinc and FGFs play an important role in preventing the development of diabetes and diabetic complications.
The ubiquitous role of zinc in health and disease
Cummings JE, Kovacic JP.
Fox Valley Animal Referral Center, Appleton, WI 54914, USA. J Vet Emerg Crit Care (San Antonio). 2009
OBJECTIVE: To review zinc physiology and pathophysiology and the importance of zinc toxicity and deficiency in veterinary patients. DATA SOURCES: A review of human and veterinary medical literature. HUMAN DATA SYNTHESIS: There is a significant amount of original research in humans and animals on the role of zinc in multiple organ systems. There is also significant data available on human patients with zinc abnormalities. VETERINARY DATA SYNTHESIS: Zinc deficiency has been studied in dogs with genetic disease and dietary deficiency leading to dermatological disease and immune deficiency. Zinc toxicity has been described after ingestion of metallic foreign bodies containing zinc. CONCLUSIONS: Historically, the role of zinc in health and disease has been studied through patients with toxicity or severe deficiency with obvious clinical signs. As the ubiquitous contribution of zinc to structure and function in biological systems was discovered, clinically significant but subtle deficiency states have been revealed. In human medicine, mild zinc deficiencies are currently thought to cause chronic metabolic derangement leading to or exacerbating immune deficiency, gastrointestinal problems, endocrine disorders, neurologic dysfunction, cancer, accelerated aging, degenerative disease, and more. Determining the causal relationships between mild zinc deficiency and concurrent disease is complicated by the lack of sensitive or specific tests for zinc deficiency. The prevalence of zinc deficiency and its contribution to disease in veterinary patients is not well known. Continued research is warranted to develop more sensitive and specific tests to assess zinc status, to determine which patients are at risk for deficiency, and to optimize supplementation in health and disease.
Zinc deficiency
Tuerk MJ, Fazel N.
Department of Dermatology, University of California, Davis, Sacramento,, USA.
Curr Opin Gastroenterol. 2009
PURPOSE OF REVIEW: Zinc plays an essential role in numerous biochemical pathways. Zinc deficiency affects many organ systems, including the integumentary, gastrointestinal, central nervous system, immune, skeletal, and reproductive systems. This article aims to discuss zinc metabolism and highlights a few of the diseases associated with zinc deficiency. RECENT FINDINGS: Zinc deficiency results in dysfunction of both humoral and cell-mediated immunity and increases the susceptibility to infection. Supplementation of zinc has been shown to reduce the incidence of infection as well as cellular damage from increased oxidative stress. Zinc deficiency is also associated with acute and chronic liver disease. Zinc supplementation protects against toxin-induced liver damage and is used as a therapy for hepatic encephalopathy in patients refractory to standard treatment. Zinc deficiency has also been implicated in diarrheal disease, and supplementation has been effective in both prophylaxis and treatment of acute diarrhea. SUMMARY: This article is not meant to review all of the disease states associated with zinc deficiency. Rather, it is an introduction to the influence of the many roles of zinc in the body, with an extensive discussion of the influence of zinc deficiency in selected diseases. Zinc supplementation may be beneficial as an adjunct to treatment of many disease states.
Clinical and biochemical manifestations of zinc deficiency in human subjects
Prasad AS
J Am Coll Nutr. 1985
During the past two decades, essentiality of zinc for man has been established. Deficiency of zinc in man attributable to nutritional factors and several diseased states has been recognized. High phytate content of cereal proteins decreases availability of zinc; thus the prevalence of zinc deficiency is likely to be high in the population subsisting mainly on cereal proteins. Zinc deficiency has been noted to occur in patients with malabsorption syndrome, chronic renal disease, cirrhosis of the liver, sickle cell disease, AE (acrodermatitis enteropathica), and other chronically debilitating diseases. Growth retardation, male hypogonadism, skin changes, poor appetite, mental lethargy, and delayed wound healing are some of the manifestations of chronically zinc-deficient human subjects. In severely zinc-deficient patients, dermatological manifestations, diarrhea, alopecia, mental disturbances, and intercurrent infections predominate. If untreated, the condition becomes fatal. Zinc deficiency affects testicular functions adversely in man and animals. This effect of zinc is at the end-organ level. It appears that zinc is essential for spermatogenesis. Zinc is involved in many biochemical functions. Several zinc metalloenzymes have been recognized in the past decade. Zinc is required for each step of cell cycle in microorganisms and is essential for DNA synthesis. The effect of zinc on protein synthesis may be attributable to its vital role in nucleic acid metabolism. The activities of many zinc-dependent enzymes have been shown to be affected adversely in zinc-deficient tissues.
Zinc requirements and the risks and benefits of zinc supplementation
Maret W, Sandstead HH.
Department of Preventive Medicine and Community Health, Division of Human Nutrition, University of Texas Medical Branch
J Trace Elem Med Biol. 2006
The adult human contains 2-3g of zinc, about 0.1% of which are replenished daily. On this basis and based on estimates of bioavailability of zinc, dietary recommendations are made for apparently healthy individuals. Absent chemical, functional, and/or physical signs of zinc deficiency are assumed indicative of adequacy. More specific data are seldom available. Changing food preferences and availability, and new food preparation, preservation, and processing technologies may require re-evaluation of past data. Conservative estimates suggest that 25% of the world's population is at risk of zinc deficiency. Most of the affected are poor, and rarely consume foods rich in highly bioavailable zinc, while subsisting on foods that are rich in inhibitors of zinc absorption and/or contain relatively small amounts of bioavailable zinc. In contrast, among the relatively affluent, food choice is a major factor affecting risk of zinc deficiency. An additional problem, especially among the relatively affluent, is risk of chronic zinc toxicity caused by excessive consumption of zinc supplements. High intakes of zinc relative to copper can cause copper deficiency. A major challenge that has not been resolved for maximum health benefit is the proximity of the recommended dietary allowance (RDA) and the reference dose (RfD) for safe intake of zinc. Present recommendations do not consider the numerous dietary factors that influence the bioavailability of zinc and copper, and the likelihood of toxicity from zinc supplements. Thus the current assumed range between safe and unsafe intakes of zinc is relatively narrow. At present, assessment of zinc nutriture is complex, involving a number of chemical and functional measurements that have limitations in sensitivity and specificity. This approach needs to be enhanced so that zinc deficiency or excess can be detected early. An increasing number of associations between diseases and zinc status and apparently normal states of health, where additional zinc might be efficacious to prevent certain conditions, point at the pharmacology of zinc compounds as a promising area. For example, relationships between zinc and diabetes mellitus are an area where research might prove fruitful. In our opinion, a multidisciplinary approach will most likely result in success in this fertile area for translational research.
The immune system and the impact of zinc during aging
Costello RB.
NIH Office of Dietary Supplements, Bethesda, Maryland 20892, USA.
Am J Med Sci. 2009 Jul;338(1):34-9.
ABSTRACT: The trace element zinc is essential for the immune system, and zinc deficiency affects multiple aspects of innate and adaptive immunity. There are remarkable parallels in the immunological changes during aging and zinc deficiency, including a reduction in the activity of the thymus and thymic hormones, a shift of the T helper cell balance toward T helper type 2 cells, decreased response to vaccination, and impaired functions of innate immune cells. Many studies confirm a decline of zinc levels with age. Most of these studies do not classify the majority of elderly as zinc deficient, but even marginal zinc deprivation can affect immune function. Consequently, oral zinc supplementation demonstrates the potential to improve immunity and efficiently downregulates chronic inflammatory responses in the elderly. These data indicate that a wide prevalence of marginal zinc deficiency in elderly people may contribute to immunosenescence.
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