Iron and zinc have achieved prominence among the micronutrients due to the wealth of research detailing their fundamental importance to a multitude of basic cellular physiological mechanisms. The complexity of the immune system ensures that both divalent cations are necessary for normal function. The effects of deficiency and supplementation on the immune functioning of both deficient and replete individuals have provided valuable clues to the specific immune processes in which they are involved. However, single nutrient deficiencies rarely occur alone and the effects of coexisting macro- and micronutrient deficiencies have contributed to the continuing debate on individual nutrient importance. Individuals and populations respond differently to supplementation. The basis of this variability is poorly understood but key to the improved targeting of supplementation. Specific mechanisms to explain the immune effects of zinc supplementation of deficient individuals have been particularly difficult to characterize as zinc is involved in so many cellular processes.

These nutrients are also important for prokaryotes and their acquisition by invading microbes is an important step in the development of a potential pathogen. The host action of micronutrient withdrawal is recognized as a mechanism of immune defense. In the era of genomic medicine the characterization of the molecular determinants of acquisition, storage, flux, and excretion of iron have increased our understanding and illustrated the complexity of iron homeostasis. In this article the evidence for the immune importance of both iron and zinc from in vitro experimentation and in vivo studies of human deficiency and supplementation is considered. The objective of supplementation, dose, route, preexisting level of deficiency, immunocompetence, coexistent deficiencies, genetic determinants, and the presence of infection should all be considered in the decision of who to supplement and when.

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