Moreover, over 40% were considered deficient or severely deficient. Unfortunately, vitamin D deficiency remains widespread a study of adolescents in several European countries found that vitamin D levels in 80% of subjects were below the threshold of sufficiency. Relevant to this review, a diagnosis of rickets is also associated with increased risk of development of diseases unrelated to calcium homeostasis, notably a number of immune disorders. Vitamin D was discovered for its capacity to prevent rickets, a disease of bone growth that arises from insufficient uptake of dietary calcium. Consequently, it cannot be produced at latitudes of 45° or higher (which includes Canada and several European countries) during 6 months of the year or longer, a period known as vitamin D winter. However, the angle of the sun has to be greater than 45° for efficient synthesis of vitamin D to occur in skin. Vitamin D is obtained from few dietary sources such as oily fish and egg yolks, or from photochemical and thermal transformation of the cholesterol precursor 7-dehydrocholesterol in skin exposed to ultraviolet B radiation. It also provides an assessment of the therapeutic potential of vitamin D supplementation in infectious diseases, including an up-to-date analysis of the putative benefits of vitamin D supplementation in the ongoing COVID-19 crisis. This review outlines of our current knowledge of the mechanisms of action of vitamin D signaling in the innate immune system. Although the severity of the COVID-19 pandemic has been alleviated in some areas by the arrival of vaccines, it remains important to identify therapeutic interventions that reduce disease severity and mortality, and accelerate recovery. Poor vitamin D status is associated with greater susceptibility to viral infections, including those of the respiratory tract. 1,25D is also active in signaling cascades that promote antiviral innate immunity 1,25D-induced expression of the antimicrobial peptide CAMP/L元7, originally characterized for its antibacterial properties, is a key component of antiviral responses. Strong laboratory and epidemiological evidence links vitamin D deficiency to increased rates of conditions such as dental caries, as well as inflammatory bowel diseases arising from dysregulation of innate immune handling intestinal flora. Moreover, 1,25D stimulates autophagy, which has emerged as a mechanism critical for control of intracellular pathogens such as M. Vitamin D signaling is active upstream and downstream of pattern recognition receptors, which promote front-line innate immune responses. In immune cells such as macrophages, expression of CYP27B1, the 25-hydroxyvitamin D 1α-hydroxylase, is induced by immune-specific inputs, leading to local production of hormonal 1,25-dihydroxyvitamin D (1,25D) at sites of infection, which in turn directly induces the expression of genes encoding antimicrobial peptides. Vitamin D, best known for its role in skeletal health, has emerged as a key regulator of innate immune responses to microbial threat.
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