Immune support by micronutrients is historically based on vitamin C deficiency and supplementation in scurvy in early times. It has since been established that the complex, integrated immune system needs multiple specific micronutrients, including vitamins A, D, C, E, B6, and B12, folate, zinc, iron, copper, and selenium, which play vital, often synergistic roles at every stage of the immune response. Adequate amounts are essential to ensure the proper function of physical barriers and immune cells; however, daily micronutrient intakes necessary to support immune function may be higher than current recommended dietary allowances. Certain populations have inadequate dietary micronutrient intakes, and situations with increased requirements (e.g., infection, stress, and pollution) further decrease stores within the body. Several micronutrients may be deficient, and even marginal deficiency may impair immunity. Although contradictory data exist, available evidence indicates that supplementation with multiple micronutrients with immune-supporting roles may modulate immune function and reduce the risk of infection. Micronutrients with the strongest evidence for immune support are vitamins C and D and zinc. Better design of human clinical studies addressing dosage and combinations of micronutrients in different populations are required to substantiate the benefits of micronutrient supplementation against infection.

The innate immune system of mammals provides a rapid response to repel assaults from numerous infectious agents including bacteria, viruses, fungi, and parasites. A major component of this system is a diverse combination of cationic antimicrobial peptides that include the alpha- and beta-defensins and cathelicidins. In this study, we show that 1,25-dihydroxyvitamin D3 and three of its analogs induced expression of the human cathelicidin antimicrobial peptide (CAMP) gene. This induction was observed in acute myeloid leukemia (AML), immortalized keratinocyte, and colon cancer cell lines, as well as normal human bone marrow (BM) -derived macrophages and fresh BM cells from two normal individuals and one AML patient. The induction occurred via a consensus vitamin D response element (VDRE) in the CAMP promoter that was bound by the vitamin D receptor (VDR). Induction of CAMP in murine cells was not observed and expression of CAMP mRNA in murine VDR-deficient bone marrow was similar to wild-type levels. Comparison of mammalian genomes revealed evolutionary conservation of the VDRE in a short interspersed nuclear element or SINE in the CAMP promoter of primates that was absent in the mouse, rat, and canine genomes. Our findings reveal a novel activity of 1,25-dihydroxyvitamin D3 and the VDR in regulation of primate innate immunity.

Public health practices including handwashing and vaccinations help reduce the spread and impact of infections. Nevertheless, the global burden of infection is high, and additional measures are necessary. Acute respiratory tract infections, for example, were responsible for approximately 2.38 million deaths worldwide in 2016. The role nutrition plays in supporting the immune system is well-established. A wealth of mechanistic and clinical data show that vitamins, including vitamins A, B 6 , B 12 , C, D, E, and folate; trace elements, including zinc, iron, selenium, magnesium, and copper; and the omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid play important and complementary roles in supporting the immune system. Inadequate intake and status of these nutrients are widespread, leading to a decrease in resistance to infections and as a consequence an increase in disease burden. Against this background the following conclusions are made: (1) supplementation with the above micronutrients and omega-3 fatty acids is a safe, effective, and low-cost strategy to help support optimal immune function; (2) supplementation above the Recommended Dietary Allowance (RDA), but within recommended upper safety limits, for specific nutrients such as vitamins C and D is warranted; and (3) public health officials are encouraged to include nutritional strategies in their recommendations to improve public health.

In recent experiments, we have shown that activation of the TLR-2,1 signaling cascade by a 19 kDa lipopeptide from Mycobacterium tuberculosis (M. tb) increases expression of both CYP27b1 and VDR in monocyte/macrophages from normal human hosts (5). The resulting 1,25(OH) 2 D-VDR transcription complex is then able to stimulate expression of the cathelicidin antimicrobial protein (hCAP) with concomitant killing of phagocytosed mycobacteria. This induction of innate immune responses was hindered by incubation of TLR-stimulated human monocyte/macrophages with serum from vitamin D (25OHD)-insufficient subjects and rescued in vitro by the simple addition of supplemental 25OHD to medium conditioning those cells.Serum levels of 25OHD are a direct reflection of vitamin D "status," and several reports have highlighted the worldwide prevalence of 25OHD-insufficiency as a consequence of inadequate oral consumption or cutaneous biosynthesis of vitamin D (10, 11). In view of the link between 25OHD and macrophage function outlined above, we have proposed that populations with known susceptibility to vitamin D insufficiency may also exhibit impaired innate immunity. To test this hypothesis, we used cells and serum from a cohort of human subjects pre-and postvitamin D supplementation to assess various parameters associated with responses to TLR activation. Data reveal a direct correlation between serum concentration of 25OHD and monocyte expression of hCAP following treatment with ligands to pathogen-responsive TLRs. Furthermore, we show that in vivo supplementation of vitamin D insufficient patients significantly enhanced ex vivo innate immune responses by rescuing TLRmediated suppression of hCAP expression.

Vitamin D deficiency has been correlated with increased rates of infection. Since the early 19th century, both environmental (i.e., sunlight) and dietary sources (cod liver) of vitamin D have been identified as treatments for TB. The recent discovery that vitamin D induces antimicrobial peptide gene expression explains, in part, the ‘antibiotic’ effect of vitamin D and has greatly renewed interest in the ability of vitamin D to improve immune function. Subsequent work indicates that this regulation is biologically important for the response of the innate immune system to wounds and infection and that deficiency may lead to suboptimal responses toward bacterial and viral infections. The regulation of the cathelicidin antimicrobial peptide gene is a human/primate-specific adaptation and is not conserved in other mammals. The capacity of the vitamin D receptor to act as a high-affinity receptor for vitamin D and a low-affinity receptor for secondary bile acids and potentially other novel nutritional compounds suggests that the evolutionary selection to place the cathelicidin gene under control of the vitamin D receptor allows for its regulation under both endocrine and xenobiotic response systems. Future studies in both humans and humanized mouse models will elucidate the importance of this regulation and lead to the development of potential therapeutic applications.

The CCAAT/enhancer binding protein ␣ (C/EBP␣) protein is essential for proper lung and liver function and granulocytic and adipose tissue differentation. It was hypothesized that abnormalties in C/EBP␣ function contribute to the development of malignancies in a variety of tissues. To test this, genomic DNA from 408 patient samples and 5 cell lines representing 11 different cancers was screened for mutations in the C/EBP␣ gene. Two silent polymorphisms termed P1 and P2 were present at frequencies of 13.5% and 2.2%, respectively. Of the12 mutations detected in 10 patients, silent changes were identified in one nonsmall cell lung cancer, one prostate cancer, and one acute myelog- IntroductionThe CCAAT/enhancer binding protein ␣ (C/EBP␣) belongs to a family of proteins that possess a bipartite DNA-binding domain composed of a positively charged basic (b) region that contacts the DNA and a leucine zipper (ZIP) in the C terminus that mediates dimerization. 1 The less-conserved N terminus contains regulatory and transactivation domains. 2-5 C/EBP␣ is expressed in a number of tissues, most prominently in the highly differentiated cells of the liver, white and brown adipose, lung, and myeloid-lineage cells. [6][7][8][9] It has also been detected in the adrenal gland, skin, pancreas, prostate, differentiated enterocytes in the intestine, and, during follicular development, the ovary. [9][10][11][12] C/EBP␣ is proposed to be a regulator of energy metabolism and transcriptionally activates the promoters of energy-related genes such as GLUT4 and PEPCK in hepatocytes and adipocytes. [13][14][15] In myeloid cells, C/EBP␣ transcriptionally activates the promoters of the myeloid-specific receptors for the growth factors macrophage colony-stimulating factor, granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor. [16][17][18] Studies demonstrate that C/EBP␣ is critical for the process of terminal differentiation of adipocytes. C/EBP␣ is upregulated in adipocyte differentiation, and blocking its expression halts differentiation of preadipocytes into adipocytes, while overexpression induces differentiation and inhibits proliferation. [19][20][21][22][23] Also, overexpression of C/EBP␣ induces differentiation of myeloid leukemia cell lines and inhibits the proliferation of a number of cell lines and tumor cells. [24][25][26][27] The inhibition of proliferation is partly due to the ability of C/EBP␣ to activate transcription and induce posttranscriptional stabilization of the cyclin-dependent kinase inhibitor p21 (WAF-1). 28,29 These studies suggest a central role for C/EBP␣ in the regulation of cell proliferation and differentiation.Targeted inactivation of C/EBP␣ in mice demonstrates its importance in the proper development and function of liver, adipose, lung, and hematopoietic tissues. 8,30,31 Within 8 hours after birth, the mice die of impaired glucose metabolism, and adipose metabolism is altered with a failure of adipocytes to accumulate lipids. 30,31 The lung shows hyperproliferati...

Electrospun nanofibers represent a novel class of materials that show great potential in many biomedical applications including biosensing, regenerative medicine, tissue engineering, drug delivery and wound healing. In this work, we review recent advances in electrospun nanofibers for wound healing. This article begins with a brief introduction on the wound, and then discusses the unique features of electrospun nanofibers critical for wound healing. It further highlights recent studies that have used electrospun nanofibers for wound healing applications and devices, including sutures, multifunctional dressings, dermal substitutes, engineered epidermis and full-thickness skin regeneration. Finally, we finish with conclusions and future perspective in this field.

Transferrin receptor (TfR) plays a major role in cellular iron uptake through binding and internalizing a carrier protein transferrin (Tf). We have cloned, sequenced, and mapped a human gene homologous to TfR, termed TfR2. Two transcripts were expressed from this gene: ␣ (ϳ2.9 kilobase pairs), and ␤ (ϳ2.5 kilobase pairs). The predicted amino acid sequence revealed that the TfR2-␣ protein was a type II membrane protein and shared a 45% identity and 66% similarity in its extracellular domain with TfR. The TfR2-␤ protein lacked the aminoterminal portion of the TfR2-␣ protein including the putative transmembrane domain. Northern blot analysis showed that the ␣ transcript was predominantly expressed in the liver. In addition, high expression occurred in K562, an erythromegakaryocytic cell line. To analyze the function of TfR2, Chinese hamster ovary TfR-deficient cells (CHO-TRVb cells) were stably transfected with FLAG-tagged TfR2-␣. These cells showed an increase in biotinylated Tf binding to the cell surface, which was competed by nonlabeled Tf, but not by lactoferrin. Also, these cells had a marked increase in Tfbound 55 Fe uptake. Taken together, TfR2-␣ may be a second transferrin receptor that can mediate cellular iron transport.