Educating Future Physicians in Nutritional Science and Practice: The Time Is Now.

The need to educate and train future physicians about nutrition and wellness has become increasingly apparent in the past decade. A rising incidence of chronic health conditions with a nutrition background (e.g., obesity, cardiovascular disease, type 2 diabetes) has led to an even greater need for nutrition educational content in medical school curricula so that physicians may counsel patients regarding their lifestyle factors. This review provides an overview of the successful development and integration of a nutrition thread in a 5-year medical school curriculum. Based on a survey conducted in our medical school program, students beginning medical school are lacking formal nutrition education, as only 8% arrived with some form of exposure. Despite this, nearly 85% of these medical students recognized that nutrition education is necessary in their training, and 70% state that the nutrition education they have received has influenced the way they care for patients. Key teaching points Physicians are faced with rising incidence of chronic health conditions that have a nutritional risk factor Physician self-care including optimal nutrition to support resilience is gaining importance. Nutrition education in medical schools is inadequate to address these rising needs. Implementing a comprehensive nutrition curricula that addresses personal wellness strategies, basic science concepts related to nutrition, and diagnosis and management of diseases that can be modified by or are related to nutrition as a topic thread that is woven throughout all years of the curriculum highlights the importance of nutrition in health and disease.

Chemokine and chemoattractant receptor expression: post-transcriptional regulation.

The magnitude and character of the inflammatory process are determined in part via the trafficking of leukocytes into sites of injury and infection, and this process depends on proper control of the expression of genes encoding chemoattractant peptides and their receptors. Although these controls operate at multiple mechanistic levels, recent evidence indicates that post-transcriptional events governing the half-life of select mRNAs are important determinants. Adenine-uridine rich elements (AREs) located within 3' untranslated regions (UTRs) confer constitutive mRNA instability and in some cases, stabilization following stimulation by ligands of the Toll-IL-1 receptor (TIR) family. Although the importance of AREs in determining activity and mRNA half-life is well-recognized, the mechanistic scope and diversity remain poorly understood. Using the mouse KC or CXCL1 gene as a model, we have demonstrated that the abundance of mRNA and protein produced during an inflammatory response depends on multiple mechanistically distinct AREs present in the 3' UTR of the mRNA. The mRNA encoding the receptor for N-terminal formyl-methionine-containing peptides is also unstable and subject to stabilization in response to TIR ligands. These two models can, however, be readily distinguished from one another on the basis of specific stimulus sensitivity and the signaling pathways, through which such stimuli couple to the control of mRNA decay. These models demonstrate the substantial diversity operative in the post-transcriptional regulation of inflammatory gene expression.

Regulation of chemokine expression by antiinflammatory cytokines.

The antiinflammatory cytokines IL-4 and IL- 10 are well recognized as important negative regulators of proinflammatory gene expression in mononuclear phagocytes. The intracellular mechanisms that mediate these responses appear to be multifactorial. IL-4 is able to suppress transcriptional activation of IFNgamma- and LPS-responsive genes; IL-4 activated STAT6 is required for the suppressive activity of IL-4. IL-4 and STAT6 appear to suppress transcription of select proinflammatory genes through the ability of STAT6 to sequester coactivator molecules that may be required for the transcriptional action of STAT1 and NFkappaB. In contrast, IL-10 suppresses the expression of genes induced in lipopolysaccharide (LPS)-stimulated macrophages by modulating both the transcription and stability of specific mRNAs. AU-rich nucleotide sequence elements in the 3'untranslated region of IL-10-sensitive genes confer sensitivity to IL-10-mediated destabilization. Thus mechanisms through which IL-10 and IL-4 act to dampen inflammatory responses are mechanistically distinct and involve diverse intracellular signaling pathways.

Regulation of chemokine mRNA stability by lipopolysaccharide and IL-10.

IL-10 has been reported to inhibit the expression of LPS-induced proinflammatory cytokines and chemokines by altering the rate of specific mRNA decay although the molecular target(s) for its action remain unknown. In the present study, using primary peritoneal exudate macrophages and a cell culture model in which a tetracycline-responsive promoter controls transcription of CXC ligand 1 (KC) mRNA, we demonstrate that LPS promotes a time-dependent increase in KC mRNA stability. Although IL-10 had no direct effect on mRNA decay, this treatment antagonized the stabilizing action of LPS. The mechanisms involved were further explored using a cell-free mRNA degradation system. A 5'-capped, polyadenylated in vitro transcript derived from the 3'-untranslated region of KC mRNA exhibited time-dependent decay in the presence of protein extracts prepared from untreated RAW264.7 macrophages. Extracts prepared from LPS-treated RAW264.7 cells had reduced decay activity and this change was antagonized if the cells were costimulated with IL-10. A substrate in which the AU-rich element motifs were mutated exhibited minimal decay that did not vary using extracts prepared from cells treated with LPS or LPS and IL-10. A nonadenylated RNA substrate was also degraded and that activity was diminished by LPS. In concert, these findings demonstrate that KC mRNA stability is regulated by LPS-induced alterations in activities that govern both deadenylation and degradation of the mRNA body. The effects of IL-10 on KC mRNA stability reflect antagonism of the response to LPS.

Toll IL-1 receptors differ in their ability to promote the stabilization of adenosine and uridine-rich elements containing mRNA.

Several ligands for Toll IL-1R (TIR) family are known to promote stabilization of a subset of short-lived mRNAs containing AU-rich elements (AREs) in their 3' untranslated regions. It is now evident however, that members of the TIR family may use distinct intracellular signaling pathways to achieve a spectrum of biological end points. Using human embryonic kidney 293 cells transfected to express different TIRs we now report that signals initiated through IL-1R1 or TLR4 but not TLR3 can promote the stabilization of unstable chemokine mRNAs. Similar results were obtained when signaling from endogenous receptors was examined using a mouse endothelial cell line (H5V). The ability of TIR family members to stabilize ARE-containing mRNAs results from their differential use of signaling adaptors MyD88, MyD88 adaptor-like protein, Toll receptor IFN-inducing factor (Trif), and Trif-related adaptor molecule. Overexpression of MyD88 or MyD88 adaptor-like protein was able to promote enhanced stability of ARE-containing mRNA, whereas Trif and Trif-related adaptor molecule exhibited markedly reduced capacity. Hence the ability of TIRs to signal stabilization of mRNA appears to be linked to the MyD88-dependent signaling pathway.

Heterogeneity in control of mRNA stability by AU-rich elements.

AU-rich elements (AREs), located in the 3'-untranslated region of unstable cytokine and chemokine mRNAs, promote rapid decay of otherwise stable mRNAs and may mediate selective mRNA stabilization in response to stimulation with interleukin-1 (IL-1). AREs vary considerably, however, in both size and sequence context. To assess the heterogeneity involved in control of mRNA stability by ARE motifs, human mRNA sequences from IL-1alpha-stimulated HEK293 cells and T98G cells were screened for either instability or stability using both cDNA (950 ARE containing sequences) and Affymetrix oligonucleotide (U95Av2 GeneChip) array analysis. Although ARE-containing mRNAs exhibited a broad range of stability, IL-1alpha promoted stability in a subset of mRNAs that were unstable when transcriptionally induced by tumor necrosis factor alpha. Stabilization of granulocyte/macrophage-colony stimulating factor and IL-8 mRNAs by IL-1alpha was achieved only after 2 h of stimulation, required ongoing protein synthesis, and depended on the activation of p38 MAPK. In contrast, stabilization of Gro3 mRNA in response to IL-1alpha was achieved immediately and was insensitive to inhibitors of protein synthesis and p38 MAPK activation. In concert, these findings demonstrate that ARE sequences are functionally heterogeneous; only a subset of unstable mRNAs is sensitive to stabilization by IL-1alpha. Moreover, IL-1alpha promotes stabilization of unstable mRNAs through distinct mechanistic pathways that distinguish between specific mRNA sequences.