A Decade of Nutrition and Health Disparities Research at NIH, 2010-2019.

INTRODUCTION: Nutrition health disparities include differences in incidence, prevalence, morbidity, and mortality of diet-related diseases and conditions. Often, race, ethnicity, and the social determinants of health are associated with dietary intake and related health disparities. This report describes the nutrition health disparities research supported by NIH over the past decade and offers future research opportunities relevant to NIH's mission as described in the Strategic Plan for NIH Nutrition Research. METHODS: Data were extracted from an internal reporting system from FY2010 to FY2019 using the Research, Condition, and Disease Categorization spending categories for Nutrition and Health Disparities. RESULTS: Over the past decade, NIH-supported nutrition and health disparities research increased, from 860 grants in 2010 to 937 grants in FY2019, whereas total nutrition and health disparities funding remained relatively stable. The top 5 Institutes/Centers that funded nutrition and health disparities research (on the basis of both grant numbers and dollars) were identified. Principal areas of focus included several chronic diseases (e.g., obesity, diabetes, cancer, heart disease) and research disciplines (e.g., clinical research and behavioral and social science). Focus areas related to special populations included pediatrics, minority health, aging, and women's health. CONCLUSIONS: The gaps and trends identified in this analysis highlight the need for future nutrition and health disparities research, including a focus on American Indian and Asian populations and the growing topics of rural health, maternal health, and food insecurity. In alignment with the Strategic Plan for NIH Nutrition Research, health equity may be advanced through innovative research approaches to develop effective targeted interventions to address these disparities.

Knowledge gaps in understanding the metabolic and clinical effects of excess folates/folic acid: a summary, and perspectives, from an NIH workshop.

Folate, an essential nutrient found naturally in foods in a reduced form, is present in dietary supplements and fortified foods in an oxidized synthetic form (folic acid). There is widespread agreement that maintaining adequate folate status is critical to prevent diseases due to folate inadequacy (e.g., anemia, birth defects, and cancer). However, there are concerns of potential adverse effects of excess folic acid intake and/or elevated folate status, with the original concern focused on exacerbation of clinical effects of vitamin B-12 deficiency and its role in neurocognitive health. More recently, animal and observational studies have suggested potential adverse effects on cancer risk, birth outcomes, and other diseases. Observations indicating adverse effects from excess folic acid intake, elevated folate status, and unmetabolized folic acid (UMFA) remain inconclusive; the data do not provide the evidence needed to affect public health recommendations. Moreover, strong biological and mechanistic premises connecting elevated folic acid intake, UMFA, and/or high folate status to adverse health outcomes are lacking. However, the body of evidence on potential adverse health outcomes indicates the need for comprehensive research to clarify these issues and bridge knowledge gaps. Three key research questions encompass the additional research needed to establish whether high folic acid or total folate intake contributes to disease risk. 1) Does UMFA affect biological pathways leading to adverse health effects? 2) Does elevated folate status resulting from any form of folate intake affect vitamin B-12 function and its roles in sustaining health? 3) Does elevated folate intake, regardless of form, affect biological pathways leading to adverse health effects other than those linked to vitamin B-12 function? This article summarizes the proceedings of an August 2019 NIH expert workshop focused on addressing these research areas.

Improving natural product research translation: From source to clinical trial.

While great interest in health effects of natural product (NP) including dietary supplements and foods persists, promising preclinical NP research is not consistently translating into actionable clinical trial (CT) outcomes. Generally considered the gold standard for assessing safety and efficacy, CTs, especially phase III CTs, are costly and require rigorous planning to optimize the value of the information obtained. More effective bridging from NP research to CT was the goal of a September, 2018 transdisciplinary workshop. Participants emphasized that replicability and likelihood of successful translation depend on rigor in experimental design, interpretation, and reporting across the continuum of NP research. Discussions spanned good practices for NP characterization and quality control; use and interpretation of models (computational through in vivo) with strong clinical predictive validity; controls for experimental artefacts, especially for in vitro interrogation of bioactivity and mechanisms of action; rigorous assessment and interpretation of prior research; transparency in all reporting; and prioritization of research questions. Natural product clinical trials prioritized based on rigorous, convergent supporting data and current public health needs are most likely to be informative and ultimately affect public health. Thoughtful, coordinated implementation of these practices should enhance the knowledge gained from future NP research.

Advancing Nutrition Education, Training, and Research for Medical Students, Residents, Fellows, Attending Physicians, and Other Clinicians: Building Competencies and Interdisciplinary Coordination.

Nutrition plays an important role in health promotion and disease prevention and treatment across the lifespan. Physicians and other healthcare professionals are expected to counsel patients about nutrition, but recent surveys report minimal to no improvements in medical nutrition education in US medical schools. A workshop sponsored by the National Heart, Lung, and Blood Institute addressed this gap in knowledge by convening experts in clinical and academic health professional schools. Representatives from the National Board of Medical Examiners, the Accreditation Council for Graduate Medical Education, the Liaison Committee on Medical Education, and the American Society for Nutrition provided relevant presentations. Reported is an overview of lessons learned from nutrition education efforts in medical schools and health professional schools including interprofessional domains and competency-based nutrition education. Proposed is a framework for coordinating activities of various entities using a public-private partnership platform. Recommendations for nutrition research and accreditation are provided.

The vitamin D paradox in Black Americans: a systems-based approach to investigating clinical practice, research, and public health - expert panel meeting report.

The Office of Dietary Supplements, the National Institute on Minority Health and Health Disparities, the National Institute on Aging, and the National Institute of Diabetes and Digestive and Kidney Diseases, all components of the U.S. National Institutes of Health, co-sponsored an expert panel meeting to discuss the vitamin D paradox in Black Americans. The paradox is that despite markedly low (or "deficient") measures of vitamin D status in Black Americans, the incidence of falls, fractures, or osteopenia are significantly lower compared to White American counterparts with similar vitamin D status. Six panelists were invited to engage in guided discussions on the state of the science with respect to key knowledge gaps impacting vitamin D status and bone health. They were also asked to reflect on best approaches for advancing the science. A central theme throughout the discussions was that there may be many factors that impact Vitamin D levels in Black Americans and understanding these factors may be key to understanding mechanisms for improving bone health in all populations. Data presented showed that although adiposity, skin pigmentation, vitamin D binding protein polymorphisms, and genetics all contributed to differences in 25(OH)D levels in Black vs. White Americans, no one factor alone could fully explain the vitamin D paradox in Black Americans. However, the panelists did agree that the paradox is significant and warrants further investigation. There was consensus that Black Americans gained no skeletal benefits from high doses of vitamin D supplementation, and that high levels of the biomarker of vitamin D status, serum 25-hydroxyvitamin D or 25(OH)D, in this population are almost certain to result in adverse effects. Some panelists proposed that additional studies are needed so that the Institute of Medicine (IOM) can better define the safe upper limits of vitamin D intake in this and other subpopulations. Others suggested a need for better, more generalizable biomarkers of bone health to advance the science.

Tumor dormancy and the neuroendocrine system: an undisclosed connection?

Tumor dormancy is a poorly understood phenomenon conceptualized as a protracted quiescent state during which cancer cells are present but clinical disease is not apparent, a condition referred to as "cancer without disease" by Folkman. Examples include the incidental detection of occult in situ tumors in post-mortem organ analysis and cancer recurrence after long disease-free periods. Lack of angiogenic competency has been proposed as a major determinant of the fate of dormant tumors. Other proposed processes include establishment of homeostatic equilibrium between tumor cells and the host's immune system response and a non-permissive microenvironment for tumor growth. Recent cellular and molecular studies suggest that neuroendocrine mediators regulate the biology of tumor progression and act as endogenous modulators of angiogenesis, inflammation, and other molecular processes involved in tumor reactivation from dormancy. We review experimental and clinical evidence and propose that neuroendocrine dynamics of the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis might contribute to the loss of tumor dormancy.

IGFBP-3, hypoxia and TNF-alpha inhibit adiponectin transcription.

The thiazolidinedione rosiglitazone, an agonist ligand for the nuclear receptor PPAR-gamma, improves insulin sensitivity in part by stimulating transcription of the insulin-sensitizing adipokine adiponectin. It activates PPAR-gamma-RXR-alpha heterodimers bound to PPAR-gamma response elements in the adiponectin promoter. Rosiglitazone-stimulated adiponectin protein synthesis in 3T3-L1 mouse adipocytes has been shown to be inhibited by IGFBP-3, which can be induced by hypoxia and the proinflammatory cytokine, TNF-alpha, two inhibitors of adiponectin transcription. The present study demonstrates that IGFBP-3, the hypoxia-mimetic agent cobalt chloride, and TNF-alpha inhibit rosiglitazone-induced adiponectin transcription in mouse embryo fibroblasts that stably express PPAR-gamma2. Native IGFBP-3 can bind RXR-alpha and inhibited rosiglitazone stimulated promoter activity, whereas an IGFBP-3 mutant that does not bind RXR-alpha did not. These results suggest that IGFBP-3 may mediate the inhibition of adiponectin transcription by hypoxia and TNF-alpha, and that IGFBP-3 binding to RXR-alpha may be required for the observed inhibition.

Induction of apoptosis in human prostate cancer cells by insulin-like growth factor binding protein-3 does not require binding to retinoid X receptor-alpha.

IGF binding protein (IGFBP)-3 can induce apoptosis in human prostate cancer cells directly without sequestering IGF-I and -II. The molecular mechanisms responsible for the IGF-independent actions of IGFBP-3 remain unclear. IGFBP-3, a secreted protein, can be internalized and translocate to the nucleus. It binds to the nuclear retinoid X receptor (RXR)-alpha. Binding to RXR-alpha has been proposed to be required for IGFBP-3 to induce apoptosis. The present study tests this hypothesis in the PC-3 human prostate cancer cell line. PC-3 cells express RXR-alpha, and apoptosis is induced by incubation with RXR-specific ligand. A COOH-terminal region in IGFBP-3 (residues 215-232) contains a nuclear localization signal, and binding domains for RXR-alpha and heparin (HBD). Different combinations of the 11 amino acids in this region that differ from IGFBP-1, a related IGFBP, which does not localize to the nucleus or bind RXR-alpha, were mutated to the IGFBP-1 sequence. By confocal imaging, mutation of residues 228-KGRKR-232 in nonsecreted IGFBP-3 diminished its nuclear localization. IGFBP-3 binding to glutathione S-transferase-RXR-alpha only was lost when all 11 sites were mutated (HBD-11m-IGFBP-3). Expressed nuclear RXR-alpha did not transport cytoplasmic IGFBP-3 nuclear localization signal mutants that can bind RXR-alpha to the nucleus even after treatment with RXR ligand. Expressed HBD-11m-IGFBP-3 still induced apoptosis in PC-3 cells in an IGF-independent manner as determined by flow cytometric analysis of Annexin V staining. We conclude that in PC-3 cells, RXR-alpha is not required for the nuclear translocation of IGFBP-3 and that IGFBP-3 can induce apoptosis in human prostate cancer cells without binding RXR-alpha.

Nonsecreted insulin-like growth factor binding protein-3 (IGFBP-3) can induce apoptosis in human prostate cancer cells by IGF-independent mechanisms without being concentrated in the nucleus.

Insulin-like growth factor binding protein-3 (IGFBP-3), a secreted protein, has the intrinsic ability to induce apoptosis directly without binding insulin-like growth factors. Previous studies suggested that IGFBP-3 must be secreted to exert its biological functions. IGFBP-3 contains a nuclear localization signal (NLS), and exogenous IGFBP-3 is translocated into the nucleus, suggesting that both secretion and nuclear localization may play important roles in IGFBP-3 action. To address these questions, we fused yellow fluorescent protein (YFP) to mature IGFBP-3 lacking its signal peptide so that it would remain intracellular and mutated the C-terminal NLS of IGFBP-3, (228)KGRKR(232), to MDGEA. Following transfection of PC-3 human prostate cancer cells with these constructs, Western blots indicated that YFP-IGFBP-3 lacking a signal peptide was cell-associated and not present in the extracellular media. Moreover, the fusion protein was not N-glycosylated, indicating that it had not entered the secretory pathway. Confocal imaging showed that intracellular YFP-MDGEA-IGFBP-3 was predominantly cytoplasmic. Transient transfection of nonsecreted YFP-wild-type IGFBP-3 decreased cell viability, as assessed by staining with annexin V followed by flow cytometry. Induction of cell death was caspase-dependent, indicative of apoptosis. Apoptosis also was induced by the nonsecreted NLS mutant (YFP-MDGEA-IGFBP-3) alone and when the IGF-binding site also had been mutated. These results indicate that IGFBP-3 can induce apoptosis in an IGF-independent manner without being secreted or concentrated in the nucleus.

Nerve growth factor-endothelial cell interaction leads to angiogenesis in vitro and in vivo.

Nerve growth factor (NGF) has important functions during embryonic development and on various tissues and organs under normal and pathological conditions during the extrauterine life. RT-PCR analysis and immunological methods demonstrate that human umbilical vein endothelial cells (HUVECs) express the NGF receptors trkA(NGFR) and p75NTR. NGF treatment caused a rapid phosphorylation of trkA(NGFR) in HUVECs, determining a parallel increase of phosphorylated ERK1/2. Accordingly, NGF induced a significant increase in HUVEC proliferation that was abolished by the trkA(NGFR) inhibitor K252a. Also, HUVECs express significant levels of NGF under standard culture conditions that were up-regulated during serum starvation. Endogenous NGF was responsible for the basal levels of trkA(NGFR) and ERK1/2 phosphorylation observed in untreated HUVEC cultures. Finally, NGF exerted a potent, direct, angiogenic activity in vivo when delivered onto the chorioallantoic membrane of the chicken embryo. The data indicate that NGF may play an important role in blood vessel formation in the nervous system and in several pathological processes, including tumors and inflammatory diseases. Unraveling mechanisms of NGF-dependent angiogenesis could provide valuable tools for novel therapeutic approaches in antiangiogenic therapy.