Brain iron acquisition depends on age and sex in iron-deficient mice.

Adequate and timely delivery of iron is essential for brain development. The uptake of transferrin-bound (Tf) iron into the brain peaks at the time of myelination, whereas the recently discovered H-ferritin (FTH1) transport of iron into the brain continues to increase beyond the peak in myelination. Here, we interrogate the impact of dietary iron deficiency (ID) on the uptake of FTH1- and Tf-bound iron. In the present study, we used C57BL/6J male and female mice at a developing (post-natal day (PND) 15) and adult age (PND 85). In developing mice, ID results in increased iron delivery from both FTH1 and Tf for both males and females. The amount of iron uptake from FTH1 was higher than the Tf and this difference between the iron delivery was much greater in females. In contrast, in the adult model, ID was associated with increased brain iron uptake by both FTH1 and Tf but only in the males. There was no increased uptake from either protein in the females. Moreover, transferrin receptor expression on the microvasculature as well as whole brain iron, and H and L ferritin levels revealed the male brains became iron deficient but not the female brains. Last, under normal dietary conditions, 55 Fe uptake was higher in the developing group from both delivery proteins than in the adult group. These results indicate that there are differences in iron acquisition between the developing and adult brain for FTH1 and Tf during nutritional ID and demonstrate a level of regulation of brain iron uptake that is age and sex-dependent.

Common Mutation in the HFE Gene Modifies Recovery After Intracerebral Hemorrhage.

BACKGROUND: Intracerebral hemorrhage (ICH) is characterized by bleeding into the brain parenchyma. During an ICH, iron released from the breakdown of hemoglobin creates a cytotoxic environment in the brain through increased oxidative stress. Interestingly, the loss of iron homeostasis is associated with the pathological process of other neurological diseases. However, we have previously shown that the H63D mutation in the homeostatic iron regulatory (HFE) gene, prevalent in 28% of the White population in the United States, acts as a disease modifier by limiting oxidative stress. The following study aims to examine the effects of the murine homolog, H67D HFE, on ICH. METHODS: An autologous blood infusion model was utilized to create an ICH in the right striatum of H67D and wild-type mice. The motor recovery of each animal was assessed by rotarod. Neurodegeneration was measured using fluorojade-B and mitochondrial damage was assessed by immunofluorescent numbers of CytC+ (cytochrome C) neurons and CytC+ astrocytes. Finally, the molecular antioxidant response to ICH was quantified by measuring Nrf2 (nuclear factor-erythroid 2 related factor), GPX4 (glutathione peroxidase 4), and FTH1 (H-ferritin) levels in the ICH-affected and nonaffected hemispheres via immunoblotting. RESULTS: At 3 days post-ICH, H67D mice demonstrated enhanced performance on rotarod compared with wild-type animals despite no differences in lesion size. Additionally, H67D mice displayed higher levels of Nrf2, GPX4, and FTH1 in the ICH-affected hemisphere; however, these levels were not different in the contralateral, non-ICH-affected hemisphere. Furthermore, H67D mice showed decreased degenerated neurons, CytC+ Neurons, and CytC+ astrocytes in the perihematomal area. CONCLUSIONS: Our data suggest that the H67D mutation induces a robust antioxidant response 3 days following ICH through Nrf2, GPX4, and FTH1 activation. This activation could explain the decrease in degenerated neurons, CytC+ neurons, and CytC+ astrocytes in the perihematomal region, leading to the improved motor recovery. Based on this study, further investigation into the mechanisms of this neuroprotective response and the effects of the H63D HFE mutation in a population of patients with ICH is warranted.

Novel whole blood transcriptome signatures of changes in maximal aerobic capacity in response to endurance exercise training in healthy women.

Maximal aerobic exercise capacity [maximal oxygen consumption (V̇o2max)] is one of the strongest predictors of morbidity and mortality. Aerobic exercise training can increase V̇o2max, but inter-individual variability is marked and unexplained physiologically. The mechanisms underlying this variability have major clinical implications for extending human healthspan. Here, we report a novel transcriptome signature related to ΔV̇o2max with exercise training detected in whole blood RNA. We used RNA-Seq to characterize transcriptomic signatures of ΔV̇o2max in healthy women who completed a 16-wk randomized controlled trial comparing supervised, higher versus lower aerobic exercise training volume and intensity (4 training groups, fully crossed). We found significant baseline gene expression differences in subjects who responded to aerobic exercise training with robust versus little/no ΔV̇o2max, and differentially expressed genes/transcripts were mostly related to inflammatory signaling and mitochondrial function/protein translation. Baseline gene expression signatures associated with robust versus little/no ΔV̇o2max were also modulated by exercise training in a dose-dependent manner, and they predicted ΔV̇o2max in this and a separate dataset. Collectively, our data demonstrate the potential utility of using whole blood transcriptomics to study the biology of inter-individual variability in responsiveness to the same exercise training stimulus.

The Effects of Exercise Duration and Intensity on Breast Cancer-Related DNA Methylation: A Randomized Controlled Trial.

Emerging research suggests that one mechanism through which physical activity may decrease cancer risk is through its influence on the methylation of genes associated with cancer. The purpose of the current study was to prospectively test, using a rigorous experimental design, whether aerobic exercise affects DNA methylation in genes associated with breast cancer, as well as whether quantity of exercise completed affects change in DNA methylation in a dose-response manner. 276 women (M age = 37.25, SD = 4.64) were recruited from the Denver metro area for a randomized controlled trial in which participants were assigned to a supervised aerobic exercise program varying in a fully crossed design by intensity (55-65% versus 75-85% of VO2max) and duration (40 versus 20 min per session). DNA methylation was assessed via blood samples provided at baseline, after completing a 16-week supervised exercise intervention, and six months after the intervention. 137 participants completed the intervention, and 81 had viable pre-post methylation data. Contrary to our hypotheses, total exercise volume completed in kcal/kg/week was not associated with methylation from baseline to post-intervention for any of the genes of interest. An increase in VO2max over the course of the intervention, however, was associated with decreased post-intervention methylation of BRCA1, p = 0.01. Higher levels of self-reported exercise during the follow-up period were associated with lower levels of GALNT9 methylation at the six-month follow-up. This study provides hypothesis-generating evidence that increased exercise behavior and or increased fitness might affect methylation of some genes associated with breast cancer to reduce risk.

Few Structural Brain Changes Associated With Moderate-Intensity Interval Training and Low-Intensity Continuous Training in a Randomized Trial of Fitness and Older Adults.

This study utilized a randomized control trial to examine whether structural changes in the precuneus, insula, caudate, hippocampus, and putamen were related to exercise. A total of 197 healthy older adults with no evidence of dementia participated in moderate-intensity interval training or low-intensity continuous training for 16 weeks. Size decreased in the right hippocampus such that the effect of time was significant but the interaction with condition was not. For the left hippocampus, size decreased in the low-intensity continuous training condition but increased in the moderate-intensity continuous training plus interval training condition at the trend level. Finally, there was a significant time-by-condition interaction such that the thickness of the left insula increased for low-intensity continuous training and decreased for moderate-intensity continuous training plus interval training. Few structural changes were associated with the exercise intervention. Future studies should examine the effects of exercise on brain structure in high-risk or clinical populations for a longer period of time.

Validation of a multisubstance online Timeline Followback assessment.

OBJECTIVES: The Timeline Followback (TLFB) was originally developed to assess alcohol consumption patterns (American Journal of Public Health, 86, 1996, 966) and has been increasingly modified for Web-based use. Additionally, new modes of substance use administration have emerged, creating a need for an adaptable TLFB tool than can capture data such as cannabis product potency or prescription drug use. Our goal was to validate an online TLFB that reliably assesses a wide range of substances in greater detail. METHODS: Using a within-subjects counterbalanced design, daily substance use data were collected from 50 college students over a 14-day retrospective period using both the traditional in-person TLFB and online TLFB (O-TLFB). RESULTS: All substance use variables, including detailed measures of cannabis metrics, correlated significantly (r's ranged from .653 to .944, p < .001) between TLFB versions. Further, results demonstrated that both the online TLFB and in-person TLFB demonstrated concurrent validity with both the Alcohol Use Disorders Identification Test (AUDIT) and Marijuana Dependence Scale (MDS). CONCLUSION: Overall, the data suggest that this new O-TLFB demonstrates strong reliability and delivers a versatile and secure tool for substance use assessment that is relevant to a variety of biomedical and psychological research contexts.

An Overview and Proposed Research Framework for Studying Co-Occurring Mental- and Physical-Health Dysfunction.

Mental- and physical-health conditions co-occur at a rate much higher than chance. Of patients who have a mental-health condition, more than half also have a physical disease, and these cases are associated with increased human suffering and societal cost. Comorbidity research to date has focused on co-occurring mental- and physical-health disorders separately, and relatively little research has examined the co-occurrence of mental- and physical-health dysfunction. In addition, even less is known about why mental- and physical-health dysfunction co-occurs or how to treat these cases. Thus, the aims of this article are to highlight the need for research at the intersection of physical- and mental-health dysfunction and to provide guidance on how to research cases of comorbidity. Toward these ends, we begin by presenting a selective overview of the possible role of biological processes in the co-occurrence of physical- and mental-health dysfunction using specific illustrative examples. Specifically, we outline how biological processes within the immune system and gastrointestinal system could underlie depression, irritable bowel syndrome, and their co-occurrence. We then advance and discuss a proposed research framework, including methodological and analytic guidance, that researchers could use when studying the phenomenon of co-occurring physical- and mental-health dysfunction.