Exploring the Association between Vascular Dysfunction and Skeletal Muscle Mass, Strength and Function in Healthy Adults: A Systematic Review

Background: The prevalence of vascular dysfunction increases with advancing age, as does the loss of muscle mass, strength and function. This systematic review explores the association between vascular dysfunction and skeletal muscle health in healthy adults. Methods: EMBASE and MEDLINE were searched for cross-sectional and randomized controlled studies between January 2009 and April 2019, with 33 out of 1246 studies included based on predefined criteria. Assessments of muscular health included muscle mass, strength and function. Macrovascular function assessment included arterial stiffness (pulse wave velocity or augmentation index), carotid intima-media thickness, and flow-mediated dilation. Microvascular health assessment included capillary density or microvascular flow (contrast enhanced ultrasound). Results: All 33 studies demonstrated a significant association between vascular function and skeletal muscle health. Significant negative associations were reported between vascular dysfunction and -muscle strength (10 studies); -mass (9 studies); and -function (5 studies). Nine studies reported positive correlations between muscle mass and microvascular health. Conclusions: Multiple studies have revealed an association between vascular status and skeletal muscle health in healthy adults. This review points to the importance of screening for muscle health in adults with vascular dysfunction with a view to initiating early nutrition and exercise interventions to ameliorate functional decline over tim

STAT3 can be activated through paracrine signaling in breast epithelial cells

<p>Abstract</p> <p>Background</p> <p>Many cancers, including breast cancer, have been identified with increased levels of phosphorylated or the active form of Signal Transducers and Activators of Transcription 3 (STAT3) protein. However, whether the tumor microenvironment plays a role in this activation is still poorly understood.</p> <p>Methods</p> <p>Conditioned media, which contains soluble factors from MDA-MB-231 and MDA-MB-468 breast cancer cells and breast cancer associated fibroblasts, was added to MCF-10A breast epithelial and MDA-MB-453 breast cancer cells. The stimulation of phosphorylated STAT3 (p-STAT3) levels by conditioned media was assayed by Western blot in the presence or absence of neutralized IL-6 antibody, or a JAK/STAT3 inhibitor, JSI-124. The stimulation of cell proliferation in MCF-10A cells by conditioned media in the presence or absence of JSI-124 was subjected to MTT analysis. IL-6, IL-10, and VEGF levels were determined by ELISA analysis.</p> <p>Results</p> <p>Our results demonstrated that conditioned media from cell lines with constitutively active STAT3 are sufficient to induce p-STAT3 levels in various recipients that do not possess elevated p-STAT3 levels. This signaling occurs through the JAK/STAT3 pathway, leading to STAT3 phosphorylation as early as 30 minutes and is persistent for at least 24 hours. ELISA analysis confirmed a correlation between elevated levels of IL-6 production and p-STAT3. Neutralization of the IL-6 ligand or gp130 was sufficient to block increased levels of p-STAT3 (Y705) in treated cells. Furthermore, soluble factors within the MDA-MB-231 conditioned media were also sufficient to stimulate an increase in IL-6 production from MCF-10A cells.</p> <p>Conclusion</p> <p>These results demonstrate STAT3 phosphorylation in breast epithelial cells can be stimulated by paracrine signaling through soluble factors from both breast cancer cells and breast cancer associated fibroblasts with elevated STAT3 phosphorylation. The induction of STAT3 phosphorylation is through the IL-6/JAK pathway and appears to be associated with cell proliferation. Understanding how IL-6 and other soluble factors may lead to STAT3 activation via the tumor microenvironment will provide new therapeutic regimens for breast carcinomas and other cancers with elevated p-STAT3 levels.</p

Exploratory Metabolomic Analyses Reveal Compounds Correlated with Lutein Concentration in Frontal Cortex, Hippocampus, and Occipital Cortex of Human Infant Brain

<div><p>Lutein is a dietary carotenoid well known for its role as an antioxidant in the macula, and recent reports implicate a role for lutein in cognitive function. Lutein is the dominant carotenoid in both pediatric and geriatric brain tissue. In addition, cognitive function in older adults correlated with macular and postmortem brain lutein concentrations. Furthermore, lutein was found to preferentially accumulate in the infant brain in comparison to other carotenoids that are predominant in diet. While lutein is consistently related to cognitive function, the mechanisms by which lutein may influence cognition are not clear. In an effort to identify potential mechanisms through which lutein might influence neurodevelopment, an exploratory study relating metabolite signatures and lutein was completed. Post-mortem metabolomic analyses were performed on human infant brain tissues in three regions important for learning and memory: the frontal cortex, hippocampus, and occipital cortex. Metabolomic profiles were compared to lutein concentration, and correlations were identified and reported here. A total of 1276 correlations were carried out across all brain regions. Of 427 metabolites analyzed, 257 were metabolites of known identity. Unidentified metabolite correlations (510) were excluded. In addition, moderate correlations with xenobiotic relationships (2) or those driven by single outliers (3) were excluded from further study. Lutein concentrations correlated with lipid pathway metabolites, energy pathway metabolites, brain osmolytes, amino acid neurotransmitters, and the antioxidant homocarnosine. These correlations were often brain region—specific. Revealing relationships between lutein and metabolic pathways may help identify potential candidates on which to complete further analyses and may shed light on important roles of lutein in the human brain during development.</p></div

Fatty acid correlations with lutein in human infant brain.^a

<p>^aSubject ages ranged from 1 to 488 days old, and the median age was 100.5 days. 30 total decedents were studied and included both male (n = 21) and female (n = 9) infants. A total of 81 tissues were analyzed from three brain regions, including the frontal cortex (FC, n = 29), hippocampus (HPC, n = 24), and the occipital cortex (OC, n = 28).</p><p>^bAll values are significant (P < 0.05). Fatty acid metabolites:lutein correlations with r values ≥ |0.45| and P < 0.05 are reported.</p><p>Fatty acid correlations with lutein in human infant brain.<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0136904#t002fn001" target="_blank">^a</a></p

Taurine negatively correlated with lutein concentrations in pediatric hippocampus.

<p>Post-mortem infant brain tissues (age 1 to 488 days) from the frontal cortex, hippocampus, and occipital cortex were analyzed for lutein, fatty alcohol metabolites, and energy pathway metabolites. A negative correlation between taurine and lutein concentrations was unique to the hippocampus (n = 24). Results are shown as taurine (scaled intensity) by lutein concentration (pmol/g). Taurine:lutein correlations with r values ≥ |0.45| and P < 0.05 are reported.</p

Lysophospholipid correlations with lutein in human infant brain.^a

<p>^aSubject ages ranged from 1 to 488 days old, and the median age was 100.5 days. 30 total decedents were studied and included both male (n = 21) and female (n = 9) infants. A total of 81 tissues were analyzed from three brain regions, including the frontal cortex (FC, n = 29), hippocampus (HPC, n = 24), and the occipital cortex (OC, n = 28).</p><p>^bAll values are significant (P < 0.05). Lysophospholipid metabolites:lutein correlations with r values ≥ |0.45| and P < 0.05 are reported.</p><p>Lysophospholipid correlations with lutein in human infant brain.<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0136904#t003fn001" target="_blank">^a</a></p

Lutein accretion in infant brain did not correlate with age.

<p>Post-mortem infant brain tissues (age 1 to 488 days) were analyzed for lutein by HPLC. Increasing lutein concentration (pmol/g) did not correlate with age in the (A) frontal cortex (n = 29), (B) hippocampus (n = 24), or (C) occipital cortex (n = 28). FC: frontal cortex; HPC: hippocampus; OC: occipital cortex; n.s.: not-significant.</p

<i>scyllo</i>-Inositol is positively correlated with lutein concentrations in infant frontal cortex, hippocampus, and occipital cortex.

<p>Post-mortem infant brain tissues (age 1 to 488 days) from the frontal cortex, hippocampus, and occipital cortex were analyzed for both lutein and <i>scyllo</i>-inositol. Results are shown as <i>scyllo</i>-inositol (scaled intensity) by lutein concentration (pmol/g). Positive correlations between <i>scyllo</i>-inositol and lutein were observed in the (A) frontal cortex (n = 29), (B) hippocampus (n = 24), or (C) occipital cortex (n = 28). <i>scyllo</i>-Inositol:lutein correlations with r values ≥ |0.45| and P < 0.05 are reported. FC: frontal cortex; HPC: hippocampus; OC: occipital cortex.</p

Decedent Characteristics.

<p>Decedent Characteristics.</p