Feasibility and Preliminary Efficacy of American Elderberry Juice for Improving Cognition and Inflammation in Patients with Mild Cognitive Impairment.

Despite data showing that nutritional interventions high in antioxidant/anti-inflammatory properties (anthocyanin-rich foods, such as blueberries/elderberries) may decrease risk of memory loss and cognitive decline, evidence for such effects in mild cognitive impairment (MCI) is limited. This study examined preliminary effects of American elderberry (Sambucus nigra subsp. canadensis) juice on cognition and inflammatory markers in patients with MCI. In a randomized, double-blind, placebo-controlled trial, patients with MCI (n = 24, Mage = 76.33 ± 6.95) received American elderberry (n = 11) or placebo (n = 13) juice (5 mL orally 3 times a day) for 6 months. At baseline, 3 months, and 6 months, patients completed tasks measuring global cognition, verbal memory, language, visuospatial cognitive flexibility/problem solving, and memory. A subsample (n = 12, 7 elderberry/5 placebo) provided blood samples to measure serum inflammatory markers. Multilevel models examined effects of the condition (elderberry/placebo), time (baseline/3 months/6 months), and condition by time interactions on cognition/inflammation outcomes. Attrition rates for elderberry (18%) and placebo (15%) conditions were fairly low. The dosage compliance (elderberry-97%; placebo-97%) and completion of cognitive (elderberry-88%; placebo-87%) and blood-based (elderberry-100%; placebo-100%) assessments was high. Elderberry (not placebo) trended (p = 0.09) towards faster visuospatial problem solving performance from baseline to 6 months. For the elderberry condition, there were significant or significantly trending decreases over time across several markers of low-grade peripheral inflammation, including vasorin, prenylcysteine oxidase 1, and complement Factor D. Only one inflammatory marker showed an increase over time (alpha-2-macroglobin). In contrast, for the placebo, several inflammatory marker levels increased across time (L-lactate dehydrogenase B chain, complement Factor D), with one showing deceased levels over time (L-lactate dehydrogenase A chain). Daily elderberry juice consumption in patients with MCI is feasible and well tolerated and may provide some benefit to visuospatial cognitive flexibility. Preliminary findings suggest elderberry juice may reduce low-grade inflammation compared to a placebo-control. These promising findings support the need for larger, more definitive prospective studies with longer follow-ups to better understand mechanisms of action and the clinical utility of elderberries for potentially mitigating cognitive decline.

Randomized controlled trial of propranolol on social communication and anxiety in children and young adults with autism spectrum disorder.

RATIONALE: Autism spectrum disorder (ASD) is characterized by impaired social communication and is also frequently characterized by co-occurring anxiety. Propranolol is widely utilized to treat performance and public speaking anxiety. Single-dose psychopharmacological challenge studies suggested benefits using propranolol for verbal tasks and social interaction. OBJECTIVE: We conducted a double-blinded, placebo-controlled trial of the ß-adrenergic antagonist propranolol in ASD for social interaction, anxiety, and language. METHODS: Seventy-four participants with ASD, age 7-24 years, were enrolled and randomized to a 12-week course of propranolol or placebo, with blinded assessments at baseline, 6 weeks, and 12 weeks. The primary outcome was the General Social Outcome Measure-2 (GSOM-2) for social interaction, and secondary outcomes were the Clinician Global Clinical Impression-Improvement (CGI-I) ratings independently conducted for social interaction, anxiety, and language at 6 weeks and 12 weeks. RESULTS: Sixty-nine participants completed the 12-week visit. No significant effect of drug was found for the GSOM-2 or the CGI-I for social interaction or language. CGI-I for anxiety showed greater improvement with propranolol at the 12-week time point (p = 0.045, odds ratio = 2.58 (95% CI = 1.02-6.52). Expected decreases in heart rate and blood pressure were observed with propranolol, and side effects were uncommon. CONCLUSIONS: Propranolol did not impact social interaction measures or language, but there were indications of a beneficial effect for anxiety. This will need confirmation in a larger multicenter trial, monitoring markers or characteristics to identify those participants most likely to respond to propranolol for anxiety, and determine whether there is a subset of participants that are responsive for other previously reported outcomes.

Memory performance on the ChAMP in autism spectrum disorder with and without attention-deficit/hyperactivity disorder.

Memory difficulties have been identified in youth with neurodevelopmental conditions including autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). The Child and Adolescent Memory Profile (ChAMP) is a newer memory measure with a burgeoning research base. This study seeks to explore memory performance on the Lists and Objects subtests of the ChAMP in a clinical sample of those with ASD with/without co-occurring ADHD. Participants were 146 youth referred for a neuropsychological evaluation (M age = 11.8 years; 76.03% male) diagnosed with ASD (N = 92 with ADHD, N = 54 without). Logistic regression (p = .393) indicated ChAMP performance is not predictive of whether the ASD group had co-occurring ADHD indicating there is no additive effect on memory. Compared to the ChAMP examiner's manual ASD sample, this study sample performed significantly better (p <.001) on all ChAMP measures. While the ChAMP is sensitive to memory difficulties in neurodevelopmental disorders, as indicated by the performance of the manual sample, the ASD sample of the manual may differ from other ASD samples. There were no differences between verbal and visual memory performance across the present study's sample.

Remotely supervised at-home delivery of taVNS for autism spectrum disorder: feasibility and initial efficacy.

Background: Transcutaneous auricular vagus nerve stimulation (taVNS) has potential clinical application for autism spectrum disorder (ASD). At-home sessions are necessary to allow delivery of repeated sessions, and remove burden on patients for daily visits, and reduce costs of clinic delivery. Our objective was to validate a protocol for remote supervised administration for home delivery of taVNS using specially designed equipment and platform. Methods: An open-label design was followed involving administration by caretakers to 12 patients with ASD (ages:7-16). Daily 1-h sessions over 2 weeks were administered under remote supervision. The primary outcome was feasibility, which was assessed by completion rate, stimulation tolerability, and confirmation of programmed stimulation delivery. The secondary measures were initial efficacy assessed by Childhood Anxiety Sensitivity Index-Revised (CASI-R), Parent Rated Anxiety Scale for Youth with ASD (PRAS-ASD), and Clinician Global Impression (CGI) scales. Sleep measures were also tracked using Cleveland Adolescent Sleep Questionnaire (CASQ). Results: Across 132 sessions, we obtained an 88.5% completion rate. A total of 22 expected adverse events were reported with headache being the most common followed by transient pain, itchiness, and stinging at the electrode site. One subject dropped out of the study unrelated to the stimulation or the study. Average scores of anxiety (CASI-R, PRAS-ASD, and CGI) and sleepiness (CASQ) were all improved at the 2 week time point. While not powered to determine efficacy, benefits were suggested in this open label pilot. Conclusion: Remotely supervised, proxy-administered, at-home delivery of taVNS is feasible in patients with ASD. Initial efficacy supports pursuing larger scale trials.

Emodin Inhibited Pathological Cardiac Hypertrophy in Response to Angiotensin-Induced Hypertension and Altered the Gut Microbiome.

OBJECTIVE: Evidence suggests that food bioactives affect the epigenome to prevent pathological cardiac hypertrophy. Recently, we showed that emodin, an anthraquinone, attenuated pathological cardiac hypertrophy and histone deacetylase (HDAC) activity. However, we only examined the cardioprotective effects of emodin's parent compound and not those of emodin metabolites or of emodin-gut microbiome interactions. The microbiome has emerged as a key player in chronic diseases such as metabolic and cardiac disease. Thus, we hypothesized that emodin could reverse hypertension-induced changes in microbial communities. METHODS: Normo- and hypertensive (angiotensin II) C57/BL6 female mice were randomly assigned to receive a vehicle (Veh; DMSO:PEG 1:1) or emodin (Emod; 30 mg/kg) for 14 days. Body weights were collected pre- and post-treatment, and blood pressure was assessed via tail cuff. At the study's end, the mice were euthanized and assessed for their heart weights. In addition, stool samples and cecal contents were collected to elucidate changes in the microbial populations using 16S rRNA sequencing. Lastly, the tissue was lysed, and RNA was isolated for qPCR. One-way ANOVA with Tukey's post hoc test was performed unless otherwise specified, and p < 0.05 was considered significant. RESULTS: Emodin significantly attenuated cardiac hypertrophy in the female mice. No significant changes were observed in body weight or systolic blood pressure in response to hypertension or emodin. Lastly, analysis suggests that hypertension altered the microbiome in the cecum and cecal content, with additional evidence to support that emodin affects gut microbiota in the feces and colon. CONCLUSIONS: Our data demonstrate that emodin attenuates pathological hypertrophy in female mice. Future research is needed to dissect if changes in the microbiome contributes to emodin-mediated attenuation in cardiac remodeling.

Potential Neuroprotective Effects of Dietary Omega-3 Fatty Acids on Stress in Alzheimer's Disease.

BACKGROUND: A large number of individual potentially modifiable factors are associated with risk for Alzheimer's disease (AD). However, less is known about the interactions between the individual factors. METHODS: In order to begin to examine the relationship between a pair of factors, we performed a pilot study, surveying patients with AD and controls for stress exposure and dietary omega-3 fatty acid intake to explore their relationship for risk of AD. RESULTS: For individuals with the greatest stress exposure, omega-3 fatty acid intake was significantly greater in healthy controls than in AD patients. There was no difference among those with low stress exposure. CONCLUSIONS: These initial results begin to suggest that omega-3 fatty acids may mitigate AD risk in the setting of greater stress exposure. This will need to be examined with larger populations and other pairs of risk factors to better understand these important relationships. Examining how individual risk factors interact will ultimately be important for learning how to optimally decrease the risk of AD.

Class I HDAC inhibitors attenuate dexamethasone-induced muscle atrophy via increased protein kinase C (PKC) delta phosphorylation.

Skeletal muscle atrophy is defined by wasting or decrease in muscle mass owing to injury, aging, malnutrition, chronic disuse, or physical consequences of chronic illness. Under normal physiological conditions, a network of signal transduction pathways serves to balance muscle protein synthesis and proteolysis; however, metabolic shifts occur from protein synthesis to protein degradation that leads to a reduction in cross-sectional myofibers and can result in loss of skeletal muscle mass (atrophy) over time. Recent evidence highlights posttranslational modifications (PTMs) such as acetylation and phosphorylation in contractile dysfunction and muscle wasting. Indeed, histone deacetylase (HDAC) inhibitors have been shown to attenuate muscle atrophy and delay muscle damage in response to nutrient deprivation, in models of metabolic dysfunction and genetic models of muscle disease (e.g., muscle dystrophy). Despite our current understanding of lysine acetylation in muscle physiology, a role for HDACs in the regulation of muscle signal transduction remains a 'black box.' Using C2C12 myotubes stimulated with dexamethasone (Dex) as a model of muscle atrophy, we report that protein kinase C delta (PKCδ) phosphorylation decreased at threonine 505 (T505) and serine 643 (S643) in myotubes in response to muscle atrophy; these residues are important for PKCδ activity. Interestingly, PKCδ phosphorylation was restored/increased in myotubes treated with a pan-HDAC inhibitor or a class I selective HDAC inhibitor targeting HDACs1, -2, and - 3 in response to Dex. Moreover, we observed that Dex induced atrophy in skeletal muscle tissue in mice; this reduction in atrophy occurred rapidly, with weight loss noted by day 3 post-Dex and muscle weight loss noted by day 7. Similar to our findings in C2C12 myotubes, Dex attenuated phosphorylation of PKCδ at S643, while HDAC inhibition restored or increased PKCδ phosphorylation at both T505 and S643 in the tibialis anterior. Consistent with this hypothesis, we report that HDAC inhibition could not restore myotube size in response to Dex in the presence of a PKCδ inhibitor or when overexpressing a dominant negative PKCδ. Additionally, the overexpression of a constitutively active PKCδ prevented Dex-induced myotube atrophy. Combined, these data suggest that HDACs regulate muscle physiology via changes in intracellular signaling, namely PKCδ phosphorylation. Whether HDACs regulate PKCδ through canonical (e.g. gene-mediated regulation of phosphatases) or non-canonical (e.g. direct deacetylation of PKCδ to change phosphorylation states) mechanisms remain unclear and future research is needed to clarify this point.

The Relationship between Maternal Antibodies to Fetal Brain and Prenatal Stress Exposure in Autism Spectrum Disorder.

Environmental and genetic factors contribute to the etiology of autism spectrum disorder (ASD), but their interaction is less well understood. Mothers that are genetically more stress-susceptible have been found to be at increased risk of having a child with ASD after exposure to stress during pregnancy. Additionally, the presence of maternal antibodies for the fetal brain is associated with a diagnosis of ASD in children. However, the relationship between prenatal stress exposure and maternal antibodies in the mothers of children diagnosed with ASD has not yet been addressed. This exploratory study examined the association of maternal antibody response with prenatal stress and a diagnosis of ASD in children. Blood samples from 53 mothers with at least one child diagnosed with ASD were examined by ELISA. Maternal antibody presence, perceived stress levels during pregnancy (high or low), and maternal 5-HTTLPR polymorphisms were examined for their interrelationship in ASD. While high incidences of prenatal stress and maternal antibodies were found in the sample, they were not associated with each other (p = 0.709, Cramér's V = 0.051). Furthermore, the results revealed no significant association between maternal antibody presence and the interaction between 5-HTTLPR genotype and stress (p = 0.729, Cramér's V = 0.157). Prenatal stress was not found to be associated with the presence of maternal antibodies in the context of ASD, at least in this initial exploratory sample. Despite the known relationship between stress and changes in immune function, these results suggest that prenatal stress and immune dysregulation are independently associated with a diagnosis of ASD in this study population, rather than acting through a convergent mechanism. However, this would need to be confirmed in a larger sample.

Altered Allocation of Vertical Attention in Individuals With Autism Spectrum Disorder.

BACKGROUND: Typical adults most frequently orient their attention to other people's eyes, whereas individuals with autism spectrum disorder (ASD) orient their attention to other people's mouths. Typical adults also reveal visuospatial biases on tasks such as vertical and horizontal line bisections. Therefore, the difference in face viewing might be related to a more general group difference in the allocation of vertical attention. OBJECTIVE: To use vertical line bisection and quadrisection tasks to evaluate whether individuals with ASD have a more downward-oriented vertical attentional bias than do typical individuals. METHOD: We recruited 20 individuals with ASD and 20 control participants matched for age (6-23 years), IQ, and sex. We asked the individuals to bisect and quadrisect lines on the top and bottom when the vertical lines were placed at the intersection of their right, left, and center egocentric sagittal planes and their coronal plane. The distances from the true midpoint and quadripoint were measured, and between-group performances were compared. RESULTS: No significant difference was found between the ASD and control groups for vertical line bisections or lower line quadrisections. However, when the ASD group was compared with the control group for higher line quadrisections, the ASD group exhibited a greater upward deviation. CONCLUSION: There is no downward vertical attentional spatial bias associated with ASD that could help to explain these individuals' attentional bias toward the mouth. However, additional studies are required to learn if this atypical upward vertical attentional bias might account for some of the symptoms and signs associated with ASD.

HDAC8 regulates protein kinase D phosphorylation in skeletal myoblasts in response to stress signaling.

Skeletal muscle differentiation involves activation of quiescent satellite cells to proliferate, differentiate and fuse to form new myofibers; this requires coordination of myogenic transcription factors. Myogenic transcription is tightly regulated by various intracellular signaling pathways, which include members of the protein kinase D (PKD) family. PKD is a family of serine-threonine kinases that regulate gene expression, protein secretion, cell proliferation, differentiation and inflammation. PKD is a unique PKC family member that shares distant sequence homology to calcium-regulated kinases and plays an important role in muscle physiology. In this report, we show that class I histone deacetylase (HDAC) inhibition, and in particular HDAC8 inhibition, attenuated PKD phosphorylation in skeletal C2C12 myoblasts in response to phorbol ester, angiotensin II and dexamethasone signaling independent of changes in total PKD protein expression. As class I HDACs and PKD signaling are requisite for myocyte differentiation, these data suggest that HDAC8 functions as a potential feedback regulator of PKD phosphorylation to control myogenic gene expression.

Pilot Study of the Effects of Paced Breathing on Measures of Convergent and Divergent Thinking.

BACKGROUND: The ability of the autonomic nervous system's stress response to impair aspects of cognitive flexibility is known. However, the ability to modulate the sympathetic response and improve these cognitive impairments via nonpharmacological intervention, such as paced breathing (PB), requires further investigation. OBJECTIVE: To better elucidate the effects of PB on cognition. METHOD: We employed a PB protocol in a total of 52 healthy men and women and measured performance on convergent and divergent cognitive tasks, perceived stress, and physiological measures (eg, blood pressure, heart rate). Participants attended two experimental sessions consisting of either PB or normal breathing followed by cognitive assessments including convergent (compound remote associate, anagram) and divergent (alternate use, fluency) tasks. Experiment 2 consisted of more difficult versions of cognitive tasks compared with Experiment 1. RESULTS: In Experiment 1, PB significantly reduced the female participants' systolic and diastolic blood pressure immediately after the breathing protocol without affecting their cognition. In Experiment 2, PB significantly reduced perceived stress immediately after the breathing protocol, regardless of sex. There was no effect on cognition in Experiment 2, but a correlation was observed between perceived stress change and anagram number solved change. CONCLUSION: While PB modulates sympathetic activity in females, there was a lack of improvement in cognitive flexibility performance. At least for a single trial of PB, cognitive flexibility did not improve.

Bidirectional relationship between internalizing symptoms and gastrointestinal problems in youth with Autism Spectrum Disorder.

Many youth with autism spectrum disorder (ASD) experience co-occurring conditions, such as gastrointestinal (GI) problems and internalizing symptoms. However, the relationship among these co-occurring problems is not well-understood. We analyzed parent reports of GI problems and internalizing symptoms of 621 youth with ASD using path models in a structural equation modeling framework. The best-fitting model was a bidirectional model wherein internalizing symptoms, including withdrawn and anxious behavior, were correlated with GI problems, including constipation, diarrhea, nausea, and stomach pain. This study provides a better understanding of the relationship among co-occurring conditions in youth with ASD and should encourage clinicians to consider treatment of underlying internalizing symptoms or GI problems when providing services for individuals with ASD.

Pilot Study of Real-World Monitoring of the Heart Rate Variability in Amyotrophic Lateral Sclerosis.

Aims: Cardiovascular dysautonomia may impact the quality of life and survival in amyotrophic lateral sclerosis (ALS). Such dysfunction is not systematically assessed in these patients. Wearable devices could help. The feasibility of a wearable biosensor to detect heart rate variability (HRV), a physiological marker of sympathovagal balance, was studied for the first time in real-world settings in ALS. Methods: Five ALS patients (two early/three late; one bulbar-onset; mildly-to-moderately disabled) and five age/sex/BMI/comorbidities-matched controls underwent assessment of 3-day HRV via VitalConnect biosensor (worn on the left thorax). De-identified data captured by the biosensor were transferred to a secure cloud server via a relay Bluetooth device. Baseline ALS severity/anxiety and physical activity during testing were documented/quantified. Time-domain HRV measures (i.e., pNN50) were analyzed. Results: An overall 3-day abnormal HRV (pNN50 < 3%), was found in three out of five patients (mean ± SD for the group, 2.49 ± 1.51). Similar changes were reported in controls (12.32 ± 21.14%). There were no statistically significant relationships between pNN50 values and baseline anxiety or physical activity during the tested days (p > 0.05 for both groups). A negative correlation was found between pNN50 values and age in patients (p = 0.01) and controls (p = 0.09), which is similar with what is found in the general population. In line with prior studies, pNN50 values were independent of disease stage (p = 0.6) and disability (p = 0.4). Conclusions: These preliminary results suggest that remote HRV measures using the VitalConnect is feasible and may constitute an improved strategy to provide insights into sympathovagal balance in ALS. Further work with larger sample sizes is warranted.

Examination of five- and four-subtest short form IQ estimations for the Wechsler Intelligence Scale for Children-Fifth edition (WISC-V) in a mixed clinical sample.

Evaluating general cognitive ability (i.e., intelligence) is common in neuropsychological practice, and identifying abbreviated assessments of intelligence is often advantageous. Despite the Wechsler Intelligence Scale for Children, Fifth Edition's (WISC-V) widespread contemporary use, limited research has identified clinically useful short form (SF) full scale IQ (FSIQ) estimations in clinical samples. This study sought to address this gap in the literature. Two hundred sixty-eight pediatric participants (M age = 9.79; 69% male; 88% Caucasian/White) who underwent psychological/neuropsychological evaluation were included. Mean scores for WISC-V scores fell in the low average-to-average ranges, consistent with the clinical nature of this sample (e.g., M FSIQ = 85.3). Ten unique SF combinations with five (pentad) and four (tetrad) subtests, each intentionally selected to represent a breadth of domains subsumed by WISC-V FSIQ, were described by summing subtest age-corrected scaled scores. Regression-based and prorated FSIQ estimates were calculated, and mean differences suggested some prorated estimates should be arithmetically adjusted. Both regression-based and prorated/adjusted methods provided FSIQ estimates that were accurate within five Standard Score points of true FSIQ for approximately 81-92% (pentad) and 65-76% (tetrads) of participants. Prorated/adjusted estimates appeared to provide somewhat better accuracy than regression-based estimates. Relationships between SFs and true FSIQ did not appear to be moderated by participant age, gender, nor how many WISC-V subtests were administered to participants within this archival sample (i.e., 7 vs. 10). Implications of these findings, including benefits, detriments, and other considerations of each SF combination, in addition to limitations of this study, are discussed in detail.

The dimensionality of the Behavior Rating Inventory of Executive Function, Second Edition in a clinical sample.

The parent-report Behavior Rating Inventory of Executive Function, Second Edition (BRIEF-2) is a widely used pediatric neuropsychological measure. Unfortunately, despite meaningful changes from its predecessor, few studies have examined its internal factor structure (now with Behavioral Regulation [BRI], Emotion Regulation [ERI], and Cognitive Regulation [CRI]), and no available literature has investigated higher order models for the BRIEF-2. This study sought to address this shortcoming in the literature by investigating and reporting on the dimensionality of the parent-report BRIEF-2 in a clinical sample. Two hundred and two (202) pediatric neuropsychology examinees (M age = 9.90; 68% males) with complete data for the parent-report BRIEF-2 were included. Descriptive results revealed generally elevated scores across BRIEF-2 scales (Global Executive Composite M T = 70.16). Exploratory factor analyses suggested two factors (CRI and BRI/ERI) should be extracted, and that higher order models should be considered. Confirmatory factor analyses suggested that a direct hierarchical/bifactor two-factor structure (which was more parsimonious than the theoretical three-factor model) provided the best fit, with a bulk of the variance explained by the general GEC factor. The BRIEF-2 may be best interpreted at the overall level, with relatively less weight given to the index variables, particularly within clinical samples with high levels of reported executive functioning difficulties. Implications of these findings, limitations of the present study, and appropriate directions for future inquiry were discussed.

Effects of stimulant medication on divergent and convergent thinking tasks related to creativity in adults with attention-deficit hyperactivity disorder.

RATIONALE: Common pharmacological treatments for attention-deficit hyperactivity disorder (ADHD) are central nervous system stimulants acting as norepinephrine-dopamine reuptake inhibitors. The noradrenergic and dopaminergic systems have been shown to impact performance on tasks assessing creativity. Some previous studies suggest higher performance on creativity tasks in ADHD. Stimulant medication has been shown to differentially impact creativity in those without ADHD. However, the full range of effects of stimulant medication on creativity in those with ADHD is not known. OBJECTIVES: This study examined the effects of stimulants on convergent and divergent tasks associated with creativity in adults with ADHD. METHOD: Seventeen adults diagnosed with ADHD who were prescribed stimulant medication attended two counterbalanced sessions: one after taking their prescribed stimulant dose and one after the dose was withheld. Participants completed convergent problem-solving (anagrams, Compound Remote Associates) and divergent generative (letter/semantic fluency, Torrance Test for Creative Thinking (TTCT)-Verbal) tasks. RESULTS: There was a significant increase in words generated on the semantic fluency task for the stimulant session. Additionally, significant increases were found in the stimulant session for originality, flexibility, and fluency scores on the TTCT. Stimulant medication did not have an effect on any of the problem-solving tasks. CONCLUSIONS: Stimulant medication enhanced verbal fluency in adults with ADHD but had no effect on convergent abilities. Furthermore, stimulants enhanced fluency, flexibility, and originality scores on the TTCT. Therefore, stimulants appear to have positive effects on divergent task performance in adults with ADHD, but not convergent tasks. This finding warrants further studies into the specific roles of norepinephrine and dopamine in this effect.

microRNAs and Gene-Environment Interactions in Autism: Effects of Prenatal Maternal Stress and the SERT Gene on Maternal microRNA Expression.

Background: Genetics and environment both are critical in autism spectrum disorder (ASD), but their interaction (G × E) is less understood. Numerous studies have shown higher incidence of stress exposures during pregnancies with children later diagnosed with ASD. However, many stress-exposed mothers have unaffected children. The serotonin transporter (SERT) gene affects stress reactivity. Two independent samples have shown that the association between maternal stress exposure and ASD is greatest with maternal presence of the SERT short (S)-allele (deletion in the promoter region). MicroRNAs play a regulatory role in the serotonergic pathway and in prenatal stress and are therefore potential mechanistic targets in this setting. Design/methods: We profiled microRNA expression in blood from mothers of children with ASD, with known stress exposure during pregnancy. Samples were divided into groups based on SERT genotypes (LL/LS/SS) and prenatal stress level (high/low). Results: Two thousand five hundred mature microRNAs were examined. The ANOVA analysis showed differential expression (DE) of 119 microRNAs; 90 were DE in high- vs. low-stress groups (stress-dependent). Two (miR-1224-5p, miR-331-3p) were recently reported by our group to exhibit stress-dependent expression in rodent brain samples from embryos exposed to prenatal stress. Another, miR-145-5p, is associated with maternal stress. Across SERT genotypes, with high stress exposure, 20 significantly DE microRNAs were detected, five were stress-dependent. These microRNAs may be candidates for stress × SERT genotype interactions. This is remarkable as these changes were from mothers several years after stress-exposed pregnancies. Conclusions: Our study provides evidence for epigenetic alterations in relation to a G × E model (prenatal maternal stress × SERT gene) in ASD.

DUSP5-mediated inhibition of smooth muscle cell proliferation suppresses pulmonary hypertension and right ventricular hypertrophy.

Pulmonary hypertension (PH) is associated with structural remodeling of pulmonary arteries (PAs) because of excessive proliferation of fibroblasts, endothelial cells, and smooth muscle cells (SMCs). The peptide hormone angiotensin II (ANG II) contributes to pulmonary vascular remodeling, in part, through its ability to trigger extracellular signal-regulated kinase (ERK1/2) activation. Here, we demonstrate that the ERK1/2 phosphatase, dual-specificity phosphatase 5 (DUSP5), functions as a negative regulator of ANG II-mediated SMC proliferation and PH. In contrast to wild-type controls, Dusp5 null mice infused with ANG II developed PH and right ventricular (RV) hypertrophy. PH in Dusp5 null mice was associated with thickening of the medial layer of small PAs, suggesting an in vivo role for DUSP5 as a negative regulator of ANG II-dependent SMC proliferation. Consistent with this, overexpression of DUSP5 blocked ANG II-mediated proliferation of cultured human pulmonary artery SMCs (hPASMCs) derived from patients with idiopathic PH or from failed donor controls. Collectively, the data support a role for DUSP5 as a feedback inhibitor of ANG II-mediated ERK signaling and PASMC proliferation and suggest that disruption of this circuit leads to adverse cardiopulmonary remodeling.NEW & NOTEWORTHY Dual-specificity phosphatases (DUSPs) serve critical roles in the regulation of mitogen-activated protein kinases, but their functions in the cardiovascular system remain poorly defined. Here, we provide evidence that DUSP5, which resides in the nucleus and specifically dephosphorylates extracellular signal-regulated kinase (ERK1/2), blocks pulmonary vascular smooth muscle cell proliferation. In response to angiotensin II infusion, mice lacking DUSP5 develop pulmonary hypertension and right ventricular cardiac hypertrophy. These findings illustrate DUSP5-mediated suppression of ERK signaling in the lungs as a protective mechanism.

Divergent and Overlapping Roles for Selected Phytochemicals in the Regulation of Pathological Cardiac Hypertrophy.

Plant-based foods, like fruits, vegetables, whole grains, legumes, nuts, seeds and other foodstuffs, have been deemed as heart healthy. The chemicals within these plant-based foods, i.e., phytochemicals, are credited with protecting the heart. However, the mechanistic actions of phytochemicals, which prevent clinical endpoints, such as pathological cardiac hypertrophy, are still being elucidated. We sought to characterize the overlapping and divergent mechanisms by which 18 selected phytochemicals prevent phenylephrine- and phorbol 12-myristate 13-acetate-mediated cardiomyocyte enlargement. Of the tested 18 compounds, six attenuated PE- and PMA-mediated enlargement of neonatal rat ventricular myocytes. Cell viability assays showed that apigenin, baicalein, berberine hydrochloride, emodin, luteolin and quercetin dihydrate did not reduce cell size through cytotoxicity. Four of the six phytochemicals, apigenin, baicalein, berberine hydrochloride and emodin, robustly inhibited stress-induced hypertrophy and were analyzed further against intracellular signaling and genome-wide changes in mRNA expression. The four phytochemicals differentially regulated mitogen-activated protein kinases and protein kinase D. RNA-sequencing further showed divergence in gene regulation, while pathway analysis demonstrated overlap in the regulation of inflammatory pathways. Combined, this study provided a comprehensive analysis of cardioprotective phytochemicals. These data highlight two defining observations: (1) that these compounds predominantly target divergent gene pathways within cardiac myocytes and (2) that regulation of overlapping signaling and gene pathways may be of particular importance for the anti-hypertrophic actions of these phytochemicals. Despite these new findings, future works investigating rodent models of heart failure are still needed to understand the roles for these compounds in the heart.

The interplay between diet, gut microbes, and host epigenetics in health and disease.

The mechanisms linking the function of microbes to host health are becoming better defined but are not yet fully understood. One recently explored mechanism involves microbe-mediated alterations in the host epigenome. Consumption of specific dietary components such as fiber, glucosinolates, polyphenols, and dietary fat has a significant impact on gut microbiota composition and function. Microbial metabolism of these dietary components regulates important epigenetic functions that ultimately influences host health. Diet-mediated alterations in the gut microbiome regulate the substrates available for epigenetic modifications like DNA methylation or histone methylation and/or acetylation. In addition, generation of microbial metabolites such as butyrate inhibits the activity of core epigenetic enzymes like histone deacetylases (HDACs). Reciprocally, the host epigenome also influences gut microbial composition. Thus, complex interactions exist between these three factors. This review comprehensively examines the interplay between diet, gut microbes, and host epigenetics in modulating host health. Specifically, the dietary impact on gut microbiota structure and function that in-turn regulates host epigenetics is evaluated in terms of promoting protection from disease development.