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Alzheimer's disease (AD) is the leading cause of mortality, disability, and long‐term care burden in the United States, with women comprising the majority of AD diagnoses. While AD‐related dementia is associated with tau and amyloid beta accumulation, concurrent derangements in cerebral blood flow have been observed alongside these proteinopathies in humans and rodent models. The homeostatic production of nitric oxide synthases (NOS) becomes uncoupled in AD which leads to decreased NO‐mediated vasodilation and oxidative stress via the production of peroxynitrite (ONOO−∙) superoxide species. Here, we investigate the role of the novel protein arginine methyltransferase 4 (PRMT4) enzyme function and its downstream product asymmetric dimethyl arginine (ADMA) as it relates to NOS dysregulation and cerebral blood flow in AD. ADMA (type‐1 PRMT product) has been shown to bind NOS as a noncanonic ligand causing enzymatic dysfunction. Our results from RT‐qPCR and protein analyses suggest that aged (9−12 months) female mice bearing tau‐ and amyloid beta‐producing transgenic mutations (3xTg‐AD) express higher levels of PRMT4 in the hippocampus when compared to age‐ and sex‐matched C57BL6/J mice. In addition, we performed studies to quantify the expression and activity of different NOS isoforms. Furthermore, laser speckle contrast imaging analysis was indicative that 3xTg‐AD mice have dysfunctional NOS activity, resulting in reduced production of NO metabolites, enhanced production of free‐radical ONOO−, and decreased cerebral blood flow. Notably, the aforementioned phenomena can be reversed via pharmacologic PRMT4 inhibition. Together, these findings implicate the potential importance of PRMT4 signaling in the pathogenesis of Alzheimer's‐related cerebrovascular derangement. [ABSTRACT FROM AUTHOR]

African American (AA) women in the United States have a 40% higher breast cancer mortality rate than Non-Hispanic White (NHW) women. The survival disparity is particularly striking among (estrogen receptor positive) ER+ breast cancer cases. The purpose of this study is to examine whether there are racial differences in metabolic pathways typically activated in patients with ER+ breast cancer. We collected pretreatment plasma from AA and NHW ER+ breast cancer cases (AA n = 48, NHW n = 54) and cancer-free controls (AA n = 100, NHW n = 48) to conduct an untargeted metabolomics analysis using gas chromatography mass spectrometry (GC–MS) to identify metabolites that may be altered in the different racial groups. Unpaired t-test combined with multiple feature selection and prediction models were employed to identify race-specific altered metabolic signatures. This was followed by the identification of altered metabolic pathways with a focus in AA patients with breast cancer. The clinical relevance of the identified pathways was further examined in PanCancer Atlas breast cancer data set from The Cancer Genome Atlas Program (TCGA). We identified differential metabolic signatures between NHW and AA patients. In AA patients, we observed decreased circulating levels of amino acids compared to healthy controls, while fatty acids were significantly higher in NHW patients. By mapping these metabolites to potential epigenetic regulatory mechanisms, this study identified significant associations with regulators of metabolism such as methionine adenosyltransferase 1A (MAT1A), DNA Methyltransferases and Histone methyltransferases for AA individuals, and Fatty acid Synthase (FASN) and Monoacylglycerol lipase (MGL) for NHW individuals. Specific gene Negative Elongation Factor Complex E (NELFE) with histone methyltransferase activity, was associated with poor survival exclusively for AA individuals. We employed a comprehensive and novel approach that integrates multiple machine learning and statistical methods, coupled with human functional pathway analyses. The metabolic profile of plasma samples identified may help elucidate underlying molecular drivers of disproportionately aggressive ER+ tumor biology in AA women. It may ultimately lead to the identification of novel therapeutic targets. To our knowledge, this is a novel finding that describes a link between metabolic alterations and epigenetic regulation in AA breast cancer and underscores the need for detailed investigations into the biological underpinnings of breast cancer health disparities. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To examine whether the association between dopamine‐related genotype and gait speed differs according to frailty status or race. DESIGN: Cross‐sectional population‐based study (Cardiovascular Health Study). SETTING: Multicenter study, four U.S. sites. PARTICIPANTS: Volunteer community‐dwelling adults aged 65 years and older, without evidence of Parkinsonʼs disease (N = 3,744; 71 years; 82% White; 39% male). MEASUREMENTS: Gait speed (usual pace; m/s), physical frailty (Fried definition), and genetic polymorphism of catechol‐O‐methyltransferase (COMT; rs4680), an enzyme regulating tonic brain dopamine levels, were assessed. Interaction of COMT by frailty and by race predicting gait speed were tested, and, if significant, analyses were stratified. Multivariable regression models of COMT predicting gait speed were adjusted for demographics and locomotor risk factors. Sensitivity analyses were repeated, stratified by clinical cutoffs of gait speed (0.6 and 1.0 m/s) instead of frailty status. RESULTS: The interaction of COMT by frailty and COMT by race were P =.02 and P =.01, respectively. Compared with Met/Met (higher dopaminergic signaling), the Val/Val group (lower dopaminergic signaling) walked marginally more slowly in the full cohort (0.87 vs 0.89 m/s; P =.2). Gait speed differences were significant for frail (n = 220; 0.55 vs 0.63 m/s; P =.03), but not for prefrail (n = 1,691; 0.81 vs 0.81 m/s; P =.9) or nonfrail (n = 1,833; 0.98 vs 0.97 m/s; P =.7); results were similar in fully adjusted models. Among frail, associations were similar for Whites and Blacks, with statistical significance for Whites only. Associations stratified by clinical cutoffs of gait speed were not significant. CONCLUSION: The association of dopamine‐related genotype with gait speed is stronger among adults with frailty compared with those without frailty. The potential effects of dopaminergic signaling on preserving physical function in biracial cohorts of frail adults should be further examined. [ABSTRACT FROM AUTHOR]

Study Design: Development of an in vitro model for assessing the anti-inflammatory efficacies of naringin (Nar) and naringenin (NG). Purpose: To evaluate the efficacy of natural flavonoids as therapeutic drugs against anti-inflammatory processes in the nucleus pulposus (NP) cells using in-vitro and in-silico methods. Overview of Literature: Intervertebral disc (IVD) disease is a common cause of low back pain. Chronic inflammation and degeneration play a significant role in its etiopathology. Thus, a better understanding of anti-inflammatory agents and their role in IVD degeneration and pro-inflammatory cytokines expression is necessary for pain management and regeneration in IVD. Methods: We performed primary cell culture of NP cells; immunocytochemistry; gene expression studies of cytokines, metalloproteases, extracellular proteins, and apoptotic markers using quantitative polymerase chain reaction and reverse transcription-polymerase chain reaction (RT-PCR); cytotoxicity assay (MTT); and molecular docking studies using AutoDock 4.2 software (Molecular Graphics Laboratory, La Jolla, CA, USA) to confirm the binding mode of proteins and synthesized complexes. We calculated the mean±standard deviation values and performed analysis of variance and t -test using SPSS ver. 17.0 (SPSS Inc., Chicago, IL, USA). Results: Molecular docking showed that both Nar and NG bind to the selected genes of interest. Semi-quantitative RT-PCR analysis reveals differential gene expression of collagen (COL)9A1, COL9A2, COL9A3, COL11A2, COMT (catechol-O-methyltransferase), and THBS2 (thrombospondin 2); up regulation of ACAN (aggrecan), COL1A1, COL11A1, interleukin (IL)6, IL10, IL18R1, IL18RAP, metalloprotease (MMP)2, MMP3, MMP9, ADAMTS5 (a disintegrin and metalloproteinase with thrombospondin motifs 5), IGF1R (insulin-like growth factor type 1 receptor), SPARC (secreted protein acidic and cysteine rich), PARK2 (parkin), VDR (vitamin D receptor), and BCL2 (B-cell lymphoma 2); down regulation of IL1A, CASP3 (caspase 3), and nine genes with predetermined concentrations of Nar and NG. Conclusions: The present study evaluated the anti-inflammatory and regenerative efficiencies of Nar and NG in degenerated human NP cells. Altered gene expressions of cytokines, metalloproteases, extracellular proteins, apoptotic genes were dose responsive. The molecular docking (in silico) studies showed effective binding of these native ligands (Nar and NG) with genes identified as potent inhibitors of inflammation. Thus, these natural flavonoids could serve as anti-inflammatory agents in the treatment of low back pain and sciatica. [ABSTRACT FROM AUTHOR]

Objective: To examine whether COMT (catechol-O-methyltransferase) polymorphism modulates aspects of sleep in children diagnosed with attention-deficit/hyperactivity disorder (ADHD).Method: Nightly sleep actigraphic recordings during a double-blind, placebo-controlled, crossover clinical study (1 week of 0.5 mg/kg MPH; 1 week of placebo) were obtained for 34 children, 7.4 to 12 years old, diagnosed with ADHD (DSM-IV). Diagnosis was generated by the Diagnostic Interview Schedule for Children and was confirmed by multidisciplinary consensus.Results: Children who were Val allele carriers had poorer sleep continuity compared with children with the Met-Met genotype while receiving a placebo and while receiving methylphenidate.Conclusions: The findings of the present study support the hypothesis that sleep disturbances in children with ADHD are related to the underlying pathophysiology of the disorder. [ABSTRACT FROM AUTHOR]

Introduction: Parkinson's disease (PD) is among the most common of the neurodegenerative disorders. Treatment is primarily focused on correcting neurotransmitter imbalances. Several classes of medication are available for this purpose., Areas Covered: A Medline search was performed to gather information about the safety of the medications approved for the treatment of the motor symptoms of PD. This was supplemented with additional articles obtained from online sources and information provided by the FDA and the manufacturers. The focus of this review is the side-effect and safety profiles of carbidopa/levodopa, dopamine agonists, selective monoamine oxidase inhibitors, catechol-o-methyltransferase inhibitors, anticholinergics and amantadine., Expert Opinion: Though serious side-effects may occur, as a group, the medications used for the treatment of PD motor symptoms tend to produce side-effects that are mild to moderate in nature, and that primarily reflect the focus on dopaminergic therapies. Care plans for Parkinson's patients should be approached based on the needs of the individual as disease presentation, lifestyle, level of disability, concurrent disease states and the presence of non-motor symptoms make each case unique. Patients and caregivers must have realistic expectations about the use of PD medications.