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  • SERCA2a tyrosine nitration coincides with impairments in maximal SERCA activity in left ventricles from tafazzin deficient mice

    Braun, Jessica L.; Hamstra, Sophie I.; Messner, Holt N.; Fajardo, Val A. (The Physiological Society, 2019-08)
    The sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) is imperative for normal cardiac function regulating both muscle relaxation and contractility. SERCA2a is the predominant isoform in cardiac muscles and is inhibited by phospholamban (PLN). Under conditions of oxidative stress, SERCA2a may also be impaired by tyrosine nitration. Tafazzin (Taz) is a mitochondrial specific transacylase that regulates mature cardiolipin (CL) formation, and its absence leads to mitochondrial dysfunction and excessive production of reactive oxygen/nitrogen species (ROS/RNS). In the present study, we examined SERCA function, SERCA2a tyrosine nitration, and PLN expression/phosphorylation in left ventricles (LV) obtained from young (3-5 months) and old (10-12 months) wild-type (WT) and Taz knockdown (TazKD) male mice. These mice are a mouse model for Barth syndrome, which is characterized by mitochondrial dysfunction, excessive ROS/RNS production, and dilated cardiomyopathy (DCM). Here, we show that maximal SERCA activity was impaired in both young and old TazKD LV, a result that correlated with elevated SERCA2a tyrosine nitration. In addition PLN protein was decreased, and its phosphorylation was increased in TazKD LV compared with control, which suggests that PLN may not contribute to the impairments in SERCA function. These changes in expression and phosphorylation of PLN may be an adaptive response aimed to improve SERCA function in TazKD mice. Nonetheless, we demonstrate for the first time that SERCA function is impaired in LVs obtained from young and old TazKD mice likely due to elevated ROS/RNS production. Future studies should determine whether improving SERCA function can improve cardiac contractility and pathology in TazKD mice
  • Changes to the Human Serum Proteome in Response to High Intensity Interval Exercise: A Sequential Top-Down Proteomic Analysis

    Kurgan, Nigel; Noaman, Nour; Pergande, Melissa R.; Cologna, Stephanie M.; Coorssen, Jens R.; Klentrou, Panagiota (Frontiers, 2019-04-02)
    Exercise has been shown to improve health status and prevent chronic diseases. In contrast, overtraining can lead to maladaptation and detrimental health outcomes. These outcomes appear to be mediated in part by released peptides and, potentially, alterations in protein abundances and their modified forms, termed proteoforms. Proteoform biomarkers that either predict the beneficial effects of exercise or indicate (mal)adaptation are yet to be elucidated. Thus, we assessed the influence of highintensity interval exercise (HIIE) on the human serum proteome to identify novel exerciseregulated proteoforms. To this end, a top-down proteomics approach was used, whereby two-dimensional gel electrophoresis was used to resolve and differentially profile intact proteoforms, followed by protein identification via liquid chromatographytandem mass spectrometry. Blood was collected from six young-adult healthy males, pre-exercise and 5 min and 1 h post-exercise. Exercise consisted of a maximal cycle ergometer test followed by 8 min × 1 min high-intensity intervals at 90% Wmax, with 1 min non-active recovery between intervals. Twenty resolved serum proteoforms changed significantly in abundance at 5 min and/or 1 h post-HIIE, including apolipoproteins, serpins (protease inhibitors), and immune system proteins, known to have broad anti-inflammatory and antioxidant effects, involvement in lipid clearance, and cardio-/neuro-protective effects. This initial screening for potential biomarkers indicates that a top-down analytical proteomic approach may prove useful in further characterizing the response to exercise and in understanding the molecular mechanisms that lead to health benefits, as well as identifying novel biomarkers for exercise (mal)adaptation.
  • Antidiabetic Properties of Naringenin: A Citrus Fruit Polyphenol

    Den Hartogh, Danja J.; Tsiani, Evangelia (MDPI, 2019-03-12)
    Type 2 diabetes mellitus (T2DM) is a metabolic disease characterized by insulin resistance and hyperglycemia and is associated with personal health and global economic burdens. Current strategies/approaches of insulin resistance and T2DM prevention and treatment are lacking in efficacy resulting in the need for new preventative and targeted therapies. In recent years, epidemiological studies have suggested that diets rich in vegetables and fruits are associated with health benefits including protection against insulin resistance and T2DM. Naringenin, a citrus flavanone, has been reported to have antioxidant, anti-inflammatory, hepatoprotective, nephroprotective, immunomodulatory and antidiabetic properties. The current review summarizes the existing in vitro and in vivo animal studies examining the anti-diabetic effects of naringenin
  • Acute exercise and brain BACE1 protein content: a time course study

    Yang, Alex J.; Hayward, Grant C.; MacPherson, Rebecca E. K. (American Physiological Society, 2019-04-08)
    Obesity and insulin resistance are risk factors in the development of neurodegenerative disorders. Previous work suggests that one acute bout of exercise may have beneficial neuro-protective effects in obese mice. The rate limiting enzyme in the production of amyloid-beta peptides, BACE1, was reduced in the prefrontal cortex 2 h post-exercise, however if these effects remain over time is unknown. We aimed to determine how long exercise–induced alterations persist in the prefrontal cortex and hippocampus following a single exercise bout. Male C57BL/6J mice were fed either a low (LFD, 10% kcals from lard) or a high fat diet (HFD, 60% kcals from lard) for 7 weeks. HFD mice then underwent an acute bout of treadmill running (15 m/min, 5% incline, 120 min) followed by 2-, 8-, or 24-h of recovery. The HFD increased body mass (LFD 27.8 1.05 vs. HFD 41.7 0.60 g; P < 0.05) and glucose intolerance (AUC LFD 63.27 4.5 vs. HFD 128.9 4.6; P < 0.05). Prefrontal cortex BACE1 content was reduced 2- and 8-h post-exercise compared to sedentary HFD mice, however BACE1 protein content at 24 h was not different. Hippocampal BACE1 content was reduced 8- and 24-h post-exercise. Compared to the LFD, the HFD had higher prefrontal cortex phosphorylation of p38, JNK, and AMPK, indicative of increased neuronal stress. Post–exercise prefrontal cortex p38 and JNK phosphorylation were no different between the HFD or LFD groups, while ERK phosphorylation was significantly reduced by 24 h. The HFD increased JNK phosphorylation in the hippocampus. These results demonstrate the direct and potent effects of exercise on reducing BACE1 prefrontal cortex and hippocampal content. However the reduction in prefrontal cortex BACE1 content is short lived.
  • Evaluation of neuropathological effects of a high-fat high-sucrose diet in middle-aged male C57BL6/J mice

    Baranowski, Bradley J; Bott, Kirsten N.; MacPherson, Rebecca E. K. (American Physiological Society, 2018-05-15)
    Metabolic dysfunction related to diet-induced obesity has recently been linked to the pathogenesis of sporadic Alzheimer’s disease (AD). However, the underlying mechanisms linking obesity and AD remain unclear. The purpose of this study was to examine early alterations in brain insulin signaling, inflammatory/stress markers, and energetic stress in a model of diet-induced obesity during middle age. Male C57BL/6J mice were randomized to either a control diet (AGE n = 12) or high-fat and sucrose diet (AGE-HFS n = 12) for 13-weeks from 20-weeks of age. Prefrontal cortex and hippocampal samples were collected at 20-weeks of age (BSL n = 11) and at 33-weeks of age (AGE and AGE-HFS). The HFS diet resulted in increased body weight (30%; P = 0.0001), increased %fat mass (28%; P = 0.0001), and decreased %lean mass (33%; P = 0.0001) compared to aged controls. In the prefrontal cortex, AGE-HFS resulted in increased 50 adenosine monophosphate – activated protein kinase (AMPK) phosphorylation (P = 0.045). In the hippocampus, AGEHFS resulted in increased extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) phosphorylation and protein kinase B (Akt) serine473 and glycogen synthase kinase (GSK) phosphorylation (P < 0.05). Results from this study demonstrate that aging combined with a HFS diet results in increased inflammation (pERK and pJNK) and energetic stress (pAMPK) in the hippocampus and prefrontal cortex, respectively. Together these novel results provide important information for future targets in early AD pathogenesis.
  • Identification and Characterization of microRNAs during Retinoic Acid-Induced Regeneration of a Molluscan Central Nervous System

    Walker, Sarah E; Spencer, Gaynor E.; Necakov, Aleksander; Carlone, Robert L. (MDPI, 2018-09-13)
    Retinoic acid (RA) is the biologically active metabolite of vitamin A and has become a well-established factor that induces neurite outgrowth and regeneration in both vertebrates and invertebrates. However, the underlying regulatory mechanisms that may mediate RA-induced neurite sprouting remain unclear. In the past decade, microRNAs have emerged as important regulators of nervous system development and regeneration, and have been shown to contribute to processes such as neurite sprouting. However, few studies have demonstrated the role of miRNAs in RA-induced neurite sprouting. By miRNA sequencing analysis, we identify 482 miRNAs in the regenerating central nervous system (CNS) of the mollusc Lymnaea stagnalis, 219 of which represent potentially novel miRNAs. Of the remaining conserved miRNAs, 38 show a statistically significant up- or downregulation in regenerating CNS as a result of RA treatment. We further characterized the expression of one neuronally-enriched miRNA upregulated by RA, miR-124. We demonstrate, for the first time, that miR-124 is expressed within the cell bodies and neurites of regenerating motorneurons. Moreover, we identify miR-124 expression within the growth cones of cultured ciliary motorneurons (pedal A), whereas expression in the growth cones of another class of respiratory motorneurons (right parietal A) was absent in vitro. These findings support our hypothesis that miRNAs are important regulators of retinoic acid-induced neuronal outgrowth and regeneration in regeneration-competent species.
  • Meaningful connections in dementia end of life care in long term care homes

    McCleary, Lynn; Thompson, Genevieve N; Venturato, Lorraine; Wickson-Griffiths, Abigail; Hunter, Paulette; Sussman, Tamara; Kaasalainen, Sharon (BMC, 2018)
    Background: Most persons with dementia die in long term care (LTC) homes, where palliative approaches are appropriate. However, palliative approaches have not been widely implemented and there is limited understanding of staff and family experiences of dying and bereavement in this context. Method: This descriptive qualitative study explored family and staff experiences of end of life and end of life care for persons with dementia in LTC homes. Eighteen focus groups were conducted with 77 staff members and 19 relatives of persons with dementia at four LTC homes in four Canadian provinces. Results: Three themes emerged: knowing the resident, the understanding that they are all human beings, and the long slow decline and death of residents with dementia. Discussion: Intimate knowledge of the person with dementia, obtained through longstanding relationships, was foundational for person-centred end of life care. Health care aides need to be included in end of life care planning to take advantage of their knowledge of residents with dementia. There were unmet bereavement support needs among staff, particularly health care aides. Persons with dementia were affected by death around them and existing rituals for marking deaths in LTC homes may not fit their needs. Staff were uncomfortable answering relatives’ questions about end of life. Conclusions: Longstanding intimate relationships enhanced end of life care but left health care aides with unmet bereavement support needs. Staff in LTC homes should be supported to answer questions about the trajectory of decline of dementia and death. Further research about residents’ experiences of deaths of other residents is needed.