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  • br Conclusion The present study

    2022-01-18


    Conclusion The present study provides evidence to suggest that the ingestion of acetate as a way to augment cellular pools of acetyl-CoA and influence histone acetylation, does not replicate the epigenetic effects of the prebiotic B-GOS®. Furthermore, acetate feeding does not influence olanzapine-induced weight gain, an effect that is supressed by this prebiotic. Although acetate is the main SCFA produced from microbial fermentation of most simple carbohydrates, our data suggest that mechanisms additional to acetate underlie the central and peripheral effects of B-GOS®.
    Conflicts of interest
    Acknowledgements This study was funded by the Biotechnology, Biological Sciences Research Council (BBSRC), UK (Grant code: BB/I006311/1, awarded to PWJ Burnet). ACC Kao is a recipient of a Clarendon Graduate Scholarship (University of Oxford).
    Introduction Acute myocardial infarction (MI) is a major cause of morbidity and mortality worldwide, and myocardial ischemia/reperfusion (I/R) injury is a key factor in determining infarct size [1]. I/R injury drives a number of pathological conditions that correlate with the final infarct size, including metabolic disorders, inflammatory responses, and cardiac myocyte apoptosis and subsequent heart failure [2]. Even with limiting ischemia by early reperfusion, reperfusion injury has been estimated to cause approximately half of the final infarct size in patients [3]. Because no standard therapy is currently available to treat reperfusion injury, a better understanding of the underlying processes and mechanisms is critical for the development of effective therapies for MI patients. Cardiac mitochondria are responsible for ifenprodil mg generation, as well as many other metabolic reactions crucial for cardiac function [4]. As a result, mitochondrial dysfunction is a key contributor to myocardial injury during I/R. Signs of mitochondrial dysfunction are observed soon after ischemia, including mitochondrial calcium overload and the opening of mitochondrial permeability transition pore (mPTP); these changes lead to mitochondrial membrane depolarization, the release of pro-apoptotic proteins, and eventually cardiomyocyte death [5]. Mitochondria are the primary source of reactive oxygen species (ROS), which contribute to myocardial I/R injury [6], as well as cardiomyocyte death and heart failure [7]. These damaging ROS can also target the mitochondria themselves [8], resulting in mitochondrial DNA (mtDNA) damage, diminished mitochondrial protein synthesis, loss of mitochondrial membrane potential, and decreased energy production [5,9]. Thus, maintenance of mitochondrial homeostasis is crucial for cardiomyocyte protection during I/R injury. Autophagy is an intracellular pathway that regulates the turnover of cellular components [4]. During I/R injury, activation of autophagy helps to maintain the energetic balance by promoting ATP generation during ischemia, then subsequently switches to clearance of damaged organelles and proteins during the reperfusion phase [8]. And maintaining autophagic flux during reperfusion reduces infarct size and protects the heart from I/R Injury [10]. Mitophagy, the specific autophagic elimination of mitochondria, removes specifically damaged mitochondria to maintain mitochondrial homeostasis. Enhanced mitochondrial clearance in T lymphocytes, maintaining mitochondrial mass in skeletal muscle and mitochondrial integrity are mediated by autophagy [[11], [12], [13]]. Moreover, mitochondrial biogenesis is regulated by the transcriptional coactivator peroxisome proliferator co-activator 1 alpha (PGC-1α) [14]. However, the direct role of PGC-1α in mitochondrial biogenesis during I/R injury is currently unknown. A recent series of preclinical studies have demonstrated the potent cardioprotective benefits of histone deacetylase (HDAC) inhibitors in murine and rabbit models of I/R injury [15,16]. In particular, suberoylanilide hydroxamic acid (SAHA, Vorinostat, Zolinza®-Merck), an FDA-approved HDAC inhibitor for T cell lymphoma treatment, has been shown to blunt I/R injury by inducing cardiomyocyte autophagy [17]. However, the molecular mechanisms underlying the cardioprotective effects of SAHA have not yet been elucidated. Due to the previously described link between autophagic flux and turnover of damaged mitochondria in I/R injury, we hypothesized that SAHA protects the myocardium by maintaining mitochondrial homeostasis and reducing ROS levels during reperfusion injury. To test this hypothesis, we evaluated the effects of SAHA on ROS levels, mtDNA copy ifenprodil mg number, and mitochondrial membrane potential in cardiomyocytes subjected to I/R injury in vitro and in vivo.