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Doctor who works in busy A&E department says bosses support eight-week break for Love Island appearance   Hunky Dr Alex George, 27, will make his TV appearance in the Majorcan villa tomorrow on the show which pairs young...
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by ZwemZa on June 2nd, 2018
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Walking with the Wounded’s Walk of America, a 12-week expedition from Los Angeles to New York City, is intended to raise awareness of mental health among veterans and to raise funds to support wounded British and American veterans.

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Introduction

Chagas disease, caused by Trypanosoma cruzi (T. cruzi or Tc) infection, affects ~7 million individuals on the American continent [1]. In the US, autochthonous and congenital transmission of Tc occurs, and >300,000 individuals are infected with Tc, resulting in increased risk of transmission through blood and organ donation [2]. The presentation of chagasic cardiomyopathy and heart failure in infected individuals results in >17,000 deaths per year and costs >.0 billion per year in health care costs and lost productivity [3]. The currently available anti-parasite drugs cause significant toxicity and therapeutic failure in adults, and are not recommended [4]. New druggable targets that can halt the destructive oxidative and inflammatory processes and thereby arrest the cardiac remodeling and heart failure in Chagas disease are urgently needed.

Studies in experimental models and humans have demonstrated that the infected host sustains oxidative stress in the myocardium (reviewed in [5,6]). In vivo studies in experimental models showed that mitochondrial functional defects of respiratory chain complexes contribute to a compromise in oxidative phosphorylation (OXPHOS) capacity and an increase in mitochondrial reactive oxygen species (mtROS) in chronic Chagas disease [79]. Recent studies also noted the mitochondrial dysfunction and pro-oxidant milieu were presented with peripheral and myocardial increase in protein carbonyls and lipid hydroperoxides (LPO) in chagasic humans [1012]. Enhancing the mtROS scavenging capacity by overexpressing Mn+2 superoxide dismutase (MnSOD) improved the left ventricular (LV) function that otherwise was significantly compromised in chronically infected WT mice [13]. These studies demonstrate pathologic significance of mtROS in chagasic cardiomyopathy. Why mitochondrial defects persist in chagasic heart is not known.

The integrity and replication of mtDNA is essential for mitochondrial health. The mtDNA is synthesized by DNA polymerase ? (Pol ?) that consists a 140-kDa catalytic subunit (encoded by POLG) and two 55-kDa processive subunits (encoded by POLG2) [14]. The Pol ? possesses DNA polymerase activity as well as 3’-5’ exonuclease activity for proofreading, and functions in conjunction with a number of additional mitochondrial proteins, e.g., 5’-3’ DNA helicase (also called Twinkle, TWNK), topoisomerase I (TOP1MT), RNA polymerase (POLRMT), RNase HI (RNASEH1), exonuclease 1 (MGME1), single-stranded DNA binding protein 1 (SSBP1), DNA ligase III (LIG3), DNA helicase/nuclease 2 (DNA2), and RNA and DNA flap endonuclease 1 (FEN1), forming the mtDNA replisome. The TWNK unwinds the dsDNA; mtSSB stabilizes the single strands; and TOP1MT releases the torsional tension of mtDNA ahead of the replication fork. In addition, POLRMT and transcription factor A (TFAM) are required for mitochondrial transcription, and also provide RNA primer that initiates Pol ? dependent DNA replication. DNA primase-polymerase (PrimPol) contains both DNA primase and DNA polymerase activities, is present in both nuclear and mitochondrial compartments, and it can play an important role in re-priming DNA synthesis to rescue a stalled replication fork [15].

ROS-induced single strand breaks in DNA and oxidation of guanine to 8-oxoguanine (8-oxoG) signal the activation of members of the poly(ADP-ribose) polymerase (PARP) family to facilitate DNA repair [16]. The 113-kDa PARP1 protein (89-kDa active form) belongs to the PARP family of 7 known and 10 putative members, and it accounts for >85% of the PARP activity in cellular systems. PARP1 catalyzes the cleavage of NAD+ into nicotinamide and ADP-ribose and uses the latter to synthesize PAR polymers. The basal level activation of PARP1 by mild genotoxic stimuli causes PARylation of histone proteins (e.g. H1 and H2B) that mediates relaxation of the chromatin superstructure and recruitment of DNA-break repair enzymes, resulting in DNA repair and cell survival. Significant research efforts have shown that PARP1 functions in chromosomal DNA repair through PARylation of histone proteins [17]. It is also suggested that PARP1 by direct binding to or PARylation of enhancers and promoters, functions as a transcriptional co-activator, and modulates the expression of self and many other genes [18]. The scientific community has; however, largely overlooked the potential role of PARP1 in maintenance of mtDNA in health and disease.

Recently, we have found that mitochondrial transport of PARP1 and PARylation were increased in Tc-infected cardiomyocytes [19]. In this study, we aimed to determine the role of PARP1 in mitochondrial health during Chagas disease. For this, we employed wild type (WT or PARP1+/+), PARP1+/-, and PARP1-/- mice. In some studies, we also treated WT chagasic mice with a selective PARP1 inhibitor PJ34 [20]. We utilized fluorescence probes, biochemical and molecular assays, and cutting-edge in situ respirometry and 3-dimensional echocardiography to test our hypothesis. Our results suggest that genetic deletion or chemical inhibition of PARP1 was beneficial in improving mitochondrial health in chagasic mice. Genetic depletion or chemical inhibition of PARP1 resulted in a decline in chronic oxidative stress and cardiac remodeling, and an improvement in mitochondrial coupled respiration and LV function. We discuss the potential mechanism of PARP1/PAR interference with mitochondrial function in Chagas disease.

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