The energy substrate switch during cardiac development, with the onset of cardiac hypertrophy and the transition to heart failure. : delineation and characterisation of gene regulatory mechanisms : "changing concepts of metabolic regulation in the h

Bibliography: leaves 168-190

Delta opioid receptor stimulation mimics ischemic preconditioning in human heart muscle

AbstractOBJECTIVESThe objective of this study was to examine whether the delta (δ) opioid receptor isoform is expressed in the human heart and whether this receptor improves contractile function after hypoxic/reoxygenation injury.BACKGROUNDDelta opioid receptor agonists mimic preconditioning (PC) in rat myocardium, corresponding to known cardiac δ opioid receptor expression in this species.METHODSThe messenger RNA transcript encoding the δ opioid receptor was identified in human atria and ventricles. To evaluate the cardioprotective role of the opioid receptor, human atrial trabeculae from patients undergoing coronary bypass grafting were isolated and superfused with Tyrode’s solution. A control group underwent 90 min of simulated ischemia and 120 min of reoxygenation. A second group was preconditioned with 3 min simulated ischemia and 7 min reoxygenation. Additional groups included: superfusion with the δ receptor agonist (DADLE) (10 nM), with the δ receptor antagonist naltrindole (10 nM) and with the mitochondrial KATP channel blocker 5-hydroxydecanoate (5HD) (100 μM) either with or without PC, respectively. A final group was superfused with 5HD before DADLE. The end point used was percentage of developed force after 120 min of reoxygenation.RESULTSResults, expressed as means ± SEM, were: control = 32.6 ± 3.8%; PC = 50.5% ± 1.8∗; DADLE = 46.0 ± 3.9%∗; PC + naltrindole = 25.5 ± 3.9%; naltrindole alone = 25.5 ± 4.3%; 5HD + PC = 28.9 ± 7.4%; 5HD alone = 24.1 ± 3.0%; 5HD + DADLE = 26.9 ± 4.4% (∗p < 0.001 vs. controls).CONCLUSIONSHuman myocardium expresses the δ opioid receptor transcript. Stimulation of this receptor appears to protects human muscle from simulated ischemia, similar to PC, and via opening of the mitochondrial KATP channel

Ambient Oxygen Promotes Tumorigenesis

Oxygen serves as an essential factor for oxidative stress, and it has been shown to be a mutagen in bacteria. While it is well established that ambient oxygen can also cause genomic instability in cultured mammalian cells, its effect on de novo tumorigenesis at the organismal level is unclear. Herein, by decreasing ambient oxygen exposure, we report a ∼50% increase in the median tumor-free survival time of p53−/− mice. In the thymus, reducing oxygen exposure decreased the levels of oxidative DNA damage and RAG recombinase, both of which are known to promote lymphomagenesis in p53−/− mice. Oxygen is further shown to be associated with genomic instability in two additional cancer models involving the APC tumor suppressor gene and chemical carcinogenesis. Together, these observations represent the first report directly testing the effect of ambient oxygen on de novo tumorigenesis and provide important physiologic evidence demonstrating its critical role in increasing genomic instability in vivo

SIRT3‐dependent deacetylation exacerbates acetaminophen hepatotoxicity

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/102226/1/embr2011121.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/102226/2/embr2011121-sup-0001.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/102226/3/embr2011121.reviewer_comments.pd

Boosting NAD preferentially blunts Th17 inflammation via arginine biosynthesis and redox control in healthy and psoriasis subjects

Acknowledgments We thank Myron Waclawiw of the NHLBI Biostatistics Branch for assistance with the clinical protocol design, Chromadex for supplying NR and matching placebo capsules for the in vivo study and NR powder for the cell culture studies, and an NIH Bench-to-Bedside award for supplemental funding. We additionally thank Dr. Nina Klimova, formerly of the NHLBI, and Dr. Yun-Wei A. Hsu for their support of the metabolomics analysis at the Northwest Metabolomics Research Center of the University of Washington (NIH grant 1S10OD021562-01). We thank and acknowledge the assistance of the NHLBI DNA Sequencing and Genomics Core in performing the RNA library sequencing and Dr. Pradeep Dagur in the NHLBI Flow Cytometry Core for performing the immunophenotyping. Trial registration was as follows: ClinicalTrials.gov: NCT01934660, NCT02812238, and NCT01143454 and NIH Clinical Center blood bank (ClinicalTrials.gov: NCT00001846). This work was supported by the NHLBI Division of Intramural Research (ZIA-HL005102 to M.N.S.), NIH Bench-to-Bedside award (HL-129510-04S1 to M.N.S. and R.T.) and the NIH Office of Dietary Supplements (J.T.), the Spanish Ministry of Science and Innovation (RYC2018-026050-I and PID2019-105665RA-I00 to J.T.), and the UK MRC (MR/P011705/2 and UKDRI-5002 to J.L.G.; MAP UK).Peer reviewedPublisher PD

N-arachidonylglycine is a caloric state-dependent circulating metabolite which regulates human CD4+T cell responsiveness

Acknowledgments We thank Drs. Zoe Hall and Sonia Liggi of the University of Cambridge Biochemistry Department for their contributions to metabolomics analysis and data processing. Shahin Hassanzadeh of the Laboratory of Mitochondrial Biology and Metabolism for developing the PBMC RNAseq library.Matthew Rodman of the Laboratory of Mitochondrial Biology and Metabolism for preparing lean/obese samples. Dr. Duck-Yeon Lee of the NHLBI Biochemistry Core for NAGly analysis in cell culture. Special thanks to the National Institutes of Health Oxford-Cambridge Scholars Program and the International Biomedical Research Alliance for their sponsorship and support. Funding: NHLBI Division of Intramural Research (MNS – ZIA-HL005199) and the UK MRC (JLG – MR/P011705/2; UKDRI-5002; MAPUK).Peer reviewedPublisher PD

Nitrite augments tolerance to ischemia/reperfusion injury via the modulation of mitochondrial electron transfer

Nitrite (NO2−) is an intrinsic signaling molecule that is reduced to NO during ischemia and limits apoptosis and cytotoxicity at reperfusion in the mammalian heart, liver, and brain. Although the mechanism of nitrite-mediated cytoprotection is unknown, NO is a mediator of the ischemic preconditioning cell-survival program. Analogous to the temporally distinct acute and delayed ischemic preconditioning cytoprotective phenotypes, we report that both acute and delayed (24 h before ischemia) exposure to physiological concentrations of nitrite, given both systemically or orally, potently limits cardiac and hepatic reperfusion injury. This cytoprotection is associated with increases in mitochondrial oxidative phosphorylation. Remarkably, isolated mitochondria subjected to 30 min of anoxia followed by reoxygenation were directly protected by nitrite administered both in vitro during anoxia or in vivo 24 h before mitochondrial isolation. Mechanistically, nitrite dose-dependently modifies and inhibits complex I by posttranslational S-nitrosation; this dampens electron transfer and effectively reduces reperfusion reactive oxygen species generation and ameliorates oxidative inactivation of complexes II–IV and aconitase, thus preventing mitochondrial permeability transition pore opening and cytochrome c release. These data suggest that nitrite dynamically modulates mitochondrial resilience to reperfusion injury and may represent an effector of the cell-survival program of ischemic preconditioning and the Mediterranean diet

B-Crystallin Protects Retinal Tissue during Staphylococcus aureus- Induced Endophthalmitis

Bacterial infections of the eye highlight a dilemma that is central to all immune-privileged sites. On the one hand, immune privilege limits inflammation to prevent bystander destruction of normal tissue and loss of vision. On the other hand, bacterial infections require a robust inflammatory response for rapid clearance of the pathogen. We demonstrate that the retina handles this dilemma, in part, by activation of a protective heat shock protein. During Staphylococcus aureus-induced endophthalmitis, the small heat shock protein αB-crystallin is upregulated in the retina and prevents apoptosis during immune clearance of the bacteria. In the absence of αB-crystallin, mice display increased retinal apoptosis and retinal damage. We found that S. aureus produces a protease capable of cleaving αB-crystallin to a form that coincides with increased retinal apoptosis and tissue destruction. We conclude that αB-crystallin is important in protecting sensitive retinal tissue during destructive inflammation that occurs during bacterial endophthalmitis