Inhibition of NAPDH Oxidase 2 (NOX2) Prevents Oxidative Stress and Mitochondrial Abnormalities Caused by Saturated Fat in Cardiomyocytes

Obesity and high saturated fat intake increase the risk of heart failure and arrhythmias. The molecular mechanisms are poorly understood. We hypothesized that physiologic levels of saturated fat could increase mitochondrial reactive oxygen species (ROS) in cardiomyocytes, leading to abnormalities of calcium homeostasis and mitochondrial function. We investigated the effect of saturated fat on mitochondrial function and calcium homeostasis in isolated ventricular myocytes. The saturated fatty acid palmitate causes a decrease in mitochondrial respiration in cardiomyocytes. Palmitate, but not the monounsaturated fatty acid oleate, causes an increase in both total cellular ROS and mitochondrial ROS. Palmitate depolarizes the mitochondrial inner membrane and causes mitochondrial calcium overload by increasing sarcoplasmic reticulum calcium leak. Inhibitors of PKC or NOX2 prevent mitochondrial dysfunction and the increase in ROS, demonstrating that PKC-NOX2 activation is also required for amplification of palmitate induced-ROS. Cardiomyocytes from mice with genetic deletion of NOX2 do not have palmitate-induced ROS or mitochondrial dysfunction. We conclude that palmitate induces mitochondrial ROS that is amplified by NOX2, causing greater mitochondrial ROS generation and partial depolarization of the mitochondrial inner membrane. The abnormal sarcoplasmic reticulum calcium leak caused by palmitate could promote arrhythmia and heart failure. NOX2 inhibition is a potential therapy for heart disease caused by diabetes or obesity

A History of Opioid Abuse: Why Buprenorphine is Superior for the Management of Opioid Use Disorder and Pain

Opioid abuse represents a public health crisis that has significant associated morbidity and mortality. Since beginning in the early 1990\u27s, the opioid abuse epidemic has been difficult to control due to regulatory, economic, and psychosocial factors that have perpetuated its existence. This era of opioid abuse has been punctuated by three distinct rises in mortality, precipitated by unique public health problems that needed to be addressed. Patients affected by opioid abuse have been historically treated with either methadone or naltrexone. While these agents have clinical utility supported by robust literature, we the authors posit that buprenorphine is a superior therapy for both opioid use disorder (OUD) as well as pain. This primacy is due to the pharmacological properties of buprenorphine which render it unique among other opioid medications. One such property is buprenorphine\u27s ceiling effect of respiratory depression, a common side effect and complicating factor in the administration of many classical opioid medications. This profile renders buprenorphine safer, while simultaneously retaining therapeutic utility in the medical practitioner\u27s pharmacopeia for the treatment of opioid use disorder and pain

Fraunhofer satellite radiation sensing systems: Paper presented at 69th International Astronautical Congress, Bremen, Germany, October 1-5, 2018

Fraunhofer INT develops systems for on-board radiation sensing. On-board in this context means inside electronic boxes on printed circuit boards (PCB) in close proximity to radiation sensitive electronic devices. The ability to measure dose and/or particle fluxes on the PCB is particularly of interest as this is where radiation hurts the most. In case of intense solar particle events the sudden increase of the measured particle fluxes could be used as an input for adaptive radiation mitigation techniques to protect important electronic parts and systems. Furthermore it can help to reduce radiation design margins for future missions because you get a better knowledge of the received dose inside your electronic box in a given radiation environment. In addition in the case of in-orbit verification or validation missions it is of major importance to verify the reliability of your design against the actual dose received. Our approach is to add as little devices as possible and make use of already installed hardware e.g. microprocessors to operate them, so the output of those sensor devices should already be digital. We propose to integrate additional memory devices for radiation sensing on the PCB: non-volatile UV-EPROMs to measure dose and/or SRAMs to detect high energy (solar) particles. The radiation-induced change of their digital content is a measure for the radiation exposure after calibration in a known radiation field. Fraunhofer On-board Radiation Sensors are already accepted to fly on the German geostationary Heinrich Hertz communication satellite as part of the Fraunhofer On-Board Processor and is foreseen to be implemented on-board of a NanoSat

Fraunhofer satellite radiation sensing systems

Fraunhofer INT develops systems for on-board radiation sensing. On-board in this context means inside electronic boxes on printed circuit boards (PCB) in close proximity to radiation sensitive electronic devices. The ability to measure dose and/or particle fluxes on the PCB is particularly of interest as this is where radiation hurts the most. In case of intense solar particle events the sudden increase of the measured particle fluxes could be used as an input for adaptive radiation mitigation techniques to protect important electronic parts and systems. Furthermore it can help to reduce radiation design margins for future missions because you get a better knowledge of the received dose inside your electronic box in a given radiation environment. In addition in the case of in-orbit verification or validation missions it is of major importance to verify the reliability of your design against the actual dose received. Our approach is to add as little devices as possible and make use of already installed hardware e.g. microprocessors to operate them, so the output of those sensor devices should already be digital. We propose to integrate additional memory devices for radiation sensing on the PCB: non-volatile UV-EPROMs to measure dose and/or SRAMs to detect high energy (solar) particles. The radiation-induced change of their digital content is a measure for the radiation exposure after calibration in a known radiation field. Fraunhofer On-board Radiation Sensors are already accepted to fly on the German geostationary Heinrich Hertz communication satellite as part of the Fraunhofer On-Board Processor and is foreseen to be implemented on-board of a NanoSat

Correction: Inhibition of NAPDH Oxidase 2 (NOX2) Prevents Oxidative Stress and Mitochondrial Abnormalities Caused by Saturated Fat in Cardiomyocytes.

[This corrects the article DOI: 10.1371/journal.pone.0145750.]

Palmitate causes a decrease in mitochondrial oxygen consumption in cardiomyocytes.

<p>A. Oxygen consumption rate is decreased by palmitate. B. Extracellular acidification rate from the same experiment. Data from WT cardiomyocytes. Measurements from three time-points were obtained under each condition, using triplicate wells. b = baseline, o = oligomycin, F = FCCP, AA = antimycin-A and rotenone. C. Respiratory control ratio is reduced significantly by palmitate. D. Electron transport chain complex III activity is significantly reduced by palmitate. Units are nanomoles substrate utilized/min/mg protein. The means of all graphs are significantly different by ANOVA, * = sig different from control by post-hoc test.</p

NOX2 inhibition reduces PMA-induced and cresol-induced ROS.

<p>A. Representative PMA experiment done with cardiomyocytes in triplicate, height is DCF fluorescence minus background, in live cells, expressed in arbitrary units, mean + SEM. B. PMA experiment using mitosox red signal. C. PMA experiment using TMRM signal. The NOX2 inhibitor and PKC inhibitors reduce depolarization. D. PMA experiment using Rhod2 signal. The NOX2 inhibitor and PKC inhibitors reduce calcium overload. E,F. Cresol increases total ROS and mitochondrial ROS. G. Cresol depolarized the mitochondrial inner membrane. H. Cresol increases mitochondrial calcium. For all panels, means are significantly different by ANOVA, * = sig different from control by post-hoc test, # = sig different from PMA by post-hoc test. PMA 100 nM, gp = gp91ds peptide 50 μM, Go = Go6983 5 μM, LY = LY333531 50 nM, Cre = cresol 1 or 3 μM.</p

NOX2 KO cardiomyocytes do not have an increase in ROS in response to palmitate or PKC activation.

<p>A. Representative experiment done with cardiomyocytes in triplicate, height is DCF fluorescence minus background, in live cells, expressed in arbitrary units, mean + SEM. B. Cardiomyocytes from the same experiment using mitosox red readout. C. Cardiomyocytes from the same experiment using TMRM readout. For all panels, means are significantly different by ANOVA, * = sig different from control by Dunnett post-hoc test. PA = palmitate 200 μM, gp = gp91ds peptide 50 μM, Go = Go6983 5 μM, LY = LY333531 50 nM, Cre = cresol 3 μM, PMA 100 nM.</p