Simone Lanini, Gina Portella, Francesco Vairo, Gary P Kobinger, Antonio Pesenti, Martin Langer, Soccoh Kabia, Giorgio Brogiato, Jackson Amone, Concetta Castilletti, Rossella Miccio, Alimuddin Zumla, Maria Rosaria Capobianchi, Antonino Di Caro, Gino Strada, Giuseppe Ippolito, INMI-EMERGENCY EBOV Sierra Leone Study group
BACKGROUND. Activation of the NLRP3 inflammasome is associated with metabolic dysfunction, and intermittent fasting has been shown to improve clinical presentation of NLRP3 inflammasome–linked diseases. As mitochondrial perturbations, which function as a damage-associated molecular pattern, exacerbate NLRP3 inflammasome activation, we investigated whether fasting blunts inflammasome activation via sirtuin-mediated augmentation of mitochondrial integrity.
METHODS. We performed a clinical study of 19 healthy volunteers. Each subject underwent a 24-hour fast and then was fed a fixed-calorie meal. Blood was drawn during the fasted and fed states and analyzed for NRLP3 inflammasome activation. We enrolled an additional group of 8 healthy volunteers to assess the effects of the sirtuin activator, nicotinamide riboside, on NLRP3 inflammasome activation.
RESULTS. In the fasting/refeeding study, individuals showed less NLRP3 inflammasome activation in the fasted state compared with that in refed conditions. In a human macrophage line, depletion of the mitochondrial-enriched sirtuin deacetylase SIRT3 increased NLRP3 inflammasome activation in association with excessive mitochondrial ROS production. Furthermore, genetic and pharmacologic SIRT3 activation blunted NLRP3 activity in parallel with enhanced mitochondrial function in cultured cells and in leukocytes extracted from healthy volunteers and from refed individuals but not in those collected during fasting.
CONCLUSIONS. Together, our data indicate that nutrient levels regulate the NLRP3 inflammasome, in part through SIRT3-mediated mitochondrial homeostatic control. Moreover, these results suggest that deacetylase-dependent inflammasome attenuation may be amenable to targeting in human disease.
TRIAL REGISTRATION. ClinicalTrials.gov NCT02122575 and NCT00442195.
FUNDING. Division of Intramural Research, NHLBI of the NIH.
Javier Traba, Miriam Kwarteng-Siaw, Tracy C. Okoli, Jessica Li, Rebecca D. Huffstutler, Amanda Bray, Myron A. Waclawiw, Kim Han, Martin Pelletier, Anthony A. Sauve, Richard M. Siegel, Michael N. Sack
David A. Zeevi, Gheona Altarescu, Ariella Weinberg-Shukron, Fouad Zahdeh, Tama Dinur, Gaya Chicco, Yair Herskovitz, Paul Renbaum, Deborah Elstein, Ephrat Levy-Lahad, Arndt Rolfs, Ari Zimran
BACKGROUND: The disrupted in schizophrenia 1 (
METHODS: We measured cortical thickness, cortical surface area, subcortical volumes, and regional cerebral blood flow (rCBF) in healthy controls (HC) (
RESULTS: Based on cortical thickness, 72% of the T– group were assigned to the HC group, 83% of the T+ group were assigned to the SCZ group, and 45% of the BP group were classified as belonging to the SCZ group, suggesting high specificity of this measurement in predicting brain-related phenotypes. Shared brain-related phenotypes between SCZ and T+ individuals were found for cortical thickness only. Finally, a classification accuracy of 73% was achieved when directly comparing the pattern of cortical thickness of T+ and T– individuals.
CONCLUSION: Together, the results of this study suggest that the
FUNDING: This work was supported by the National Health Service Research Scotland, the Scottish Translational Medicine Research Collaboration, the Innovative Medicines Initiative (IMI), the Engineering and Physical Sciences Research Council (EPSRC), The Wellcome Trust, the National Institute of Health Research (NIHR), and Pfizer.
Orla M. Doyle, Catherine Bois, Pippa Thomson, Liana Romaniuk, Brandon Whitcher, Steven C.R. Williams, Federico E. Turkheimer, Hreinn Stefansson, Andrew M. McIntosh, Mitul A. Mehta, Stephen M. Lawrie
Rose G. Radin, Sunni L. Mumford, Robert M. Silver, Laurie L. Lesher, Noya Galai, David Faraggi, Jean Wactawski-Wende, Janet M. Townsend, Anne M. Lynch, Hyagriv N. Simhan, Lindsey A. Sjaarda, Neil J. Perkins, Shvetha M. Zarek, Karen C. Schliep, Enrique F. Schisterman
Mark R. Rigby, Kristina M. Harris, Ashley Pinckney, Linda A. DiMeglio, Marc S. Rendell, Eric I. Felner, Jean M. Dostou, Stephen E. Gitelman, Kurt J. Griffin, Eva Tsalikian, Peter A. Gottlieb, Carla J. Greenbaum, Nicole A. Sherry, Wayne V. Moore, Roshanak Monzavi, Steven M. Willi, Philip Raskin, Lynette Keyes-Elstein, S. Alice Long, Sai Kanaparthi, Noha Lim, Deborah Phippard, Carol L. Soppe, Margret L. Fitzgibbon, James McNamara, Gerald T. Nepom, Mario R. Ehlers, the Immune Tolerance Network (ITN) T1DAL Study Group
Stephen E. Boag, Rajiv Das, Evgeniya V. Shmeleva, Alan Bagnall, Mohaned Egred, Nicholas Howard, Karim Bennaceur, Azfar Zaman, Bernard Keavney, Ioakim Spyridopoulos
Lisa M. Rice, Cristina M. Padilla, Sarah R. McLaughlin, Allison Mathes, Jessica Ziemek, Salma Goummih, Sashidhar Nakerakanti, Michael York, Giuseppina Farina, Michael L. Whitfield, Robert F. Spiera, Romy B. Christmann, Jessica K. Gordon, Janice Weinberg, Robert W. Simms, Robert Lafyatis
Marie Bleakley, Shelly Heimfeld, Keith R. Loeb, Lori A. Jones, Colette Chaney, Stuart Seropian, Ted A. Gooley, Franziska Sommermeyer, Stanley R. Riddell, Warren D. Shlomchik
BACKGROUND. Individuals treated with the cholesteryl ester transfer protein (CETP) inhibitor anacetrapib exhibit a reduction in both LDL cholesterol and apolipoprotein B (ApoB) in response to monotherapy or combination therapy with a statin. It is not clear how anacetrapib exerts these effects; therefore, the goal of this study was to determine the kinetic mechanism responsible for the reduction in LDL and ApoB in response to anacetrapib.
METHODS. We performed a trial of the effects of anacetrapib on ApoB kinetics. Mildly hypercholesterolemic subjects were randomized to background treatment of either placebo (
RESULTS. Anacetrapib markedly reduced the LDL-ApoB-100 pool size (PS) in both the placebo and ATV groups. These changes in PS resulted from substantial increases in LDL-ApoB-100 FCRs in both groups. Anacetrapib had no effect on LDL-ApoB-100 PRs in either treatment group. Moreover, there were no changes in the PCSK9 PS, FCR, or PR in either group. Anacetrapib treatment was associated with considerable increases in the LDL triglyceride/cholesterol ratio and LDL size by NMR.
CONCLUSION. These data indicate that anacetrapib, given alone or in combination with a statin, reduces LDL-ApoB-100 levels by increasing the rate of ApoB-100 fractional clearance.
TRIAL REGISTRATION. ClinicalTrials.gov NCT00990808.
FUNDING. Merck & Co. Inc., Kenilworth, New Jersey, USA. Additional support for instrumentation was obtained from the National Center for Advancing Translational Sciences (UL1TR000003 and UL1TR000040).
John S. Millar, Gissette Reyes-Soffer, Patricia Jumes, Richard L. Dunbar, Emil M. deGoma, Amanda L. Baer, Wahida Karmally, Daniel S. Donovan, Hashmi Rafeek, Laura Pollan, Junichiro Tohyama, Amy O. Johnson-Levonas, John A. Wagner, Stephen Holleran, Joseph Obunike, Yang Liu, Rajasekhar Ramakrishnan, Michael E. Lassman, David E. Gutstein, Henry N. Ginsberg, Daniel J. Rader
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