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Holm J.B.,Copenhagen University | Grygorczyk R.,Center Hospitalier Of Luniversite Of Montreal Crchum | Lambert I.H.,Copenhagen University
American Journal of Physiology - Cell Physiology | Year: 2013

Pathophysiological conditions challenge cell volume homeostasis and perturb cell volume regulatory mechanisms leading to alterations of cell metabolism, active transepithelial transport, cell migration, and death. We report that inhibition of the 5-lipoxygenase (5-LO) with AA861 or ETH 615-139, the cysteinyl leukotriene 1 receptor (CysLT1) with the antiasthmatic drug Zafirlukast, or the volume-sensitive organic anion channel (VSOAC) with DIDS blocks the release of organic osmolytes (taurine, meAIB) and the concomitant cell volume restoration following hypoosmotic swelling of human type II-like lung epithelial cells (A549). Reactive oxygen species (ROS) are produced in A549 cells upon hypotonic cell swelling by a diphenylene iodonium-sensitive NADPH oxidase. The swelling-induced taurine release is suppressed by ROS scavenging (butylated hydroxytoluene, N-acetyl cysteine) and potentiated by H2O2. Ca2+ mobilization with ionomycin or ATP stimulates the swelling-induced taurine release whereas calmodulin inhibition (W7) inhibits the release. Chelation of the extracellular Ca2+ (EGTA) had no effect on swelling-induced taurine release but prevented ATP-induced stimulation. H2O2, ATP, and ionomycin were unable to stimulate the taurine release in the presence of AA861 or Zafirlukast, placing 5-LO and CysLT1 as essential elements in the swelling-induced activation of VSOAC with ROS and Ca2+ as potent modulators. Inhibition of tyrosine kinases (genistein, cucurbitacin) reduces volume-sensitive taurine release, adding tyrosine kinases (Janus kinase) as regulators of VSOAC activity. Caspase-3 activity during hypoxia is unaffected by inhibition of 5-LO/CysLT1 but reduced when swelling-induced taurine loss via VSOAC is prevented by DIDS excess extracellular taurine, indicating a beneficial role of taurine under hypoxia. © the American Physiological Society.

Orlov S.N.,Moscow State University | Hamet P.,Center Hospitalier Of Luniversite Of Montreal Crchum
Pflugers Archiv European Journal of Physiology | Year: 2015

Our review focuses on the recent data showing that gene transcription and translation are under the control of signaling pathways triggered by modulation of the intracellular sodium/potassium ratio ([Na+]i/[K+]i). Side-by-side with sensing of osmolality elevation by tonicity enhancer-binding protein (TonEBP, NFAT5), [Na+]i/[K+]i-mediated excitation-transcription coupling may contribute to the transcriptomic changes evoked by high salt consumption. This novel mechanism includes the sensing of heightened Na+ concentration in the plasma, interstitial, and cerebrospinal fluids via augmented Na+ influx in the endothelium, immune system cells, and the subfornical organ, respectively. In these cells, [Na+]i/[K+]i ratio elevation, triggered by augmented Na+ influx, is further potentiated by increased production of endogenous Na+,K+-ATPase inhibitors documented in salt-sensitive hypertension. © 2014, Springer-Verlag Berlin Heidelberg.

Bruneau J.,Center Hospitalier Of Luniversite Of Montreal Crchum | Bruneau J.,University of Montreal | Roy E.,Universite de Sherbrooke | Zang G.,Center Hospitalier Of Luniversite Of Montreal Crchum | And 2 more authors.
Addiction | Year: 2012

Aims To examine trends in prescription opioid (PO) injection and to assess its association with hepatitis C virus (HCV) seroconversion among injection drug users (IDUs). Design Prospective cohort study. Setting Montreal, Canada. Participants HCV-negative IDUs at baseline, reporting injection in the past month. Measurements Semi-annual visits included HCV antibody testing and an interview-administered questionnaire assessing risk behaviours. HCV incidence rate was calculated using the person-time method. Time-updated Cox regression models were conducted to examine predictors of HCV incidence. Findings The proportion of IDUs reporting PO injection increased from 21% to 75% between 2004 and 2009 (P<0.001). Of the 246 participants (81.6% male; mean age 34.5 years; mean follow-up time 23 months), 83 seroconverted to HCV [incidence rate: 17.9 per 100 person-years; 95% confidence interval (CI) 14.3, 22.1]. Compared to non-PO injectors, PO injectors were more likely to become infected [adjusted hazard ratio (AHR): 1.87; 95%CI:1.16, 3.03]. An effect modification was also found: PO injectors who did not inject heroin were more likely to become infected (AHR: 2.88; 95%CI: 1.52, 5.45) whereas no association was found for participants using both drugs (AHR: 1.19; 95% CI: 0.61, 2.30). Other independent predictors of HCV incidence were: cocaine injection, recent incarceration and >30 injections per month. Conclusions Prescription opioid injectors who do not inject heroin are at greater risk for HCV seroconversion than are those injecting both heroin and prescription opioids. Important differences in age, behaviour and social context suggest a need for targeted outreach strategies to this population. © 2012 Society for the Study of Addiction.

Tremblay J.,Center Hospitalier Of Luniversite Of Montreal Crchum | Hamet P.,Center Hospitalier Of Luniversite Of Montreal Crchum
Metabolism: Clinical and Experimental | Year: 2010

Pain is an integral part of the defense mechanisms required for survival. Several hereditary syndromes of complete or almost complete insensitivity to pain have been identified and include channelopathy-associated pain insensitivity, of which the most likely candidate gene is the α-subunit of the voltage-gated sodium channel known as Na(v)1.7. Five hereditary sensory and autonomic neuropathy syndromes have been described. Variable pain sensitivity in the general population has been linked to common variants of the μ-opioid receptor and of the catecholamine-O-methyltransferase genes potentially leading to increased opioid tonus. Variants of the guanosine triphosphate cyclohydrolase 1/dopa-responsive dystonia gene appear to regulate nociception. Other candidate genes are the transient receptor potential cation channel, subfamily 5 member 1, gene and the melanocortin-1 receptor gene. Candidate genes for predicting opioid efficacy are drug-metabolizing enzymes and transporters-including cytochrome P450, uridine 5′-diphosphate-glucuronosyltransferases, and adenosine triphosphate-binding cassette transporters-that are involved in opioid metabolism. Most current knowledge on the genetic regulation of pain has been derived from animal models developed mainly in mice. Genomics has the potential to contribute to therapeutic advances with the promising approach of using small interfering RNA in the control of neuropathic pain. Knowledge of the genetic factors that affect opioid efficacy, metabolism, and adverse effects has the potential for personalizing both acute and chronic pain management, and for designing more useful opiate pain medications with lower adverse event profiles. © 2010 Elsevier Inc. All rights reserved.

Tremblay J.,Center Hospitalier Of Luniversite Of Montreal Crchum | Tremblay J.,Prognomix | Hamet P.,Center Hospitalier Of Luniversite Of Montreal Crchum | Hamet P.,Prognomix
Metabolism: Clinical and Experimental | Year: 2013

Technology continues to lead the field of personalized medicine as the interpretation of the human genome is progressing. The cost and duration of genomic sequencing continue to decrease sharply and there is intensive research aimed at understanding how the changes that occur within the genome can alter its function and the genomic variations that constitute individual susceptibility to diseases and responses to therapy. The overlay of a personal genome with the personal medical record of patients has a potential to improve prediction and prevention and to allow a more pro-active therapeutic strategy. It is evident that pharmacogenomics and individualized drug therapy are the building blocks of personalized medicine. A growing number of drugs are now used for the treatment of cancer in subjects selected by a companion genetic test. Personalized medicine while based upon genomic knowledge of the individual requires equally essential personalised environmental information as well as the understanding of every subject's capacity for health-promoting behaviour. © 2013 Elsevier Inc.

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