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Patients affected by glioma frequently experience epileptic discharges; however, the causes of brain tumor-related epilepsy (BTRE) are still not completely understood. We investigated the mechanisms underlying BTRE by analyzing the effects of exosomes released by U87 glioma cells and by patient-derived glioma cells. Rat hippocampal neurons incubated for 24 hours with these exosomes exhibited increased spontaneous firing, while their resting membrane potential shifted positively by 10-15 mV. Voltage clamp recordings demonstrated that the activation of the [Na.sup.+] current shifted toward more hyperpolarized voltages by 10-15 mV. To understand the factors inducing hyperexcitability, we focused on exosomal cytokines. Western blot and ELISAs showed that TNF-[alpha] was present inside glioma-derived exosomes. Remarkably, incubation with TNF-[alpha] fully mimicked the phenotype induced by exosomes, with neurons firing continuously, while their resting membrane potential shifted positively. Real-time PCR revealed that both exosomes and TNF-[alpha] induced overexpression of the voltage-gated [Na.sup.+] channel Nav1.6, a low-threshold [Na.sup.+] channel responsible for hyperexcitability. When neurons were preincubated with infliximab, a specific TNF-[alpha] inhibitor, the hyperexcitability induced by exosomes and TNF-[alpha] was drastically reduced. We propose that infliximab, an FDA-approved drug to treat rheumatoid arthritis, could ameliorate the conditions of glioma patients with BTRE., Introduction Patients with brain tumors develop symptoms ranging from headaches to epileptic discharges to impairment of specific cognitive functions (1-3). The mechanisms leading to brain tumor-related epilepsy (BTRE) are not [...]

SCN5A encodes the voltage-gated [Na.sup.+] channel [Na.sub.v]1.5 that is responsible for depolarization of the cardiac action potential and rapid intercellular conduction. Mutations disrupting the SCN5A coding sequence cause inherited arrhythmias and cardiomyopathy, and single-nucleotide polymorphisms (SNPs) linked to SCN5A splicing, localization, and function associate with heart failure-related sudden cardiac death. However, the clinical relevance of SNPs that modulate SCN5A expression levels remains understudied. We recently generated a transcriptome-wide map of microRNA (miR) binding sites in human heart, evaluated their overlap with common SNPs, and identified a synonymous SNP (rs1805126) adjacent to a miR-24 site within the SCN5A coding sequence. This SNP was previously shown to reproducibly associate with cardiac electrophysiological parameters, but was not considered to be causal. Here, we show that miR-24 potently suppresses SCN5A expression and that rs1805126 modulates this regulation. We found that the rs1805126 minor allele associates with decreased cardiac SCN5A expression and that heart failure subjects homozygous for the minor allele have decreased ejection fraction and increased mortality, but not increased ventricular tachyarrhythmias. In mice, we identified a potential basis for this in discovering that decreased 5cn5a expression leads to accumulation of myocardial reactive oxygen species. Together, these data reiterate the importance of considering the mechanistic significance of synonymous SNPs as they relate to miRs and disease, and highlight a surprising link between SCN5A expression and nonarrhythmic death in heart failure., Introduction The onset and clinical course of heart failure is shaped by a complex interplay of environmental and genetic factors that influence a host of biological processes, including gene regulatory [...]

Author(s): Ajit Vikram [1]; Christopher M Lewarchik [2]; Jin-Young Yoon [1]; Asma Naqvi [2]; Santosh Kumar [1]; Gina M Morgan [1]; Julia S Jacobs [1]; Qiuxia Li [1]; Young-Rae Kim [...]

Baicalin has been reported to attenuate lung edema in the process of lung injury. However, the effect of baicalin on alveolar fluid clearance (AFC) and epithelial sodium channel (ENaC) expression has not been tested. Sprague-Dawley rats were anesthetized and intratracheally injected with either 1 mg/kg lipopolysaccharide (LPS) or saline vehicle. Baicalin with various concentrations (10, 50, and 100 mg/kg) was injected intraperitoneally 30 min before administration of LPS. Then lungs were isolated for measurement of AFC, cyclic adenosine monophosphate (cAMP) level, and cellular localization of α-ENaC. Moreover, mouse alveolar type II (ATII) epithelial cell line was incubated with baicalin (30 µmol/L), adenylate cyclase inhibitor SQ22536 (10 µmol/L), or cAMP-dependent protein kinase inhibitor (PKA) KT5720 (0.3 µmol/L) 15 min before LPS (1 µg/mL) incubation. Protein expression of α-ENaC was detected by Western blot. Baicalin increased cAMP concentration and AFC in a dose-dependent manner in rats with LPS-induced acute lung injury. The increase of AFC induced by baicalin was associated with an increase in the abundance of α-ENaC protein. SQ22536 and KT5720 prevented the increase of α-ENaC expression caused by baicalin in vitro. These findings suggest that baicalin prevents LPS-induced reduction of AFC by upregulating α-ENaC protein expression, which is activated by stimulating cAMP/PKA signaling pathway. Key words: baicalin, acute lung injury, alveolar fluid clearance, epithelial sodium channel. On a rapporte que la baicaline permet d'attenuer l'redeme pulmonaire alors que le poumon subit des lesions. Cependant, l'effet de la baicaline sur la clairance du liquide alveolaire (CLA) et l'expression des canaux sodiques de la membrane apicale des cellules epitheliales (ENaC) n'apas ete teste. Nous avons injecte parvoie intratracheale des lipopolysaccharides (LPS) a 1 mg/kg ou le vehicule de solution saline a des rats Sprague-Dawley anesthesies. Trente minutes avant l'administration des LPS, nous avons injecte par voie intraperitoneale de la baicaline a diverses concentrations (10, 50 et 100 mg/kg). Puis, nous avons isole les poumons en vue de mesurer la CLA et les taux d'adenosine monophosphate cyclique (AMPc) ainsi que de localiser les canaux ENaCa dans les cellules. En outre, 15 minutes avant une incubation en presence des LPS (a 1 µg/mL), nous avons incube des lignees de cellules epitheliales alveolaires de type II (ATII) de souris en presence de baicaline (a 30 µmol/L), de SQ22536, un inhibiteur de l'adenylate cyclase, (a 10 µmol/L) ou de KT5720, un inhibiteur de la proteine kinase dependante de l'AMPc [PKA] (a 0,3 µmol/L). Enfin, nous avons determine l'expression des canaux ENaCα par immunobuvardage de western. Chez les rats presentant des lesions pulmonaires aigues provoquees par les LPS, la baicaline entrainait une augmentation proportionnelle a la dose des concentrations d'AMPc et de la CLA. L'augmentation de la CLA engendree par la baicaline etait associee a une augmentation des taux de proteines des canaux ENaC-α. Par ailleurs, le SQ22536 et le KT5720 ont empeche l'augmentation de l'expression des canaux ENaCa engendree par la baicaline in vitro. Ces resultats laissent entendre que la baicaline previendrait la diminution de la CLA provoquee par les LPS en regulant a la hausse l'expression des proteines des canaux ENaCa activee par la stimulation de la voie de signalisation AMPc/PKA. [Traduit par la Redaction] Mots-cles: baicaline, lesion pulmonaire aigue, clairance du liquide alveolaire, canaux sodiques de la membrane apicale des cellules epitheliales., Introduction Acute lung injury (ALI) is associated with high morbidity and mortality in critically ill patients. It is a distinct form of acute respiratory failure characterized by diffuse pulmonary infiltrates, [...]

Using the UM-X7.1 hereditary cardiomyopathic and muscular dystrophy hamsters (HCMH), we tested the effects of lifelong preventive or curative treatments during the heart failure phase with the NHE-1 inhibitor EMD 87580 (EMD) or with the angiotensin-converting enzyme inhibitor cilazapril on the intracellular [Na.sup.+] and [Ca.sup.2+] overloads, elevated level of NHE-1, necrosis, hypertrophy, heart failure, and early death. Our results showed that 310-day pretreatment of 30-day-old HCMHs with EMD significantly prevented cardiac necrosis, cardiomyocyte hypertrophy, and reduced the heart to body mass ratio. This treatment significantly prevented [Na.sup.+] and [Ca.sup.2+] overloads and the increase in NHE-1 protein level observed in HCMHs. Importantly, this lifelong preventive treatment significantly decreased the levels of creatine kinase and prevented early death of HCMHs. Curative 0treatment of hypertrophic 275-day-old HCMHs for 85 days with EMD significantly prevented hypertrophy and early death of HCMHs. However, treatments with cilazapril did not have any significant effects on the cardiac parameters studied or on early death of HCMHs. Our results suggest that the increase in the NHE-1 level and the consequent [Na.sup.+] and [Ca.sup.2+] overloads are implicated in the pathological process leading to heart failure and early death in HCMHs, and treatment with the NHE-1 inhibitor is promising for preventing early death in hereditary cardiomyopathy. Key words: cardiomyopathy, early death, heart failure, NHE-1, NHE-1 inhibitor EMD 87580, ACE inhibitor. A l'aide d'un modele de hamster atteint de cardiomyopathie et de dystrophie musculaire hereditaires (souche UM-X7.1), nous avons etudie les effets de traitements preventifs a vie et de traitements curatifs pendant la phase d'insuffisance cardiaque par l'administration de l'EMD 87580, un inhibiteur de la NHE-1 (isoforme 1 de la proteine echangeuse d'ions sodium-proton), ou de cilazapril, un IECA (inhibiteur de l'enzyme de conversion de l'angiotensine), sur l'etablissement de surcharges intracellulaires en [Na.sup.+] et en [Ca.sup.2+], l'augmentation des taux de NHE-1, la necrose, l'hypertrophie, l'insuffisance cardiaque et la mort prematuree. Nos resultats ont montre qu'un pretraitement des hamsters UM-X7.1 par l'EMD 87580 pendant 310 jours permettait manifestement de prevenir la necrose cardiaque, l'hypertrophie des cardiomyocytes et l'augmentation du rapport entre le poids du creur et le poids corporel total. Ce traitement permettait de prevenir l'etablissement de surcharges en [Na.sup.+] et en [Ca.sup.2+] et d'augmenter les taux de proteine NHE-1 observes dans ce modele. Mais avant tout, administre a vie de maniere preventive, ce traitement permettait de diminuer les taux de creatine kinase et de prevenir la mort prematuree de maniere importante chez les hamsters UM-X7.1. Un traitement curatif par l'EMD 87580 pendant 85 jours administre a des hamsters UM-X7.1ages de 275 jours permettait de prevenir l'hypertrophie et la mort prematuree dans ce modele. Cependant, les traitements par le cilazapril n'avaient aucun effet notable sur les parametres cardiaques etudies ni sur la mort prematuree chez les hamsters UM-X7.1. Nos resultats indiquent que l'augmentation des taux de NHE-1 et les surcharges en [Na.sup.+] et en [Ca.sup.2+] qui en decoulent joueraient un role dans les processus pathologiques entrainant l'insuffisance cardiaque et la mort prematuree chez les hamsters UM-X7.1. En fait, l'administration d'inhibiteurs de la NHE-1 pourrait etre une avenue therapeutique prometteuse pour la prevention de la mort prematuree en cas de cardiomyopathie hereditaire. [Traduit par la Redaction] Mots-cles: cardiomyopathie, mort prematuree, insuffisance cardiaque, NHE-1, inhibiteur de la NHE-1 EMD 87580, IECA., Introduction An important characteristic of several types of hypertrophy and congestive heart failure (HF) is a disturbed intracellular calcium ([[[Ca.sup.2+]].sub.i]) handling in heart muscles (Jasmin and Proschek 1984, 1994; Bkaily [...]