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Tyrosine kinases inhibitors (TKIs) may alter glycaemia and may be cardiotoxic with importance in the diabetic heart. We investigated the effect of multi-TKI crizotinib after short-term administration on metabolic modulators of the heart of diabetic rats. Experimental diabetes mellitus (DM) was induced by streptozotocin (STZ; 80 mg * [kg.sup.-1], i.p.), and controls (C) received vehicle. Three days after STZ, crizotinib (STZ+CRI; 25 mg * [kg.sup.-1] per day p.o.) or vehicle was administered for 7 days. Blood glucose, C-peptide, and glucagon were assessed in plasma samples. Receptor tyrosine kinases (RTKs), cardiac glucose transporters, and peroxisome proliferator-activated receptors (PPARs) were determined in rat left ventricle by RTqPCR method. Crizotinib moderately reduced blood glucose (by 25%, P < 0.05) when compared to STZ rats. The drug did not affect levels of C-peptide, an indicator of insulin secretion, suggesting altered tissue glucose utilization. Crizotinib had no impact on cardiac RTKs. However, an mRNA downregulation of insulin-dependent glucose transporter Glut4 in the hearts of STZ rats was attenuated after crizotinib treatment. Moreover, crizotinib normalized Ppard and reduced Pparg mRNA expression in diabetic hearts. Crizotinib decreased blood glucose independently of insulin and glucagon. This could be related to changes in regulators of cardiac metabolism such as GLUT4 and PPARs. Key words: crizotinib, heart, diabetes mellitus, GLUT4, peroxisome proliferator-activated receptors, tyrosine kinases inhibitors, cardiotoxicity. Les inhibiteurs des tyrosine kinases (ITK) peuvent alterer la glycemie et presenter une cardiotoxicite importante dans le coeur diabetique. Nous avons etudie l'effet de l'administration a court terme de crizotinib, un ITK multiple, sur des modulateurs metaboliques du coeur de rats diabetiques. Nous avons provoque un diabete sucre (DS) experimental a l'aide de streptozotocine (STZ; 80 mg * [kg.sup.-1], i.p.), et les temoins (TEM) ont recu le vehicule. Trois jours apres l'administration de STZ, nous avons administre du crizotinib (STZ + CRI; 25 mg * [kg.sup.-1] * [jour.sup.-1] , p.o.) ou le vehicule sur 7 jours. Nous avons evalue la glycemie ainsi que les taux de peptide C et de glucagon dans des echantillons de plasma. A l'aide de la methode de PCR quantitatif en temps reel, nous avons evalue les recepteurs des tyrosine kinases (RTK), les transporteurs cardiaques du glucose et les recepteurs actives par les proliferateurs de peroxysomes (PPAR) dans le ventricule gauche des rats. Le crizotinib entrainait une diminution moderee de la glycemie (de 25 %, p < 0,05) par rapport aux rats STZ. Le medicament n'avait pas d'effet sur les taux de peptide C, un indicateur de la secretion d'insuline, ce qui laisse entrevoir une alteration de l'utilisation du glucose dans les tissus. Le crizotinib n'avait pas d'influence sur les RTK cardiaques. Cependant, une regulation a la baisse de l'ARNm du transporteur de glucose dependant de l'insuline (GLUT4) dans le coeur des rats STZ s'attenuait apres l'administration de crizotinib. De plus, le crizotinib permettait de normaliser et de reduire l'expression en ARNm des Ppard et des Pparg, respectivement, dans les coeurs diabetiques. Le crizotinib entrai nait un abaissement de la glycemie de maniere independante de l'insuline et du glucagon. Ce phenomene pourrait etre lie a des variations dans des regulateurs du metabolisme cardiaque comme GLUT4 et les PPAR. [Traduit par la Redaction] Mots-cles : crizotinib, coeur, diabete sucre, GLUT4, recepteurs actives par les proliferateurs de peroxysomes, inhibiteurs de la tyrosine kinases, cardiotoxicite., Introduction Tyrosine kinases inhibitors (TKIs) are widely used for the treatment of cancer. Several experimental studies and clinical trials reported changes in blood glucose level as a side effect of [...]

Aims: Parkinson's disease (PD) is a progressive and age-dependent neurodegenerative disease characterised clinically by a variety of motor symptoms and cognitive impairment. PD was initially considered to be a grey matter disease; however, recently, evidence has emerged that white matter changes in PD precede the neuronal loss seen in the grey matter. The cause of these initial white matter changes is yet to be elucidated. Here, we explored whether dysregulated miRNAs and their target mRNA could provide insight into the underlying mechanisms of early white matter changes in PD. Methods: We analysed the expression of miRNAs in three different stages of PD through RNA-sequencing and validated the differential expression of miRNAs through quantitative reverse transcription polymerase chain reaction. With bioinformatic analyses, we predicted target genes of dysregulated miRNAs and investigated their biomarker potential. Finally, in vitro, we confirmed the targetting of the gene SIRT1 by miR-543. Results: We identified 12 dysregulated miRNAs in PD and found that miR-543 holds potential as a biomarker for late-stage PD with dementia. We report upregulation of miR-543 in early PD white matter tissue and downregulation of SIRT1. In vitro experiments showed that the upregulation of miR-543 results in the downregulation of SIRT1 in the white matter, but not in the grey matter. Conclusions: We validated SIRT1 as a target of miR-543 in the brain and showed its function as a potential biomarker. Our results highlight the idea that dysregulation of miR-543 in early PD white matter, resulting in the dysregulation of SIRT1, potentially influencing the early white matter changes observed in PD. [ABSTRACT FROM AUTHOR]

Objective: Depressive disorders are common among about 50% of the patients with drug‐resistant temporal lobe epilepsy (TLE). The underlying etiology remains elusive, but hypothalamus‐pituitary‐adrenal (HPA) axis activation due to changes in glucocorticoid receptor (GR) protein expression could play an important role. Therefore, we set out to investigate expression of the GR in the hippocampus, an important brain region for HPA axis feedback, of patients with drug‐resistant TLE, with and without comorbid depression. Methods: GR expression was studied using immunohistochemistry on hippocampal sections from well‐characterized TLE patients with depression (TLE + D, n = 14) and without depression (TLE − D, n = 12) who underwent surgery for drug‐resistant epilepsy, as well as on hippocampal sections from autopsy control cases (n = 9). Video–electroencephalography (EEG), magnetic resonance imaging (MRI), and psychiatric and memory assessments were performed prior to surgery. Results: Abundant GR immunoreactivity was present in dentate gyrus granule cells and CA1 pyramidal cells of controls. In contrast, neuronal GR expression was lower in patients with TLE, particularly in the TLE + D group. Quantitative analysis showed a smaller GR+ area in TLE + D as compared to TLE − D patients and controls. Furthermore, the ratio between the number of GR+/NeuN+ cells was lower in patients with TLE + D as compared to TLE − D and correlated negatively with the depression severity based on psychiatric history. The expression of the GR was also lower in glial cells of TLE + D compared to TLE − D patients and correlated negatively to the severity of depression. Significance: Reduced hippocampal GR expression may be involved in the etiology of depression in patients with TLE and could constitute a biological marker of depression in these patients. [ABSTRACT FROM AUTHOR]

Abstract: Diabetic cardiomyopathy shows ECG alterations related to cardiac repolarization and manifested by increased duration of QT interval. Although the mechanism is unknown, it is widely believed that the reduction of hyperglycaemia might prevent such alterations. To test this hypothesis, we used the standardized extract of French pine bark – Pycnogenol® (PYC) with hypoglycaemic and antioxidant properties in 8–9 week old rats with experimentally (streptozotocin) induced diabetes mellitus (DM). PYC was administered orally for 6 weeks in three different doses (10, 20, and 50mg/kg b.w., resp.). Experimental DM was manifested by hyperglycaemia (four to six-fold increase in plasma glucose concentration; p <0.05) and significantly increased mean arterial blood pressure (by 19%; p <0.05) measured using catheterization of carotid artery in vivo. Both abnormalities were dose-dependently reduced by PYC. In addition, diabetic cardiomyopathy was associated with a significant increase in left ventricular weight to body weight ratio (by 21%; p <0.05) and a significant decrease of the width of cardiomyocytes (by 23%; p <0.05) indicating cardiac edema on the one side, and hypotrophy of cardiomyocytes on the other. Both of these changes were not affected by PYC. Consequently to metabolic and hemodynamic alterations, significant prolongation of QT interval (by 20%; p <0.05) was present in diabetic rats, however, PYC failed to correct it. Conclusively, PYC fails to correct QT prolongation in spite of dose-dependent reduction of glycaemia and high blood pressure in streptozotocin-induced diabetic cardiomyopathy. [Copyright &y& Elsevier]

Diabetic cardiomyopathy shows ECG alterations related to cardiac repolarization and manifested by increased duration of QT interval. Although the mechanism is unknown, it is widely believed that the reduction of hyperglycaemia might prevent such alterations. To test this hypothesis, we used the standardized extract of French pine bark - Pycnogenol(®) (PYC) with hypoglycaemic and antioxidant properties in 8-9 week old rats with experimentally (streptozotocin) induced diabetes mellitus (DM). PYC was administered orally for 6 weeks in three different doses (10, 20, and 50 mg/kg b.w., resp.). Experimental DM was manifested by hyperglycaemia (four to six-fold increase in plasma glucose concentration; p<0.05) and significantly increased mean arterial blood pressure (by 19%; p<0.05) measured using catheterization of carotid artery in vivo. Both abnormalities were dose-dependently reduced by PYC. In addition, diabetic cardiomyopathy was associated with a significant increase in left ventricular weight to body weight ratio (by 21%; p<0.05) and a significant decrease of the width of cardiomyocytes (by 23%; p<0.05) indicating cardiac edema on the one side, and hypotrophy of cardiomyocytes on the other. Both of these changes were not affected by PYC. Consequently to metabolic and hemodynamic alterations, significant prolongation of QT interval (by 20%; p<0.05) was present in diabetic rats, however, PYC failed to correct it. Conclusively, PYC fails to correct QT prolongation in spite of dose-dependent reduction of glycaemia and high blood pressure in streptozotocin-induced diabetic cardiomyopathy., (Copyright © 2012 Elsevier GmbH. All rights reserved.)