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Methamphetamine is one of the most commonly used illicit drugs during pregnancy. Most studies investigating the impact of maternal use of methamphetamine on children have focused on neurological outcomes. In contrast, cardiovascular outcomes in these children have not been characterized. Recent studies in rodents provide evidence that prenatal exposure to methamphetamine induces changes in cardiac gene expression, changes in the heart's susceptibility to ischemic injury, and changes in vascular function that may increase the risk of developing cardiovascular disorders later in life. Importantly these changes are sex-dependent. This review summarizes our current understanding of how methamphetamine use during pregnancy impacts the cardiovascular function of adult offspring and highlights gaps in our knowledge of the potential cardiovascular risks associated with prenatal exposure to methamphetamine. Key words: methamphetamine, cardiovascular, pregnancy, substance use disorder, heart, Introduction The 2020 National Survey of Drug Use and Health estimated that more than 15 million United States residents 12 years of age and older had used methamphetamine at least [...]

The present study aims to explore the role of microRNA 145-5p (miR-145-5p) in hyperlipidemia. Using bioinformatics tools and a wide range of function and mechanism assays, we attempted to understand the specific function and potential mechanism of miR-145-5p in hyperlipidemia. A cholesterol-enriched diet induced an increase of serum cholesterol and triacylglycerol but a decrease of serum high-density lipoprotein. MiR-145-5p level was decreased in hyperlipidemia rat models. MiR-145-5p regulated lipid metabolism by antagonizing the alteration of high-density lipoprotein, cholesterol, and triacylglycerol in serum mediated by a cholesterol-enriched diet. In mechanism, miR-145-5p directly bound with p21 protein (RAC1)-activated kinase 7 (PAK7) and negatively regulated mRNA and protein levels of PAK7 in THP-1 cells. Furthermore, miR-145-5p level was negatively associated with PAK7 level in rat cardiac tissues. Finally, overexpression of PAK7 reversed the effects of miR-145-5p on [beta]-catenin activation and M2 macrophages polarization in THP-1 cells. In conclusion, MiR145-5p modulated lipid metabolism and M2 macrophage polarization by targeting PAK7 and regulating [beta]-catenin signaling in hyperlipidemia, which may provide a potential biomarker for the treatment of hyperlipidemia-induced cardiovascular diseases. Key words: miR-145-5p, PAK7, hyperlipidemia, [beta]-catenin signaling, M2 macrophage polarization. La presente etude vise a explorer le role du microARN 145-5p (miR-145-5p) dans l'hyperlipidemie. A l'aide d'outils bioinformatiques et d'un large eventail d'epreuves fonctionnelles et sur les modes d'action, nous avons tente de comprendre le fonctionnement specifique et le mode d'action eventuel du miR- 145-5p dans l'hyperlipidemie. Le regime alimentaire a teneur elevee en cholesterol a entraine une hausse du cholesterol total et du triacylglycerol seriques, mais un abaissement des lipoproteines de haute densite dans le serum. Le taux de miR-145-5p s'abaissait dans des modeles de rats en hyperlipidemie. Le miR-145-5p participait a la regulation du metabolisme lipidique par l'antagonisme des modifications apportees dans le serum aux lipoproteines de haute densite, au cholesterol et au triacylglycerol par un regime alimentaire a teneur elevee en cholesterol. Au point de vue des modes d'action, le miR-145-5p se liait directement a la PAK7 (proteine kinase activee par la proteine p21 (RAC1)) et assurait une regulation a la baisse des taux de PAK7 en ARNm et en proteines dans les cellules THP1. En outre, les taux de miR-145-5p etaient inversement proportionnels au taux de PAK7 dans les tissus cardiaques de rat. Enfin, la surexpression de la PAK7 entrainait une inversion des effets du miR-145-5p sur l'activation de la [beta]-catenine et la polarisation des macrophages M2 dans les cellules THP-1. En conclusion, le miR-145-5p participait a la modulation du metabolisme lipidique et a la polarisation des macrophages M2 en ciblant la PAK7 et en regulant la voie de signalisation de la [beta]-catenine dans l'hyperlipidemie, ce qui pourrait fournir un biomarqueur eventuel pour le traitement des maladies cardiovasculaires provoquees par l'hyperlipidemie. [Traduit par la Redaction] Mots-cles : miR-145-5p, PAK7, hyperlipidemie, voie de signalisation de la [beta]-catenine, polarisation des macrophages M2., Introduction In the recent decades, many modern technologies have been applied in the improvement of cardiovascular disorders (Phillips and Guazzi 2015; Van Camp 2014). However, cardiovascular diseases remain to be [...]

Ruthenium(II) complexes offer the potential for lower toxicity compared with platinum(II) complexes. Our study aimed to compare cardiotoxicity of [Ru(Cl-tpy)(en)Cl][Cl], [Ru(Cl-tpy)(dach)Cl][Cl], [Ru(Cl-tpy)(bpy)Cl][Cl], cisplatin, and saline through assessment of redox status and relative expression of apoptosis-related genes. A total of 40 Wistar albino rats were divided into five groups. Ruthenium groups received a single dose of complexes intraperitoneally (4 mg/kg/week) for a 4-week period; cisplatin group received cisplatin (4 mg/kg/week) and control group received saline (4 mL/kg/week) in the same manner as ruthenium groups. In collected blood and heart tissue samples, spectrophotometric determination of oxidative stress biomarkers was performed. The relative expression of apoptosis-related genes (Bcl-2, Bax, and caspase-3) in hearts was examined by real-time polymerase chain reaction. Our results showed that systemic and cardiac pro-oxidative markers (thiobarbituric acid reactive substances and nitrite) were significantly lower in ruthenium groups compared with cisplatin group, while concentrations of antioxidative parameters (catalase, superoxide dismutase, and oxidized glutathione) were significantly higher. Ruthenium administration led to significantly lower gene expression of Bax and caspase-3 compared with cisplatin-treated rats, while Bcl-2 remained unchanged. Applied ruthenium complexes have less pronounced potential for induction of oxidative stress-mediated cardiotoxicity compared with cisplatin. These findings may help for future studies that should clarify the mechanisms of cardiotoxicity of ruthenium-based metallodrugs. Key words: ruthenium(II) complexes, cisplatin, cardiotoxicity, oxidative stress, apoptosis. Les complexes de ruthenium(II) offrent la possibility d'obtenir une toxicite moindre qu'avec les complexes de platine(II). Notre etude visait a comparer la cardiotoxicite entre [Ru(Cl-tpy)(en)Cl][Cl], [Ru(Cl-tpy)(dach)Cl][Cl], [Ru(Cl-tpy) (bpy)Cl][Cl], le cisplatine et une solution saline a l'aide de revaluation du statut d'oxydoreduction et de l'expression relative des genes lies a l'apoptose. Nous avons reparti au total 40 rats Wistar albinos dans cinq groupes. Dans les groupes ruthenium, nous avons administre par voie intraperitoneale une dose unique des complexes a raison de 4 mg/kg/semaine sur une periode de 4 semaines; dans le groupe cisplatine du cisplatine a raison de 4 mg/kg/semaine et dans le groupe temoin une solution saline (4 ml/kg/semaine) de la meme maniere que dans les groupes ruthenium. Nous avons preleve des echantillons de sang et de tissu cardiaque et procede a une caracterisation des biomarqueurs du stress oxydatif a l'aide de la spectrophotometrie. Nous avons examine l'expression relative des genes lies a l'apoptose (Bcl-2, Bax et caspase-3) dans le creur a l'aide de la technique de PCR en temps reel. Nos resultats ont montre qu'en circulation et dans le creur, les marqueurs pro-oxydatifs (TBARS et N[O.sub.2.sup.-]) s'abaissaient de faqon nettement plus marquee dans les groupes ruthenium qu'avec le cisplatine, tandis que les concentrations des parametres anti-oxydatifs (CAT, SOD et disulfure de glutathion) etaient nettement plus elevees. L'administration de ruthenium a mene a une diminution nettement plus marquee de l'expression genique de Bax et de la caspase-3 qu'avec le cisplatine, sans variation en matiere de Bcl-2. L'administration de complexes de ruthenium est moins susceptible d'engendrer une cardiotoxicite mediee par le stress oxydatif que celle du cisplatine. Ces resultats pourraient etre utiles pour de futures etudes visant a clarifier les modes d'action de la cardiotoxicite de medicaments metalliques a base de ruthenium. [Traduit par la Redaction] Mots-cles: complexes de ruthenium(II), cisplatine, cardiotoxicite, stress oxydatif, apoptose., Introduction Despite advances in the diagnosis and treatment of malignant tumors in recent years, cancer is still the leading cause of death in developed countries, while in developing countries it [...]

Author(s): Julie Helms [sup.1] [sup.2] [sup.3], Alain Combes [sup.4] [sup.5], Nadia Aissaoui [sup.6] [sup.7] Author Affiliations: (1) grid.11843.3f, 0000 0001 2157 9291, Faculté de Médecine, Université de Strasbourg (UNISTRA), , [...]

Evidence has demonstrated that resveratrol preconditioning exhibits neuroprotection against cerebral ischemiareperfusion (IR) injury. The current investigation aimed to explore whether pharmacological postconditioning, by administering resveratrol, after a sustained ischemia and prior to prolonged reperfusion abrogates cerebral IR injury. Cerebral IR-induced injury mice model was employed in this study to evaluate the neuroprotective effects of pharmacological postconditioning with resveratrol (30 mg/kg; i.p.) administered 5 min before reperfusion. We administered sirtinol, a SIRT1/2 selective inhibitor (10 mg/kg; i.p.) 10 min before ischemia (17 min) and reperfusion (24 h), to elucidate whether the neuroprotection with resveratrol postconditioning depends on SIRT1 activation. Various biochemical and behavioural parameters and histopathological changes were assessed to examine the effect of pharmacological postconditioning. Infarct size is estimated using TTC staining. It was established that resveratrol postconditioning abrogated the deleterious effects of IR injury expressed with regard to biochemical parameters of oxidative stress (TBARS, SOD, GSH), acetylcholinesterase activity, behavioural parameters (memory, motor coordination), infarct size, and histopathological changes. Sirtinol significantly reversed the effect of resveratrol postconditioning. We conclude that induced neuroprotective benefits of resveratrol postconditioning may be the consequence of SIRT1 activation and resveratrol can be considered, for further studies, as potential agent inducing pharmacological postconditioning in clinical situations. Key words: pharmacological postconditioning, global cerebral ischemia, resveratrol, SIRT, sirtinol. Des donnees probantes ont montre que le preconditionnement par le resveratrol permet d'obtenir une neuroprotection contre les lesions d'ischemie-reperfusion (IR) cerebrales. Les presents travaux visaient a evaluer si le postconditionnement pharmacologique par l'administration de resveratrol apres une ischemie soutenue et avant une reperfusion prolongee empeche les lesions d'IR cerebrales. A l'aide d'un modele de lesions cerebrales provoquees par l'IR chez la souris, nous avons etudie les effets neuroprotecteurs du postconditionnement pharmacologique par le resveratrol (a 30 mg/kg; i.p.) administre 5 minutes avant la reperfusion. Nous avons administre du sirtinol, un inhibiteur selectif de SIRT1/2 (a 10 mg/kg; i.p.) 10 minutes avant une ischemie (17 min) et une reperfusion (24 h), en vue d'elucider si la neuroprotection obtenue avec le postconditionnement par le resveratrol depend de l'activation de SIRT1. Nous avons evalue divers parametres biochimiques et comportementaux, ainsi que les modifications histopathologiques en vue d'etudier l'effet du postconditionnement pharmacologique. Nous avons estime la taille de l'infarctus a l'aide de la coloration au TTC. Nous avons etabli que le postconditionnement par le resveratrol entrainait une inhibition complete des effets deleteres des lesions d'IR quant a des parametres biochimiques du stress oxydatif (TBARS, SOD, GSH), a l'activite de l'acetylcholinesterase, a des parametres comportementaux (memoire, coordination motrice), a la taille de l'infarctus et aux modifications histopathologiques. Le sirtinol entrainait une inversion notable de l'effet du postconditionnement par le resveratrol. Nous en arrivons a la conclusion que les bienfaits neuroprotecteurs obtenus avec le postconditionnement par le resveratrol pourraient etre consecutifs a l'activation de SIRT1, et que le resveratrol pourrait etre pris en compte dans des etudes futures comme agent potentiel pour engendrer un postconditionnement pharmacologique dans un contexte clinique. [Traduit par la Redaction] Mots-cles: postconditionnement pharmacologique, ischemie cerebrale globale, resveratrol, SIRT, sirtinol., Introduction Reperfusion is a strategy to salvage the brain after ischemia but is also inimical to brain leading to damaging cerebral ischemia-reperfusion injury (Lin et al. 2016). Various cerebroprotective preconditioning [...]

It has been assumed that the cardioprotective effects of propofol are due to its non-anesthetic pleiotropic cardiac and vasodilator effects, in which gasotransmitters (NO, [H.sub.2]S, and CO) as well as calcium influx could be involved. The study on isolated rat heart was performed using 4 experimental groups (n = 7 in each): (1) bolus injection of propofol (100 mg/kg body mass, i.p.); (2) L-NAME (NO synthase inhibitor, 60 mg/kg body mass, i.p.) + propofol; (3) DL-PAG ([H.sub.2]S synthase inhibitor, 50 mg/kg body mass, i.p.) + propofol; (4) ZnPPIX (CO synthase inhibitor, 50 [micro]mol/kg body mass, i.p.) + propofol. Before and after the verapamil (3 [micro]mol/L) administration, cardiodynamic parameters were recorded (dp/[dt.sub.max], dp/[dt.sub.min], systolic left ventricular pressure, diastolic left ventricular pressure, heart rate, coronary flow), as well as coronary and cardiac oxidative stress parameters. The results showed significant increases of diastolic left ventricular pressure following NO and CO inhibition, but also increases of coronary flow following [H.sub.2]S and CO inhibition. Following verapamil administration, significant decreases of dp/[dt.sub.max]were noted after NO and CO inhibition, then increase of diastolic left ventricular pressure following CO inhibition, and increase of coronary flow following NO, [H.sub.2]S, or CO inhibition. Oxidative stress markers were increased but catalase activity was significantly decreased in cardiac tissue. Gasotransmitters and calcium influx are involved in pleiotropic cardiovascular effects of propofol in male Wistar rats. Key words: propofol, L-NAME, DL-PAG, ZnPPIX, verapamil, cardiodynamics, oxidative stress, antioxidative enzymes. Nous avons formule l'hypothese selon laquelle les effets cardioprotecteurs du propofol sont lies a ses effets cardiaques pleiotropiques et vasodilatateurs non anesthesiques dans lesquels des gazotransmetteurs (NO, [H.sub.2]S et CO), ainsi que l'influx de calcium pourraient jouer un role. L'etude de creurs isoles de rats a ete effectuee sur 4 groupes experimentaux (n = 7 pour chacun): (1) injection de propofol par bolus (100 mg/kg de masse corporelle, i.p.); (2) L-NAME (inhibiteur de la NO synthase, 60 mg/kg de masse corporelle, i.p.) + propofol; (3) DL-PAG (inhibiteur de la [H.sub.2]S synthase, 50 mg/kg de masse corporelle, i.p.) + propofol; (4) ZnPPIX (inhibiteur de la CO synthase, 50 [micro]mol/kg de masse corporelle, i.p.) + propofol. Nous avons enregistre des parametres cardiodynamiques (dp/[dt.sub.max] et dp/[dt.sub.min], pression ventriculaire gauche systolique et pression ventriculaire gauche diastolique, frequence cardiaque et flux coronarien) avant et apres l'administration de verapamil (3 [micro]mol/L), ainsi que des parametres de stress oxydatif coronariens et cardiaques. Les resultats ont montre des augmentations marquees de la pression ventriculaire gauche diastolique a la suite de l'inhibition du NO et du CO, mais aussi une augmentation du flux coronarien a la suite de l'inhibition du [H.sub.2]S et du CO. Apres l'administration de verapamil, nous avons observe de nettes diminutions du dp/[dt.sub.max] a la suite de l'inhibition du NO et du CO, puis une augmentation de la pression ventriculaire gauche diastolique a la suite de l'inhibition du CO, ainsi qu'une augmentation du flux coronarien a la suite de l'inhibition du NO, du [H.sub.2]S ou du CO. Nous avons observe une hausse des marqueurs du stress oxydatif, mais une diminution notable de l'activite de la catalase dans le tissu cardiaque. En somme, les gazotransmetteurs et l'influx de calcium jouent un role dans les effets cardiovasculaires pleiotropiques du propofol chez le rat Wistar male. [Traduit par la Redaction] Mots-cles: propofol, L-NAME, DL-PAG, ZnPPIX, verapamil, cardiodynamie, stress oxydatif, enzymes antioxydantes., Introduction Propofol (2,6-diisopropylphenol) belongs to a group of general anesthetics, which is used for sedation or for anesthesia induction during surgery. In relation to other anesthetics, propofol has several significant [...]

We aimed to investigate whether the cardioprotection of sevoflurane against ischemia-reperfusion (IR) injury is via inhibiting endoplasmic reticulum stress. The rat in vivo model of myocardial IR injury was induced by ligation of the left anterior descending coronary artery. Sevoflurane significantly ameliorated the reduced cardiac function, increased infarct size, and elevated troponin I level and lactate dehydrogenase activity in plasma induced by IR injury. Sevoflurane suppressed the IR-induced myocardial apoptosis. The increased protein levels of glucose-regulated protein 78 and C/EBP homologous protein (CHOP) after myocardial IR were significantly reduced by sevoflurane. The protein levels of phosphorylated protein kinase RNA-like endoplasmic reticulum kinase (PERK), phosphorylated eukaryotic initiation factor 2 (eIF2a), and activating transcription factor 4 (ATF4) were significantly increased in rats with IR and attenuated by sevoflurane treatment. The phosphorylation of Akt was further activated by sevoflurane. The cardioprotection of sevoflurane could be blocked by wortmannin, a PI3K/Akt inhibitor. Our results suggest that the cardioprotection of sevoflurane against IR injury might be mediated by suppressing PERK/eIF2a/ATF4/CHOP signaling via activating the Akt pathway, which helps in understanding the novel mechanism of the cardioprotection of sevoflurane. Key words: sevoflurane, cardioprotection, ischemia-reperfusion injury, endoplasmic reticulum stress, Akt. Nous avons vise a etudier si l'effet cardioprotecteur du sevoflurane contre les lesions d'ischemie/reperfusion (IR) est lie a l'inhibition du stress du reticulum endoplasmique. Nous avons obtenu un modele de lesions d'IR myocardique in vivo chez le rat par l'occlusion de l'artere coronaire interventriculaire anterieure. Le sevoflurane a nettement permis d'attenuer le dysfonctionnement cardiaque engendre par les lesions d'IR, ainsi que de faire diminuer le degre d'augmentation de la taille de l'infarctus, des taux de troponine I et de l'activite de la deshydrogenase lactique plasmatiques engendres par les lesions d'IR. Le sevoflurane a permis de faire disparaitre l'apoptose engendree par l'IR dans le myocarde. Le sevoflurane a nettement permis faire diminuer le degre d'augmentation des taux de la proteine 78 regulee par le glucose et de la proteine homologue de la C/EBP (pour << CCAAT/enhancer-binding protein >>) ou CHOP observes apres l'IR myocardique. L'administration de sevoflurane a permis de faire diminuer le degre d'augmentation des taux de proteine PERK (pour << protein kinase RNA-like endoplasmic reticulum kinase >>) phosphorylee, de facteur eIF2a (pour << eukaryotic initiation factor 2 >>) phosphoryle et d'ATF4 (pour << activating transcription factor 4 >>) observees de facon notable chez les rats soumis a l'IR. Le sevoflurane permettait d'activer davantage la phosphorylation de l'Akt. Il etait possible d'inhiber les effets cardioprotecteurs du sevoflurane par la wortmannine, un inhibiteur de la voie de signalisation PI3K/Akt. Nos resultats laissent entendre que les effets cardioprotecteurs du sevoflurane contre les lesions d'IR pourraient etre medies par l'inhibition de l'axe PERK/eIF2a/ATF4/CHOP par l'intermediaire de l'activation de la voie de signalisation de l'Akt, ce qui contribue a la comprehension du nouveau mode d'action des effets cardioprotecteurs du sevoflurane. [Traduit par la Redaction] Mots-cles: sevoflurane, cardioprotection, lesions d'ischemie-reperfusion, stress du reticulum endoplasmique, Akt., Introduction Ischemic heart disease is still one of the leading causes of mortality and morbidity worldwide (Ferdinandy et al. 2007; Xia et al. 2016). Despite the development and improvement of [...]

The present study was designed to examine the possible neuroprotective and antiepileptic effects of metformin (Metf) in a rat model of pentylenetetrazole (PTZ)-induced epilepsy and its possible underlying mechanisms. Forty male albino rats were assigned to 4 groups of equal size: (1) normal control (NC) group, (2) Metf group: daily treatment with Metf (200 mg/kg, i.p.) for 2 weeks, (3) PTZ group: treatment with PTZ (50 mg/kg, i.p.) every other day for 2 weeks, and (4) Metf + PTZ group: daily treatment with PTZ and metformin (200 mg/kg, i.p.) for 2 weeks. Administration of PTZ caused a significant increase in seizure score and duration, induced a state of oxidative stress (high malondialdehyde, low reduced glutathione and catalase activity), and led to the upregulation of [beta]-catenin, caspase-3, and its cleavage products, Hsp70 and [alpha]-synuclein, in hippocampal regions as well as a significant reduction in seizure latency. While Metf treatment significantly ameliorated PTZ-induced seizures, attenuated oxidative stress, and upregulated [alpha]-synuclein and [beta]-catenin expression, it also inhibited caspase-3 activation and the release of the cleavage product and caused more upregulation in Hsp70 expression in hippocampal regions (p < 0.05). In conclusion, the antiepileptic and neuroprotective effects of Metf in PTZ-induced epilepsy might be due to the inhibition of apoptosis, attenuation of oxidative stress and [alpha]-synuclein expression, and upregulation of Hsp70.Key words: metformin, pentylenetetrazole, epilepsy, Hsp70, [alpha]-synuclein, caspase-3, [beta]-catenin.Cette etude avait pour but d'examiner les effets neuroprotecteurs et antiepileptiques eventuels de la metformine (Metf), ainsi que des modes d'action sous-jacents eventuels dans un modele d'epilepsie provoquee par le pentylenetetrazole (PTZ) chez le rat. Nous avons reparti 40 rats albinos males dans 4 groupes de tailles egales : (1) temoins normaux, (2) Metf (200 mg/kg i.p.) quotidiennement pendant 2 semaines, (3) PTZ (50 mg/kg, i.p.) un jour sur deux pendant 2 semaines et (4) Metf + PTZ suivant les memes posologies pendant 2 semaines. L'administration de PTZ a entraine une augmentation notable de l'indice de convulsions et de leur duree avec la production d'un etat de stress oxydatif (hausse des taux de malondialdehyde et baisse des taux de glutathion et de catalase), et menait a une regulation a la hausse de la [beta]-catenine, de la caspase-3 et de ses produits de clivage, des proteines de choc thermique Hsp70 (pour << Heat shock proteins >>) et de l'[alpha]-synucleine dans les regions de l'hippocampe, ainsi qu'une nette diminution de la latence des convulsions. Par ailleurs, l'administration de Metf permettait d'attenuer nettement les convulsions provoquees par le PTZ, ainsi que le stress oxydatif et entrainait une regulation a la hausse de l'expression de l'[alpha]-synucleine et de la [beta]-catenine, avec aussi une inhibition de l'activation de la caspase-3 et la liberation de produits de clivage entrainant une augmentation de la regulation a la hausse de l'expression des Hsp70 dans les regions de l'hippocampe (p < 0,05). En conclusion, les proprietes antiepileptiques et neuroprotectrices de la Metf dans l'epilepsie provoquee par le PTZ pourraient etre le fait de l'inhibition de l'apoptose, l'attenuation du stress oxydatif et de l'expression de l'[alpha]-synucleine avec une regulation a la hausse des Hsp70. [Traduit par la Redaction]Mots-cles : metformine, pentylenetetrazole, epilepsie, Hsp70, [alpha]-synucleine, caspase-3, [beta]-catenine., IntroductionEpilepsy is a common neurological disease that affects about 0.5%-2% of the world's population (Naseer et al. 2009). According to previous clinical studies, nearly 30% of patients suffer from resistant [...]

BACKGROUND: The concept of chemical agents having properties that confer potential hazard called key characteristics (KCs) was first developed to identify carcinogenic hazards. Identification of KCs of cardiovascular (CV) toxicants could facilitate the systematic assessment of CV hazards and understanding of assay and data gaps associated with current approaches. OBJECTIVES: We sought to develop a consensus-based synthesis of scientific evidence on the KCs of chemical and nonchemical agents known to cause CV toxicity along with methods to measure them. METHODS: An expert working group was convened to discuss mechanisms associated with CV toxicity. RESULTS: The group identified 12 KCs of CV toxicants, defined as exogenous agents that adversely interfere with function of the CV system. The KCs were organized into those primarily affecting cardiac tissue (numbers 1-4 below), the vascular system (5-7), or both (8-12), as follows: 1) impairs regulation of cardiac excitability, 2) impairs cardiac contractility and relaxation, 3) induces cardiomyocyte injury and death, 4) induces proliferation of valve stroma, 5) impacts endothelial and vascular function, 6) alters hemostasis, 7) causes dyslipidemia, 8) impairs mitochondrial function, 9) modifies autonomic nervous system activity, 10) induces oxidative stress, 11) causes inflammation, and 12) alters hormone signaling. DISCUSSION: These 12 KCs can be used to help identify pharmaceuticals and environmental pollutants as CV toxicants, as well as to better understand the mechanistic underpinnings of their toxicity. For example, evidence exists that fine particulate matter [PM [less than or equal to]2.5 [micro]m in aerodynamic diameter (P[M.sub.2.5])] air pollution, arsenic, anthracycline drugs, and other exogenous chemicals possess one or more of the described KCs. In conclusion, the KCs could be used to identify potential CV toxicants and to define a set of test methods to evaluate CV toxicity in a more comprehensive and standardized manner than current approaches. https://doi.org/10.1289/EHP9321, Introduction According to the World Health Organization, cardiovascular disease (CVD) is the leading cause of death worldwide, taking 1.7 million lives annually (WHO 2017). Four of five of those deaths [...]

Exercise preconditioning has been shown to be effective in improving behavioral and neuropathological indices after cerebral ischemia. We evaluated the effect of exercise preconditioning, 17[beta]-estradiol, and their combination on stroke outcome using an experimental model of stroke in ovariectomized (OVX) mice. OVX mice were randomly assigned to 4 groups as follows: control (stroke), exercise (exercise and stroke), estradiol (17[beta]-estradiol and stroke), and exercise+estradiol (exercise and 17[beta]estradiol and stroke). Exercise preconditioning was performed on a treadmill 5 days/week, 40 min/day, at a speed of 18 m/min for 4 weeks. 17[beta]-estradiol was gavaged (40 [micro]g/kg per day) for 4 weeks. Stroke was induced by permanent middle cerebral artery occlusion (pMCAO), and neurological deficits were evaluated 1, 2, and 7 days after stroke. Then, the serum concentrations of matrix metalloproteinase-9 (MMP-9) and interleukin-10 (IL-10) and infarct volumes were assessed. Exercise preconditioning and 17[beta]-estradiol induced a better outcome compared with the control ischemic mice, which was manifested by decrease in MMP-9, increase in IL-10, diminished infarct volume, and improved neurological deficits. Concomitant administration of 17[beta]-estradiol and exercise also significantly improved these parameters. Exercise preconditioning or administration of 17[beta]-estradiol alone or in combination before pMCAO induced significant neuroprotection in OVX mice. Key words: exercise preconditioning, estradiol, stroke, permanent middle cerebral artery occlusion, interleukin 10, matrix metalloproteinase-9. On a montre que le preconditionnement par l'exercice physique est efficace en vue d'ameliorer les indices comportementaux et neuropathologiques apres une ischemie cerebrale. Nous avons evalue les effets du preconditionnement par l'exercice, du 17[beta]-estradiol et de leur association sur les resultats de l'accident vasculaire cerebral (AVC) a l'aide d'un modele experimental d'AVC chez la souris ovariectomisee (OVX). Nous avons reparti aleatoirement des souris OVX dans les quatre groupes suivants : temoin (AVC), exercice (exercice et AVC), estradiol (17[beta]-estradiol et AVC) et exercice+estradiol (exercice avec 17[beta]-estradiol et AVC). Les souris se pretaient au preconditionnement par l'exercice sur tapis roulant, 5 jours/semaine, 40 min/jour, a une vitesse de 18 m/min, sur 4 semaines. Nous avons administre le 17[beta]- estradiol par gavage (40 [micro]g/kg par jour) sur 4 semaines. Nous avons provoque l'AVC par l'occlusion permanente de l'artere cerebrale moyenne (OpACM) et evalue les deficits neurologiques 1, 2 et 7 jours apres l'AVC. Puis, nous avons evalue les concentrations seriques de metalloproteinase matricielle 9 (MMP-9) et d'interleukine 10 (IL-10), ainsi que le volume de l'infarctus. Le preconditionnement par l'exercice et le 17[beta]-estradiol permettaient d'obtenir de meilleurs resultats que chez les souris temoins avec ischemie, ce qui se manifestait par une diminution des taux de MMP-9, une augmentation des taux d'IL-10, ainsi qu'une diminution du volume de l'infarctus, avec une amelioration sur le plan des deficits neurologiques. L'administration concomitante de 17[beta]-estradiol et d'exercice permettait aussi d'obtenir des ameliorations notables sur le plan de ces parametres. Le preconditionnement par l'exercice ou l'administration de 17[beta]-estradiol, seuls ou en association, avant l'OpACM entrainaient une neuroprotection marquee chez les souris OVX. [Traduit par la Redaction] Mots-cles : preconditionnement par l'exercice physique, estradiol, AVC, occlusion permanente de l'artere cerebrale moyenne, interleukine 10, metalloproteinase matricielle 9., Introduction Stroke is one of the most common causes of death and permanent disability in adults, with a worldwide prevalence of about 0.25% (Mozaffarian et al. 2015). Transient or permanent [...]

Background Cardiovascular disease is a leading cause of death in general population and the second leading cause of mortality and morbidity in cancer survivors after recurrent malignancy in the United States. The growing awareness of cancer therapy-related cardiac dysfunction (CTRCD) has led to an emerging field of cardio-oncology; yet, there is limited knowledge on how to predict which patients will experience adverse cardiac outcomes. We aimed to perform unbiased cardiac risk stratification for cancer patients using our large-scale, institutional electronic medical records. Methods and findings We built a large longitudinal (up to 22 years' follow-up from March 1997 to January 2019) cardio-oncology cohort having 4,632 cancer patients in Cleveland Clinic with 5 diagnosed cardiac outcomes: atrial fibrillation, coronary artery disease, heart failure, myocardial infarction, and stroke. The entire population includes 84% white Americans and 11% black Americans, and 59% females versus 41% males, with median age of 63 (interquartile range [IQR]: 54 to 71) years old. We utilized a topology-based K-means clustering approach for unbiased patient-patient network analyses of data from general demographics, echocardiogram (over 25,000), lab testing, and cardiac factors (cardiac). We performed hazard ratio (HR) and Kaplan-Meier analyses to identify clinically actionable variables. All confounding factors were adjusted by Cox regression models. We performed random-split and time-split training-test validation for our model. We identified 4 clinically relevant subgroups that are significantly correlated with incidence of cardiac outcomes and mortality. Among the 4 subgroups, subgroup I (n = 625) has the highest risk of de novo CTRCD (28%) with an HR of 3.05 (95% confidence interval (CI) 2.51 to 3.72). Patients in subgroup IV (n = 1,250) had the worst survival probability (HR 4.32, 95% CI 3.82 to 4.88). From longitudinal patient-patient network analyses, the patients in subgroup I had a higher percentage of de novo CTRCD and a worse mortality within 5 years after the initiation of cancer therapies compared to long-time exposure (6 to 20 years). Using clinical variable network analyses, we identified that serum levels of NT-proB-type Natriuretic Peptide (NT-proBNP) and Troponin T are significantly correlated with patient's mortality (NT-proBNP > 900 pg/mL versus NT-proBNP = 0 to 125 pg/mL, HR = 2.95, 95% CI 2.28 to 3.82, p 0.05 [mu]g/L versus Troponin T [less than or equal to] 0.01 [mu]g/L, HR = 2.08, 95% CI 1.83 to 2.34, p < 0.001). Study limitations include lack of independent cardio-oncology cohorts from different healthcare systems to evaluate the generalizability of the models. Meanwhile, the confounding factors, such as multiple medication usages, may influence the findings. Conclusions In this study, we demonstrated that the patient-patient network clustering methodology is clinically intuitive, and it allows more rapid identification of cancer survivors that are at greater risk of cardiac dysfunction. We believed that this study holds great promise for identifying novel cardiac risk subgroups and clinically actionable variables for the development of precision cardio-oncology., Author(s): Yuan Hou 1, Yadi Zhou 1, Muzna Hussain 2,3, G. Thomas Budd 4, Wai Hong Wilson Tang 1,2,5, James Abraham 4, Bo Xu 2, Chirag Shah 6, Rohit Moudgil [...]

Atherosclerosis is a chronic inflammatory disease resulting in the formation of the atherosclerotic plaque. Plaque formation starts with the inflammation in fatty streaks and progresses through atheroma, atheromatous plaque, and fibroatheroma leading to development of stable plaque. Hypercholesterolemia, dyslipidemia, and hyperglycemia are the risk factors for atherosclerosis. Inflammation, infection with viruses and bacteria, and dysregulation in the endothelial and vascular smooth muscle cells leads to advanced plaque formation. Death of the cells in the intima due to inflammation results in secretion of damage-associated molecular patterns (DAMPs) such as high mobility group box 1 (HMGB1), receptor for advanced glycation end products (RAGE), alarmins (S100A8, S100A9, S100A12, and oxidized low-density lipoproteins), and infection with pathogens leads to secretion of pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharides, lipoteichoic acids, and peptidoglycans. DAMPs and PAMPs further activate the inflammatory surface receptors such as TREM-1 and toll-like receptors and downstream signaling kinases and transcription factors leading to increased secretion of pro-inflammatory cytokines such as tumor necrosis factor a, interleukin (IL)-1[beta], IL-6, and interferon-[gamma] and matrix metalloproteinases (MMPs). These mediators and cytokines along with MMPs render the plaque vulnerable for rupture leading to ischemic events. In this review, we have discussed the role of DAMPs and PAMPs in association with inflammation-mediated plaque vulnerability. Key words: inflammation, atherosclerotic arterial plaque, DAMPs, PAMPs, oxidized LDL, plaque vulnerability. L'atherosclerose est une maladie inflammatoire chronique entrainant la formation de la plaque atherosclerotique. La formation de la plaque commence avec l'inflammation dans des strates de matieres grasses et evolue vers l'atherome, la plaque atheromateuse et le fibroatherome, menant a la formation d'une plaque stable. L'hypercholesterolemie, la dyslipidemie et l'hyperglycemie constituent des facteurs de risque de l'atherosclerose. L'inflammation, l'infection par des virus et des bacteries et le dereglement des cellules endotheliales et musculaires lisses vasculaires menent a la formation de la plaque avancee. La mort des cellules de l'intima en raison de l'inflammation entraine la secretion de motifs moleculaires associes aux dommages (DAMP pour <>) comme l'HMGB1 (pour<< high mobility group box 1>>), les recepteurs des produits de glycation avancee (RAGE), les alarmines (S100A8, S100A9, S100A12 et LDL oxydees), et l'infection par des agents pathogenes mene a la secretion de motifs moleculaires associes aux agents pathogenes (PAMP pour << pathogen-associated molecular pattern>>) comme les lipopolysaccharides, les acides lipoteichoiques et les peptidoglycans. Les DAMP et les PAMP activent a leur tour les recepteurs de surface inflammatoires comme TREM-1 et les recepteurs de type Tol, ainsi que des kinases de signalisation et des facteurs de transcription, ce qui mene a une augmentation de la secretion de cytokines pro-inflammatoires comme le facteur de necrose tumorale a, l'interleukine (IL)-1[beta], IL-6 et l'interferon-[gamma], ainsi que les metalloproteinases matricielles (MMP). Ces mediateurs et cytokines, ainsi que les MMP rendent la plaque vulnerable a la rupture menant a des evenements ischemiques. Dans cet article de synthese, nous avons discute du role des DAMP et des PAMP en association avec la vulnerabilite de la plaque dont la mediation est assuree par l'inflammation. [Traduit par la Redaction] Mots-cles: inflammation, plaque atherosclerotique arterielle, DAMP, PAMP, LDL oxyde, vulnerabilite de la plaque., Introduction Atherosclerosis, a chronic disease characterized by the deposition of excessive lipids in the arterial intima, is associated with inflammation, hyperglycemia, hyperlipidemia, and dysregulation of the angiotensin system (Xu et [...]

Currently, there are no satisfactory interventions to protect the heart against the detrimental effects of ischemiareperfusion injury. Although ischemic preconditioning (PC) is the most powerful form of intrinsic cardioprotection, its application in humans is limited to planned interventions, due to its short duration and technical requirements. However, many organs/tissues are capable of producing 'remote' PC (RPC) when subjected to brief bouts of ischemia- reperfusion. RPC was first described in the heart where brief ischemia in one territory led to protection in other area. Later on, RPC started to be used in patients with acute myocardial infarction, albeit with ambiguous results. It is hypothesized that the connection between the signal triggered in remote organ and protection induced in the heart can be mediated by humoral and neural pathways, as well as via systemic response to short sublethal ischemia. However, although RPC has a potentially important clinical role, our understanding of the mechanistic pathways linking the local stimulus to the remote organ remains incomplete. Nevertheless, RPC appears as a cost-effective and easily performed intervention. Elucidation of protective mechanisms activated in the remote organ may have therapeutic and diagnostic implications in the management of myocardial ischemia and lead to development of pharmacological RPC mimetics. Key words: ischemia-reperfusion, myocardial infarction, remote preconditioning, innate cardioprotection, cell signaling. Resume: Il n'existe actuellement aucune intervention permettant de proteger le coeur de maniere satisfaisante contre les effets deleteres des lesions d'ischemie-reperfusion. Meme si le preconditionnement ischemique (PC) constitue la plus puissante forme de cardioprotection intrinseque, son application chez l'homme se limite a des interventions planifiees, en raison de sa courte duree et des techniques necessaries. Cependant, bien des organes et des tissus sont en mesure de produire un PC << a distance >> (PCD) quand ils sont soumis a de brefs episodes d'ischemie-reperfusion. Le PCD a tout d'abord ete decrit pour des coeurs dans lesquels une breve ischemie d'un territoire donne menait a une protection dans une autre region. Par la suite, on a commence a autiliser le PCD chez des patients atteints d'infarctus du myocarde aigu, mais les resultats sont demeures ambigus. On a formule une hypothese selon laquelle la connexion entre le signal declenche dans un organe distant et la protection obtenue dans le coeur pourrait etre mediee par des voies de signalisation humorales et nerveuses, ainsi que par l'intermediaire d'une reaction generale a une ischemie subletale de courte duree. Cependant, bien que le PCD puisse eventuellement jouer un role important en clinique, notre comprehension des voies mecaniques liant le stimulus local a l'organe distant demeure incomplete. Neanmoins, le PCD semble correspondre a une intervention rentable et facile a effectuer. L'elucidation des modes d'action protecteurs qui sont actives dans l'organe distant pourrait avoir des retombees sur la prise en charge de l'ischemie myocardique en fournissant des outils therapeutiques et diagnostiques. Cela pourrait mener au developpement d'agents pharmacologiques mimant le PCD. [Traduit par la Redaction] Mots-cles: ischemie-reperfusion, infarctus du myocarde, pre conditionnement a distance, cardioprotection innee, signalization cellulaire., Introduction Ischemic heart disease--in particular, its most serious manifestation, an acute myocardial infarction (AMI)--still remains the number-one cause of death in the modern world. Early restoration of blood flow in [...]

Diabetes mellitus, besides having deleterious effects, induces cardiac adaptation that may reduce the heart's susceptibility to ischemia-reperfusion (IR) injury. This study aimed to investigate whether changes in mitochondrial properties are involved in the mechanisms of increased resistance of the diabetic heart to IR. Adult male Wistar rats were made diabetic by a single dose of streptozotocin (65 mg-[kg.sup.-1], i.p.), and on the day 8, Langendorff-perfused hearts were subjected to 30 min global ischemia and 40 min reperfusion. Baseline preischemic parameters in the diabetic hearts did not differ markedly from those in the nondiabetic controls, except for lower left ventricular developed pressure, higher mitochondrial membrane fluidity, and protein levels of manganese superoxide dismutase. On the other hand, diabetic hearts showed significantly better post-IR functional restoration and reduced arrhythmogenesis associated with lower reactive oxygen species production as compared with healthy controls. IR decreased membrane fluidity in both experimental groups; however, it led to a complete recovery of mitochondrial [Mg.sup.2+]-ATPase activity in diabetics in contrast to its reduction in nondiabetics. These findings indicate that the heart may become adapted to diabetes-induced alterations that might increase its tolerance to an ischemic insult. Preserved mitochondrial function might play a role in the mechanisms of the heart's resistance to IR injury in diabetics. Key words: streptozotocin-induced diabetes, ischemia-reperfusion, adaptation, membrane fluidity, mitochondrial [Mg.sup.2+]-ATPase. Qu'outre ses effets deleteres, le diabete sucre entraine une adaptation du creur qui pourrait permettre de reduire sa susceptibilite aux lesions d'ischemie-reperfusion (IR). Ces travaux visaient a etudier si les proprietes des mitochondries jouent un role dans les modes d'action de l'augmentation de la resistance des creurs de patients diabetiques a l'IR. Chez des rats Wistar males adultes, nous avons provoque un diabete a l'aide d'une dose unique de streptozotocine (65 mg-[kg.sup.-1], i.p.), et au jour 8, nous avons perfuse les creurs en Langendorff et provoque une ischemie globale de 30 min, avec une reperfusion de 40 min. Avant l'ischemie, les parametres initiaux des creurs de rats diabetiques n'etaient pas differents de facon notable de ceux des rats temoins non-diabetiques, a l'exception d'un abaissement de la pression ventriculaire developpee, d'une augmentation de la fluidite des membranes mitochondriales et d'une augmentation des taux proteiques de superoxyde dismutase au manganese. Comparativement aux temoins en bonne sante, le retablissement du fonctionnement des creurs de rats diabetiques etait par ailleurs nettement superieur apres l'IR, avec une diminution de l'arythmogenese associee a une diminution de la production de derives reactifs de l'oxygene. L'IR entrainait une diminution de la de la fluidite des membranes mitochondriales dans les deux groupes a l'etude, mais nous avons observe un retablissement complet de l'activite de la [Mg.sup.2+]-ATPase mitochondriale chez les rats diabetiques, contrairement a sa diminution chez les rats non diabetiques. Ces resultats montrent que le creur peut s'adapter aux modifications provoquees par le diabete, ce qui pourrait entrainer une augmentation de sa tolerance a une agression ischemique. En somme, la preservation de la fonction mitochondriale pourrait jouer un role dans les modes d'action de la resistance aux lesions d'IR chez les patients diabetiques. [Traduit par la Redaction] Mots-cles : diabete provoque par la streptozotocine, ischemie-reperfusion, adaptation, fluidite membranaire, [Mg.sup.2+]-ATPase mitochondriale., Introduction Diabetes mellitus and ischemic heart disease belong to a broad range of civilization diseases that share a common feature, namely the presence of tissue hypoxia. However, unlike the ischemic [...]

Wound healing is important for longevity. Midkine is a cytokine involved in controlling tissue repair and new tissue development, and in regulating inflammation. We investigated the effect of midkine on wound healing in rats. In total, 108 Wistar albino rats were used: 12 as healthy and diabetic controls; 96 were split into 4 groups: healthy, saline treated; healthy, midkine (10 ng/kg, 48 h intervals) treated; diabetic, saline treated; and diabetic, midkine treated. Following wound creation, 6 rats per group were euthanized on days 3, 7, 14, and 28; the wounded skin was removed. Levels of epidermal growth factor (EGF), matrix metalloproteinase-8 (MMP-8), transforming growth factor beta (TGF-[beta]), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and thiobarbituric acid reactive substances (TBARS) were measured. MMP-8 and PDGF levels fluctuated in all groups; TGF-[beta] fluctuated in the diabetic groups and was significantly higher in the HM group than other groups after 14 days. EGF and VEGF levels were increased in the HM group after 3 days. TBARS levels were highest in the diabetic groups. Macroscopically, the midkine-treated groups healed better. Midkine can accelerate wound healing by influencing growth factors and oxidative status in wound tissues. Key words: midkine, wound healing, growth factors. La guerison de plaie est un important facteur de longevite. Par ailleurs, la midkine est une cytokine qui joue un role dans la reparation des tissus et la formation de nouveaux tissus, ainsi que dans la regulation de l'inflammation. Nous avons etudie l'effet de la midkine sur la guerison de plaie chez le rat. Nous avons utilise 108 rats Wistar albinos : 12 comme temoins en bonne sante ou atteints de diabete; 96 repartis dans 4 groupes : bonne sante avec exposition a une solution saline; bonne sante avec exposition la midkine (a 10 ng/kg, 48 heures d'intervalle); diabete avec exposition une solution saline; diabete avec exposition la midkine. Apres avoir la formation d'une plaie, nous avons euthanasie 6 rats par groupe aux jours 3, 7, 14 et 28; nous avons preleve la peau lesee. Nous avons mesure les taux de facteur de croissance epidermique (EGF), de metalloproteinase matricielle 8 (MMP-8), de facteur de croissance transformant beta (TGF-[beta]), de facteur de croissance derive des plaquettes (PDGF), de facteur de croissance endothelial vasculaire (VEGF) et des substances reagissant l'acide thiobarbiturique (TBARS). Les taux de MMP-8 et de PDGF fluctuaient dans tous les groupes; les taux de TGF-[beta] fluctuaient dans les groupes diabete et etaient nettement plus eleves dans le groupe SM que dans les autres groupes apres 14 jours. Apres 3 jours, nous avons observe une augmentation des taux d'EGF et de VEGF dans le groupe SM. Les taux de TBARS etaient les plus eleves dans les groupes diabete. Au point de vue macroscopique, la guerison etait meilleure dans les groupes de rats exposes a la midkine. La midkine peut accelerer la guerison de plaie en influencant des facteurs de croissance et l'etat oxydatif dans les tissus de plaie. [Traduit par la Redaction] Mots-cles : midkine, guerison de plaie, facteurs de croissance., Introduction A wound is defined as the impairment of tissue or organ integrity. The normal wound healing process is a well-orchestrated, complex, and interlinked series of different processes (Guo and [...]

Chronic alcohol consumption is a well-known risk factor for tissue injury. The link between alcohol use disorder (AUD) and kidney injury is intriguing but controversial, and the molecular mechanisms by [...]

Purpose Sevoflurane preconditioning (SevoPreC) has been proved to prevent organ ischemia/reperfusion (I/R) injury in various animal models and preclinical studies. Clinical trials on cardioprotection by SevoPreC for adult patients undergoing coronary artery bypass graft (CABG) revealed mixed results. The aim of this meta-analysis was to evaluate the cardiac effect of SevoPreC in on-pump CABG. Methods Randomized controlled trials (RCT) comparing the cardiac effect of SevoPreC (compared with control) in adult patients undergoing CABG were searched from PubMed, Embase, and the Cochrane Library (up to November 2015). The primary endpoints were postoperative troponin levels. Additional endpoints were CK-MB levels, mechanic ventilation (MV) duration, intensive care unit (ICU) stay, and hospital length of stay (LOS). Results Six trials with eight comparisons enrolling a total of 384 study patients reporting postoperative troponin levels were identified. Compared with controls, SevoPreC decreased postoperative myocardial troponin levels [standardized mean difference (SMD) = -0.38; 95 % CI, -0.74 to -0.03; P = 0.04; I.sup.2 = 63.9 %]. However, no significant differences were observed in postoperative CK-MB levels [weighted mean difference (WMD) = -1.71; P = 0.37; I.sup.2 = 37.7 %], MV duration (WMD = -0.53; P = 0.47; I.sup.2 = 0.0 %), ICU stay (WMD = -0.91; P = 0.39; I.sup.2 = 0.9 %), and hospital LOS (WMD = 0.08; P = 0.86; I.sup.2 = 8.0 %). Conclusion Available evidence from the present systematic review and meta-analysis suggests that sevoflurane preconditioning may reduce troponin levels in on-pump CABG. Future high-quality, large-scale clinical trials should focus on the early and long-term clinical effect of SevoPreC in on-pump CABG., Author(s): Yan Lu[sup.1] , Liwei Wang[sup.1] , Na Liu[sup.1] , Tianxin Dong[sup.1] , Ruhong Li[sup.1] Author Affiliations: (1) Department of Anesthesiology, Affiliated Hospital of Chengde Medical College, No. 36 NanYingzi [...]

ABSTRACT Hypothesis/Purpose: The aim of the present study was to evaluate in vivo the potential anti-ischemic and antiatheromatic activity of Chios Mastic gum, the resin of the trunk and branches [...]

Purpose The aim of the study was to evaluate the effects of high-dose nitroglycerine (NTG) on glucose metabolism, tissue oxygenation and postoperative recovery in cardiac surgical patients. Methods Cardiac surgical patients in the retrospective survey were classified into two groups based on the NTG regimen. NTG group had intravenous loading of NTG (infusion rate 10-20 mg/h with total dose of ≥0.5 mg/kg) starting at rewarming of cardiopulmonary bypass (CPB) (n = 101), and control group had no intravenous loading of NTG (n = 151). Data for intraoperative plasma glucose and lactate levels, and regular insulin consumption were collected. Propensity score methodology was utilized to adjust for potential confounders. Results After adjustment for propensity score, the plasma glucose was significantly lower in the NTG group during (161 ± 39 versus 179 ± 45 mg/dl, p = 0.005) and after CPB (167 ± 41 versus 184 ± 48 mg/dl, p = 0.012). Total consumption of regular insulin was significantly lower in the NTG group, median 8 (range 0-50) versus 13 (0-90) international units, p = 0.005. There was a trend towards statistical significance in a lower incidence of hyperlactatemia (>2.2 mmol/l) in the NTG group during CPB, 21/100 (21 %) versus 40/132 (30.3 %), p = 0.065. The mixed venous oxygen saturation in the intensive care unit was higher in the NTG group, 65 ± 9 versus 62 ± 11 %, p = 0.056. Conclusions Intravenous loading of NTG during and after CPB is safe and effective for attenuating the hyperglycemic response and reduce the incidence of hyperlactatemia during cardiac surgery with CPB., Author(s): Ying-Hsuan Tai[sup.1] [sup.2] , Kuang-Yi Chang[sup.2] , Shu-Wei Liao[sup.2] , Kwei-Chun Chung[sup.3] , Chun-Che Shih[sup.4] , Shung-Tai Ho[sup.2] , Chih-Cherng Lu[sup.2] , Mei-Yung Tsou[sup.2] Author Affiliations: (1) Department of [...]

ABSTRACT Background: Mitraphylline (MTP) is the major pentacydic oxindolic alkaloid presented in Uncaria tomentosa. It has traditionally been used to treat disorders including arthritis, heart disease, cancer, and other inflammatory [...]

Endoplasmic reticulum (ER) stress is involved in inflammation-induced neurotoxicity. Mitofusin 2 (Mfn2), a member of the GTPase family of proteins, resides in the ER membrane and is known to regulate ER stress. However, the potential role and underlying mechanism of Mfn2 in inflammation-induced neuronal dysfunction is unknown. In our study, we explored the potential of Mfn2 to attenuate inflammation-mediated neuronal dysfunction by inhibiting ER stress. Our data show that Mfn2 overexpression significantly ameliorated tumor necrosis factor alpha (TNF[alpha])-induced ER stress, as indicated by the downregulation of the ER stress proteins PERK, GRP78 and CHOP. Mfn2 overexpression also prevented the TNF[alpha]-mediated activation of caspase-3, caspase-12 and cleaved poly (ADP-ribose) polymerase (PARP). Cellular antioxidant dysfunction and reactive oxygen species overproduction were also improved by Mfn2 in the setting of TNF[alpha] in mouse neuroblastoma N2a cells in vitro. Similarly, disordered calcium homeostasis, indicated by disturbed levels of calcium-related proteins and calcium overloading, was corrected by Mfn2, as evidenced by the increased expression of store-operated calcium entry (SERCA), decreased levels of inositol trisphosphate receptor (IP3R), and normalized calcium content in TNF[alpha]-treated N2a cells. Mfn2 overexpression was found to elevate Yes-associated protein (Yap) expression; knockdown of Yap abolished the regulatory effects of Mfn2 on ER stress, oxidative stress, calcium balance, neural death and inflammatory injury. These results lead us to conclude that re-activation of the Mfn2-Yap signaling pathway alleviates TNF[alpha]-induced ER stress and dysfunction of mouse neuroblastoma N2a cells. Our findings provide a better understanding of the regulatory role of Mfn2-Yap-ER stress in neuroinflammation and indicate that the Mfn2-Yap axis may be a focus of research in terms of having therapeutic value for the treatment of neurodegenerative diseases. Keywords: Yap, Mfn2, ER stress, Neuroinflammation, Dysfunction of mouse neuroblastoma N2a cells, Author(s): Shu Hou[sup.1], Lili Wang[sup.1] and Guoping Zhang[sup.1] Introduction Huntington's disease (HD), a neurodegenerative disorder primarily caused by instable and abnormally long expansion of the polyglutamine (polyQ) tract, is characterized [...]

Background/objectives The consumption of antioxidant-rich cooking oil such as red palm olein may be cardioprotective from the perspective of subclinical inflammation and endothelial function. Subjects/methods Using a crossover design, we conducted a randomised controlled trial in 53 free-living high-risk abdominally overweight subjects, comparing the effects of incorporating red palm olein (with palm olein as control) in a supervised isocaloric 2100 kcal diet of 30% en fat, two-thirds (45 g/day) of which were derived from the test oil for a period of 6 weeks each. Results We did not observe a significant change in interleukin-6 (IL-6), in parallel with other pro-inflammatory (tumour necrosis factor-[beta], interleukin-1[beta], IL-1[beta], high sensitivity C-reactive protein, hsCRP) and endothelial function (soluble intercellular adhesion molecules, sICAM, soluble intravascular adhesion molecules, sVCAM) parameters. Interestingly, we observed a significant reduction in oxidised LDL levels (P < 0.0386) while on the red palm olein diet, together with the increase in plasma alpha tocopherol (P < 0.0002), alpha carotene (P < 0.0001) and beta carotene (P < 0.0001) concentrations compared with palm olein diet. Conclusion Red palm olein did not improve subclinical inflammation and endothelial function despite profound increase in antioxidant levels. The positive improvement in oxidised LDL merits further attention in this group of subjects at risk of developing cardiovascular disease., Author(s): Radhika Loganathan [sup.1] [sup.2] , Shireene Ratna Vethakkan [sup.2] , Ammu K. Radhakrishnan [sup.3] , Ghazali Abd Razak [sup.1] , Teng Kim-Tiu [sup.1] Author Affiliations: (1) Malaysian Palm Oil [...]

An organism stems from assemblies of a variety of cells and proteins. This complex system serves as a unit, and it exhibits highly sophisticated functions in response to exogenous stimuli that change over time. The complete sequencing of the entire human genome has allowed researchers to address the enigmas of life and disease at the gene- or molecular-based level. The consequence of such studies is the rapid accumulation of a multitude of data at multiple levels, ranging from molecules to the whole body, that has necessitated the development of entirely new concepts, tools, and methodologies to analyze and integrate these data. This necessity has given birth to systems biology, an advanced theoretical and practical research framework that has totally changed the directions of not only basic life science but also medicine. During the symposium of the 95th Annual Meeting of The Physiological Society of Japan 2018, five researchers reported on their respective studies on systems biology. The topics included reactions of drugs, ion-transport architecture in an epithelial system, multi-omics in renal disease, cardiac electrophysiological systems, and a software platform for computer simulation. In this review article these authors have summarized recent achievements in the field and discuss next-generation studies on health and disease. Keywords: Systems biology, Physiological experiments, Omics study, Computer simulation, Software platform, Author(s): Shinichi Uchida[sup.1], Yoshiyuki Asai[sup.2], Yoshiaki Kariya[sup.3], Kunichika Tsumoto[sup.4,5,6], Hiroshi Hibino[sup.7,8], Masashi Honma[sup.3], Takeshi Abe[sup.2], Fumiaki Nin[sup.7,8], Yasutaka Kurata[sup.6], Kazuharu Furutani[sup.9], Hiroshi Suzuki[sup.3], Hiroaki Kitano[sup.10], Ryuji Inoue[sup.11] and Yoshihisa Kurachi[sup.4,5] [...]

Background: Recently, extract of Ginkgo biloba leaves (GbE) have become widely known phytomedicines and have shown various pharmacological activities, including improvement of blood circulation, protection of oxidative cell damage, prevention of Alzheimer's disease, treatment of cardiovascular disease and diabetes complications. This study was designed to investigate the effects of an ethanolic GbE on renal fibrosis in diabetic nephropathy (DN) and to clarify the possible mechanism by which GbE prevents renal fibrosis. Study design: We investigated the protective effects of GbE on renal fibrosis in STZ-induced diabetic rats. Rats were randomized into six groups termed normal control, diabetes mellitus, low dose of GbE (50 mg/kg/d), intermediate dose of GbE (100 mg/kg/d), high dose of GbE (200 mg/kg/d) and rapamycin (1 mg/kg/d). Methods: After 12 weeks, the rats were sacrificed and then fasting blood glucose (FBG), creatinine (Cr), blood urea nitrogen (BUN), urine protein, relative kidney weight, glycogen and collagen accumulation, and collagen IV and laminin expression were measured by different methods. The amounts of E-cadherin, a-SMA and snail, as well as the phosphorylation of Akt, mTOR and p70S6K in the renal cortex of rats, were examined by western blotting. Results: Compared with diabetic rats, the levels of Cr, BUN, urine protein, relative kidney weight, accumulation of glycogen and collagen, and expression of collagen IV and laminin in the renal cortex were all decreased in GbE treated rats. In addition, GbE reduced the expression of E-cadherin, α-SMA, snail and the phosphorylation of Akt, mTOR and p70S6K in diabetic renal cortex. Conclusion: GbE can prevent renal fibrosis in rats with diabetic nephropathy, which is most likely to be associated with its abilities to inhibit the Akt/mTOR signaling pathway. Keywords: Diabetic nephropathy Renal fibrosis Akt mTOR Ethanolic ginkgo biloba extract, Introduction According to the estimate released by the World Health Organization, the number of diabetic people has reached to approximately 347 million worldwide in 2008, accounting for 9.5% of the [...]

Ischaemia-reperfusion (IR) injury is a composite of the injury sustained during a period of reduced or absent blood flow to a tissue or organ and the additional insult sustained upon reperfusion that limits the amount of tissue that can be salvaged. IR injury plays a central role in both native and transplant acute kidney injury (AKI). Native AKI is associated with increased morbidity and mortality in hospital inpatients, and transplant AKI contributes to graft dysfunction, ultimately limiting graft longevity. In this review, we discuss the potential therapeutic benefits of a cost-effective and low-risk intervention, remote ischaemic preconditioning (RIPC), and its applicability in the prevention and reduction of AKI., Author(s): Kristin Veighey[sup.1] [sup.2] , Raymond MacAllister[sup.1] Author Affiliations: (1) UCL Centre for Clinical Pharmacology & Therapeutics, University College London, The Rayne Building, University Street, WC1E 6JJ, London, UK (2) [...]

Monoamine oxidases (MAOs) have recently emerged as important mitochondrial sources of oxidative stress in the cardiovascular system. Generation of reactive oxygen species during the brief episodes of ischemic preconditioning (IPC) is responsible for the cardioprotection at reperfusion. The aim of this study was to assess the effects of two MAO inhibitors (clorgyline and pargyline) on the IPC-related protection in isolated rat hearts. Animals subjected to 30 min global ischemia and 120 min reperfusion were assigned to the following groups: (i) Control, no additional intervention; (ii) IPC, 3 cycles of 5 min ischemia and 5 min reperfusion before the index ischemia; (iii) IPC-clorgyline, IPC protocol bracketed for 5 min with clorgyline (50 µmol/L); (iv) IPC-pargyline, IPC protocol bracketed for 5 min with pargyline (0.5 mmol/L). The postischemic functional recovery was assessed by the left ventricular developed pressure (LVDP) and the indices of contractility (+dLVP/dt max) and relaxation (-dLVP/dt max). Infarct size (IS) was quantified by TTC staining. In both genders, IPC significantly improved functional recovery that was further enhanced in the presence of either clorgyline or pargyline. IS reduction was comparable among all the preconditioned groups, regardless of the presence of MAO inhibitors. In isolated rat hearts, acute inhibition of MAOs potentiates the IPC-induced postischemic functional recovery without interfering with the anti-necrotic protection. Key words: monoamine oxidase, MAO inhibitors, ischemic preconditioning, isolated rat heart. Les monoamine oxydases (MAOs) se sont recemment revelees d'importantes sources de stress oxydatif mitochondrial dans le systeme cardiovasculaire. La generation de derives reactifs de l'oxygene au cours d'episodes brefs de preconditionnement ischemique (PCI) est responsable de la cardioprotection lors de la reperfusion. La presente etude visait a evaluer les effets de deux inhibiteurs de la MAO (la clorgyline et la pargyline) sur le PCI dans un modele de caeur isole de rat. Nous avons soumis les animaux a une ischemie globale de 30 min, puis a une reperfusion de 120 min et les avons repartis dans les groupes suivants: (i) temoin (aucune intervention supplementaire), (ii) PCI (3 cycles de 5 min d'ischemie suivis de 5 min de reperfusion avant l'ischemie de reference), (iii) PCI-clorgyline (protocole de PCI alternant avec l'administration de clorgyline a 50 µmol/L pendant 5 min) et (iv) PCI-pargyline (protocole de PCI alternant avec l'administration de pargyline a 0,5 mmol/L pendant 5 min). Nous avons ensuite evalue le retablissement fonctionnel post-ischemique en mesurant la pression ventriculaire gauche developpee (PVGD) ainsi que les indices de contractilite (+dP/dt max) et de relaxation (-dP/dt max). Enfin, nous avons quantifie la taille de l'infarctus par la technique de coloration au TTC. Chez les animaux des deux sexes, le PCI a permis d'ameliorer clairement le retablissement fonctionnel qui a ete accentue en presence de clorgyline ou de pargyline. Par ailleurs, la diminution de la taille de l'infarctus etait comparable dans tous les groupes soumis au preconditionnement, et ce, sans egard a la presence d'inhibiteurs de la MAO. En somme, dans les caeurs isoles de rat, l'administration a court terme d'inhibiteurs de la MAO potentialise la recuperation fonctionnelle post-ischemique induite par le PCI, sans nuire a la protection contre la necrose. [Traduit par la Redaction] Mots-cles: monoamine-oxydase, inhibiteurs de la MAO, preconditionnement ischemique, caeur isole de rat., Introduction Coronary heart disease remains the leading cause of mortality and morbidity due to heart failure worldwide (Go et al. 2014). In the past decades, mitochondria have emerged as key [...]

Even though stress belongs to the most common lifestyle risk factors of cardiovascular diseases, there are only limited data on direct influence of stressors on the heart. The aim of the present study was to explore selected protein signaling pathways in response to repeated immobilization stress in the heart tissue. Effects of simultaneous treatment with atosiban, an oxytocin receptor antagonist, on stress-induced changes in the heart were also investigated. Male Wistar rats were exposed to repeated immobilization (2 h daily, lasting 2 weeks). The results showed increased phosphorylation of Akt kinase, enhanced levels of Bcl-2, and decreased levels of cleaved caspase-3 in the left ventricle in response to chronic stress independently of the treatment. Exposure to restraint led to the rise of HSP-90 and p53 in vehicle-treated rats only. Stress failed to modify MMP-2 activity and ultrastructure of the heart tissue. Treatment with the oxytocin/vasopressin receptor antagonist atosiban reversed stress-induced rise in HSP-90 and p53 proteins. In conclusion, our data demonstrate that repeated restraint stress induces Akt kinase activation and this is associated with elevation of anti-apoptotic proteins (Bcl-2) and down-regulation of pro-apoptotic proteins (cleaved caspase-3). These findings suggest that activation of pro-survival anti-apoptotic Akt kinase pathway plays an important role in molecular mechanisms underlying responses and adaptation of the rat heart to repeated stress exposure. The results further indicate a regulatory role of oxytocin/vasopressin in the control of stress-induced activation in HSP-90 and related proteins. Key words: restraint stress, heart, protein signaling, atosiban. Meme si le stress fait partie des facteurs les plus communs relies au style de vie quant au risque de maladies cardiovasculaires, les donnees relatives a l'influence directe des stresseurs sur le coeur sont limitees. Le but de l'etude presente etait d'explorer des voies de signalisation proteiques selectionnees activees en reponse a une immobilisation repetee dans le tissu cardiaque. Les effets d'un traitement simultane a l'atosiban, un antagoniste du recepteur de l'ocytocine, sur les changements induits par le stress dans le coeur ont aussi ete examines. Des rats Wistar males ont ete exposes a des immobilisations repetees (2 h par jour, pendant 2 semaines). Les resultats ont montre un accroissement de la phosphorylation de la kinase Akt, une augmentation des niveaux de Bcl-2 et une diminution des niveaux de la caspase-3 dans le ventricule gauche, en reponse au stress chronique, independamment du traitement. La soumission a la contention resultait en un accroissement de HSP-90 et p53 chez les rats traites au vehicule seulement. Le stress ne modifiait pas l'activite de MMP-2 ni l'ultrastructure du tissu cardiaque. Le traitement avec l'antagoniste du recepteur de l'ocytocine/vasopressine, l'atosiban, renversait l'accroissement de HSP-90 et de p53 induit par le stress. En conclusion, les donnees des auteurs demontrent que le stress cause par une contention repetee induit l'activation de la kinase Akt et cela est associe a l'elevation des proteines anti-apoptose (Bcl-2) et a regulation a la baisse des proteines pro-apoptose (caspase-3 clivee). Ces donnees suggerent que l'activation de la voie d'Akt pro-survie et anti- apoptose joue un role important dans les mecanismes moleculaires qui sous-tendent les reponses et l'adaptation du coeur de rat a une exposition repetee a un stress. Les resultats indiquent de plus que l'ocytocine/vasopressine joue un role regulateur dans le controle de l'activation induite par le stress de HSP-90 et les proteines qui lui sont reliees. [Traduit par la Redaction] Mots-cles: stress de contention, coeur, signalisation proteique, atosiban., Introduction Stressful stimuli evoke complex endocrine, autonomic, and behavioral responses that are highly variable and specific depending on the type and nature of the stressors (Jezova and Skultetyova 1997; Jezova [...]

Sex and social stress may represent risk factors in the etiology of hypertension and heart response to ischemiareperfusion (I/R) injury. Phosphatidylinositol 3-kinase/protein kinase B (Akt) plays an important role in the processes associated with hypertension and myocardial tolerance to I/R, and may be involved in myocardial stress reaction. The impact of chronic stress on the response to I/R was investigated in the hearts of 7-week-old spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats of both sexes. Stress was induced by reducing living space to 70 [cm.sup.2]/100 g body mass of rat for 2 weeks, while the controls were kept at 200 [cm.sup.2]/100 g. Langendorff-perfused hearts, subjected to I/R, exhibited higher vulnerability to ventricular tachycardia in crowd-stressed SHR vs. the control rats, and this was more pronounced in the males. Myocardial infarction was not affected by crowding stress in any of the groups. Male and female SHR showed increased activation of cardiac Akt, whereas nitric oxide synthase activity (NOS) with pro-apoptotic signaling decreased in the males but was not altered in the females (vs. WKY rats). NOS was enhanced in the female SHR and WKY groups by comparison with the respective males. Stress only reduced NOS activity in the SHR groups, and without changes in apoptotic markers. In conclusion, we showed that stress in young SHR mainly affects the nonlethal markers for I/R, and has no impact on myocardial infarction and apoptosis, despite reduced NOS activity. Key words: social stress, sex differences, myocardial ischemia-reperfusion, apoptosis. Le sexe et le stress social peuvent representer des facteurs de risque dans l'etiologie de l'hypertension et de la reponse du caeur a l'ischemie-reperfusion (I/R). La phosphatidylinositol 3-kinase/proteine kinase B (Akt) joue un role important dans les processus associes a l'hypertension et a la tolerance myocardique a l'I/R, et elle peut etre impliquee dans la reaction myocardique au stress. L'impact d'un stress chronique sur la reponse a l'I/R a ete etudie dans des caeurs de rats SHR et WKY de 7 semaines des 2 sexes. Le stress a ete induit par une reduction de l'espace vital a 70 [cm.sup.2]/100 g pendant 2 semaines, alors que les controles etaient gardes dans un espace de 200 [cm.sup.2]/100 g. Les caeurs perfuses au tampon de Langendorff soumis a l'I/R presentaient une plus grande vulnerabilite a la tachycardie ventriculaire chez les animaux SHR stresses comparativement aux animaux non stresses, et elle etait plus prononcee chez les males. L'infarctus du myocarde n'etait affecte par le stress chez aucun de ces groupes. Les males et les femelles SHR presentaient une activation de l'Akt cardiaque elevee, alors que l'activite de l'oxyde nitrique synthase (NOS) et la signalisation pro-apoptotique diminuaient chez les males contrairement aux femelles (vs. WKY). L'activite de la NOS etait accrue chez les femelles SHR et WKY comparativement aux males correspondants. Le stress reduisait l'activite de la NOS seulement chez les SHR sans changer les marqueurs de l'apoptose. En conclusion, les auteurs ont montre que le stress de jeunes rats SHR affecte principalement les marqueurs non letaux de l'I/R mais il n'avait toutefois pas d'impact sur l'infarctus du myocarde et l'apoptose, malgre une reduction de l'activite de la NOS. [Traduit par la Redaction] Mots-cles: stress social, differences sexuelles, ischemie-reperfusion myocardique, apoptose., Introduction Decades of experimental and clinical research in the fields of cardiovascular health and disease have brought new approaches and facilities for understanding the underlying mechanisms and effective tools for [...]

Although pleiotropy, which is defined as multiple effects derived from a single gene, was recognized many years ago, and considerable progress has since been achieved in this field, it is not very clear how much this feature of a drug is clinically relevant. During the last decade, beneficial pleiotropic effects from hypolipidemic drugs (as in, effects that are different from the primary ones) have been associated with reduction of cardiovascular risk. As with statins, the agonists of peroxisome proliferator-activated receptors (PPARs), niacin and fibrates, have been suggested to exhibit pleiotropic activity that could significantly modify the outcome of a cardiovascular ailment. This review examines findings demonstrating the impacts of treatment with hypolipidemic drugs on cardiac response to ischemia in a setting of acute ischemia-reperfusion, in relation to PPAR activation. Specifically, it addresses the issue of susceptibility to ischemia, with particular regard to the preconditioning-like cardioprotection conferred by hypolipidemic drugs, as well as the potential molecular mechanisms behind this cardioprotection. Finally, the involvement of PPAR activation in the mechanisms of non-metabolic cardioprotective effects from hypolipidemic drugs, and their effects on normal and pathologically altered myocardium (in the hearts of hypertensive rats) is also discussed. Key words: acute myocardial ischemia-reperfusion, hypolipidemic drugs, pleiotropic effects, PPARα activation. Bien que l'action pleiotropique caracterisee par la manifestation d'effets multiples derivant d'un gene unique ait ete reconnue il y a bien des annees et que des progres considerables aient ete realises dans ce domaine, la portee clinique de cette caracteristique des medicaments n'est pas tres bien definie. Au cours de la derniere decennie, on a montre que les bienfaits tires des effets pleiotropiques des medicaments hypolipidemiants (differents de leurs effets principaux) sous-tendent la reduction du risque cardiovasculaire. De maniere similaire aux statines, on a laisse entendre que la niacine et les fibrates, des agonistes des recepteurs actives par les proliferateurs des peroxisomes (PPARs), ont une action pleiotropique, ce qui pourrait moduler de maniere appreciable l'issue des maladies cardiovasculaires. Le present article fait la synthese certaines observations mettant en evidence les effets du traitement par des medicaments hypolipidemiants sur la reponse du creur a l'ischemie dans un contexte d'ischemie-reperfusion, et ce, en correlation avec l'activation des PPAR. Tout particulierement, cet article traite du probleme de la susceptibilite a l'ischemie en lien direct avec la cardioprotection de type preconditionnement que procurent les medicaments hypolipidemiants, ainsi qu'avec ses eventuels mecanismes moleculaires sous-jacents. Enfin, nous discutons aussi du role de l'activation des PPAR parmi les mecanismes des effets cardioprotecteurs non metaboliques des medicaments hypolipidemiants ainsi que de son role dans le myocarde normal ou pathologique (dans les creurs de rats hypertendus). [Traduit par la Redaction] Mots-cles: ischemie aigue-reperfusion du myocarde, medicaments hypolipidemiants, effets pleiotropiques, activation des PPARα., Introduction Pleiotropy as an important pharmacodynamic feature of drugs Most drugs used in the treatment of cardiovascular diseases are assumed to have more than one pharmacodynamic action. Therefore, the end-points [...]

Little is known about metabolic syndrome (MetS)-associated cardiomyopathy, especially in relation to the role and contribution of beta-adrenoceptor (β-AR) subtypes. Therefore, we examined the roles of β-AR subtypes in the cardiac function of rats with MetS (MetS group) and compared it with that of rats with streptozotocin (STZ)-induced diabetes (STZ group). Compared with the normal control rats, the protein levels of cardiac [β.sub.1]-and [β.sub.2]-AR in the MetS group were significantly decreased and with no changes in their mRNA levels, whereas the protein levels of [β.sub.3]-AR were similar to those of the controls. However, as shown previously, the protein levels of cardiac [β.sub.1]-and [β.sub.2]-AR in the STZ group were decreased, whereas the [β.sub.3]-AR levels were significantly increased by comparison with the controls. Additionally, the mRNA levels of [β.sub.2]-and [β.sub.3]-AR were increased, but [β.sub.1]-AR mRNA was decreased in the STZ group. Furthermore, left ventricular developed pressure responses to [β.sub.3]-AR agonist BRL37344 were increased in the STZ group but not in the MetS group, whereas for both groups, the responses to noradrenaline were not different from those of the controls. However, the response to stimulation with high concentrations of fenoterol was depressed in the MetS group, compared with the controls, but not in the STZ group. Consequently, our data suggest that the contribution of the β-AR system to cardiac dysfunction in the rats with MetS is not the same as that in the STZ group, although they have similar cardiac dysfunction with similar ultrastructural changes to the myocardium. Key words: sympathetic stimulation, high-sucrose diet, type 1 diabetes, cardiac dysfunction, intracellular calcium homeostasis. On sait peu de choses de la cardiomyopathie associee au syndrome metabolique, particulierement en ce qui concerne le role et la contribution des sous-types de recepteurs β-adrenergiques. En consequence, nous avons etudie le role de sous-types des recepteurs β-adrenergiques sur la fonction cardiaque chez des rats presentant un syndrome metabolique en les comparant a ceux de rats atteints de diabete induit par la streptozotocine. Comparativement a chez les temoins, les taux de proteines des recepteurs [β.sub.1]-et [β.sub.2]-adrenergiques etaient nettement diminues chez les rats presentant un syndrome metabolique alors que les taux de leurs ARNm demeuraient inchanges. Par contre, ces valeurs etaient similaires a celles des temoins pour les recepteurs [β.sub.3]-adrenergiques. Cependant, comme on l'a montre precedemment, dans le groupe streptozotocine, les taux de proteines des recepteurs [β.sub.1] et [β.sub.2]-adrenergiques cardiaques diminuaient et les taux de recepteurs [β.sub.3]-adrenergiques augmentaient par rapport a chez les temoins, et ce, de maniere notable. De plus, les taux d'ARNm des recepteurs [β.sub.2]-et [β.sub.3]-adrenergiques etaient augmentes et ceux des recepteurs β-adrenergiques etaient diminues dans le groupe streptozotocine. En outre, les reponses au BRL37344 (un agoniste [β.sub.3]-adrenergique), sur le plan de la pression ventriculaire gauche exercee, etaient augmentees dans le groupe streptozotocine, mais pas dans le groupe syndrome metabolique, alors que les reponses a la noradrenaline observees dans les deux groupes n'etaient pas differentes de celles des temoins. Cependant, comparativement aux temoins, les reponses a des stimulations par l'administration de fenoterol a concentration elevee etaient diminuees dans le groupe syndrome metabolique, mais pas dans le groupe streptozotocine. Par consequent, nos donnees laissent croire que la contribution du systeme β-adrenergique a la dysfonction cardiaque observee dans le syndrome metabolique ne correspond pas a celle que l'on observe avec la streptozotocine. Pourtant, la dysfonction cardiaque et les modifications observees dans les ultrastructures myocardiques leur sont semblables. [Traduit par la Redaction] Mots-cles: stimulation sympathique, regime a teneur elevee en glucose, diabete de type 1, dysfonction cardiaque, homeostasie du calcium intracellulaire., Introduction Beta-adrenoceptors (β-ARs) play important roles in the regulation of normal cardiac function under physiological conditions. Any abnormality in this pathway has been demonstrated to be an important determinant of [...]

This study investigates the modulatory effect of tadalafil, a selective phosphodiesterase (PDE-5) inhibitor, on the neuroprotective effects of ischemic postconditioning (iPoCo) in mice. Bilateral carotid artery occlusion (BCAO) for 12 min followed by reperfusion for 24 h was employed to produce ischemia and reperfusion induced cerebral injury. Cerebral infarct size was measured using TTC staining. Memory was assessed using the Morris water maze test. Degree of motor incoordination was evaluated using inclined beam-walking, rota-rod, and lateral push tests. Brain nitrite/nitrate, acetylcholinesterase activity, TBARS, and glutathione levels were also estimated. BCAO followed by reperfusion produced a significant increase in cerebral infarct size, brain nitrite/nitrate and TBARS levels, and acetylcholinesterase activity along with a reduction in glutathione. Marked impairment of memory and motor coordination was also noted. iPoCo consisting of 3 episodes of 10 s carotid artery occlusion and reperfusion instituted immediately after BCAO significantly decreased infarct size, memory impairment, motor incoordination, and altered biochemistry. Pretreatment with tadalafil mimicked the neuroprotective effects of iPoCo. The tadalafil-induced neuroprotective effects were significantly attenuated by l-NAME, a nonselective NOS inhibitor. We concluded that tadalafil mimics the neuroprotective effects of iPoCo, probably through a nitric oxide dependent pathway, and PDE-5 could be a target of interest with respect to the neuroprotective mechanism of iPoCo. Key words: cerebral ischemia, ischemic postconditioning, neuroprotection, tadalafil, l-NAME. Cette etude examine l'effet modulateur du tadalafil, un inhibiteur selectif de phosphodiesterases (PDE5), sur l'effet neuro-protecteur du post-conditionnement ischemique (iPoCo) chez la souris. Une occlusion bilaterale de l'artere carotide (OBAC) de 12 min suivie d'une reperfusion de 24 h a ete utilisee pour produire un dommage cerebral induit par l'ischemie et la reperfusion. La taille de l'infarctus cerebral a ete mesuree par coloration au CTT. La memoire a ete evaluee par le test de la piscine de Morris. Le degre d'incoordination motrice a ete evalue par un test de marche sur plan incline, un test sur un Rotarod et un test de poussee laterale. Le rapport nitrite/nitrate du cerveau, l'activite de l'acetylcholinesterase et les niveaux de TBARS et de glutathion ont aussi ete estimes. L'OBAC suivie d'une reperfusion produisait une augmentation significative de la taille de l'infarctus cerebral, du rapport nitrite/nitrate du cerveau, des niveaux de TBARS et de l'activite de l'acetycholinesterase, parallelement aun abaissement du niveau de glutathion. Un deficit marque de la memoire et de la coordination motrice avait aussi ete note. L'iPoCo, consistant en 3 episodes d'occlusion de l'artere carotide et de reperfusion de 10 s, realises immediatement apres l'OBAC, diminuait significativement la taille de l'infarctus, ameliorait le deficit de la memoire et l'incoordination motrice, et contrait la modification des parametres biochimiques. Le pretraitement au tadalafil mimait l'effet neuro-protecteur de l'iPoCo. L'effet neuro-protecteur induit par le tadalafil etait significativement attenue par le l-NAME, un inhibiteur non-selectif de NOS. En conclusion, le tadalafil mime les effets neuro-protecteurs de l'iPoCo probablement a travers une voie dependante de l'oxyde nitrique, et la PDE5 pourrait constituer une cible d'interet du mecanisme neuro-protecteur de l'iPoCo. [Traduit par la Redaction] Mots-cles: ischemie cerebrale, post-conditionnement ischemique, neuro-protection, tadalafil, l-NAME., Introduction Injury due to cerebral ischemia and ischemia-reperfusion is an important contributor to acute cerebral stroke (Ryou et al. 2012; Gulati et al. 2013). Ischemic stroke remains the second leading [...]

BACKGROUND/OBJECTIVES: Oxidative stress and micronutrient deficiencies have been related to lower birth weight (BW), small for gestational age (SGA) offspring and preterm delivery. SUBJECTS/METHODS: The relation between neonatal outcome (BW, head circumference, SGA, preterm delivery) with markers of oxidative stress and micronutrients in maternal and cord blood was to be examined. Oxidative stress markers (protein carbonyls (PrCarb), 3-nitrotyrosine (3NT), malondialdehyde (MDA)), total protein concentration and lipid-soluble micronutrients (carotenoids, retinol, tocopherols) were measured in 200 newborns (11% preterms, 13% SGA) and 151 mothers. Associations between target parameters in cord plasma and maternal serum with BW, head circumference and risk of being SGA or preterm were explored. RESULTS: Maternal protein concentration, PrCarb, MDA and all lipid-soluble micronutrients were significantly higher compared with newborns, except for 3NT, which was significantly elevated in newborns. Newborn parameters correlated positively with those of mothers. Preterms had lower proteins and retinol but higher PrCarb than terms. Maternal PrCarb and retinol were inversely associated with BW and head circumference. Mothers with PrCarb, MDA and retinol in the highest quintile had a 3.3-fold (0.9; 12.1), 2.1-fold (0.7;6.4) and 3.3-fold (1.2;9.4) risk, respectively, for delivering an SGA newborn, whereas the lowest quintile of retinol in cord blood was associated with an increased risk for preterm delivery. CONCLUSIONS: Oxidative stress (elevated PrCarb) was associated with lower BW/head circumference and SGA. Inadequate hemodilution may explain the inverse relation of maternal retinol with BW and head circumference, and the association between highest maternal retinol and risk for SGA. European Journal of Clinical Nutrition (2014) 68, 215-222; doi: 10.1038/ejcn.2013.263; published online 11 December 2013 Keywords: newborn; preterm delivery; lipid-soluble micronutrients; oxidative stress; cord plasma; mothers, INTRODUCTION The risks for various acute and chronic health conditions during the course of life are influenced by low birth weight (LBW) and prematurity, both in developing and developed countries. [...]

The success of any work with isolated cardiomyocytes depends on the reproducibility of cell isolation, because the cells do not divide. To date, there is no suitable in vitro model to study human adult cardiac cell biology. Although embryonic stem cells and induced pluripotent stem cells are able to differentiate into cardiomyocytes in vitro, the efficiency of this process is low. Isolation and expansion of human cardiomyocyte progenitor cells from cardiac surgical waste or, alternatively, from fetal heart tissue is another option. However, to overcome various issues related to human tissue usage, especially ethical concerns, researchers use large- and small-animal models to study cardiac pathophysiology. A simple model to study the changes at the cellular level is cultures of cardiomyocytes. Although primary murine cardiomyocyte cultures have their own advantages and drawbacks, alternative strategies have been developed in the last two decades to minimise animal usage and interspecies differences. This review discusses the use of freshly isolated murine cardiomyocytes and cardiomyocyte alternatives for use in cardiac disease models and other related studies. Key words: cardiomyocytes, myocardial ischemia, perfusion, primary culture, cardiac cell lines, cardiac differentiation, cardiotoxicity. Le succes de toute experience realisee avec des cardiomyocytes isoles depend de la reproductibilite de l'isolement cellulaire car ces cellules ne se divisent pas. Jusqu'a present, il n'existe aucun modele in vitro convenable qui permette d'etudier la biologie cellulaire de la cellule cardiaque adulte. Meme si les cellules souches embryonnaires et les cellules pluripotentes induites peuvent se differencier en cardiomyocytes in vitro, l'efficacite de ce processus est faible. L'isolement et la croissance des cellules souches humaines de cardiomyocytes a partir de dechets chirurgicaux ou de tissu cardiaque foetal constituent une autre option. Toutefois, afin de contourner les problemes de differents ordres relies a l'utilisation de tissu humain, notamment les preoccupations ethiques, les chercheurs utilisent des modeles animaux de grande ou de petite taille afin d'etudier la pathophysiologie cardiaque. Les cultures de cardiomyocytes constituent un modele simple permettant d'etudier les changements au niveau cellulaire. Meme si les cultures de cardiomyocytes de souris possedent leurs propres avantages et inconvenients, des strategies alternatives se sont developpees au cours des deux dernieres decennies afin de minimiser l'utilisation d'animaux et les differences inter-especes. Cet article de revue discute de l'utilisation des cardiomyocytes de souris frais et d'alternatives aux cardiomyocytes comme modeles de maladies cardiaques et d'autres maladies reliees. [Traduit par la Redaction] Mots-cles : cardiomyocytes, ischemie myocardique, perfusion, culture primaire, lignees cellulaires cardiaques, differenciation cardiaque, cardiotoxicite., Introduction The menace of cardiac diseases is rapidly increasing throughout the world. Recent scientific advances have helped in providing a greater understanding of the underlying causes of cardiac diseases. Various [...]

The past few decades have witnessed an enormous number of research strategies aimed at protecting the heart against myocardial ischemia-reperfusion injury. Several randomized clinical trials are nowadays in progress testing whether promising therapeutic strategies aimed at preventing lethal reperfusion injury can be translated from bench to bedside. Many of these interventions, either pharmacological or mechanical, are targeting mitochondria as the final effectors of cardioprotection. Despite encouraging pre-clinical studies and small proof of concept clinical trials, there are still several limitations that may jeopardize the efficacy of cardioprotective strategies. These limitations include clinical setting, patient profile, drug administration, and methods for evaluating treatment efficacy. Identifying potential mechanistic and methodological pitfalls in the field may improve future translational research. Key words: ischemia-reperfusion injury, cardioprotection, conditioning, translation, mitochondria. La derniere decennie a ete temoin du developpement d'un grand nombre de strategies de recherche visant a proteger le coeur du dommage d'ischemie-reperfusion myocardique. Plusieurs essais cliniques aleatoires sont actuellement en cours, afin de determiner si des strategies therapeutiques prometteuses visant a prevenir un dommage de reperfusion letal peuvent etre transferees de la paillasse au patient. Plusieurs de ces interventions, qu'elles soient pharmacologiques ou mecaniques, ciblent les mitochondries comme effecteurs finaux de la cardioprotection. Malgre les etudes precliniques et les petits essais cliniques de demonstration de faisabilite encourageants, il existe encore plusieurs limitations qui peuvent mettre en peril l'efficacite des strategies de cardioprotection. Ces limitations incluent le contexte clinique, le profil du patient, l'administration de medicaments et les methodes d'evaluation d'efficacite du traitement. L'identification des ecueils mecaniques et methodologiques potentiels dans ce domaine peut ameliorer la recherche translationnelle future. [Traduit par la Redaction] Mots-cles : dommage d'ischemie-reperfusion, cardioprotection, conditionnement, transfert, mitochondrie., Introduction Cardiovascular diseases, and in particular, coronary heart disease, remain the number one cause of death worldwide and have rapidly risen in prevalence in the past few years in the [...]

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors regulating cardiac lipid metabolism and energy homeostasis. Although the activation of PPARs has been implicated in cardioprotection, the molecular mechanisms are largely unexplored. In this study, we aimed to investigate the effect of the PPAR-α agonist WY- 14643 (WY), mimicking a delayed effect of preconditioning in rat hearts exposed to acute ischaemia-reperfusion (I/R) 24 h later, and to define whether antioxidative and antiapoptotic mechanisms are involved. Treatment with WY markedly attenuated post-ischaemic contractile dysfunction (as evidenced by the reduced infarct size), the higher left ventricular developed pressure (LVDP) recovery, and the decreased occurrence of arrhythmias. These effects were abolished in the presence of the PPAR-α antagonist MK886. Heme oxygenase-1, a key antioxidative enzyme implicated in cytoprotection, was upregulated in response to WY at baseline, but was markedly reduced after I/R, indicating reduced oxidative stress. WY treatment was also associated with decreased mRNA levels and enzymatic activity of matrix metalloproteinase-2, and increased ratios of Bcl-2:Bax proteins. These results indicate that PPAR-α activation by its selective ligand WY may confer delayed preconditioning-like protection in rat hearts subjected to I/R by modulating oxidative stress, activation of matrix metalloproteinase-2, and expression of Bcl-2 and Bax. Key words: PPAR-α, myocardial ischaemia-reperfusion, WY-14643, MK886, HO-1, MMP-2, Bcl-2, Bax. Les PPAR (Peroxisome proliferator-activated receptors) sont des facteurs de transcription actives par leurs ligands qui regulent le metabolisme des lipides cardiaques et l'homeostasie energetique. Meme si l'activation des PPAR a ete impliquee dans la cardioprotection, les mecanismes moleculaires impliques sont en majorite inexplores. Dans cette etude, nous visions a examiner l'effet d'un agoniste du PPAR-α, le WY-14643 (WY), qui mime un effet retarde du preconditionnement dans le coeur de rat expose a une I/R aigue 24 h plus tard, et a definir si des mecanismes anti-oxydants ou anti-apoptotiques sont impliques. Le traitement au WY attenuait de facon marquee la dysfonction contractile post-ischemique, comme le demontrait une reduction de la taille de l'infarctus, une reprise plus elevee de la pression ventriculaire gauche developpee et une frequence reduite d'arythmie. Ces effets etaient abolis en presence de l'antagoniste du PPAR-α MK886. L'heme oxygenase-1, une enzyme anti-oxydante importante impliquee dans la cytoprotection, etait regulee a la hausse en reponse au WY au niveau de base alors qu'elle etait fortement reduite apres l'I/R, indiquant une diminution du stress oxydant. Le traitement au WY etait aussi associe a une diminution des niveaux d'ARNm et d'activite enzymatique de la MMP-2 et a une augmentation du rapport Bcl-2/Bax. Ces resultats indiquent que l'activation du PPAR-α par son ligand selectif, le WY, peut conferer une protection retardee qui s'apparente au preconditionnement dans le coeur de rat soumis a I'I/R en modulant le stress oxydant, l'activation de la MMP-2 et l'expression de Bcl-2 et Bax. [Traduit par la Redaction] Mots-cles: PPAR-α, ischemie-reperfusion du myocarde, WY-14643, MK886, HO-1, MMP-2, Bcl-2, Bax., Introduction Ischaemic heart disease remains the leading cause of morbidity and mortality in western countries. Current treatments mainly rely on the rapid restoration of blood flow in the previously occluded [...]

The antioxidant glutathione-S-transferase (GST) is a crucial determinant of the development of ischaemic-reperfusion (I/R) injury, and plays a pivotal role in the regulation of the mitogen activated protein kinase (MAPK) pathways involved in stress response and apoptosis. The aim of this study was to investigate whether inhibition of GST can abolish the benefit of ischaemic postconditioning (IPoC). A neonatal rat cardiomyocyte cell culture was prepared and divided into 6 groups: (I) control group without treatment; (II) cells exposed to simulated I/R; (III) simulated I/R (sI/R) with IPoC; (IV) ethacrynic acid (EA) alone; (V) sI/R with EA; and (VI) sI/R and IPoC together with EA. Viability of the cells was measured by MTT assay, the quantity of apoptotic cells was assessed by flow cytometry following annexin V-FITC--propidium-iodide double staining. The activation of JNK, p38, ERK/p42-p44 MAPKs, and GSK-3β protein kinase was determined by flow-cytometric assay. GST inhibition markedly increased the apoptosis and decreased the cell viability despite IPoC. The protective effect of IPoC was lost in GST-inhibited groups for all MAPKs and GSK-3fS. GST activity is required for the survival of cultured cardiomyocytes under stress conditions. GST inhibition was associated with differential activation of MAP and the protein kinases regulating these pathways in the process of ischaemic postconditioning. Key words: primer cardiomyocyte cell culture, ischaemic postconditioning (IPoC), glutathione-S-transferase (GST), ethacrynic acid (EA), cell viability, apoptosis, mitogen activated protein kinase (MAPK). Laglutathion-S-transferase (GST), un antioxydant, constitue un determinant crucial du developpement des dommages d'ischemie-reperfusion (I/R) et elle joue un role cle en regulant l'activite des voies MAPK impliquees dans la reponse au stress et dans l'apoptose. Le but de cette etude etait d'examiner si l'inhibition de la GST pouvait abolir le benefice du post- conditionnement ischemique (PoCI). Une culture de cardiomyocytes de rats nouveau-nes a ete preparee et divisee en 6 groupes : (I) groupe controle sans traitement; (II) cellules exposees a une I/R simulee; (III) une sI/R avec PoCI; (IV) acide ethacrynique (AE) seul; (V) sI/R avec AE; sI/R et (VI) PoCI et AE. La viabilite des cellules a ete mesuree par un dosage au MTT et la quantite de cellules en apoptose a ete evaluee par cytometrie de flux apres une double coloration de l'annexine Vau FITC--iodure de propidium. L'activite des kinases JNK, p38, ERK/p42-p44 et GSK-3β a ete determinee par un dosage en cytometrie de flux. L'inhibition de la GST augmentait de facon marquee l'apoptose et diminuait la viabilite cellulaire malgre le PoCI. L'effet protecteur du PoCI etait perdu chez les groupes dont la GST etait inhibee dans le cas de toutes les MAPK et de la GSK-3β. L'activite de la GST est requise a la survie des cardiomyocytes en culture en conditions de stress. L'inhibition de la GST etait associee a l'activation des differentes MAPK et des proteines kinases qui regulent ces sentiers dans le processus de post-conditionnement ischemique. [Traduit par la Redaction] Mots-cles: culture cellulaire de cardiomyocytes primaires, post-conditionnement ischemique (PoCI), glutathion-S- transferase (GST), acide ethacrynique (AE), viabilite cellulaire, apoptose, proteine kinases MAPK., Introduction Oxidative stress after ischaemia-reperfusion (I/R) injury in any organ can lead to apoptotic, necrotic disorders in cells. Free radicals of oxygen are highly reactive molecules with an unpaired electron, [...]

Orotic acid and its salts chronically administered have been shown to significantly improve cardiac function in pathological settings associated with ischemia-reperfusion (I/R) injury. The aim of our study was to investigate the effect of magnesium orotate (Mg-Or) administration at the onset of post-ischemic reperfusion on myocardial function and infarct size (IS). Ex-vivo experiments performed on isolated perfused rat hearts were used to compare Mg-Or administration with a control group (buffer treated), ischemic post-conditioning, orotic acid treatment, and Mg[Cl.sub.2] treatment. Mg-Or administration was also investigated in an in-vivo model of regional I/R performed in rats undergoing reversible coronary ligation. The effect of Mg-Or on mitochondrial permeability transition pore (mPTP) opening after I/R was investigated in vitro to gain mechanistic insights. Both ex-vivo and in-vivo experiments showed a beneficial effect from Mg-Or administration at the onset of reperfusion on myocardial function and IS. In-vitro assays showed that Mg-Or significantly delayed mPTP opening after I/R. Our data suggest that Mg-Or administered at the very onset of reperfusion may preserve myocardial function and reduce IS. This beneficial effect may be related to a significant reduction of mPTP opening, a usual trigger of cardiac cell death following I/R. Key words: magnesium orotate, cardioprotection, ischemia-reperfusion, ischemic post-conditioning, in vivo. L'administration au long cours d'acide orotique ou de ses sels a montre un effet benefique sur la fonction cardiaque dans plusieurs situations pathologiques associees aux lesions d'ischemie-reperfusion (I/R). L'objectif de notre etude etait d'evaluer l'effet de l'orotate de magnesium (Mg-Or) administre en tout debut de reperfusion myocardique post ischemique sur la taille d'infarctus (TI) et la fonction cardiaque. Un modele ex vivo d'I/R sur cceur isole perfuse de rats a compare l'administration de Mg-Or avec les groupes experimentaux control (tampon), post conditionnement ischemique, acide orotique, et Mg[Cl.sub.2]. L'effet de Mg-Or a egalement ete evalue sur un modele in vivo d'I/R myocardique regional par ligature coronaire chez le rat. Une etude mecanistique a evalue l'effet de Mg-Or sur l'ouverture du port de permeabilite de transition mitochondriale (mPTP). L'administration de Mg-Or en debut de reperfusion sur les modeles ex vivo et in vivo entrame une diminution de la TI et une preservation de la fonction cardiaque. L'etude mecanistique montre que Mg-Or retarde l'ouverture du mPTP apres I/R myocardique. Nos resultats suggerent que Mg-Or administre en debut de reperfusion est susceptible de diminuer la TI et de preserver la fonction cardiaque. Cet effet est vraisemblablement lie a son action inhibitrice sur l'ouverture du mPTP, phenomene implique dans les processus de mort cellulaire post I/R myocardique. Mots-cles: orotate de magnesium, cardioprotection, ischemie-reperfusion, post conditionnement ischemique, in vivo., Introduction Myocardial infarction represents a major cause of morbidity and mortality worldwide. The cornerstone of treatment is represented by timely restoration of coronary reperfusion achieved either pharmacologically by thrombolysis and [...]

Acute myocardial infarction (MI) is a major cause of death and disability worldwide. In patients with MI, the treatment of choice for reducing acute myocardial ischemic injury and limiting MI [...]

The purpose of this study was to test our hypothesis that red palm oil (RPO) intake may affect abnormalities of myocardial connexin-43 (Cx43) and protein kinase Ce (PKCζ) signaling, and consequently the propensity of the spontaneously hypertensive rat heart (SHR) heart to arrhythmias. SHR and Wistar-Kyoto (WKY) rats fed a standard rat chow plus red palm oil (200 µL/day) for 5 weeks were compared with untreated rats. Cytosolic but not particulate PKCζ expression as well as Cx43-mRNA, total Cx43 proteins, and its phoshorylated forms were increased, and disordered localization of Cx43 was attenuated in the left ventricle of RPO-fed SHR compared with untreated rats. These alterations were associated with suppression of early post-ischemic-reperfusion-related ventricular tachycardia and electrically inducible ventricular fibrillation. However, the treatment dose of RPO caused down-regulation of myocardial Cx43, but did not alter its cell membrane distribution or overall PKCζ expression in WKY rats. It was, however, associated with poor arrhythmia protection, suggesting overdosing. Results indicate that SHR benefit from RPO intake, particularly because of its apparent anti-arrhythmic effects. This protection can be, in part, attributed to the preservation of cell-to-cell communication via up-regulation of myocardial Cx43, but not with PKCζ activation. Key words: heart, connexin-43, PKCζ, arrhythmias, SHR, red palm oil. Resume : Le but de cette etude etait de tester notre hypothese a l'effet que l'ingestion d'huile de palme rouge (HPR) peut agir sur les anomalies de la connexine-43 (Cx43) du myocarde et la signalisation de la proteine kinase Cζ (PKCζ), et consequemment agir sur la propension des coeurs de rats spontanement hypertendus (SHR) a l'arythmie. Des rats SHR et Wistar Kyoto (WKY) nourris avec une moulee standard contenant de l'huile de palme rouge (200 µL/jour) ont ete compares a des rats non traites. Lexpression de la PKC cytosolique mais pas la PKC particulaire, de meme que lexpression de lARNm de la Cx43, de la Cx43 totale et de ses formes phosphorylees etaient accrues, et la localisation desordonnee de la Cx43 etait amoindrie dans le ventricule gauche des rats SHR nourris a l'HPR comparativement aux rats non traites. es modifications etaient associees a la suppression de la tachycardieventriculaire liee a la reperfusion post-schemique precoce et de la fibrillation ventriculaire inductible electriquement. Cependant, la dose de traitement d'HPR regulait a la baisse la Cx43 du myocarde mais n'affectait pas la distribution membranaire de meme que l'expression globale de la PKC chez les rats WKY. Ce phenomene etait associe a une faible protection contre l'arythmie, suggerant une surdose. Les resultats indiquent que les rats SHR peuvent beneficier de l'ingestion d'HPR, a cause notamment de ses effets anti-arythmiques. Cette protection peut etre attribuee en partie a la preservation de la communication cellule-cellule par l'intermediaire d'une regulation a la hausse de la Cx43 du myocarde mais non a l'activation de la PKC. Mots-cles : coeur, connexine-43, PKC, arythmie, SHR, huile de palme rouge. [Traduit par la Redaction], Introduction The link between dietary fats and cardiovascular disease has initiated a growing interest in dietary red palm oil (RPO) research. In spite of its high saturated fatty acid content [...]

Dexrazoxane (DEX), an inhibitor of topoisomerase II and intracellular iron chelator, is believed to reduce the formation of reactive oxygen species (ROS) and protects the heart from the toxicity of anthracycline antineoplastics. As ROS also play a role in the pathogenesis of cardiac ischaemia/reperfusion (I/R) injury, the aim was to find out whether DEX can improve cardiac ischaemic tolerance. DEX in a dose of 50, 150, or 450 mg x [(kg body mass).sup.-1] was administered intravenously to rats 60 min before ischaemia. Myocardial infarct size and ventricular arrhythmias were assessed in anaesthetized open-chest animals subjected to 20 min coronary artery occlusion and 3 h reperfusion. Arrhythmias induced by I/R were also assessed in isolated perfused hearts. Only the highest dose of DEX significantly reduced infarct size from 53.9% ± 4.7% of the area at risk in controls to 37.5% ± 4.3% without affecting the myocardial markers of oxidative stress. On the other hand, the significant protective effect against reperfusion arrhythmias occurred only in perfused hearts with the dose of DEX of 150 mg x [kg.sup.-1], which also tended to limit the incidence of ischaemic arrhythmias. It is concluded that DEX in a narrow dose range can suppress arrhythmias in isolated hearts subjected to I/R, while a higher dose is needed to limit myocardial infarct size in open-chest rats. Key words: heart, dexrazoxane, ischaemia, reperfusion, infarct size, arrhythmias, cardioprotection, reactive oxygen species. Le dexrazoxane (DEX), un inhibiteur de topoisomerase II et un chelateur de fer intracellulaire, est presume reduire la formation d'especes reactives d'oxygene (ERO) et proteger le coeur de la toxicite d'antineoplasiques de la famille des anthracyclines. Puisque les ERO jouent aussi un role dans la pathogenese des dommages d'ischemie/reperfusion (I/R), notre but etait de determiner si le DEX pouvait ameliorer la tolerance cardiaque a l'ischemie. Une dose de 50, 150 ou 450 mg x [(kg de poids corporel).sup.-1] de DEX a ete administree a des rats par injection intraveineuse 60 minutes avant l'ischemie. La taille de l'infarctus du myocarde et l'arythmie ventriculaire ont ete evaluees sur des animaux anesthesies a thorax ouvert soumis a une occlusion de l'artere coronaire de 20 minutes et une reperfusion de 3 heures. L'arythmie induite par l'I/R a aussi ete evaluee sur des coeurs perfuses isoles. Seule la dose la plus elevee de DEX reduisait significativement la taille de l'infarctus de 53,9 [+ ou -] 4,7 % de la zone a risque des controles a 37,5 [+ ou -] 4,3 % sans affecter les marqueurs myocardiques du stress oxydant. D un autre cote, l'effet protecteur significatif contre l'arythmie de reperfusion survenait seulement sur les coeurs perfuses a une dose de 150 mg x [kg.sup.-1] de DEX, qui tendait aussi a limiter l'incidence d arythmie ischemique. Nous concluons que le DEX peut supprimer l'arythmie de coeurs isoles soumis a une I/R dans une fenetre de concentrations etroite, alors qu une dose plus elevee est requise pour limiter la taille de l'infarctus du myocarde des rats a thorax ouvert. Mots-cles : coeur, dexrazoxane, ischemie, reperfusion, taille de l'infarctus, arythmie, cardioprotection, especes reactives d'oxygene. [Traduit par la Redaction], Introduction A bisdioxopiperazine derivative, dexrazoxane (DEX), which is a strong catalytic inhibitor of topoisomerase II (Hasinoff et al. 1995), is currently the only drug approved for the protection of myocardium [...]

Ischemic heart disease is the leading cause of morbi-mortality in developed countries. Both ischemia-reperfusion injury and mechanisms of cardioprotection have been studied for more than 50 years. It is known that the physiopathological mechanism of myocardial ischemia involves several factors that are closely related to its development, of which hypercholesterolemia is one of the main ones. Therefore, the objective of this review was to elucidate the effects of a high-cholesterol diet on normal ventricular function and ischemia-reperfusion injury associated phenomenon such as post-ischemic ventricular dysfunction (stunned myocardium). Although there exist many studies considering several aspects of this physiopathological entity, the majority were carried out on normal animals. Thus, experiments carried out on hypercholesterolemic models are controversial, in particular those evaluating different mechanisms of cardioprotection such as ischemic preconditioning and postconditioning, and cardioprotection granted by drugs such as statins, which apart from exerting a lipid-lowering effect, exert pleiotropic effects providing cardioprotection against ischemia-reperfusion injury. These controversial results concerning the mechanisms of cardioprotection vary according to quality, composition, and time of administration of the high-cholesterol diet, as well as the species used in each experiment. Thus, to compare the results it is necessary to take all of these variables into account, since they can change the obtained results. Key words: hypercholesterolemia, ischemia-reperfusion injury, ventricular function, myocardial infarction, ischemic preconditioning, ischemic postconditioning, statins. La maladie cardiaque ischemique est la principale cause de morbidite/mortalite dans les pays developpes. Les lesions d'ischemie-reperfusion et les mecanismes de protection cardiaque ont tous deux ete etudies depuis plus de 50 ans. On sait que le mecanisme physiopathologique de l'ischemie myocardique implique plusieurs facteurs qui sont etroitement relies a son developpement, l' hypercholesterolemie en etant l' un des principaux. En consequence, l'objectif de cet article de revue etait d' examiner les effets d' une diete riche en cholesterol sur la fonction ventriculaire normale et les phenomenes associes aux lesions d'ischemie/reperfusion comme la dysfonction ventriculaire post-ischemique (myocarde sidere). Meme s'il existe plusieurs etudes qui considerent differents aspects de cette entite physiopathologique, la majorite a ete realisee sur des animaux normaux. C' est ainsi que les experiences realisees sur des modeles hypercholesterolemiques sont controversees, en particulier celles qui evaluent differents mecanismes de cardioprotection comme le preconditionnement ou le postconditionnement ischemique, et la protection cardiaque conferee par des medicaments comme les statines qui, mis a part leur effet hypolipemiant, exercent des effets pleiotropiques qui conferent une protection cardiaque contre les lesions d'ischemie-reperfusion. Ces resultats controverses concernant les mecanismes de protection cardiaque varient en fonction de : la qualite, la composition et le moment de l' administration de la diete riche en cholesterol, ainsi que des differentes especes utilisees dans chaque etude. Ainsi, afin de comparer les resultats, il est necessaire de prendre en compte toutes ces variables car elles peuvent changer les resultats obtenus. Mots-cles : hypercholesterolemie, lesion d'ischemie-reperfusion, fonction ventriculaire, infarctus du myocarde, preconditionnement ischemique, postconditionnement ischemique, statines. [Traduit par la Redaction], Overview Ischemic heart disease is the leading cause of morbi-mortality in the Western world, and by 2020 it will be the leading cause of death worldwide (Roger et al. 2011). [...]

This study used a model of ischemia-reperfusion injury to the brachial artery endothelium to investigate whether the protective role of ischemic postconditioning (IPostC) is impaired in patients with major depressive episode. Flow-mediated dilation (FMD) was measured before and after ischemia-reperfusion in the absence or presence of IPostC in 24 patients with major depressive disorder and 20 healthy controls. In addition, the severity of the depression, as assessed by the Hamilton Depression Rating Scale (HDRS) and Beck Depression Inventory (BDI) scores, and plasma nitrogen dioxide (N[O.sub.x]) levels were also determined. Ischemia-reperfusion resulted in a significant decrease in FMD in both patients with a major depressive episode and healthy controls. IPostC effectively prevented this decrease in FMD in healthy controls, but not in patients with a major depressive episode. HDRS and BDI scores were markedly increased, but plasma N[O.sub.x] levels decreased, in patients with a major depressive episode compared with those in healthy controls. Correlation analysis showed that HDRS and BDI scores and plasma NOx levels were significantly associated with post-ischemiareperfusion FMD. These results suggest that endothelial protection by IPostC is impaired in patients with major depressive disorder, which may be related to the decrease in endothelial nitric oxide production and the severity of the depression. Key words: ischemic postconditioning, ischemia-reperfusion, major depressive disorder, nitric oxide. Resume : Un modele d'ischemie-reperfusion de l'endothelium de l'artere brachiale a ete utilise afin de determiner si le role protecteur d'un post-conditionnement ischemique (PostCI) est affaibli chez les patients qui presentent un episode de depression majeure. La dilatation induite par le flux (DIF) a ete mesuree avant et apres l' ischemie-reperfusion en absence ou en presence de PostCI chez 24 patients atteints de depression majeure et 20 individus sains. De plus, la severite de la depression a ete evaluee par l'Echelle de depression de Hamilton (EDH) et par l'Inventaire de depression de Beck (IDB), et le niveau de dioxydes d'azote (N[O.sub.x]) plasmatiques a aussi ete determine. L'ischemie-reperfusion a resulte en une diminution significative de la DIF chez les patients presentant un episode de depression majeure et les individus controles sains. Le PostCI a prevenu efficacement cette diminution de la DIF chez les individus sains, mais pas chez les patients presentant un episode de depression majeure. Les scores de EDH et de IDB etaient fortement augmentes chez les patients presentant un episode de depression majeure, mais les niveaux plasmatiques de NOx etaient diminues comparativement aux controles sains. L' analyse de correlation a montre que les scores de EDH et de IDB et les niveaux plasmatiques de N[O.sub.x] etaient significativement associes a la DIF post-ischemie-reperfusion. Ces resultats suggerent que la protection endotheliale conferee par le PostCI est affaiblie chez les patients presentant un episode de depression majeure, ce qui pourrait etre relie a la diminution de la production de nitric oxide endothelial et a la severite de la depression. Mots-cles: post-conditionnement ischemique, ischemie-reperfusion, depression majeure, oxyde nitrique. [Traduit par la Redaction], Introduction After acute myocardial infarction, timely and successful reperfusion is the most effective strategy for reducing the infarct size and improving the clinical outcome. However, blood restoration by reperfusion of [...]

doi: 10.1016/j.phymed.2011.03.006 ABSTRACT Danshen-Gegen (DG) decoction, an herbal formulation comprising Radix Salvia Miltiorrhiza and Radix Puerariae Lobatae, is prescribed for the treatment of coronary heart disease in Chinese medicine. Experimental [...]

ABSTRACT Background: Ginseng is the most popular herb used for treatment of ischemic heart diseases in Chinese community; ginsenosides are considered to be the major active ingredients. However, whether ginsenosides [...]

Dysfunction of capsaicin-sensitive sensory nerves is involved in cardiac remodeling, and rutaecarpine has been shown to exert a beneficial effect on cardiac function through activating the sensory nerves. This study was conducted to explore the potential inhibitory effect of rutaecarpine on cardiac remodeling and the underlying mechanisms. A rat cardiac remodeling model was established by injection of isoprenaline (5 mg/kg per day, s.c.) for 10 days. Rutaecarpine (10 or 40 mg/kg, i.g.) was coadministrated with isoprenaline to evaluate the effect of rutaecarpine on cardiac remodeling. After echocardiographic analysis was performed, blood samples were collected to quantify calcitonin gene-related peptide (CGRP), dorsal root ganglia were isolated for examining CGRP mRNA expression, and the hearts were weighed and saved for evaluating the parameters related to apoptosis and hypertrophy. Isoprenaline significantly increased the ratio of left ventricle weight to body weight, the cross-sectional area of cardiomyocytes, cardiac apoptosis, and collagen deposition concomitantly with decreased CGRP production, which were reversed by rutaecarpine treatment. The beneficial effects of rutaecarpine were attenuated by pretreatment with capsaicin, which selectively depleted CGRP. These results suggest that rutaecarpine was able to reverse isoprenaline-induced cardiac remodeling through stimulating CGRP production. Key words: rutaecarpine, calcitonin gene-related peptide, cardiac remodeling, isoprenaline. Le dysfonctionnement des nerfs sensitifs sensibles a la capsalcine est implique dans le remodelage cardiaque. Par ailleurs, des travaux ont montre que la rutEecarpine a des effets beenefiques sur la fonction cardiaque en activant les nerfs sensitifs. La presente etude a eu pour but d'examiner l'effet inhibiteur potentiel de la rutaecarpine sur le remodelage cardiaque et les mecanismes sous-jacents. On a realise; un modele de remodelage cardiaque chez le rat injection d'isoprenaline (5 mg/kg s.c. par jour.) pendant 10 jours. On a coadministre la rutEecarpine (10 ou 40 mg/kg i.g.) et l'isoprenaline pour evaluer l'effet de la rutEecarpine sur le remodelage. Apres une analyse echocardiographique, on a preleve des echantillons de sang pour quantifier le peptide relie au gene de la calcitonine (CGRP), isole les ganglions des racines dorsales pour examiner l'expression de l'ARNm du CGRP, pese et conserve; les coeurs pour evaluer les parametres associeesa l'apoptose et a l'hypertrophie. L'isoprenaline a augmente de manieere significative le rapport ventricule gauche/poids corporel, l'aire de section des cardiomyocytes, l'apoptose cardiaque et le depot de collage;ne, et diminuee la production de CGRP; le traitement a la rutaecarpine a renverse ces effets. Les effets benefiques de la rutaecarpine ont eete; attends par un preetraitement a la capsalcine, qui a appauvri selectivement les CGRP. Ces reesultats donnent a penser que la rutaecarpine a pu renverser le remodelage cardiaque induit par l'isoprenaline en stimulant la production de CGRP. Mots-cles: rutEecarpine, peptide relie au gene de la calcitonine, remodelage cardiaque, isoprenaline. [Traduit par la Redaction], Introduction Cardiac remodeling is a pathological condition that ultimately progresses into heart failure if not treated properly (Lips et al. 2003). It is characterized by cardiac hypertrophy, apoptosis, and accumulation [...]

Cardiac toxicity from recreational drug use remains difficult to establish. We report the cases of 3 young patients who were hospitalized for cardiogenic shock. All were bridged to transplantation with implantation of a left ventricular assist device (LVAD). They underwent uneventful heart transplantation. The patients did not have any significant personal or family medical history, but all admitted consuming large quantities of recreational drugs daily. Histological examination of the native heart did not show any inflammation or infiltrative myocardial disease. In this series of young patients presenting in cardiogenic shock with minimal histologic findings on examination of the native hearts, the association between cardiac toxicity and active use of recreational drugs remains a strong possibility. The transplant community should be made aware of this possible association in the current era of legalization and social trivialization of drug consumption., Cardiac toxicity from recreational drugs such as cannabis, amphetamines and cocaine has been recognized in the past. Although secondary cardiac toxicity has been established, clinical cases of myocardial effect are [...]

Pulmonary hypertension (PH) is an unremitting disease defined by a progressive increase in pulmonary vascular resistance leading to right-sided heart failure. Using mice with genetic deletions of caveolin 1 (Cav1) and eNOS (Nos3), we demonstrate here that chronic eNOS activation secondary to loss of caveolin-1 can lead to PH. Consistent with a role for eNOS in the pathogenesis of PH, the pulmonary vascular remodeling and PH phenotype of Cav1-/- mice were absent in Cav1-/-Nos3-/- mice. Further, treatment of Cav1-/- mice with either MnTMPyP (a superoxide scavenger) or L-NAME (a NOS inhibitor) reversed their pulmonary vascular pathology and PH phenotype. Activation of eNOS in Cav1-/- lungs led to the impairment of PKG activity through tyrosine nitration. Moreover, the PH phenotype in Cav1-/- lungs could be rescued by overexpression of PKG-1. The clinical relevance of the data was indicated by the observation that lung tissue from patients with idiopathic pulmonary arterial hypertension demonstrated increased eNOS activation and PKG nitration and reduced caveolin-1 expression. Together, these data show that loss of caveolin-1 leads to hyperactive eNOS and subsequent tyrosine nitration--dependent impairment of PKG activity, which results in PH. Thus, targeting of PKG nitration represents a potential novel therapeutic strategy for the treatment of PH., Introduction Pulmonary hypertension (PH) is characterized by a progressive increase in pulmonary vascular resistance (PVR) and vascular remodeling, which without treatment leads to right-heart failure and death often within 2-3 [...]

Cardioprotection due to angiotensin enzyme inhibitors is attributed, at least in part, to the inhibition of bradykinin breakdown and the preconditioning effect of the elevated endogenous bradykinin level. We have previously shown that in patients undergoing percutaneous coronary intervention, one 120-second balloon inflation is insufficient to precondition the heart. The objective of the present study was to examine whether the administration of enalaprilat to these patients results in protection. Twenty patients underwent two 120-second coronary artery occlusions separated by a reperfusion interval of 10 min. Ten patients were given 50 µg x [min.sup.-1] enalaprilat in an intracoronary infusion between the balloon inflations, whereas the others received an infusion of saline. In the latter control patients, there were no significant differences in ST-segment elevation between the consecutive occlusions (peak ST: 1.61 ± 0.17 vs. 1.61 ± 0.16 mV; time to reach 0.5 mV ST elevation: 16 ± 4 vs. 22 ± 7 s; mean ST: 1.03 ± 0.12 vs. 1.02 ± 0.11 mV). In the patients who received enalaprilat before the second balloon inflation, the ST-segment elevation was significantly less pronounced and slower during the second inflation than during the first (peak ST: 1.80 ± 0.18 vs. 1.41 ± 0.19 mV; time to reach 0.5 mV ST elevation: 18 ± 4 vs. 30 ± 4 s; mean ST: 1.04 ± 0.11 vs. 0.85 ± 0.14 mV). We conclude that enalaprilat administered during percutaneous coronary intervention provides protection to patients who do not have a protective response to the initial balloon inflation Key words: preconditioning, angioplasty, intracoronary ECG, ST-segment changes, enalaprilat La cardioprotection induite par les inhibiteurs de l'enzyme de conversion de l'angiotensine est attribuee, du moins en partie, a l'inhibition de la degradation de la bradykinine et a l'effet de preconditionnement du taux eleve de bradykinine endogene. Nous avons deja demontre que, chez les patients soumis a une intervention coronaire percutanee, le gonflement du ballonnet pendant 120 s ne suffit pas pour preconditionner le ccour. La presente etude a pour objectif d'examiner si l'administration d'enalaprilat a ces patients entraine une protection. Vingt patients ont subi deux occlusions de l'artere coronaire d'une duree de 120 s, separees par une reperfusion de 10 min. Dix patients ont rerqu 50 µg x [min.sup.-1] d'enalaprilat sous forme de perfusion intracoronaire entre les gonflements du ballonnet, alors que les autres ont rerqu une perfusion de solution saline. Chez le groupe temoin, il n'y a eu aucune difference significative dans l'elevation du segment ST entre les occlusions (elevation ST maximale : 1,61 ± 0,17 vs. 1,61 ± 0,16 mV; temps pour atteindre une elevation du segment ST de 0,5 mV : 16 ± 4 vs. 22 ± 7 s; elevation ST moyenne: 1,03 ± 0,12 vs. 1,02 ± 0,11 mV). Chez les patients ayant recu l'enalaprilat avant le deuxieme gonflement du ballon, l'elevation du segment ST a ete significativement moins prononcee et plus lente durant le deuxieme gonflement que durant le premier (elevation ST maximale : 1,80 ± 0,18 vs. 1,41 ± 0,19 mV; temps pour atteindre une elevation du segment ST de 0,5 mV : 18 ± 4 vs. 30 ± 4 s; elevation ST moyenne 1,04 ± 0,11 vs. 0,85 ± 0,14 mV). L'administration d'enalaprilat durant une intervention coronaire percutanee assure une protection aux patients qui ne repondent an premier episode de gonflement du ballonnet Mots-cles : preconditionnement, angioplastie, ECG intracoronaire, modifications du segment ST, enalaprilat. [Traduit par la Redaction], Introduction Ischemic preconditioning was originally defined as an endogenous adaptive response to brief periods of ischemic stress that protects the myocardium against the severe consequences of a subsequent and more [...]

Abstract The aim of the study was to investigate the effect of aqueous extract of Ajuga iva (Ai) on serum and tissues lipid peroxidation as well as antioxidant enzymes activities [...]