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Mitochondrial dysfunctions are responsible for myocardial injury upon ischemia/reperfusion (I/R), and mitochondrial E3 ubiquitin ligase 1 (Mul1) plays an important role in maintaining mitochondrial functions. This study aims to explore the function of Mull in myocardial I/R injury and the underlying mechanisms. The Sprague-Dawley rat hearts were subjected to 1 h of ischemia plus 3 h of reperfusion, which showed the I/R injury (increase in infarct size and creatine kinase release) and the elevated total and mitochondrial protein levels of Mul1 and p53 accompanied by the enhanced interactions between Mul1 and p53 as well as p53 and small a ubiquitin-like modifier (SUMO1). Consistently, hypoxia/reoxygenation (H/R) treated cardiac (H9c2) cells displayed cellular injury (apoptosis and necrosis), upregulation of total and mitochondrial protein levels of Mul1 and p53, and enhanced interactions between p53 and SUMO1 concomitant with mitochondrial dysfunctions (an increase in mitochondrial membrane potential and reactive oxygen species production with a decrease in ATP production); these phenomena were attenuated by knockdown of Mul1 expression. Based on these observations, we conclude that a novel role of Mul1 has been identified in the myocardial mitochondria, where Mul1 stabilizes and activates p53 through its function of SUMOylation following I/R, leading to p53-mediated mitochondrial dysfunction and cell death. Key words: ischemia/reperfusion, myocardial injury, mitochondrial E3 ubiquitin ligase 1, p53, SUMOylation, hypoxia/reoxygenation, mitochondria. Les dysfonctionnements mitochondriaux sont responsables de lesions myocardiques lors de l'ischemie/reperfusion (I/R) et l'E3 ubiquitine ligase mitochondriale 1 (Mul1) joue un role important dans le maintien du fonctionnement des mitochondries. Cette etude portait sur le fonctionnement de la Mul1 dans les lesions d'I/R myocardiques et les modes d'action sous-jacents. Nous avons procede a une ischemie d'une heure suivie d'une reperfusion de trois heures sur des creurs de rats Sprague-Dawley, et observe la presence de lesions d'I/R (augmentation de la taille de l'infarctus et liberation de creatine kinase), l'augmentation des taux de Mul1 et de p53 en proteines totales et mitochondrials, accompagnees de l'augmentation des interactions entre la Mul1 et le p53, ainsi qu'entre le p53 et le petit modificateur ressemblant a l'ubiquitine (ou SUMO1 pour << small ubiquitin-like modifier >>). Les cellules cardiaques H9c2 soumises a l'hypoxie/reoxygenation (H/R) presentaient systematiquement des lesions cellulaires (apoptose et necrose), une regulation a la hausse des taux de Mul1 et de p53 en proteines totales et mitochondriales, avec une augmentation des interactions entre le p53 et le SUMO1 en concomitance avec des dysfonctionnements mitochondriaux (augmentation du potentiel transmembranaire mitochondrial et de la production de derives reactifs de l'oxygene, avec une diminution de la production d'ATP); ces phenomenes s'attenuaient avec la repression de l'expression (<< knockdown >>) du gene Mul1. Sur la foi de ces observations, nous en arrivons a la conclusion que nous avons cerne un nouveau role du gene Mul1 dans la mitochondrie myocardique, par lequel le gene Mul1 entraine une stabilisation et une activation de p53 par l'intermediaire de sa fonction de<< SUMOylation>>consecutive a l'I/R et menant a des dysfonctionnements mitochondriaux et a une mort cellulaire medies par le p53. [Traduit par la Redaction] Mots-cles : ischemie/reperfusion, lesions myocardiques, E3 ubiquitine ligase mitochondriale 1, p53, SUMOylation, hypoxie/ reoxygenation, mitochondrie., Introduction Multiple mechanisms including energy metabolic disorders, calcium overload, oxidative stress, and inflammation are involved in various cardiovascular disorders (Anupama et al. 2018; Kiyuna et al. 2018), all of which [...]

Breast cancer and osteosarcoma are common cancers in women and children, respectively, but ideal drugs for treating patients with breast cancer or osteosarcoma remain to be found. Micafungin is an antifungal drug with antitumor activity on leukemia. Based on the notion of drug repurposing, this study aims to evaluate the antitumor effects of micafungin on breast cancer and osteosarcoma in vitro and in vivo, and to elucidate the underlying mechanisms. Five breast cancer cell lines (MDA-MB-231, BT-549, SK-BR-3, MCF-7, and 4T1) and one osteosarcoma cell line (143B) were chosen for the in vitro studies. Micafungin exerted an inhibitory effect on the viability of all cell lines, and MCF-7 cells were most sensitive to micafungin among the breast cancer cell lines. In addition, micafungin showed an inhibitory effect on the proliferation, clone formation, and migration in MCF7 and 143B cells. The inhibitory effect of micafungin on the growth of breast cancer and osteosarcoma was further confirmed with xenograft tumor mouse models. To explore the underlying mechanisms, the effect of micafungin on epithelial-mesenchymal transition (EMT) was examined. As expected, the levels of matrix metalloproteinase 9 and vimentin in MCF-7 and 143B cells were notably reduced in the presence of micafungin, concomitant with the decreased levels of ubiquitin-specific protease 7 (USP7), p-AKT, and p-GSK-3β. Based on these observations, we conclude that micafungin exerts antitumor effect on breast cancer and osteosarcoma through preventing EMT in an USP7/AKT/GSK-3β pathway-dependent manner. [ABSTRACT FROM AUTHOR]

NADPH oxidase (NOX) is a major source of reactive oxygen species (ROS) in the body and it plays a key role in mediation of oxidative injury in the cardiovascular system. The purposes of this study are to evaluate the status of NOX in endothelial progenitor cells (EPCs) of hyperlipidemic rats and to determine whether NOX-derived ROS promotes the dysfunction of EPCs. The rats were fed on a high-fat diet for 8 weeks to establish a hyperlipidemic rat model, which showed the increased plasma lipids and the impaired functions of circulating EPCs (including the reduced abilities in migration and adhesion) accompanied by an increase in NOX activity and ROS production. Next, EPCs were isolated from normal rats and they were treated with oxidized low-density lipoprotein (ox-LDL) (100 [micro]g/mL) for 24 h to induce a dysfunctional model in vitro. In agreement with our findings in vivo, ox-LDL treatment increased the dysfunctions of EPCs concomitant with an increase in NOX activity and ROS production; these phenomena were reversed by the NOX inhibitor. Based on these observations, we conclude that NOX-derived ROS involved in the dysfunctions of circulating EPCs in hyperlipidemic rats and inhibition of NOX might provide a novel strategy to improve EPC functions in hyperlipidemia. Key words: hyperlipidemia, NADPH oxidase, endothelial progenitor cells, reactive oxygen species, oxidized low-density lipoprotein. La NADPH oxydase (NOX) est une importante source de derives reactifs de l'oxygene (ROS) dans l'organisme, qui joue un role cle dans la mediation des lesions oxydatives dans le systeme cardiovasculaire. Cette etude avait pour buts d'evaluer le statut de la NOX dans les cellules endotheliales progenitrices (CEP) de rats hyperlipidemiques et d'etablir si les ROS derives de la NOX favorisent le dysfonctionnement des CEP. Nous avons donc administre aux rats un regime haute teneur en matieres grasses pendant 8 semaines en vue d'obtenir un modele de rat hyperlipidemique, dans lequel nous avons observe une augmentation des taux plasmatiques de lipides et une deterioration du fonctionnement des CEP en circulation (y compris de la diminution des capacites de migration et d'adherence), accompagnees d'une augmentation de l'activite de la NOX et de la production de ROS. Nous avons ensuite isole des CEP de rats normaux et nous les avons exposees ;a des lipoproteines de basse densite oxydees (LDL-ox) (a 100 [micro]g/mL) pendant 24 h en vue d'obtenir un modele dysfonctionnel in vitro. En accord avec les resultats que nous avons obtenus in vivo, l'exposition aux LDL-ox a entraine une augmentation des dysfonctionnements au niveau des CEP, qui etait concomitante ;a une augmentation de l'activite de la NOX et de la production de ROS; un inhibiteur de la NOX a permis de neutraliser ces phenomenes. D'apres ces observations, nous en arrivons la conclusion qu'en jouant un role dans le dysfonctionnement des CEP en circulation chez le rat hyperlipidemique et dans l'inhibition de la NOX, les ROS derives de la NOX pourraient permettre d'obtenir une nouvelle strategie visant ;a ameliorer le fonctionnement des CEP dans un contexte d'hyperlipidemie. [Traduit par la Redaction] Mots-cles : hyperlipidemie, NADPH oxydase, cellules endotheliales progenitrices, derives reactifs de l'oxygene, lipoproteines de basse densite oxydees., Introduction It is well known that hyperlipidemia contributes greatly to atherosclerosis and atherosclerosis-associated diseases such as coronary heart disease, hypertension, and stroke. Numerous studies from animals and humans have demonstrated [...]