Ciblage pharmacologique du phénotype angiogénique et inflammatoire des cellules endothéliales cérébrales

Les cellules endothéliales (CE) vasculaires cérébrales jouent un rôle important en tant que composantes structurales et fonctionnelles de la barrière hémato-encéphalique. L'angiogenèse tumorale, un processus important pour la croissance tumorale et pour le processus métastasique, régule le recrutement des CE qui, lorsqu'activées, prolifèrent et se différencient pour générer des structures capillaires afin de livrer les nutriments et l'oxygène au sein du compartiment tumoral. Les recherches rapportées dans ce mémoire nous ont permis de cibler, d'un point de vue pharmacologique, l'angiogenèse tumorale cérébrale. Dans le premier volet de cette étude, nous avons évalué l'impact anti-angiogénique in vitro de l'AD4-015, un inhibiteur du transporteur du glucose-6-phosphate (G6PT), sur les CE vasculaires cérébrales. Nous avons observé une inhibition de la migration cellulaire, de la tubulogenèse in vitro et de l'inhibition de la sécrétion et de l'expression génique de la métalloprotéinase matricielle-9 induite par le phorbol 12-myristate 13-acétate (PMA), un carcinogène promoteur de tumeur. L'expression de la cyclooxygénase-2 (cox-2) était aussi inhibée. L'inhibition pharmacologique de G6PT pourrait être une importante avenue thérapeutique ciblant la néo-vascularisation tumorale. Dans le deuxième volet de notre étude, nous avons investigué les effets du 2-déoxy-D-glucose (2DG), un analogue du glucose ayant comme rôle d'inhiber la glycolyse par la déplétion d'ATP, sur les propriétés angiogéniques des CE vasculaires cérébrales. Nous avons observé une diminution de la tubulogenèse conséquente à une diminution du niveau d'ATP. L'induction de l'expression de cox-2 et de GRP78 a été potentialisée par la combinaison du 2DG avec le PMA. Le niveau de la sécrétion de protéine et de l'expression génique de MMP-9 a été diminué en présence du 2DG, un phénomène impliquant la signalisation par le facteur nucléaire kappa-B. Nous fournissons donc des preuves que l'ATP est nécessaire au processus de la tubulogenèse et nous établissons un lien entre le stress du réticulum endoplasmique et l'inflammation. Dans le troisième volet de notre étude, nous avons investigué les propriétés inhibitrices de plusieurs flavonoïdes et la voie de signalisation du facteur nucléaire kappa-B, qui est une voie commune pour la régulation de l'expression de cox-2 et de MMP-9. Nous avons observé une diminution de l'expression génique et des niveaux de protéines de cox-2 et de MMP-9 par la fisetine, l'apigénine et la lutéoline. Il a également été démontré qu'il y a inhibition des niveaux de phosphorylation d'IkB prouvant leur impact sur l'activité de phosphorylation des IkB kinases. Nos résultats démontrent donc que la perturbation de la barrière hémato-encéphalique pourrait être minimisée par certains flavonoïdes qui agissent comme des inhibiteurs de la voie de signalisation de NF-kB. Collectivement, nos résultats démontrent les effets de différents inhibiteurs sur la tubulogenèse médiée par les CE vasculaires cérébrales. Dans le futur, ceci permettra le ciblage pharmacologique de l'angiogenèse tumorale cérébrale avec l'utilisation de molécules inhibitrices comme l'analogue de la mumbaistatine, le 2DG et certains flavonoïdes. \ud ______________________________________________________________________________ \ud MOTS-CLÉS DE L’AUTEUR : cellules endothéliales vasculaires cérébrales, angiogenèse, cox-2, MMP-9

Concept and challenges of delivering preventive and care services in prehospital emergency medical service: A qualitative study

Background and purpose: Prehospital emergency medical service (EMS) is an important part of the health care system. Today, the need for integrated emergency care services and delivering qualified preventive and care services felt more than before in accidents and emergencies. This survey aimed to investigate the views of emergency medical personnel on the concept and nature of preventive and care services and current challenges in delivering these services in prehospital EMS centers in Golestan province, Iran. Materials and methods: A qualitative study was done with 16 emergency medical personnel working in EMS sites in Golestan province using purposeful sampling. Data was collected by semistructured interview guide and framework analysis was implemented to analyze the data. Results: Two general themes were identified including 1) the concept of preventive and care services in the EMS and 2) the challenges in providing qualified services in the EMS sites in Golestan province. Also, five sub-themes and 12 subclasses were determined. Conclusion: To enhance and promote services, the EMS system of Golestan province need reforms in organizational structure, laws and administrative regulations, training programs, the system of monitoring and evaluation of personnel, also provision of equipment and manpower and provision of personnel amenities to improve the staff performance. Furthermore, it is necessary to boost emergency services at the community level through training people and enhancing collaboration and participation with other organizations. © 2015, Mazandaran University of Medical Sciences. All rights reserved

The Mediating Role of Psychological Capital in the Effect of Authentic Leadership on Job Satisfaction and Life Satisfaction

The main purpose of this research was to study mediating role of psychological capital in the effect of authentic leadership on job satisfaction and life satisfaction. The study was correlational and statistical population included all employees of organization, out of which 112 employees were selected through convenience sampling method, in autumn 1396. The research instruments consisted of authentic leadership, Job Satisfaction, Life Satisfaction and Psychological Capital. The data were analyzed with use of structural equation modeling (SEM). Results revealed that, there were significant positive effect of authentic leadership on psychological capital, job satisfaction and life satisfaction. Moreover, there were significant positive effects of psychological capital on job satisfaction and life satisfaction. Furthermore, result of structural equation modeling showed that there was significant positive indirect effect of authentic leadership on job satisfaction and life satisfaction through psychological capital. According to the findings of this study, it can be concluded that authentic leadership directly affects psychological capital and through the effect on the psychological capital, increases job and life satisfaction

Influence of Gum Arabic Enriched with GABA Coating on Oxidative Damage of Walnut Kernels

Jezgra oraha je zbog velikog udjela nezasićenih masnih kiselina i fenolnih spojeva osjetljiva na oksidacijska oštećenja poput užeglosti i posmeđivanja, koja mogu nastati nepažljivim rukovanjem nakon berbe. U ovom je radu ispitan utjecaj omotača od gume arabike obogaćenog γ-aminomaslačnom kiselinom na sprečavanje pojave užeglosti i posmeđivanja jezgri oraha tijekom skladištenja na 20 °C. Rezultati pokazuju da je jezgra oraha u omotaču od 5 %-tne gume arabike obogaćenom s 0,1 mM γ-aminomaslačne kiseline bila manje osjetljiva na oksidacijska oštećenja, što je vidljivo iz manjih vrijednosti peroksidnog broja i akumulacije malondialdehida, te većeg stupnja bjeline. Osim toga, jezgre oraha su zbog smanjene aktivnosti lipoksigenaze i manje akumulacije H2O2 imale veći omjer nezasićenih i zasićenih masnih kiselina. Uz smanjen intenzitet oksidacijskog posmeđivanja, u tretiranim se orasima aktivnost polifenolne oksidaze smanjila, a fenilalanin-amonij-lijaze povećala, što je dovelo do povećanja koncentracije fenolnih spojeva i pojačanog uklanjanja DPPH radikala. Na temelju ovih rezultata može se zaključiti da bi se omotač od 5 % arapske gume obogaćen s 0,1 mM γ-aminomaslačne kiseline mogao komercijalno upotrijebiti za očuvanje hranjive vrijednosti jezgre oraha.Because of the higher content of unsaturated fatty acids (UNSFA) and phenolics, walnut kernels are vulnerable to oxidative rancidity and browning due to unfavorable postharvest handling procedures. This study investigates the impact of gum arabic coating enriched with γ-aminobutyric acid (GABA) on oxidative rancidity and browning of kernels during storage at 20 °C. The results showed that the walnut kernels coated with gum arabic (5 %) enriched with GABA (0.1 mM) exhibited lower oxidative rancidity and browning, manifested by lower peroxide value and malondialdehyde accumulation along with higher whiteness index. Moreover, kernels had higher UNSFA/SFA ratio as a response to lower lipoxygenase activity and H2O2 accumulation. The reduced oxidative browning in coated kernels was accompanied with lower polyphenol oxidase and higher phenylalanine ammonia-lyase activity leading to higher accumulation of phenolics and increased DPPH• scavenging capacity. Based on our findings, gum arabic coating (5 %) enriched with GABA (0.1 mM) may have a commercial potential for maintaining nutritional quality of walnut kernels

Modeling the Electronic Marketing System Representation of Sepahan Isfahan Oil Company based on Interactive / Qualitative Analysis (IQA)

The purpose of this study is to model the electronic marketing system representation of Sepahan Isfahan Oil Company based on interactive/ quantitative analysis (IQA). The methodology of this research is developmental based on the conceptual and analytical nature of the mentioned result, because it seeks to develop the electronic marketing model of Sepahan Isfahan Oil Company with the aim of linking the stimuli and consequences of the electronic marketing dimensions of Sepahan Isfahan Oil Company. Combined research category (qualitative / quantitative). In this study, three simultaneous meta-synthesis and Delphi analysis in the qualitative part and systematic representation analysis based on interaction with focus groups in the quantitative part were used. The results in the qualitative section, reviewing 32 studies in the period 2018 to 2020, indicate the existence of 12 approved studies, based on which the two main components of communication function and accelerated e-marketing were identified with 15 propositional themes. Lead to the consequence of ownership in network marketing in the region of Sepahan Oil Company in terms of distribution and major sales of its products. It was also found that presenting the products of the day through holding conferences and special exhibitions as a stimulus for the accelerated functions of electronic marketing in Sepahan Oil Company can have the consequence of eliminating intermediaries for fast delivery of products to customers.Keywords: Systematic Representation Modeling; Electronic Marketing; Sepahan Isfahan Oil Company

Resveratrol Targeting of Carcinogen-Induced Brain Endothelial Cell Inflammation Biomarkers MMP-9 and COX-2 is Sirt1-Independent

The occurrence of a functional relationship between the release of metalloproteinases (MMPs) and the expression of cyclooxygenase (COX)-2, two inducible pro-inflammatory biomarkers with important pro-angiogenic effects, has recently been inferred. While brain endothelial cells play an essential role as structural and functional components of the blood-brain barrier (BBB), increased BBB breakdown is thought to be linked to neuroinflammation. Chemopreventive mechanisms targeting both MMPs and COX-2 however remain poorly investigated. In this study, we evaluated the pharmacological targeting of Sirt1 by the diet-derived and antiinflammatory polyphenol resveratrol. Total RNA, cell lysates, and conditioned culture media from human brain microvascular endothelial cells (HBMEC) were analyzed using qRT-PCR, immunoblotting, and zymography respectively. Tissue scan microarray analysis of grade I–IV brain tumours cDNA revealed increased gene expression of Sirt-1 from grade I–III but surprisingly not in grade IV brain tumours. HBMEC were treated with a combination of resveratrol and phorbol 12-myristate 13-acetate (PMA), a carcinogen known to increase MMP-9 and COX-2 through NF-κB. We found that resveratrol efficiently reversed the PMA-induced MMP-9 secretion and COX-2 expression. Gene silencing of Sirt1, a critical modulator of angiogenesis and putative target of resveratrol, did not lead to significant reversal of MMP-9 and COX-2 inhibition. Decreased resveratrol inhibitory potential of carcinogen-induced IκB phosphorylation in siSirt1-transfected HBMEC was however observed. Our results suggest that resveratrol may prevent BBB disruption during neuroinflammation by inhibiting MMP-9 and COX-2 and act as a pharmacological NF-κB signal transduction inhibitor independent of Sirt1

Attenuation of urokinase activity during experimental ischaemia protects the cerebral barrier from damage through regulation of matrix metalloproteinase-2 and NAD(P)H oxidase

Ischaemic injury impairs the integrity of the blood–brain barrier (BBB). In this study, we investigated the molecular causes of this defect with regard to the putative correlations among NAD(P)H oxidase, plasminogen–plasmin system components, and matrix metalloproteinases. Hence, the activities of NAD(P)H oxidase, matrix metalloproteinase-2, urokinase-type plasminogen activator (uPA), and tissue-type plasminogen activator (tPA), and superoxide anion levels, were assessed in human brain microvascular endothelial cells (HBMECs) exposed to oxygen–glucose deprivation (OGD) alone or OGD followed by reperfusion (OGD + R). The integrity of an in vitro model of BBB comprising HBMECs and astrocytes was studied by measuring transendothelial electrical resistance and the paracellular flux of albumin. OGD with or without reperfusion (OGD ± R) radically perturbed barrier function while concurrently enhancing uPA, tPA and NAD(P)H oxidase activities and superoxide anion release in HBMECs. Pharmacological inactivation of NAD(P)H oxidase attenuated OGD ± R-mediated BBB damage through modulation of matrix metalloproteinase-2 and tPA, but not uPA activity. Overactivation of NAD(P)H oxidase in HBMECs via cDNA electroporation of its p22-phox subunit confirmed the involvement of tPA in oxidase-mediated BBB disruption. Interestingly, blockade of uPA or uPA receptor preserved normal BBB function by neutralizing both NAD(P)H oxidase and matrix metalloproteinase-2 activities. Hence, selective targeting of uPA after ischaemic strokes may protect cerebral barrier integrity and function by concomitantly attenuating basement membrane degradation and oxidative stress

Very compact UWB antenna with group delay improvement

In this paper, very compact (12mm×17mm) and simple UWB antenna is proposed. The achieved bandwidth of the presented antenna is from 3.05 GHz to 12.5 GHz and in the most of the bandwidth, the return loss is less than -20dB. In addition to frequency characteristics, time characteristics such as group delay variations for three different antenna positions, namely, front to front, back to back and side by side using CST MW studio are simulated and discussed. To improve the group delay variations, by changing the radius of the circle on the back side of the antenna, the antenna gain in different frequencies will be tuned, therefore, the time domain characteristics of the proposed antenna are greatly improved