Relevant bibliographies by topics / Inhibiteurs de la PCSK9

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Academic literature on the topic 'Inhibiteurs de la PCSK9'

Author: Grafiati
Published: 11 June 2021
Last updated: 10 February 2022

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Journal articles on the topic "Inhibiteurs de la PCSK9"

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Vergès, Bruno, Cécile Dubois, and Pauline Legris. "Inhibiteurs PCSK9 en pratique clinique : données et interrogations." Médecine des Maladies Métaboliques 14, no. 6 (2020): 524–28. http://dx.doi.org/10.1016/j.mmm.2020.06.010.

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Dijk, W., C. Le May, and B. Cariou. "Efficacité et sécurité des inhibiteurs de PCSK9 dans le diabète." Médecine des Maladies Métaboliques 13, no. 2 (2019): 147–55. http://dx.doi.org/10.1016/s1957-2557(19)30044-6.

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Sabouret, Pierre, Michel Farnier, and Etienne Puymirat. "Inhibiteurs de PCSK9 : quelle place dans la prise en charge actuelle des dyslipidémies ?" La Presse Médicale 48, no. 3 (2019): 227–37. http://dx.doi.org/10.1016/j.lpm.2019.01.009.

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Cariou, B. "Traitement innovant de l’hypercholesterolémie (ARN interférence et inhibiteur de PCSK9)." Annales d'Endocrinologie 82, no. 5 (2021): 227. http://dx.doi.org/10.1016/j.ando.2021.07.026.

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Seidah, Nabil G., Zuhier Awan, Michel Chrétien, and Majambu Mbikay. "PCSK9." Circulation Research 114, no. 6 (2014): 1022–36. http://dx.doi.org/10.1161/circresaha.114.301621.

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Shapiro, Michael D., Hagai Tavori, and Sergio Fazio. "PCSK9." Circulation Research 122, no. 10 (2018): 1420–38. http://dx.doi.org/10.1161/circresaha.118.311227.

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McKenney, James M. "Understanding PCSK9 and anti-PCSK9 therapies." Journal of Clinical Lipidology 9, no. 2 (2015): 170–86. http://dx.doi.org/10.1016/j.jacl.2015.01.001.

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Lecompte, T. "Nouveaux inhibiteurs plaquettaires ?" Journal des Maladies Vasculaires 33 (March 2008): S10—S11. http://dx.doi.org/10.1016/j.jmv.2008.01.061.

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Reboud-Ravaux, Michèle. "Les inhibiteurs d’élastases." Journal de la Société de Biologie 195, no. 2 (2001): 143–50. http://dx.doi.org/10.1051/jbio/2001195020143.

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Chabanon, Roman M., and Sophie Postel-Vinay. "Inhibiteurs de PARP." médecine/sciences 35, no. 10 (2019): 728–31. http://dx.doi.org/10.1051/medsci/2019148.

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Dissertations / Theses on the topic "Inhibiteurs de la PCSK9"

1

Ramin-Mangata, Stéphane. "Le rôle du récepteur aux LDL et de PCSK9 dans le diabète de type 2." Thesis, La Réunion, 2020. http://www.theses.fr/2020LARE0005.

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Les statines sont des médicaments hypolipémiants largement prescrits dans le cadre des maladies cardiovasculaires. Elles inhibent la synthèse endogène de cholestérol et induisent l’activation de l’expression du LDLR par le facteur de transcription SREBP-2. Ce sont des médicaments dont le bénéfice est indiscutable d’un point de vue cardiovasculaire. Néanmoins, l’action des statines est limitée par la proprotéine convertase subtilisin kexin type 9 (PCSK9), l’inhibiteur naturel du récepteur aux LDL (LDLR), qui est également sous la dépendance de SREBP-2. Ainsi, de nouvelles stratégies hypolipémiantes ciblant la forme circulante de PCSK9 ont été développées et autorisées. Ce sont les inhibiteurs de PCSK9. Bien que bénéfique, l’utilisation de statines à forte dose et à long terme induit dans certains cas l’apparition d’un diabète de type 2 chez les individus prédisposés. De plus, des variants génétiques « perte de fonction » de PCSK9 sont associés à l’apparition du diabète de type 2. Les effets des inhibiteurs de PCSK9 sur la survenue du diabète de type 2 à long terme ne sont pas connus à ce jour. Ainsi, nous avons émis l’hypothèse que l’engorgement en cholestérol des cellules β pancréatiques associé à des niveaux très élevés d’abondance du LDLR à la membrane suite à l’utilisation des statines et d’inhibiteurs de PCSK9 induit un dysfonctionnement cellulaire, une altération de la sécrétion d’insuline et à terme le diabète de type 2. Les objectifs de mes travaux de thèse ont été (i) de déterminer la modulation des taux de PCSK9 par les statines chez des individus diabétiques de type 2, (ii) d’étudier si les niveaux circulants réduits en PCSK9 seraient prédictifs de la survenue du diabète de type 2 et enfin (iii) d’évaluer l’effet des statines, de PCSK9 et des inhibiteurs de PCSK9 sur la sécrétion d’insuline par les cellules β. Au moyen de trois cohortes de patients, nous avons montré que la concentration plasmatique de PCSK9 est augmentée chez les diabétiques de types 2 et que les niveaux de PCSK9 circulants réduits sont négativement associés à une résistance à l’insuline et à une altération de la glycémie à jeun. En utilisant des sections de pancréas humains et des lignées de cellules β pancréatiques humaines, nous avons démontré pour la première fois que PCSK9 est exprimé, synthétisé et sécrété uniquement par les cellules β pancréatiques au niveau des îlots de Langerhans. Nous n’avons pas observé d’effet de PCSK9 et de ses inhibiteurs sur la sécrétion d’insuline en réponse au glucose. L’ensemble des résultats de mes travaux de thèse indiquent que l’inhibition de PCSK9 n’aura vraisemblablement pas d’effet pro-diabétogène, ce qui est rassurant pour le développement de ces nouvelles thérapies hypocholestérolémiants<br>Statins are lipid-lowering drugs widely prescribed to prevent cardiovascular diseases. They inhibit the endogenous synthesis of cholesterol and thereby increase LDLR gene expression by activating the SREPB-2 transcription factor. The positive effects of statins regarding cardiovascular diseases are undisputable. However, their action is limited by the proprotein convertases subtilisin kexin type 9 (PCSK9), the natural inhibitor of the LDL receptor (LDLR), which is also activated by the SREBP-2 transcription factor. As a result, novel lipid-lowering strategies targeting circulating PCSK9 have emerged and have been approved recently. These are the PCSK9 inhibitors. Despite their well-established beneficial effects, the use of high doses of statins for long-term treatments induces in rare instances the onset of type 2 diabetes in predisposed individuals. In addition, “loss of function” genetic variants of PCSK9 are associated with an increased risk of type 2 diabetes. The effects of long term use of PCSK9 inhibitors on the risk of type 2 diabetes remain to be established. Thus, we hypothesized that cholesterol overload of insulin secreting pancreatic beta cells induced by the overexpression of the LDLR at their plasma membranes following treatment with statins and PCSK9 inhibitors may cause cell dysfunction, lower insulin secretion, and ultimately type 2 diabetes. The aims of my thesis were (i) to determine the circulating levels of PCSK9 and their modulation by statins in patients with type 2 diabetes, (ii) to determine if reduced circulating PCSK9 levels are predictive of new onset type 2 diabetes and finally (iii) to investigate the effect of statins, PCSK9, and PCSK9 inhibitors on beta cell function. Using three cohorts of patients, we showed that circulating PCSK9 plasma levels are increased in patients with type 2 diabetes and that reduced circulating PCSK9 levels are negatively associated with insulin resistance and elevated fasting blood glucose. In human pancreatic sections and human pancreatic beta cell lines, we showed for the first time that PCSK9 is expressed, synthesized and secreted only by beta cells in pancreatic islets. We did not find any significant effect of PCSK9 or PCSK9 inhibitors on glucose stimulated insulin secretion. Altogether, my thesis works underpin that the use of PCSK9 inhibitors in the clinic will probably not be diabetogenic. This is reassuring regarding the development of these new lipid-lowering therapies
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Bhat, Mamatha. "Expression of PCSK9 in Hepatocellular Carcinoma." Thesis, McGill University, 2012. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=106271.

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Hepatocellular carcinoma (HCC) is an often fatal condition due to late diagnosis, resistance to existing anticancer agents, as well as underlying liver disease that can limit the use of hepatotoxic chemotherapy. Proprotein convertases (PCs) are serine proteases that convert a variety of growth factors, cell surface glycoproteins, receptors and metalloproteinases into their active forms, thus regulating the biological activity of these proteins. PCs have been found to be upregulated in various malignancies. Growth factors implicated in HCC, such as IGF-1, HGF, VEGF and PDGF, have all been shown to be converted into their active forms by PCs. In this study, I explored the hypothesis that expression of proprotein convertases, specifically PCSK9, furin and PC5, is elevated in HCC. This was evaluated through construction of a Tissue Microarray and staining for these proteins. We found that PCSK9 expression was significantly downregulated in HCC tumours associated with poorer survival. PCSK9 is upregulated in the context of liver regeneration and has been involved in cholesterol metabolism, with development of monoclonal antibodies against PCSK9 to treat hypercholesterolemia. Its altered expression in aggressive HCC tumours potentially indicates that HCC is able to modulate its local microenvironment to enable a constant energy supply. There has recently been a move in oncology research to study suppression of suppress tumour growth by modifying energy supply and metabolism (for eg, metformin in prostate and breast cancer). Further confirmation at the mRNA level is required to confirm the altered expression of PCSK9, however this appears to be a promising finding and potential chemotherapeutic target.<br>Contexte et hypothèses: Le carcinome hépatocellulaire (CHC) est le 5e cancer le plus courant dans le monde entier et la 3ème cause de décès par cancer dans le monde entier, avec une survie médiane à 5 ans de 8,9%. La reconnaissance tardive en raison du manque de biomarqueurs pour détecter la maladie résécable, une résistance aux agents anticancéreux, ainsi qu'une maladie du foie sous-jacente limitant l'utilisation de chimiothérapie hépatotoxique sont des facteurs qui diminuent le taux de survie. Les proprotéines convertases (PCs) sont des sérine-protéases qui convertissent une variété de facteurs de croissance, glycoprotéines de surface cellulaire, les récepteurs, et les métalloprotéinases à leurs formes actives, contrôlant ainsi l'activité biologique de ces protéines. On a démontré l'expression augmentée de PCs dans de diverses tumeurs malignes. On a prouvé que les facteurs de croissance impliqués dans le CHC, tels que l'IGF-1, HGF, VEGF et PDGF, sont convertis à leurs forme actives par les PC. Notre hypothèse est que l'expression de proprotéines convertases est élevée dans le CHC, permettant l'activation de différentes protéines essentielles dans le développement et la progression du CHC. L'objectif de recherche était d'évaluer l'expression des PCs PCSK9, furine et PC5 dans le CHC par rapport aux stroma environnant, zones péri-cirrhotiques, et foie normal afin de déterminer si un gradient d'expression existe. PCSK9 en particulier est connu comme étant plus exprimé chez le foie régénérateur post-hepatectomie. Les diapositives de pathologie de CHC stockés dans le département de pathologie du CUSM ont été examinés par une pathologiste, et les zones appropriées (tumeur de CHC, interface de tumeur et du foie, le foie cirrhotique, et d'autres échantillons d'hépatite et de foie normal) dans les blocs de tissu correspondants ont été creusés et ont été incorporées dans un microarray de tissu (TMA). Des lignes cellulaires de CHC etablies, dont le HepG2 et le Huh7, avec des profils d'expression de PC connus, ont été incorporées sous forme de pastilles de cellules dans la TMA, afin de servir de témoins positifs et négatifs. La TMA a été sectionnée en diapositives, qui ont été colorées avec des anticorps de la PCSK9, furine et PC5. On a découvert que le niveau d'expression de PCSK9 était diminuée dans les CHC avec un pire prognostique. L'expression augmentée de PCSK9 dans les CHC plus aggressifs pourrait indiquer un rôle du PCSK9 dans la tumorigenèse, directement ou indirectement. Il se peut que les CHCs plus aggressifs sont capables de modifier l'environnement local pour apprivoiser l'énergie métabolique, et que le PCSK9 permet que le cholestérol soit utilisé comme source d'énergie. La confirmation de son importance fonctionnelle avec mRNA pourrait potentiellement mener au développement de chimiothérapie ciblée avec des anticorps contre le PCSK9 (stratégie en étude pour l'hypercholestérolémie). Compte tenu des options chimiothérapeutiques actuellement limitées pour le CHC, une telle constatation pourrait améliorer la prise en charge clinique du CHC.
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Kourimate, Sanae. "Pcsk9 : régulation et implication dans le syndrome métabolique." Nantes, 2008. https://archive.bu.univ-nantes.fr/pollux/show/show?id=4ac185ba-f999-45ff-9241-4278a9699b5c.

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Proprotein convertase subtilisin/kexin type 9 (PCSK9) est une serine protéase, jouant un rôle important dans la régulation des niveaux de cholestérol circulant. Les mutations gains de fonctions de PCSK9 sont associées à une hypercholestérolémie autosomale dominante due à une élévation des concentrations en Low Density Lipoprotein associées au cholestérol (LDLc). A l'inverse, des mutations perte de fonction de PCSK9, sont associées à une diminution de ces concentrations et à une réduction de 88% du risque d'apparition de maladies coronariennes. Dans le réticulum endoplasmique, Pro-PCSK9 subit un autoclivage indispensable à sa maturation et à sa sécrétion. PCSK9 circulante se lie au domaine EGF-A du récepteur aux LDL (LDLR) et entraîne sa dégradation lysosomale. Tout comme le LDLR, PCSK9 est positivement régulé par les statines via le Sterol Responsive element Binding Protein -2 (SREBP2). Les statines sont très utilisées en clinique pour leurs effets hypocholestérolémiants, ajouter des inhibiteurs de PCSK9 pourrait améliorer leur efficacité. Le premier objectif a été de caractériser la régulation négative de PCSK9 par le récepteur nucléaire Peroxisome Proliferator Activated Receptor alpha (PPARα) et ses agonistes synthétiques : les fibrates. Les résultats obtenus in vitro sur des lignées d’hépatocytes humains révèlent que l’activation de PPARα réprime la transcription de PCSK9 -via une répression de son promoteur- suppriment son activation par les statines, et potentialise l’effet des statines sur l’activité du LDLR. De plus, ces résultats révélèrent que la furine et PC5/6A -deux protéines convertases qui dégradent PCSK9- sont également régulées positivement par PPARα. Au-delà de PCSK9, cette étude a permis d’identifier une nouvelle famille d’enzyme régulée par les fibrates : les pro-protéines convertases. La deuxième partie de mes travaux de thèse a porté sur la mise au point d’un test flurorométrique de dosage de l’activité autocatalytique de PCSK9. La spécificité de notre approche a été de considérer non pas la protéine recombinante purifiée, qui semble dépourvue d’activité pour une raison inconnue, mais la forme endogène des hépatocytes. Après avoir validé ce test sur des hépatocytes primaires de souris PCSK9-/-, je l’ai appliqué à l’étude de divers mutants de PCSK9. Enfin, suite aux travaux du laboratoire sur la régulation de PCSK9 par l'insuline, j’ai également caractérisé l’expression de PCSK9 dans divers modèles animaux de diabète et d’insulinorésistance. PCSK9 est une cible thérapeutique sérieuse pour diminuer le LDL-c. D'après ces résultats, l’inhibition transcriptionnelle de PCSK9 par les fibrates semble être très prometteuse. Cependant, en clinique les fibrates sont préférentiellement utilisés pour leurs propriétés hypotriglycéridémiantes, puisque leurs effets sur le cholestérol restent limités. Existerait-il in vivo un mécanisme inhibiteur de cette voie? L'identifier serait une des perspectives qu'ouvre cette thèse<br>Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a member of the serine protease family. Gain of function mutations within PCSK9 are associated with dominant forms of familial hypercholesterolemia. Inversely, humans harbouring loss of function mutations have a significant plasma LDLc reduction and a 88% decrease of the risk of coronary heart disease. In the endoplasmic reticulum Pro-PCSK9 undergoes an autocalytique clivage that is crucial for its secretion. Then, this secreted protein binds to the EGF-A domain of the LDLR and targets it to the lysosomes rather than to the cell surface. Both PCSK9 and the LDLR are up-regulated by statins via SREBP2. Using PCSK9 inhibitors may optimize the effects of this hypocholesterolemic drug. The first aim of my thesis was to investigate in vitro the mechanisms of PCSK9 repression by the fibrates which are PPARα synthetic agonists. Activation of PPARα down-regulates PCSK9 transcription at the promoter level and increase the expression of two others Proprotein convertases: furin and PC5/6A which are known to degrade PCSK9. Fibrates counteracts PCSK9 induction by statins and amplifies the effects of this hypocholesterolemic drugs on the LDLR acitivity. The second part of my studies was based on measuring the endogenous cleavage activity of PCSK9, using a fluorogenic peptide corresponding to the cleavage site of Pro-PCSK9. After validation of the specificity of this assay on mice primary hepatocytes from PCSK9-/-, I applied it to the test of several PCSK9 variants. The final part of my studies dealt about the characterisation of PCSK9 expression in diabetic and insulin resistant animal models. PCSK9 is an attractive therapeutic target for lowering plasma LDLc levels. This study clearly showed that PCSK9 transcriptional inhibition by fibrates might be envisaged in combination with statins. However, in vivo, in humans, the fibrates are rather known for their hypotriglyceridemic properties. The limited effect of fibrates on lowering LDLc might be explained by a counteracting pathway. Identifying this pathway is one of the promising perspectives of this thesis
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Roubtsova, Anna. "Partial hepatectomy and liver regeneration in PCSK9 knockout mice." Thesis, McGill University, 2008. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=112356.

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The proprotein convertase subtilisin/kexin type 9, PCSK9, belongs to the proprotein convertase (PC) family. Human mutations in the gene encoding PCSK9 lead to either familial hyper- or hypocholesterolemia, resulting from a gain or loss of function, respectively. Mice lacking PCSK9 are viable and show a 42% decrease in plasma cholesterol levels. The enzyme triggers the degradation of the low density lipoprotein receptor (LDLR) through a partially unknown mechanism.<br>PCSK9 is very abundant in the liver and intestine during development and adulthood. Hepatocytes have a capacity to reproduce themselves and, upon injury, can repopulate the liver. For a better understanding of the role of PCSK9 in the liver, partial hepatectomy was performed on Pcsk9 +/+, Pcsk9+/- and Pcsk9-/- mice. The absence of PCSK9 resulted in defective liver regeneration, while wild type (WT) and heterozygous mice had no phenotype. Regeneration defects could be prevented by a high cholesterol diet. PCSK9 deficiency, by contributing to maintaining low circulating cholesterol levels may thus hamper liver regeneration. This knowledge is critical for the analysis of future PCSK9 inhibitors expected to be developed in the near future.<br>Key words. Proprotein convertase subtilisin/kexin 9 (PCSK9), a familial hyper- or hypocholesterolemia, low density lipoprotein receptor, knockout mouse model, partial hepatectomy.
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Torrinha, José Maria de Queiroz e. Lencastre Fleming. "Inibidores PCSK9: nova estratégia para o tratamento da hipercolesterolemia." Master's thesis, [s.n.], 2015. http://hdl.handle.net/10284/5293.

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Projeto de Pós-Graduação/Dissertação apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Mestre em Ciências Farmacêuticas<br>As doenças cardiovasculares são uma das principais causas de morbilidade e mortalidade a nível mundial. Neste enquadramento, um dos principais fatores de risco associado às doenças cardiovasculares é a hipercolesterolemia. As opções farmacológicas existentes para o tratamento e prevenção desta dislipidemia centram-se, sobretudo, no uso de fármacos como as estatinas, a ezetimiba, os fibratos, o ácido nicotínico e as resinas sequestradoras de ácidos biliares. Porém, esta abordagem farmacológica no combate da hipercolesterolemia caracteriza-se pelo prolongado período terapêutico decorrendo daí possíveis efeitos laterais a longo prazo, pela intolerância a grupos terapêuticos observada em alguns doentes (como acontece com as estatinas) ou, ainda, pela eficácia limitada de alguns grupos terapêuticos (como é o caso, dos fibratos), o que suscita preocupação. Os avanços científicos no conhecimento dos processos que envolvem a hipocolesterolemia e a incessante procura de fármacos mais seguros e eficazes impulsionou o desenvolvimento dos inibidores da pró-proteína convertase subtilisina/kexina tipo 9 (PCSK9), afirmando-se como uma nova e promissora estratégia terapêutica. Os níveis plasmáticos elevados de colesterol proveniente das lipoproteínas de baixa densidade (C-LDL) são um fator de risco, no desenvolvimento de aterosclerose e de doença vascular isquémica. O recetor LDL (R-LDL) é essencial no metabolismo do colesterol, uma vez que ao se ligar ao C-LDL é capaz de eliminá-lo da circulação. É aqui, que reside o principal foco de interesse desta nova estratégia terapêutica, uma vez que a PCSK9 promove a degradação do recetor R-LDL, conduzindo a uma redução da depuração de LDL, aumentando os níveis de colesterol LDL. Desta forma, a inibição da atividade da PCSK9, veio revelar-se como uma nova abordagem potencialmente interessante para o desenvolvimento de novos fármacos destinados à redução do C-LDL. Os anticorpos monoclonais humanos contra PCSK9 estão em desenvolvimento clínico e são, neste momento, a aposta mais promissora de inibição da PCSK9. Até ao momento, os resultados dos ensaios clínicos demonstraram a eficácia destas moléculas com redução do C-LDL na ordem dos 60%. Adicionalmente, os seus efeitos na redução do C-LDL são aditivos aos das estatinas e até à data, não mostraram qualquer efeito tóxico a nível muscular, como acontece com estas últimas, sendo fármacos bem tolerados e aparentemente seguros.<br>Cardiovascular diseases are a major cause of morbidity and mortality worldwide. In this context, one of the main risk factor associated with cardiovascular disease is hypercholesterolemia. The treatment and prevention of this dyslipidemia is mainly focused on the use of drugs such as statins, ezetimibe, fibrates, nicotinic acid and bile acid sequestrants. However, the pharmacological approach in hypercholesterolemia treatment is characterized by prolonged therapeutic period elapsing possible long-term side effects, by the intolerance to treatment in some patients (as is the case of statins), or by the limited efficacy of various drugs/pharmaceuticals (as for example of fibrates), which raise concerns. Scientific advances in the understanding of hypercholesterolemia and the constant need for safer and more effective drugs prompted the development of the convertase pro-protein subtilisin inhibitor/kexin type 9 (PCSK9), as a promising new therapeutic strategy. Elevated plasma LDL cholesterol (LDL-C) levels are a risk factor for atherosclerosis and ischemic vascular disease. The LDL receptor (LDL-R) has an essential role in the cholesterol metabolism, since it binds to LDL-C removing it from circulation. Here, lies the main focus of interest of this novel therapeutic strategy, since PCSK9 promotes LDL-R the degradation, leading to a reduction of LDL clearance, increasing levels of LDL cholesterol. Therefore, inhibition of PCSK9 activity is a potentially interesting new approach for the development of new drugs to reduce LDL-C. Human monoclonal antibodies against PCSK9 are in clinical development and are presently the most promising strategy for the inhibition of PCSK9. At the moment, results of clinical trials show the efficacy of these molecules with reductions efficiencies of LDL-C in the order of 60%. Furthermore, this LDL-C reduction are additive to those of statins and until now have not shown any toxic effect in muscle, as observed with statins, and have a good record for safety and tolerability.
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Dewpura, Thilina. "Importance of phosphorylation in PCSK9 processing, stability and function." Thesis, University of Ottawa (Canada), 2010. http://hdl.handle.net/10393/28604.

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Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted glycoprotein regulating the degradation of low density lipoprotein receptor. Single nucleotide polymorphisms in PCSK9 associate with both hyper- and hypo-cholesterolemia; studies show significant reduction in risk of coronary heart disease for 'loss of function' PCSK9 carriers. We used a combination of mass spectrometry and radiolabeling to report that PCSK9 is phosphorylated at two sites, Ser47 in its propeptide, and Ser688 in its C-terminus. Site directed mutagenesis (SDM) demonstrated that a Golgi casein kinase-like kinase was responsible for PCSK9 phosphorylation based on the consensus site, SXE/S(p). PCSK9 phosphorylation is cell-type specific; phosphorylation status did not affect PCSK9 processing or secretion. Phosphorylated PCSK9 propeptide is protected against proteolysis. Immunoblotting demonstrated that PCSK9 mutants engineered by SDM to prevent phosphorylation at either site (substitution to Ala) or in combination resulted in significantly increased LDLR levels in HuH7 cells by up to -25%. PCSK9 mutants engineered by SDM to mimick phosphorylation (substitution to Asp/Glu) at the N-terminus, but not at the C-terminus or in combination, promoted LDLR degradation significantly more than wild-type. Far western analysis demonstrated that preventing PCSK9 phosphorylation promoted its interaction with the endogenous inhibitor Annexin A2.
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Sarkar, Samantha Khadija. "The Regulation of PCSK9 Structure and Function Through Lipoprotein Interactions." Thesis, Université d'Ottawa / University of Ottawa, 2019. http://hdl.handle.net/10393/39099.

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Proprotein convertase subtilisin / kexin type 9 (PCSK9) is a negative regulator of the low-density lipoprotein receptor, and PCSK9 inhibition has become an important cholesterol-lowering therapeutic strategy. PCSK9 also associates with LDL particles, and evidence suggests that the activity of PCSK9 may be regulated by LDL binding. We have investigated the biochemistry of the interaction between PCSK9 and lipoproteins. Through mutagenesis and in-vitro binding assays, we found conserved motifs in the PCSK9 N-terminus that play a role in LDL binding. Through secondary structure studies using circular dichroism and computational modelling, we determined that the N-terminal region of the PCSK9 prodomain undergoes an environment-dependent structural shift that affects the ability of PCSK9 to bind LDL. We also found that the commonly found loss-of-function polymorphism R46L is capable of modulating this structural shift. Importantly, we found a surface-exposed region of the PCSK9 prodomain that maps a cluster of gain-of-function mutations (L108R, S127R, and D129G) that severely disrupt LDL binding. Through gel shift assays and density gradient centrifugation, we observed that PCSK9 shows remodeling-dependent ability to bind different classes of lipoprotein particles in vitro, binding strongly to LDL and IDL but showing barely detectable association to VLDL. Further, in human plasma, we found that lipoprotein-bound populations of PCSK9 shifted in response to differences in lipoprotein profiles between normolipidemic and hypercholesterolemic or hypertriglyceridemic subjects. Overall, elucidation of how lipoproteins regulate PCSK9 activity will reveal new targets for designing cholesterol-lowering therapeutics.
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Haas, Mary Elizabeth. "Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) in Secondary Hyperlipidemias." Thesis, Harvard University, 2016. http://nrs.harvard.edu/urn-3:HUL.InstRepos:33493577.

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Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) has emerged over the past decade as an important regulator of plasma cholesterol and cardiovascular disease risk. PCSK9 promotes degradation of low density lipoprotein (LDL) receptors, thereby decreasing LDL clearance. Accordingly, patients with gain-of-function mutations in PCSK9 have increased LDL cholesterol and increased risk of cardiovascular disease. Conversely, PCSK9 inhibitors recently approved by the FDA are effective in reducing LDL cholesterol. While the contribution of PCSK9 to familial hypercholesterolemia is well-established, less is understood about the role of PCSK9 in diseases in which hyperlipidemia results secondary to an initial disease insult. Hormonal regulation of PCSK9 is also incompletely understood. Understanding the regulators of PCSK9 and specific diseases in which it contributes to hypercholesterolemia is important for identifying additional mechanisms via which PCSK9 can be manipulated, and for choosing patient populations in which PCSK9 inhibitors will be effective. Here, we investigate PCSK9 in two diseases of secondary hyperlipidemia. In nephrotic syndrome, damage to kidney podocytes causes extreme proteinuria and hypercholesterolemia of unclear etiology. We show that plasma cholesterol and PCSK9 are dramatically elevated in mice made nephrotic by nephrotoxic serum treatment or podocyte apoptosis. Moreover, knockout of Pcsk9 protects mice from the effects of nephrotic syndrome on plasma lipids, particularly increased LDL cholesterol. Similarly, nephrotic patients show decreased plasma PCSK9 and cholesterol upon disease remission. Second, loss of adipose tissue in lipodystrophy results in low levels of the hormone leptin. Treatment of lipodystrophic patients with leptin reduces LDL cholesterol through unknown mechanisms. We used this background of hypoleptinemia to investigate the effects of leptin on PCSK9. We found that in female lipodystrophic patients, leptin treatment reduced plasma PCSK9, correlating with decreased LDL cholesterol. Similarly, in male leptin-deficient ob/ob mice, leptin also decreased plasma PCSK9 but did not affect plasma lipids. Our data show that PCSK9 is a novel regulator of hypercholesterolemia in nephrotic syndrome, suggesting that PCSK9 inhibitors may be an important therapy for this patient population with ambiguous treatment options. They also show that leptin can suppress PCSK9 expression, which may explain the observed decreases in LDL cholesterol upon leptin treatment of lipodystrophic patients.<br>Medical Sciences
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Vila, Belmonte Àlex. "Estimación de la prevalencia de la Hipercolesterolemia Familiar y de las características clínicas asociadas en Cataluña." Doctoral thesis, Universitat de Girona, 2019. http://hdl.handle.net/10803/670206.

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Familial hypercholesterolemia (FH) is the most frequent hereditary cause of premature coronary heart disease. The aim of this doctoral thesis is to determine the prevalence of subjects with FH phenotype (FH-P); to describe their clinical characteristics and the lipid-lowering therapy that they follow; as well as to estimate the number and type of patients eligible for treatment with proprotein convertase subtilisin/kexin type 9 inhibitors (iPCSK9) according to the different indication criteria of the scientific societies and the National Health System (NHS). This research was done based on data from real-world clinical practice. Our study estimates that at least one in 192 and one in 425,774 people of the general population have heterozygous and homozygous FH-P, respectively. We observe that it is underdiagnosed and treated suboptimally. The number of possible candidates to receive iPCSK9 ranges, depending on which of the different scientific societies’ recommendations are used.<br>La hipercolesterolemia familiar (HF) es la causa hereditaria más frecuente de enfermedad coronaria prematura. Esta tesis doctoral pretende determinar la prevalencia de sujetos con fenotipo de HF (F-HF); describir sus características clínicas y el tratamiento hipolipemiante que realizan; así como estimar el número y tipo de pacientes candidatos a recibir inhibidores de la proproteína convertasa subtilisina/kexina tipo 9 (iPCSK9) según los diferentes criterios de indicación de las sociedades científicas y el Sistema Nacional de Salud (SNS). La investigación se ha basado en datos de la práctica clínica real. Nuestro estudio estima que al menos una de cada 192 y una de cada 425.774 personas en la población general presentan F-HF heterocigota y homocigota, respectivamente. Se observa que está infradiagnosticada y tratada de forma subóptima. El número de posibles candidatos a recibir iPCSK9 varía, en función de las recomendaciones de las diferentes sociedades científicas que se utilizan.
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Denis, Nicholas. "Quantitative Subcellular Analysis of the Effects of the Enigmatic Protein PCSK9." Thèse, Université d'Ottawa / University of Ottawa, 2011. http://hdl.handle.net/10393/20133.

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PCSK9 is the third gene implicated in autosomal dominant hypercholesterolemia, due to its role in promoting the degradation of the low density lipoprotein receptor (LDLR). Little is known regarding the mechanism by which it promotes the degradation of LDLR, nor the effects PCSK9 has on other cellular proteins. I report here the first quantitative subcellular proteomic study of proteins affected by the expression of a variant of PCSK9. I show that the expression levels of 293 proteins were affected by the expression of the PCSK9-ACE2-V5 construct. Of particular interest, is a protein involved in receptor recycling, EHBP1, which shows reduced protein levels by both PCSK9-ACE2-V5 and the PCSK9-D374Y mutant. I show that an EHBP1 binding protein, EHD4, binds with PCSK9 and LDLR. These results establish novel effects of PCSK9 on liver cell protein levels, of which some relating to endosomal sorting are shown to bind to PCSK9 and LDLR in complex, providing insight into the mechanism of PCSK9 mediated LDLR degradation.
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Books on the topic "Inhibiteurs de la PCSK9"

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Zollner, Helmward. Handbook of enzyme inhibitors. VCH, 1989.

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Zollner, Helmward. Handbook of enzyme inhibitors. 3rd ed. New York, 1999.

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Zollner, Helmward. Handbook of enzyme inhibitors. 2nd ed. VCH, 1993.

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Albert, Najman, and Université Pierre et Marie Curie. Faculté de médecine Saint-Antoine. Département d'hématologie., eds. The inhibitors of hematopoiesis =: Les inhibiteurs de l'hématopoïèse : proceedings of the First International Symposium on Inhibiting Factors in the Regulation of Hematopoiesis, Paris, (France), 26-28 April, 1987). INSERM, 1987.

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Glaxo-UCLA Colloquium on Cellular Proteases and Control Mechanisms (1988 Lake Tahoe, Calif.). Cellular proteases and control mechanisms: Proceedings of a Glaxo-UCLA Colloquium on Cellular Proteases and Control Mechanisms, held at Lake Tahoe, California, February 21-26, 1988. Edited by Hugli T. E. Liss, 1989.

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Mendel, Friedman, American Institute of Nutrition, and Federation of American Societies for Experimental Biology., eds. Nutritional and toxicological significance of enzyme inhibitors in foods. Plenum Press, 1986.

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L, Moses Harold, Lengyel Peter 1929-, Stiles Charles D, and Genentech Inc, eds. Growth inhibitory and cytotoxic polypeptides ; proceedings of a Genentech-Smith, Kline & French-Triton Biosciences-UCLA Symposium held in Keystone, Colorado, January 24-30, 1988. A.R. Liss, 1989.

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Preskorn, Sheldon H. La Pharmacologie Clinique Des Inhibiteurs Selectifs Du Recaptage de La Serotonine. Professional Communications, 1996.

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Atta-ur-Rahman and M. Iqbal Choudhary, eds. Frontiers in Cardiovascular Drug Discovery: Volume 4. BENTHAM SCIENCE PUBLISHERS, 2019. http://dx.doi.org/10.2174/97816810839951180401.

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Frontiers in Cardiovascular Drug Discovery is an eBook series devoted to publishing the latest advances in cardiovascular drug design and discovery. Each volume brings reviews on the biochemistry, in-silico drug design, combinatorial chemistry, high-throughput screening, drug targets, recent important patents, and structure-activity relationships of molecules used in cardiovascular therapy. The eBook series should prove to be of great interest to all medicinal chemists and pharmaceutical scientists involved in preclinical and clinical research in cardiology. The fourth volume of the series covers the following topics: -Aspirin administration -Adenosine receptor targeting for cardiovascular therapy -Drug treatment of patients with coronary stenting -Immunosuppressive drugs in heart transplantation -PCSK9 inhibition for lowering LDL-C levels.
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Biochemistry, Molecular Biology, and Physiology of Phospholipase A2 and Its Regulatory Factors. Springer, 1991.

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Book chapters on the topic "Inhibiteurs de la PCSK9"

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Wright, R. Scott. "PCSK9 Inhibiting siRNA." In Stroke Revisited: Dyslipidemia in Stroke. Springer Singapore, 2021. http://dx.doi.org/10.1007/978-981-16-3923-4_12.

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Ahmed, Zain, Prerak Juthani, Megan Lee, and Nihar R. Desai. "PCSK9 Inhibiting Monoclonal Antibodies." In Stroke Revisited: Dyslipidemia in Stroke. Springer Singapore, 2021. http://dx.doi.org/10.1007/978-981-16-3923-4_11.

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Desnick, Robert J., Orlando Guntinas-Lichius, George W. Padberg, et al. "FHBL due to Defective PCSK9." In Encyclopedia of Molecular Mechanisms of Disease. Springer Berlin Heidelberg, 2009. http://dx.doi.org/10.1007/978-3-540-29676-8_8889.

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Sauder, P., O. Martinet, X. Delabranche, and F. Ganster. "Intoxications par inhibiteurs calciques." In Références en réanimation. Collection de la SRLF. Springer Paris, 2013. http://dx.doi.org/10.1007/978-2-8178-0301-2_9.

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Ooi, Teik Chye, and Hussein Abujrad. "PCSK9 as a Biomarker of Cardiovascular Disease." In Biomarkers in Cardiovascular Disease. Springer Netherlands, 2016. http://dx.doi.org/10.1007/978-94-007-7678-4_20.

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Ooi, Teik Chye, and Hussein Abujrad. "PCSK9 as a Biomarker of Cardiovascular Disease." In Biomarkers in Cardiovascular Disease. Springer Netherlands, 2015. http://dx.doi.org/10.1007/978-94-007-7741-5_20-1.

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Wang, Zuo, Zhi-Han Tang, Yun-Chen Lv, Lu-Shan Liu, and Zhi-Sheng Jiang. "Bioinformatic Analysis of PCSK9 Related Caspase3 Activation." In Recent Advances in Computer Science and Information Engineering. Springer Berlin Heidelberg, 2012. http://dx.doi.org/10.1007/978-3-642-25778-0_73.

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Bozec, A., and G. Milano. "Monoclonaux contre inhibiteurs de tyrosine kinase." In Les thérapies ciblées. Springer Paris, 2008. http://dx.doi.org/10.1007/978-2-287-36008-4_6.

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Fontan, B., and O. Toulza. "Complications cardiovasculaires des inhibiteurs des cholinestérases." In Traité sur la maladie d’Alzheimer. Springer Paris, 2013. http://dx.doi.org/10.1007/978-2-8178-0443-9_16.

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Farnier, Michel. "Statins and PCSK9 Inhibitors: Defining the Correct Patients." In Combination Therapy In Dyslipidemia. Springer International Publishing, 2015. http://dx.doi.org/10.1007/978-3-319-20433-8_9.

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Conference papers on the topic "Inhibiteurs de la PCSK9"

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Niemann, B., L. Li, F. Knapp, R. Schulz, and S. Rohrbach. "Modifying Epicardial PCSK9 Expression to Protect Cardiac Function?" In 48th Annual Meeting German Society for Thoracic, Cardiac, and Vascular Surgery. Georg Thieme Verlag KG, 2019. http://dx.doi.org/10.1055/s-0039-1678923.

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Ly, Kévin, Anna Kwiatkowska, Sophie Routhier, et al. "Development of Peptide Inhibitors Disrupting PCSK9-LDLR Protein-Protein Interactions." In The Twenty-Third American and the Sixth International Peptide Symposium. Prompt Scientific Publishing, 2013. http://dx.doi.org/10.17952/23aps.2013.110.

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Martin, V. Merino, MP Ortega-Garcia, P. Blasco-Segura, et al. "4CPS-035 Effectiveness and safety of monoclonal antibody pcsk9 inhibitors." In Abstract Book, 23rd EAHP Congress, 21st–23rd March 2018, Gothenburg, Sweden. British Medical Journal Publishing Group, 2018. http://dx.doi.org/10.1136/ejhpharm-2018-eahpconf.126.

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Gabaldón Garnica, P., C. Sobrino Jiménez, F. Moreno Ramos, L. González del Valle, C. Jiménez Vicente, and A. Herrero Ambrosio. "4CPS-026 Adherence and effectiveness of PCSK9 inhibitors in routine clinical practice." In 24th EAHP Congress, 27th–29th March 2019, Barcelona, Spain. British Medical Journal Publishing Group, 2019. http://dx.doi.org/10.1136/ejhpharm-2019-eahpconf.175.

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Heslinga, M., G. Lambert, A. Thedrez, J. Kastelein, and M. Nurmohamed. "THU0154 Association between plasma lipids, disease activity and PCSK9 levels in RA patients." In Annual European Congress of Rheumatology, 14–17 June, 2017. BMJ Publishing Group Ltd and European League Against Rheumatism, 2017. http://dx.doi.org/10.1136/annrheumdis-2017-eular.2121.

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Lin, Jie, Youyan Guo, Zuo Wang, et al. "R306S gain-of-function mutation enhances PCSK9-mediated lowering of LDL-R expression." In 2011 4th International Conference on Biomedical Engineering and Informatics (BMEI). IEEE, 2011. http://dx.doi.org/10.1109/bmei.2011.6098587.

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Pannérec, V., and JC Fricain. "Traitement par corticothérapie locale et laser diode à basse énergie des ulcérations buccales induites par les inhibiteurs de mTOR." In 62ème Congrès de la SFCO. EDP Sciences, 2014. http://dx.doi.org/10.1051/sfco/20146202012.

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Hall, R., K. Hochrath, M. Krawczyk, et al. "Quantitative trait analysis in Abcb4 deficient mice identifies Pcsk9 as a potential modifier gene." In Viszeralmedizin 2019. Georg Thieme Verlag KG, 2019. http://dx.doi.org/10.1055/s-0039-1695590.

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Maray Mateos, I., L. Velasco Roces, A. Rodríguez Ferreras, et al. "6ER-001 PCSK9 inhibitors: variation in the lipid profile in a real world setting." In 25th EAHP Congress, 25th–27th March 2020, Gothenburg, Sweden. British Medical Journal Publishing Group, 2020. http://dx.doi.org/10.1136/ejhpharm-2020-eahpconf.436.

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Yáñez Feria, D., P. Selvi Sabater, A. Pelaez Bejarano, O. Montero Pérez, and MD Santos Rubio. "4CPS-030 Analysis of adaptation to a protocol of use of the PCSK9 inhibitors." In 24th EAHP Congress, 27th–29th March 2019, Barcelona, Spain. British Medical Journal Publishing Group, 2019. http://dx.doi.org/10.1136/ejhpharm-2019-eahpconf.179.

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