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1.
Fitoterapia ; 139: 104393, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31669721

RESUMO

The extract of Dioscorea zingiberensis C.H. Wright rhizomes is found to be effective in the therapy of cardiovascular disease. Steroidal saponins make substantial contribution. Previous study has proposed that methylprotodioscin (MP) may promote cholesterol efflux by increasing ABCA1 expression. But the other main saponins ingredients are not referred to. The aim of the present work was to reveal the effect and mechanism of protodioscin (PD), MP and pseudoprotodioscin (PPD) on the synthesis-related gene expression of cholesterol and triglycerides. MTT assay apoptosis assay with annexin AV-APC and 7-AAD double staining were performed. MicroRNA assay and qRT-PCR were used to analyze the gene expression which regulates synthesis of cholesterol and triglycerides. Western blot was to demonstrate the levels of target proteins. Cholesterol efflux assay was executed to study the stimulative effect of saponins on cholesterol efflux. In Hep G2 cells, PPD increased ABCA1 protein and mRNA levels, and promoted the effluxion of ApoA-1-mediated cholesterol. The underlying mechanisms involved that PPD inhibited SREBP1c and SREBP2 transcription by decreasing microRNA 33a/b levels. This procedure reciprocally led to the increase of ABCA1 levels. In THP-1 macrophages, PPD showed the similar effect, which reduced HMGCR, FAS and ACC mRNA levels and promoted low density lipoprotein receptor by decreasing the PCSK9 levels. These studies demonstrated that PPD is a potential agent for cholesterol efflux, SREBPs and microRNA 33a/b inhibition, which related to the gene expression for the synthesis of cholesterol and triglycerides.


Assuntos
Colesterol/biossíntese , Diosgenina/análogos & derivados , MicroRNAs/antagonistas & inibidores , Saponinas/farmacologia , Proteína de Ligação a Elemento Regulador de Esterol 1/antagonistas & inibidores , Proteína de Ligação a Elemento Regulador de Esterol 2/antagonistas & inibidores , Triglicerídeos/biossíntese , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Dioscorea/química , Diosgenina/farmacologia , Células Hep G2 , Humanos , MicroRNAs/genética , Extratos Vegetais/farmacologia , Pró-Proteína Convertase 9/metabolismo , Receptores de LDL/metabolismo , Rizoma/química , Células THP-1
2.
Prog Cardiovasc Dis ; 62(5): 395-400, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31715195

RESUMO

Statin therapy is effective in primary and secondary prevention, but substantial residual risk remains on statin treatment, especially among high risk and very high risk patients. Add-on therapy with ezetimibe and proprotein convertase subtilisin /kexin type 9 (PCSK9) inhibitors provides additional risk reduction through further reduction in low density lipoprotein cholesterol. Elevated triglycerides/triglyceride rich lipoproteins contribute to atherogenesis and to the residual risk on statin therapy. Addition of icosapent ethyl to statins has recently been shown to markedly lower risk of ASCVD events in patients with established atherosclerotic CVD (ASCVD) and high risk patients with type II diabetes mellitus. These data are discussed in the context of current guidelines and synthesized in a decision pathway to guide combination lipid-lowering therapy in patients at high ASCVD risk.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Dislipidemias/tratamento farmacológico , Ácido Eicosapentaenoico/análogos & derivados , Ezetimiba/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Pró-Proteína Convertase 9/antagonistas & inibidores , Ensaios Clínicos Controlados Aleatórios como Assunto , Inibidores de Serino Proteinase/uso terapêutico , Biomarcadores/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , LDL-Colesterol/sangue , Quimioterapia Combinada , Dislipidemias/sangue , Dislipidemias/diagnóstico , Dislipidemias/epidemiologia , Ácido Eicosapentaenoico/efeitos adversos , Ácido Eicosapentaenoico/uso terapêutico , Ezetimiba/efeitos adversos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Guias de Prática Clínica como Assunto , Pró-Proteína Convertase 9/metabolismo , Fatores de Risco , Inibidores de Serino Proteinase/efeitos adversos , Resultado do Tratamento , Triglicerídeos/sangue
3.
Prog Cardiovasc Dis ; 62(5): 414-422, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31669498

RESUMO

Familial hypercholesterolemia (FH) is a frequent genetic disorder characterized by elevated low-density lipoprotein (LDL)-cholesterol (LDL-C) levels and early onset of atherosclerotic cardiovascular disease. FH is caused by mutations in genes that regulate LDL catabolism, mainly the LDL receptor (LDLR), apolipoprotein B (APOB) and gain of function of proprotein convertase subtilisin kexin type 9 (PCSK9). However, the phenotype may be encountered in individuals not carrying the latter monogenic defects, in approximately 20% of these effects of polygenes predominate, and in many individuals no molecular defects are encountered at all. These so-called FH phenocopy individuals have an elevated atherosclerotic cardiovascular disease risk in comparison with normolipidemic individuals but this risk is lower than in those with monogenic disease. Individuals with FH are exposed to elevated LDL-C levels since birth and this explains the high cardiovascular, mainly coronary heart disease, burden of these subjects. However, recent studies show that this risk is heterogenous and depends not only on high LDL-C levels but also on presence of previous cardiovascular disease, a monogenic cause, male sex, smoking, hypertension, diabetes, low HDL-cholesterol, obesity and elevated lipoprotein(a). This heterogeneity in risk can be captured by risk equations like one from the SAFEHEART cohort and by detection of subclinical coronary atherosclerosis. High dose high potency statins are the main stain for LDL-C lowering in FH, however, in most situations these medications are not powered enough to reduce cholesterol to adequate levels. Ezetimibe and PCSK9 inhibitors should also be used in order to better treat LDL-C in FH patients.


Assuntos
Anticolesterolemiantes/uso terapêutico , Aterosclerose/prevenção & controle , LDL-Colesterol/sangue , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Anticolesterolemiantes/efeitos adversos , Aterosclerose/epidemiologia , Aterosclerose/genética , Biomarcadores/sangue , Ezetimiba/uso terapêutico , Predisposição Genética para Doença , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/epidemiologia , Hiperlipoproteinemia Tipo II/genética , Fenótipo , Pró-Proteína Convertase 9/antagonistas & inibidores , Pró-Proteína Convertase 9/metabolismo , Medição de Risco , Fatores de Risco , Inibidores de Serino Proteinase/uso terapêutico , Resultado do Tratamento
4.
Clín. investig. arterioscler. (Ed. impr.) ; 31(5): 241-243, sept.-oct. 2019. graf
Artigo em Espanhol | IBECS | ID: ibc-184168

RESUMO

Se trata de un paciente con hipercolesterolemia familiar heterocigota y antecedentes de infarto agudo de miocardio, que es remitido a la unidad de lípidos de nuestro centro para ajuste del tratamiento hipocolesterolemiante. Dado que no alcanza los objetivos terapéuticos con tratamiento oral, comienza tratamiento con sesiones quincenales de aféresis de colesterol LDL, que mantiene durante 8 años. Con la introducción y disponibilidad de los inhibidores de la PCSK9, se presenta una nueva opción de tratamiento para este paciente


It is a patient with heterozygous familial hypercholesterolemia and a personal history of acute myocardial infarction, which is referred to our lipid unit for hypocholesterolemic treatment adjustment. Since he does not reach therapeutic goals with oral medication, he starts a treatment with fortnightly sessions of LDL-apheresis, which he keeps for 8 years. With the introduction and availability of PCSK9 inhibitors, a new treatment option is possible for this patient


Assuntos
Humanos , Masculino , Pessoa de Meia-Idade , Pró-Proteína Convertase 9/antagonistas & inibidores , Hiperlipoproteinemia Tipo II/diagnóstico , Infarto do Miocárdio/complicações , Anticorpos Monoclonais/farmacologia , LDL-Colesterol/antagonistas & inibidores , Anticolesterolemiantes , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Hiperlipoproteinemia Tipo II/genética , Pró-Proteína Convertase 9/administração & dosagem , Pró-Proteína Convertase 9/metabolismo , Lipoproteínas LDL/efeitos dos fármacos
6.
Curr Top Med Chem ; 19(20): 1790-1817, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31400268

RESUMO

BACKGROUND: Cardiovascular diseases remain the leading cause of morbidity and mortality in the world, with elevated Low-Density Lipoprotein-Cholesterol (LDL-C) levels as the major risk factor. Lower levels of LDL-C can effectively reduce the risk of cardiovascular diseases. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in regulating the degradation of hepatic LDL receptors that remove LDL-C from the circulation. PCSK9 inhibitors are a new class of agents that are becoming increasingly important in the treatment to reduce LDL-C levels. Two PCSK9 inhibitors, alirocumab and evolocumab, have been approved to treat hypercholesterolemia and are available in the United States and the European Union. Through the inhibition of PCSK9 and increased recycling of LDL receptors, serum LDL-C levels can be significantly reduced. OBJECTIVE: This review will describe the chemistry, pharmacokinetics, and pharmacodynamics of PCSK9 inhibitors and their clinical effects.


Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Pró-Proteína Convertase 9/antagonistas & inibidores , Inibidores de Serino Proteinase/farmacologia , Animais , Doenças Cardiovasculares/metabolismo , Humanos , Pró-Proteína Convertase 9/metabolismo
7.
Nutrients ; 11(7)2019 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-31330826

RESUMO

GQEQSHQDEGVIVR (T9) is a peptide originated by the tryptic digestion of lupin ß-conglutin that is absorbed in human intestinal Caco-2 cells. A previous study has shown that T9 impairs the protein-protein interaction between mutant D374Y Proprotein Convertase Subtilisin/Kexin 9 (PCSK9D374Y) and the low-density lipoprotein receptor (LDLR), thus exerting a hypocholesterolemic effect. Moreover, a bioinformatic study predicting that T9 may potentially act as an inhibitor of 3-hydroxy-3-methylglutaryl CoA reductase (HMGCoAR), has suggested a complementary cholesterol-lowering activity. The present study demonstrates that T9 inhibits in vitro the HMGCoAR functionality with an IC50 value of 99.5 ± 0.56 µM. Through the inhibition of either HMGCoAR or PCSK9D374Y activities, T9 enhances the LDLR protein levels leading to an improved ability of HepG2 cells transfected with the mutant PCSK9D374Y-FLAG plasmid to uptake extracellular LDL with a final cholesterol-lowering effect. In addition, T9 modulates the PCSK9D374Y signaling pathway in transfected HepG2 cells leading to a decrease of PCSK9D374Y and HNF-1α protein levels. All these results indicate that the hypocholesterolemic effects of T9 are due to a dual mechanism of action involving either the modulation of the PCSK9D374Y or LDLR pathways. This may represent an added value from a therapeutic point of view.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Peptídeos/farmacologia , Pró-Proteína Convertase 9/metabolismo , Sequência de Aminoácidos , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases , Mutação , Peptídeos/química , Pró-Proteína Convertase 9/genética
8.
J Assoc Physicians India ; 67(4): 74-85, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31311223

RESUMO

The burden of atherosclerotic cardiovascular (CV) disease is alarmingly high and increasing in our country. Dyslipidemia is one of the major modifiable risk factors, and INTERHEART study showed that dyslipidemia had the highest population attributable risk for myocardial infarction. In the management of dyslipidemia, low-density lipoprotein cholesterol (LDL-C) is the primary therapeutic target. In addition to therapeutic lifestyle changes, statins and ezetimibe effectively lower LDL-C and consequently improve CV outcomes. However, there are situations where these drugs fall short of achieving the target or they may not be well tolerated.


Assuntos
Inibidores Enzimáticos/uso terapêutico , Pró-Proteína Convertase 9/antagonistas & inibidores , Anticolesterolemiantes , LDL-Colesterol , Índia , Pró-Proteína Convertase 9/metabolismo
9.
Biomed Res Int ; 2019: 7284767, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31281844

RESUMO

The potential of oxidized-LDL (Ox-LDL) to elicit inflammatory responses in macrophages leading to the atherosclerosis (AS) progression is well known. Since proprotein convertase subtilisin/Kexin-9 (PCSK-9), the posttranslational regulator of LDL-receptor, is associated with elevated LDL in the circulation, the present report was aimed to uncover the ameliorative effects of Ginkgolide B, a terpenic lactone from Ginkgo biloba, against Ox-LDL-induced alterations in cholesterol metabolism in HUVECs. Consequently, our results demonstrated that incubation with Ox-LDL significantly upregulated the PCSK-9 expression in HUVECs, which was significantly downregulated, both at mRNA and protein level, after Ginkgolide B treatment via subsequent suppression of sterol element binding protein (SREBP-2) expression. Moreover, Ginkgolide B-mediated inhibition of PCSK-9 activity was also validated by in silico methods which revealed that it interferes the PSCK-9 interaction with LDL-receptor (LDL-R). Interestingly, Ox-LDL-induced LDL-R expression was further enhanced by Ginkgolide B treatment in HUVECs. Moreover, Ginkgolide B treatment lead to downregulation of lectin-like Ox-LDL receptor (LOX-1) and NADPH oxidase (NOX-4) expression which was upregulated in Ox-LDL-treated HUVECs, along with the attenuation of mitochondrial ROS generation. Furthermore, Ginkgolide B significantly inhibited the augmented expression of intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1) in Ox-LDL-activated HUVECs. Ginkgolide B also significantly ameliorated the inflammatory response in Ox-LDL-activated HUVECs by suppressing the expression of IL-1α, IL-1ß, IL-6, CXCL-1, CXCL-2, and monocyte chemotactic protein (MCP-1), at mRNA and protein level. Our in vitro and in silico study established that Ginkgolide B alleviated the Ox-LDL-induced inflammatory cascades and altered lipid metabolism in HUVECs by suppressing the PCSK-9 and, thus, could be established as a treasured alternative therapeutic candidate in the atherosclerosis management.


Assuntos
Ginkgolídeos/uso terapêutico , Células Endoteliais da Veia Umbilical Humana/metabolismo , Inflamação/tratamento farmacológico , Lactonas/uso terapêutico , Metabolismo dos Lipídeos , Pró-Proteína Convertase 9/metabolismo , Atorvastatina/farmacologia , Moléculas de Adesão Celular/metabolismo , Colesterol/metabolismo , Citocinas/metabolismo , Regulação para Baixo/efeitos dos fármacos , Ginkgolídeos/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Lactonas/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipoproteínas LDL/metabolismo , NADPH Oxidase 4/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores de LDL/química , Receptores de LDL/metabolismo , Receptores Depuradores Classe E/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo
10.
Mol Med Rep ; 20(2): 1383-1392, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173243

RESUMO

Hypercholesterolemia is one of the major risk factors for the occurrence and development of atherosclerosis. The most common drugs used to treat hypercholesterolemia are 3­hydroxy­3­methyl­glutaryl­CoA reductase inhibitors, known as statins. Statins induce a beneficial increase in the levels of the low density lipoprotein receptor (LDLR) and additionally upregulate proprotein convertase subtilisin/kexin type 9 (PCSK9), which leads to LDLR degradation. This process causes a negative feedback response that attenuates the lipid lowering effects of statins. Therefore, the development of PCSK9 inhibitors may increase the lipid­lowering functions of statins. In the present study, a drug­screening assay was developed using the human PCSK9 promoter, based on data from a dual­luciferase reporter assay, and the efficacies of various compounds from Traditional Chinese Medicine were examined. Among the compounds examined, SIL was demonstrated to function by targeting PCSK9. It was identified that SIL treatment decreased the expression levels of PCSK9 in HepG2 cells by decreasing the activity of the PCSK9 promoter in a dose­and time­dependent manner. Notably, SIL antagonized the statin­induced phosphorylation of the p38 MAPK signaling pathway. The present study suggested that SIL may be developed as a novel PCSK9 inhibitor that may increase the efficiency of statin treatment.


Assuntos
Hepatoblastoma/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Neoplasias Hepáticas/metabolismo , Pró-Proteína Convertase 9/metabolismo , Silibina/farmacologia , Atorvastatina/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Hepatoblastoma/genética , Hepatoblastoma/patologia , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Fosforilação/efeitos dos fármacos , Regiões Promotoras Genéticas/genética , Pró-Proteína Convertase 9/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Silibina/química , Fatores de Tempo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
11.
High Blood Press Cardiovasc Prev ; 26(3): 199-207, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31236902

RESUMO

Proprotein convertase subtilisin/kexin type 9 (PCSK9)-related discoveries of the turn of the century have translated into substantial novelty in dyslipidemia treatment in the last 5 years. With chronic preventable atherosclerotic cardiovascular diseases (ASCVD) representing an epidemic of morbidity and mortality worldwide, low-density lipoprotein cholesterol (LDL-c) reduction represents a public health priority. By overcoming two major statin-related issues, namely intolerance and ineffectiveness, PCSK9 inhibitors have offered a safe and effective option in selected clinical settings where LDL-c reduction is required. Herein, we recapitulate recent findings, clinical applications, and ASCVD prevention potential of PCSK9 inhibition, with focus on anti-PCSK9 monoclonal antibodies, evolocumab and alirocumab.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Anticolesterolemiantes/uso terapêutico , Aterosclerose/prevenção & controle , LDL-Colesterol/sangue , Dislipidemias/tratamento farmacológico , Pró-Proteína Convertase 9/antagonistas & inibidores , Inibidores de Serino Proteinase/uso terapêutico , Animais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Anticolesterolemiantes/efeitos adversos , Aterosclerose/sangue , Aterosclerose/enzimologia , Aterosclerose/epidemiologia , Biomarcadores/sangue , Dislipidemias/sangue , Dislipidemias/enzimologia , Dislipidemias/epidemiologia , Humanos , Guias de Prática Clínica como Assunto , Pró-Proteína Convertase 9/metabolismo , Fatores de Risco , Inibidores de Serino Proteinase/efeitos adversos , Resultado do Tratamento
12.
Rev Cardiovasc Med ; 20(1): 1-8, 2019 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-31184090

RESUMO

Cardiovascular disease is the leading cause of morbidity and mortality globally, as estimated by the World Health Organization, where in 2016, 15.2 million deaths were attributed to ischemic heart disease and stroke. It is therefore essential to try to reduce the incidence of Cardiovascular disease by controlling modifiable risk factors. One such major modifiable risk factor is cholesterol, which influences the pathogenesis and progression of atherosclerosis. Statins are often prescribed to lower blood levels of low density lipoprotein cholesterol, thereby reducing the risk of Cardiovascular disease by approximately 25-35%. However, there is an increasing number of patients (in particular those with intolerance to statin therapy and those with familial hypercholesterolemia) for whom statin therapy alone is not enough to control low density lipoprotein cholesterol. In this review, the regulation of cholesterol metabolism will be discussed with an emphasis on novel cholesterol lowering drugs used in clinical trials. These second-generation drugs, monoclonal antibodies against the low density lipoprotein receptor gene known as proprotein convertase subtilisin/kexin type 9 inhibitors, are expected to be prescribed to patients who are intolerant to statins, as well as in conjunction with statins. Future perspectives of the clinical use of these drugs is also discussed.


Assuntos
Anticolesterolemiantes/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Colesterol/sangue , Dislipidemias/tratamento farmacológico , Pró-Proteína Convertase 9/antagonistas & inibidores , Inibidores de Serino Proteinase/uso terapêutico , Animais , Anticolesterolemiantes/efeitos adversos , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , Regulação para Baixo , Dislipidemias/sangue , Dislipidemias/enzimologia , Dislipidemias/epidemiologia , Humanos , Pró-Proteína Convertase 9/metabolismo , Fatores de Risco , Inibidores de Serino Proteinase/efeitos adversos , Resultado do Tratamento
13.
Hypertension ; 74(2): 323-330, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31177906

RESUMO

Dyslipidemia is common in chronic kidney disease (CKD). Despite statins, many patients fail to adequately lower lipids and remain at increased risk of cardiovascular disease. Selective ETA (endothelin-A) receptor antagonists reduce cardiovascular disease risk factors. Preclinical data suggest that ETA antagonism has beneficial effects on circulating lipids. We assessed the effects of selective ETA antagonism on circulating lipids and PCSK9 (proprotein convertase subtilisin/kexin type 9) in CKD. This was a secondary analysis of a fully randomized, double-blind, 3-phase crossover study. Twenty-seven subjects with predialysis CKD on optimal cardio- and renoprotective treatment were randomly assigned to receive 6 weeks dosing with placebo, the selective ETA receptor antagonist, sitaxentan, or long-acting nifedipine. We measured circulating lipids and PCSK9 at baseline and then after 3 and 6 weeks. Baseline lipids and PCSK9 did not differ before each study phase. Whereas placebo and nifedipine had no effect on lipids, 6 weeks of ETA antagonism significantly reduced total (-11±1%) and low-density lipoprotein-associated (-20±3%) cholesterol, lipoprotein (a) (-16±2%) and triglycerides (-20±4%); high-density lipoprotein-associated cholesterol increased (+14±2%), P<0.05 versus baseline for all. Additionally, ETA receptor antagonism, but neither placebo nor nifedipine, reduced circulating PCSK9 (-19±2%; P<0.001 versus baseline; P<0.05 versus nifedipine and placebo). These effects were independent of statin use and changes in blood pressure or proteinuria. Selective ETA antagonism improves lipid profiles in optimally-managed patients with CKD, effects that may occur through a reduction in circulating PCSK9. ETA receptor antagonism offers a potentially novel strategy to reduce cardiovascular disease risk in CKD. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT00810732.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Antagonistas do Receptor de Endotelina A/uso terapêutico , Nifedipino/administração & dosagem , Pró-Proteína Convertase 9/metabolismo , Insuficiência Renal Crônica/tratamento farmacológico , Adulto , Idoso , Análise de Variância , Doenças Cardiovasculares/etiologia , LDL-Colesterol/sangue , LDL-Colesterol/efeitos dos fármacos , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Seguimentos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Pessoa de Meia-Idade , Proteinúria/tratamento farmacológico , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/mortalidade , Medição de Risco , Resultado do Tratamento
14.
Adv Mater ; 31(33): e1902575, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31215123

RESUMO

A main challenge to broaden the biomedical application of CRISPR/Cas9 (clustered regularly interspaced short palindromic repeat (CRISPR) associated protein 9) genome editing technique is the delivery of Cas9 nuclease and single-guide RNA (sgRNA) into the specific cell and organ. An effective and very fast CRISPR/Cas9 genome editing in vitro and in vivo enabled by bioreducible lipid/Cas9 messenger RNA (mRNA) nanoparticle is reported. BAMEA-O16B, a lipid nanoparticle integrated with disulfide bonds, can efficiently deliver Cas9 mRNA and sgRNA into cells while releasing RNA in response to the reductive intracellular environment for genome editing as fast as 24 h post mRNA delivery. It is demonstrated that the simultaneous delivery of Cas9 mRNA and sgRNA using BAMEA-O16B knocks out green fluorescent protein (GFP) expression of human embryonic kidney cells with efficiency up to 90%. Moreover, the intravenous injection of BAMEA-O16B/Cas9 mRNA/sgRNA nanoparticle effectively accumulates in hepatocytes, and knocks down proprotein convertase subtilisin/kexin type 9 level in mouse serum down to 20% of nontreatment. The leading lipid nanoparticle, BAMEA-O16B, represents one of the most efficient CRISPR/Cas9 delivery nanocarriers reported so far, and it can broaden the therapeutic promise of mRNA and CRISPR/Cas9 technique further.


Assuntos
Proteína 9 Associada à CRISPR/genética , Edição de Genes/métodos , Lipídeos/química , Nanopartículas/química , RNA Guia/química , RNA Mensageiro/química , Animais , Transporte Biológico , Linhagem Celular Tumoral , Técnicas de Silenciamento de Genes/métodos , Técnicas de Transferência de Genes , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Camundongos , Oxirredução , Pró-Proteína Convertase 9/genética , Pró-Proteína Convertase 9/metabolismo , RNA Guia/administração & dosagem , RNA Mensageiro/administração & dosagem
15.
Eur J Pharmacol ; 855: 216-226, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31085239

RESUMO

Proprotein convertase subtilisin kexin type 9 (PCSK9) is a promising target for treating dyslipidemia and atherosclerosis. Circulating PCSK9 levels are closely related to hepatic steatosis severity and endogenous estrogen levels. Resveratrol (RSV) is a phytoestrogens that protects against atherosclerosis and hepatic steatosis. Thus, we sought to determine whether RSV had the activities to inhibit PCSK9 expression and to attenuate lipid accumulation in free fatty acid (FFA)-induced L02 cells via ERα pathway. In this study, RSV (10, 20 µM) were cultured with L02 cells in the presence of FFA (oleate:palmitate = 2:1). RSV significantly reduced the number of lipid droplets and intracellular TG in steatotic L02 cells, and Oil red O staining and Nile red staining had the same results. Western blot analysis showed that RSV significantly reduced apoB secretion and intracellular microsomal triglyceride transporter (MTP) expression under lipid-rich conditions. Treatment with RSV reduced expression of PCSK9 while maintaining LDL receptor (LDLR) expression and LDL uptake. RSV decreased SREBP-1c expression at both mRNA and protein levels. In addition, RSV significantly reduced the expression of liver X receptor α (LXRα) mRNA in L02 cells, but did not affect the expression of liver X receptor ß (LXRß) mRNA. The luciferase reporter assays suggested that RSV inhibited SREBP-mediated transcription of PCSK9. Finally, these results could be partly reversed by Estrogen receptor α (ERα) gene silencing. These results suggest that RSV attenuates steatosis and PCSK9 expression through down-regulation of SREBP-1c expression, at least in part through ERα-mediated pathway.


Assuntos
Regulação para Baixo/efeitos dos fármacos , Receptor alfa de Estrogênio/metabolismo , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Pró-Proteína Convertase 9/metabolismo , Resveratrol/farmacologia , Linhagem Celular , Ácidos Graxos não Esterificados/farmacologia , Fígado Gorduroso/patologia , Humanos , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Pró-Proteína Convertase 9/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de LDL/genética , Receptores de LDL/metabolismo , Resveratrol/uso terapêutico , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Triglicerídeos/metabolismo
16.
Food Funct ; 10(6): 3127-3134, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31140506

RESUMO

Cholesterol uptake and chylomicron synthesis are promoted by increasing glucose concentrations in both healthy and diabetic individuals during the postprandial phase. The goal of this study was to test whether acute inhibition of glucose uptake could impact cholesterol absorption in differentiated human intestinal Caco-2 cells. As expected, high glucose upregulated intestinal cholesterol metabolism promoting its uptake and incorporation in lipoproteins. This was accompanied by an increase in the gene expression of Niemann-Pick C1 Like 1 and proprotein convertase subtillisin/kexin type 9. Cholesterol uptake was attenuated by acute inhibition of glucose absorption by cytochalasin B, by a chamomile extract and by one of its main constituent polyphenols, apigenin 7-O-glucoside; however, chylomicron secretion was only reduced by the chamomile extract. These data support a potential indirect role for bioactives in modulating intestinal lipid pathways through effects on intestinal glucose uptake. This working hypothesis warrants further testing in an in vivo setting such as in hypercholesterolaemic or prediabetic individuals.


Assuntos
Colesterol/metabolismo , Glucose/metabolismo , Mucosa Intestinal/metabolismo , Polifenóis/metabolismo , Transporte Biológico , Células CACO-2 , Humanos , Lipoproteínas/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Pró-Proteína Convertase 9/genética , Pró-Proteína Convertase 9/metabolismo
17.
Clin Investig Arterioscler ; 31(3): 128-139, 2019.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-31130361

RESUMO

A group of experts convened by the Spanish Society of Arteriosclerosis (SEA) has been in charge of updating the SEA document on the indications of PCSK9 inhibitors (PCSK9i) in clinical practice that was published in 2016. This update is justified by the fact that the data from clinical trials carried out on a large scale with PCSK9i have shown that in addition to their high potency to lower atherogenic cholesterol, they reduce the risk of atherosclerotic cardiovascular disease, both in patients with stable disease, and with recent disease, and with a high degree of security. This update provides the recommendations and level of evidence for the prescription of iPCSK9 in patients with homozygous and heterozygous familial hypercholesterolemia, with atherosclerotic cardiovascular disease, and in primary prevention in patients with very high cardiovascular risk. These recommendations have been established taking into account the concentration of LDL-C, the clinical situation of the patient, the additional risk factors and the cost-effectiveness of their use.


Assuntos
Aterosclerose/tratamento farmacológico , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Pró-Proteína Convertase 9/antagonistas & inibidores , Anticolesterolemiantes/economia , Anticolesterolemiantes/farmacologia , Aterosclerose/fisiopatologia , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/prevenção & controle , LDL-Colesterol/sangue , Análise Custo-Benefício , Humanos , Hiperlipoproteinemia Tipo II/fisiopatologia , Pró-Proteína Convertase 9/metabolismo , Fatores de Risco
19.
Neurología (Barc., Ed. impr.) ; 34(3): 198-203, abr. 2019. tab
Artigo em Espanhol | IBECS | ID: ibc-180783

RESUMO

Introducción: La proproteína convertasa subtilisina kexina tipo 9 (PCSK9) desempeña un papel importante en la modulación de los niveles plasmáticos de colesterol unido a las lipoproteínas de baja densidad (LDLC). La PCSK9 se une al receptor del LDLC (LDL[R]) perturba su reciclado endocítico y lo dirige a la degradación lisosomal. Por tanto, la activación de PCSK9 disminuye la expresión de los LDL(R) a nivel hepático e inhibe la captación de LDLC, lo que provoca hipercolesterolemia. Desarrollo: Hoy se sabe que diferentes polimorfismos de la PCSK9 se asocian a la aparición de ictus isquémico. Por otra parte, los fármacos inhibidores de PCSK9 inhiben la unión de PCSK9 con el LDL(R) y evitan la degradación del LDL(R) por lo que aumentan la captación hepática de LDLC, disminuyendo sus niveles en sangre. Diferentes estudios con anticuerpos monoclonales en fase 2 y 3 como el OSLER y el ODYSSEY LONG TERM han demostrado la eficacia y seguridad de los nuevos anticuerpos monoclonales contra PCSK9 como el evolucumab y alirocumab, y los primeros análisis exploratorios ya evidencian su eficacia en la disminución de eventos vasculares, incluidos los ictus. Conclusiones: Aunque el número de ictus recogidos en estos estudios ha sido bajo, en la actualidad existen varios ensayos centrados en resultados cardiovasculares en curso con evolocumab (estudio FOURIER), con alirocumab (estudio ODYSSEY OUTCOMES) y con bococizumab (estudios SPIRE-1 y SPIRE-2) que nos desvelarán el auténtico potencial de estos fármacos en la enfermedad cardiovascular y, en particular, en la prevención del ictus


Introduction: Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in the modulation of plasma levels of low density lipoprotein cholesterol (LDLC). PCSK9 binds to the LDL receptor (LDLR), disrupts its endocytic recycling itinerary and directs it to lysosomal degradation. Activation of PCSK9 can thus decrease the expression of LDLR in the liver and inhibit LDL uptake, which leads to hypercholesterolaemia. Development: Currently we now know that different polymorphisms of PCSK9 are associated with the occurrence of ischaemic stroke. On the other hand, PCSK9 inhibitors prevent binding of PCSK9 to LDLR and inhibit degradation of LDLR, which results in increased hepatic uptake of LDL and lower LDL levels in blood. Different phase 2 and 3 studies, including OSLER and ODYSSEY LONG-TERM, have demonstrated the efficacy and safety of the new monoclonal antibodies against PCSK9 such as evolucumab and alirocumab, and the first exploratory analyses have shown evidence of their efficacy in decreasing vascular events, including stroke. Conclusions: Although few strokes have been reported by these studies, new ongoing trials examining the cardiovascular effects of evolucumab (FOURIER study), alirocumab (ODYSSEY OUTCOMES study), and bococizumab (SPIRE-1 and SPIRE-2 studies) will reveal the true potential of these drugs, particularly for the prevention of stroke


Assuntos
Humanos , Pró-Proteína Convertase 9/metabolismo , Hipercolesterolemia/fisiopatologia , Anticorpos Monoclonais/uso terapêutico , Acidente Vascular Cerebral/fisiopatologia , Hipercolesterolemia/tratamento farmacológico , Acidente Vascular Cerebral/prevenção & controle , Anticolesterolemiantes/uso terapêutico
20.
Vascul Pharmacol ; 116: 8-15, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30910670

RESUMO

BACKGROUND: Proprotein convertase subtilisin-kexin type 9 inhibitors (PCSK9-I) reduce low-density lipoprotein (LDL) cholesterol in human studies. Previous studies suggest that PCSK9-I may also affect very-low-density lipoproteins (VLDL). We therefore studied VLDL size and composition in a "real-world" study population with the use of ß-quantification. SUBJECTS AND METHODS: 350 patients (62 ±â€¯11 years old, 58% men, 22% with diabetes mellitus) with different concomitant lipid lowering therapies, and in whom PCSK9-I treatment was indicated, received either evolocumab (140 mg) or alirocumab (75 or 150 mg). The major lipoprotein fractions were separated by ß-quantification and lipid and apolipoprotein compositions were determined before and 4 weeks after initiation of PCSK9-I treatment. RESULTS: After 4 weeks of PCSK9-I treatment, the ratio of triglycerides to apolipoprotein B in VLDL particles (VLDL-TG/apoB ratio) increased by 40% (p < .0001). VLDL-associated apolipoproteins E, CII, and CIII were reduced by 29.4%, 16.4%, and 12.4%, respectively (all p < .0001). CONCLUSION: PCSK9-I treatment increased VLDL size (estimated by an increased VLDL-TG/apoB ratio) and reduced VLDL-associated apolipoproteins in a heterogeneous "real-world" study-population, reflecting a higher clearance of small atherogenic VLDL remnant particles by PCSK9-I. This may potentially lower cardiovascular risk in clinical routine patients beyond low-density cholesterol (LDL-C) reduction.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Anticolesterolemiantes/uso terapêutico , Apolipoproteína B-100/sangue , Dislipidemias/tratamento farmacológico , Lipoproteínas VLDL/sangue , Pró-Proteína Convertase 9/antagonistas & inibidores , Inibidores de Serino Proteinase/uso terapêutico , Triglicerídeos/sangue , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Anticolesterolemiantes/efeitos adversos , Biomarcadores/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Regulação para Baixo , Quimioterapia Combinada , Dislipidemias/sangue , Dislipidemias/diagnóstico , Dislipidemias/enzimologia , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Tamanho da Partícula , Pró-Proteína Convertase 9/metabolismo , Estudos Prospectivos , Inibidores de Serino Proteinase/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
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