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1.
JAMA ; 323(7): 646-655, 2020 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-32068819

RESUMO

Importance: Preclinical and epidemiological studies indicate a potential chemopreventive role of statins in epithelial ovarian cancer risk. Objective: To evaluate the association of genetically proxied inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (ie, genetic variants related to lower function of HMG-CoA reductase, target of statins) with epithelial ovarian cancer among the general population and in BRCA1/2 mutation carriers. Design, Setting, and Participants: Single-nucleotide polymorphisms (SNPs) in HMGCR, NPC1L1, and PCSK9 associated with low-density lipoprotein (LDL) cholesterol in a genome-wide association study (GWAS) meta-analysis (N ≤196 475) were used to proxy therapeutic inhibition of HMG-CoA reductase, Niemann-Pick C1-Like 1 (NPC1L1) and proprotein convertase subtilisin/kexin type 9 (PCSK9), respectively. Summary statistics were obtained for these SNPs from a GWAS meta-analysis of case-control analyses of invasive epithelial ovarian cancer in the Ovarian Cancer Association Consortium (OCAC; N = 63 347) and from a GWAS meta-analysis of retrospective cohort analyses of epithelial ovarian cancer among BRCA1/2 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA; N = 31 448). Across the 2 consortia, participants were enrolled between 1973 and 2014 and followed up through 2015. OCAC participants came from 14 countries and CIMBA participants came from 25 countries. SNPs were combined into multi-allelic models and mendelian randomization estimates representing lifelong inhibition of targets were generated using inverse-variance weighted random-effects models. Exposures: Primary exposure was genetically proxied inhibition of HMG-CoA reductase and secondary exposures were genetically proxied inhibition of NPC1L1 and PCSK9 and genetically proxied circulating LDL cholesterol levels. Main Outcomes and Measures: Overall and histotype-specific invasive epithelial ovarian cancer (general population) and epithelial ovarian cancer (BRCA1/2 mutation carriers), measured as ovarian cancer odds (general population) and hazard ratio (BRCA1/2 mutation carriers). Results: The OCAC sample included 22 406 women with invasive epithelial ovarian cancer and 40 941 control individuals and the CIMBA sample included 3887 women with epithelial ovarian cancer and 27 561 control individuals. Median ages for the cohorts ranged from 41.5 to 59.0 years and all participants were of European ancestry. In the primary analysis, genetically proxied HMG-CoA reductase inhibition equivalent to a 1-mmol/L (38.7-mg/dL) reduction in LDL cholesterol was associated with lower odds of epithelial ovarian cancer (odds ratio [OR], 0.60 [95% CI, 0.43-0.83]; P = .002). In BRCA1/2 mutation carriers, genetically proxied HMG-CoA reductase inhibition was associated with lower ovarian cancer risk (hazard ratio, 0.69 [95% CI, 0.51-0.93]; P = .01). In secondary analyses, there were no significant associations of genetically proxied inhibition of NPC1L1 (OR, 0.97 [95% CI, 0.53-1.75]; P = .91), PCSK9 (OR, 0.98 [95% CI, 0.85-1.13]; P = .80), or circulating LDL cholesterol (OR, 0.98 [95% CI, 0.91-1.05]; P = .55) with epithelial ovarian cancer. Conclusions and Relevance: Genetically proxied inhibition of HMG-CoA reductase was significantly associated with lower odds of epithelial ovarian cancer. However, these findings do not indicate risk reduction from medications that inhibit HMG-CoA reductase; further research is needed to understand whether there is a similar association with such medications.


Assuntos
Carcinoma Epitelial do Ovário/prevenção & controle , Hidroximetilglutaril-CoA Redutases/genética , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Neoplasias Ovarianas/prevenção & controle , Polimorfismo de Nucleotídeo Único , Adulto , Carcinoma Epitelial do Ovário/genética , Estudos de Casos e Controles , LDL-Colesterol/sangue , Feminino , Genes BRCA1 , Genes BRCA2 , Humanos , Proteínas de Membrana Transportadoras/genética , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Mutação , Razão de Chances , Neoplasias Ovarianas/genética , Pró-Proteína Convertase 9/genética , Estudos Retrospectivos , Risco
3.
Vnitr Lek ; 65(12): 755-760, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32013517

RESUMO

New guidelines on dyslipidemia (DLP) related problems appear earlier than planned. Primarily in view of the results of science and large clinical studies, but also with regard to the advent of biological therapy (PCSK9-i) in many Euro-pean countries. Also, the “conventional” hypolipidemic therapy is generified and therefore cheaper, more af-fordable. The recommendations are based, as the preceding ones, on the principle of estimating the overall cardiovascular risk. The innovated SCORE tables are used for this, but more emphasis is placed on non-invasive dia-gnostics using imaging methods, be it carotid ultrasound or, in particular, non-contrast CT coronarography. Perhaps the most significant outcome is the reduction of LDL-cholesterol (LDL-C) target values to 1.4 mmol/l and a 50% reduction of baseline LDL-C in patients belonging to the highest risk groups, and in secondary prevention. Moreover, in the case of “extreme” risk the goal is to reduce LDL-C below 1 mmol/l. Essential to DLP therapy is statin treatment. Especially in patients with acute coronary syndrome and those in the highest risk categories, the maximum tolerated doses of statin should be used, if necessary in combination with ezetimibe. Where this maximum “routine” treatment is insufficient to achieve the target values, PCSK9-i therapy is indicated. However the recommendations do not by any means omit non-pharmacological therapy, quite the opposite, it is always emphasized as the first step of DLP therapy. Worthy of notice is the introduction of the term “atherosclerotic cardiovascular disease” - ASCVD, which replaces the older and less accurate CVD.


Assuntos
Anticolesterolemiantes , Doenças Cardiovasculares , Dislipidemias , Inibidores de Hidroximetilglutaril-CoA Redutases , Anticolesterolemiantes/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Dislipidemias/complicações , Dislipidemias/tratamento farmacológico , Ezetimiba , Humanos , Lipídeos , Pró-Proteína Convertase 9 , Fatores de Risco
4.
Endocr Pract ; 26(1): 107-139, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32022600

RESUMO

Abbreviations: A1C = hemoglobin A1C; AACE = American Association of Clinical Endocrinologists; ABCD = adiposity-based chronic disease; ACCORD = Action to Control Cardiovascular Risk in Diabetes; ACCORD BP = Action to Control Cardiovascular Risk in Diabetes Blood Pressure; ACE = American College of Endocrinology; ACEI = angiotensin-converting enzyme inhibitor; AGI = alpha-glucosidase inhibitor; apo B = apolipoprotein B; ARB = angiotensin II receptor blocker; ASCVD = atherosclerotic cardiovascular disease; BAS = bile acid sequestrant; BMI = body mass index; BP = blood pressure; CCB = calcium channel blocker; CGM = continuous glucose monitoring; CHD = coronary heart disease; CKD = chronic kidney disease; DKA = diabetic ketoacidosis; DPP4 = dipeptidyl peptidase 4; eGFR = estimated glomerular filtration rate; EPA = eicosapentaenoic acid; ER = extended release; FDA = Food and Drug Administration; GLP1 = glucagon-like peptide 1; HDL-C = high-density-lipoprotein cholesterol; HeFH = heterozygous familial hypercholesterolemia; LDL-C = low-density-lipoprotein cholesterol; LDL-P = low-density-lipoprotein particle; Look AHEAD = Look Action for Health in Diabetes; NPH = neutral protamine Hagedorn; OSA = obstructive sleep apnea; PCSK9 = proprotein convertase subtilisin-kexin type 9 serine protease; RCT = randomized controlled trial; SU = sulfonylurea; SGLT2 = sodium-glucose cotransporter 2; SMBG = self-monitoring of blood glucose; T2D = type 2 diabetes; TZD = thiazolidinedione.


Assuntos
Diabetes Mellitus Tipo 2 , Endocrinologistas , Algoritmos , Glicemia , Automonitorização da Glicemia , Consenso , Humanos , Pró-Proteína Convertase 9 , Estados Unidos
5.
Expert Opin Pharmacother ; 21(3): 353-363, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31893957

RESUMO

Introduction: Scientific evidence on subjects treated with statin or other lipid-lowering treatments has established that treatments aiming to lower low-density lipoprotein cholesterol (LDL-C) can reduce atherosclerosis. PCSK9 inhibitors (PCSK9-i), thanks to their efficacy in reducing LDL-C constitute a further step in the treatment of dyslipidemia and cardiovascular (CV) diseases.Areas covered: The purpose of this narrative review is to summarize the current knowledge of PCSK9-i, with particular regard to pharmacodynamic, pharmacokinetic, and clinical data on evolocumab and alirocumab.Expert opinion: PCSK9-I are effective in reducing atherosclerotic events through their significant LDL-C-lowering action similarly to statins. Furthermore, these drugs can be considered safe and well-tolerated. However, some controversies remain with regard to their efficacy in reducing mortality and the paucity of data on both pleiotropic effects and long-term safety of these drugs. However, future studies will focus on understanding the effects of very low cholesterol levels on health. At present, we know that the genetic model of PCSK9 deficiency is characterized by very low LDL-C levels without particular health problems. Yet, we do not know the effect of prolonged PCSK9 inhibition induced by antibody action during the lifetime of normal subjects.


Assuntos
Hipercolesterolemia/tratamento farmacológico , Pró-Proteína Convertase 9/antagonistas & inibidores , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticolesterolemiantes/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , LDL-Colesterol/sangue , Dislipidemias/tratamento farmacológico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Lipídeos/sangue
8.
High Blood Press Cardiovasc Prev ; 27(1): 1-8, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31925708

RESUMO

Lipids and endothelium are pivotal players on the scene of atherosclerosis and their interaction is crucial for the establishment of the pathological processes. The endothelium is not only the border of the arterial wall: it plays a key role in regulating circulating fatty acids and lipoproteins and vice versa it is regulated by these lipidic molecules thereby promoting atherosclerosis. Inflammation is another important element in the relationship between lipids and endothelium. Recently, proprotein convertase subtilisin/kexin type 9 (PCSK9) has been recognized as a fundamental regulator of LDL-C and anti-PCSK9 monoclonal antibodies have been approved for therapeutic use in hypercholesterolemia, with the promise to subvert the natural history of the disease. Moreover, growing experimental and clinical evidence is enlarging our understanding of the mechanisms through which this protein may facilitate the genesis of atherosclerosis, independently of its impact on lipid metabolism. In addition, environmental stimuli may affect the post-transcriptional regulation of genes through micro-RNAs, which in turn play a key role in orchestrating the crosstalk between endothelium and cholesterol. Advances in experimental research, with development of high throughput techniques, have led, over the last century, to a tremendous progress in the understanding and fine tuning of the molecular mechanisms leading to atherosclerosis. Identification of pivotal keystone molecules bridging lipid metabolism, endothelial dysfunction and atherogenesis will provide the mechanistic substrate to test valuable targets for prediction, prevention and treatment of atherosclerosis-related disease.


Assuntos
Aterosclerose/metabolismo , Colesterol/metabolismo , Dislipidemias/metabolismo , Endotélio Vascular/metabolismo , MicroRNAs/metabolismo , Pró-Proteína Convertase 9/metabolismo , Animais , Aterosclerose/enzimologia , Aterosclerose/genética , Biomarcadores/metabolismo , Dislipidemias/enzimologia , Dislipidemias/genética , Endotélio Vascular/enzimologia , Endotélio Vascular/patologia , Regulação da Expressão Gênica , Humanos , Mediadores da Inflamação/metabolismo , MicroRNAs/genética , Placa Aterosclerótica , Transdução de Sinais
9.
Curr Cardiol Rep ; 22(3): 13, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31997026

RESUMO

The PAD population is at increased risk of major adverse cardiovascular events (MACE) and major adverse limb events (MALE). Risk factor modification, symptom control, antithrombotic, and lipid therapies are the mainstays of PAD medical therapy. Recent data has challenged prior recommendations regarding the optimal secondary prevention strategies in PAD. PURPOSE OF REVIEW: To review clinical evidence from large randomized controlled trials showing the benefit of antithrombotic and lipid therapy in the PAD population. RECENT FINDINGS: The COMPASS trial challenged prior recommendations regarding anticoagulation in PAD. Among the PAD subgroup, rivaroxaban 2.5 mg plus aspirin reduced MACE (HR 0.72, 95% CI 0.57-0.90, p = 0.0047), MALE (HR 0.54, 95% CI 0.35-0.82, p = 0.0037), and major amputation (HR 0.30, 95% CI 0.11-0.80, p = 0.011) compared with aspirin monotherapy. The THEMIS trial showed a 55% risk reduction for MALE with ticagrelor DAPT compared with aspirin monotherapy (HR 0.45, 95% CI 0.23-0.86). The FOURIER trial revealed that lowering LDL cholesterol below current targets with a PCSK9 inhibitor reduced MACE (HR 0.73, 95% CI 0.59-0.91, p = 0.0040) and MALE (HR 0.43, 95% CI 0.19-0.99, p = 0.042) in subjects with symptomatic PAD. Recent high-quality evidence shows the benefit of antiplatelet therapy, anticoagulation therapy, and lipid therapy in reducing MACE and MALE in PAD. Despite these findings, implementation remains a challenge and focus should now shift towards adopting evidence-based recommendations in clinical practice.


Assuntos
Fibrinolíticos/uso terapêutico , Doença Arterial Periférica/tratamento farmacológico , Inibidores da Agregação de Plaquetas/uso terapêutico , Humanos , Doença Arterial Periférica/sangue , Doença Arterial Periférica/diagnóstico , Pró-Proteína Convertase 9 , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Resultado do Tratamento
10.
J Stroke Cerebrovasc Dis ; 29(1): 104457, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31732461

RESUMO

BACKGROUND: Protein convertase subtilisin-kexin type 9 (PCSK9) inhibitors effectively clear low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C). We evaluated stroke admissions potentially eligible for more intensive cholesterol treatment. METHODS: Retrospective analysis of consecutive admissions to a hyperacute stroke unit over 5 months in 2017. Records were individually searched. Data were collected on diagnosis, risk factors, and stroke work-up. European Society of Cardiology and European Atherosclerosis Society guidelines for the management of dyslipidaemias were used for screening patients eligible for PCSK9 inhibitors. RESULTS: Of 650 patient admissions: 351 (54%) had acute ischemic stroke or transient ischemic attack (TIA), 80 (12%) hemorrhage, and 219 (34%) mimic syndromes. Patients with hemorrhage (n = 80), mimic syndromes (n = 219), and absent LDL-C, or non-HDL-C testing (n = 27) were subsequently excluded. 324 patients with acute ischemic stroke and TIA were further screened for PCSK9-inhibitor treatment eligibility. Forty-one (13%) patients with LDL-C greater than or equal to 1.8mmol/L (≥70 mg/dL) on maximal tolerated statin dose and with concomitant "very high vascular risk" were identified. "Very high vascular risk" was defined as a documented history of cardiovascular disease and/or peripheral arterial disease. Of 41 patients eligible for PCSK9 inhibitors, median age was 82 years (range 53-96); median vascular risk factors were 2 (range 1-5); 7 (17%) had TIA; 13 (31%) had history of preceding cerebrovascular events, 13 (31%) diabetes mellitus, 17 (42%) cardioembolic events, 9 (22%) lacunar syndrome, 11 (22%) symptomatic internal carotid artery stenosis (n = 9 were >70%), and 4 (10%) undetermined aetiology. Eighty-three percent patients eligible for PCSK9 inhibitors also had non-HDL-C values greater than or equal to 2.6 mmol/L. CONCLUSIONS: Up to 13% of unselected acute ischemic stroke or TIA patients admitted to a hyper-acute stroke unit were potentially suitable for more intensive cholesterol treatment. Our data may act as a useful guide for sample size selection in future stroke trials testing PCSK9 inhibitors.


Assuntos
Anticolesterolemiantes/uso terapêutico , LDL-Colesterol/sangue , Dislipidemias/tratamento farmacológico , Definição da Elegibilidade , Ataque Isquêmico Transitório/terapia , Pró-Proteína Convertase 9/antagonistas & inibidores , Inibidores de Serino Proteinase/uso terapêutico , Acidente Vascular Cerebral/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticolesterolemiantes/efeitos adversos , Biomarcadores/sangue , Dislipidemias/complicações , Dislipidemias/diagnóstico , Dislipidemias/enzimologia , Feminino , Humanos , Ataque Isquêmico Transitório/complicações , Ataque Isquêmico Transitório/diagnóstico , Masculino , Pessoa de Meia-Idade , Admissão do Paciente , Seleção de Pacientes , Pró-Proteína Convertase 9/metabolismo , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Inibidores de Serino Proteinase/efeitos adversos , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/diagnóstico , Adulto Jovem
13.
Curr Med Chem ; 27(2): 317-333, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-29865996

RESUMO

BACKGROUND: The Low-Density Lipoprotein (LDL) Receptor (LDL-R) is a transmembrane protein playing a crucial role in effective lipid homeostasis. Various therapeutic agents have been used in the management of dyslipidemias, however, the outcome of therapeutic target is debated. OBJECTIVE: The aim of this review is to summarize and fully understand the current concept regarding LDL-R and its molecular properties, metabolic pathway, factors affecting LDL-R activity and all available pharmacological interventions. Additionally, non-lipid related properties of LDL-R are also referred. METHODS: Literature from the PubMed database was extracted to identify papers between 1984 to 2017 regarding LDL-R and therapeutic agents on dyslipidemia management. RESULTS: We analyzed basic data regarding agents associated with LDL-R (Sterol Regulating Element-Binding Proteins - SREBPs, Protein ARH, IDOL, Thyroid Hormones, Haematologic Disorders, Protein convertase subtilisin kexintype 9 - PCSK-9, ApoC-III) as well as non-lipid related properties of LDL-R, while all relevant (common and novel) pharmacological interventions (statins, fibrates, cholesterol absorption inhibitors, bile acid sequestrants and PCSK- 9) are also referred. CONCLUSION: LDL-R and its molecular properties are involved in lipid homeostasis, so potentially sets the therapeutic goals in cardiovascular patients, which is usually debated. Further research is needed in order to fully understand its properties, as well as to find the potential pharmacological interventions that could be beneficial in cholesterol homeostasis and various morbidities in order to reach the most appropriate therapeutic goal.


Assuntos
Lipoproteínas LDL/metabolismo , Colesterol , Dislipidemias , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases , Hipolipemiantes , Pró-Proteína Convertase 9
15.
Clín. investig. arterioscler. (Ed. impr.) ; 31(6): 278-281, nov.-dic. 2019. graf
Artigo em Espanhol | IBECS | ID: ibc-185154

RESUMO

Las estatinas están contraindicadas en pacientes con miopatías. Hasta hace unos años, la alternativa en pacientes con hipercolesterolemia familiar que tenían distrofias musculares y no conseguían niveles adecuados de colesterol era la lipoaféresis. Cuando surgieron los inhibidores de PCSK9, se consiguió suspender la lipoaféresis en algunos de estos pacientes y mantenerlos con concentraciones plasmáticas de colesterol adecuadas. Presentamos el caso de un varón, diagnosticado en la infancia de distrofia muscular congénita. A los 27 años se remitió a la unidad de lípidos por hipercolesterolemia, donde tras estudio genético se confirmó una hipercolesterolemia familiar heterocigota. A pesar del tratamiento con dieta y ezetimiba continuó con cifras elevadas de cLDL por lo que se incluyó en programa de lipoaféresis. Con esto se alcanzaron niveles de cLDL de 70 mg/dl. Al disponer de los iPCSK9, se suspendió la lipoaféresis y se inició tratamiento con alirocumab 150 mg quincenal, con buena respuesta y manteniendo valores de cLDL en torno a 75 mg/dl


Statins are contraindicated in patients with myopathies. Until a few years ago, in those patients with Familial Hypercholesterolemia who also presented muscular dystrophies and didńt reach adequate cholesterol plasmatic levels, the next therapeutic ladder was lipoapheresis. When iPCSK9 first appeared, lipoapheresis could be suspended in some of these patients, sustaining nevertheless proper levels of cholesterol. We present the case of a 27 year-old male, diagnosed with Congenital Muscular Dystrophy in the early childhood. He was referred to the Unit of Lipidology presenting hypercholesterolemia which, after genetic test, was assessed as Heterozygous Familial Hypercholesterolemia. Despite of treatment with diet and ezetimibe, cLDL blood levels abide high, being consequently included in lipoapheresis programme, therewith obtained levels of cLDL of 70 mg/dl. In providing iPCSK9, lipoapheresis was withdrawn and treatment with alirocumab 150 mg fortnightly introduced, unveiling a positive response, and sustaining cLDL levels around 75 mg/dl


Assuntos
Humanos , Masculino , Adulto , Pró-Proteína Convertase 9/administração & dosagem , Hipercolesterolemia/tratamento farmacológico , Distrofias Musculares/diagnóstico , Contraindicações de Medicamentos , Distrofias Musculares/complicações , Distrofias Musculares/congênito , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Hipotonia Muscular/complicações
16.
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
17.
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
18.
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
19.
Nat Commun ; 10(1): 4897, 2019 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-31653860

RESUMO

Rare genetic disorders (RGDs) often exhibit significant clinical variability among affected individuals, a disease characteristic termed variable expressivity. Recently, the aggregate effect of common variation, quantified as polygenic scores (PGSs), has emerged as an effective tool for predictions of disease risk and trait variation in the general population. Here, we measure the effect of PGSs on 11 RGDs including four sex-chromosome aneuploidies (47,XXX; 47,XXY; 47,XYY; 45,X) that affect height; two copy-number variant (CNV) disorders (16p11.2 deletions and duplications) and a Mendelian disease (melanocortin 4 receptor deficiency (MC4R)) that affect BMI; and two Mendelian diseases affecting cholesterol: familial hypercholesterolemia (FH; LDLR and APOB) and familial hypobetalipoproteinemia (FHBL; PCSK9 and APOB). Our results demonstrate that common, polygenic factors of relevant complex traits frequently contribute to variable expressivity of RGDs and that PGSs may be a useful metric for predicting clinical severity in affected individuals and for risk stratification.


Assuntos
Estatura/genética , Índice de Massa Corporal , LDL-Colesterol/sangue , Herança Multifatorial , Obesidade/genética , Doenças Raras/genética , Apolipoproteínas B/genética , Transtorno Autístico/genética , LDL-Colesterol/genética , Deleção Cromossômica , Transtornos Cromossômicos/genética , Duplicação Cromossômica/genética , Cromossomos Humanos Par 16/genética , Cromossomos Humanos X/genética , Feminino , Humanos , Hiperlipoproteinemia Tipo II/genética , Hipobetalipoproteinemias/genética , Deficiência Intelectual/genética , Síndrome de Klinefelter/genética , Masculino , Pessoa de Meia-Idade , Pró-Proteína Convertase 9/genética , Receptor Tipo 4 de Melanocortina/deficiência , Receptor Tipo 4 de Melanocortina/genética , Receptores de LDL/genética , Aberrações dos Cromossomos Sexuais , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual/genética , Trissomia/genética , Síndrome de Turner/genética , Cariótipo XYY/genética
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