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1.
Anticancer Res ; 40(7): 4137-4145, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620663

RESUMO

BACKGROUND/AIM: Lung diseases are common in patients with abdominal aortic aneurysms (AAA). This study evaluates the prevalence of lung cancer (LC) in high-risk patients screened for AAA. PATIENTS AND METHODS: Six hundred and one male patients (≥65 years of age, cardiovascular high-risk profile) were enrolled and followed prospectively over a median of 16.5 months. RESULTS: In 29 patients (4.8%) LC and in another 50 patients (8.3%) AAA were found. The prevalence of LC among patients with AAA was even higher (9 of 50, 18.0%). Twenty-one patients had an initial diagnosis of LC, with an incidence of 12.0% (6 of 50) in patients with AAA. During follow-up, 14 of 70 patients with AAA and/ or LC (20.0%) deceased. The highest mortality was found in patients with LC only (8 of 20, 40.0%), followed by patients with both AAA and LC (3 of 9, 33.3%), while patients with AAA only had the lowest mortality rate (3 of 41, 7.3%). CONCLUSION: In patients with a high cardiovascular risk profile, a high prevalence of both AAA and LC were found, whereby the prognosis is largely determined by the LC. Therefore, LC is of particular importance in the setting of screening and surveillance of AAA.


Assuntos
Aneurisma da Aorta Abdominal/epidemiologia , Neoplasias Pulmonares/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Comorbidade , Diabetes Mellitus/epidemiologia , Humanos , Hipercolesterolemia/epidemiologia , Hipertensão/epidemiologia , Incidência , Masculino , Programas de Rastreamento , Prevalência , Prognóstico , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Fatores de Risco , Fumar/epidemiologia
2.
Nature ; 582(7810): 73-77, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32494083

RESUMO

High blood cholesterol is typically considered a feature of wealthy western countries1,2. However, dietary and behavioural determinants of blood cholesterol are changing rapidly throughout the world3 and countries are using lipid-lowering medications at varying rates. These changes can have distinct effects on the levels of high-density lipoprotein (HDL) cholesterol and non-HDL cholesterol, which have different effects on human health4,5. However, the trends of HDL and non-HDL cholesterol levels over time have not been previously reported in a global analysis. Here we pooled 1,127 population-based studies that measured blood lipids in 102.6 million individuals aged 18 years and older to estimate trends from 1980 to 2018 in mean total, non-HDL and HDL cholesterol levels for 200 countries. Globally, there was little change in total or non-HDL cholesterol from 1980 to 2018. This was a net effect of increases in low- and middle-income countries, especially in east and southeast Asia, and decreases in high-income western countries, especially those in northwestern Europe, and in central and eastern Europe. As a result, countries with the highest level of non-HDL cholesterol-which is a marker of cardiovascular risk-changed from those in western Europe such as Belgium, Finland, Greenland, Iceland, Norway, Sweden, Switzerland and Malta in 1980 to those in Asia and the Pacific, such as Tokelau, Malaysia, The Philippines and Thailand. In 2017, high non-HDL cholesterol was responsible for an estimated 3.9 million (95% credible interval 3.7 million-4.2 million) worldwide deaths, half of which occurred in east, southeast and south Asia. The global repositioning of lipid-related risk, with non-optimal cholesterol shifting from a distinct feature of high-income countries in northwestern Europe, north America and Australasia to one that affects countries in east and southeast Asia and Oceania should motivate the use of population-based policies and personal interventions to improve nutrition and enhance access to treatment throughout the world.


Assuntos
LDL-Colesterol/sangue , Hipercolesterolemia/sangue , Hipercolesterolemia/epidemiologia , Internacionalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Teorema de Bayes , HDL-Colesterol/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/sangue , Isquemia Miocárdica/epidemiologia , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/epidemiologia , Triglicerídeos/sangue , Adulto Jovem
3.
Am Heart J ; 225: 88-96, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32485329

RESUMO

Intensive lipid management is critical to reduce cardiovascular (CV) risk for patients with diabetes mellitus (DM). METHODS: We performed an observational study of 7628 patients with (n = 2943) and without DM (n = 4685), enrolled in the Provider Assessment of Lipid Management (PALM) registry and treated at 140 outpatient clinics across the United States in 2015. Patient self-estimated CV risk, patient-perceived statin benefit and risk, observed statin therapy use and dosing were assessed. RESULTS: Patients with DM were more likely to believe that their CV risk was elevated compared with patients without DM (39.1% vs 29.3%, P < .001). Patients with DM were more likely to receive a statin (74.2% vs 63.5%, P < .001) but less likely to be treated with guideline-recommended statin intensity (36.5% vs 46.9%, P < .001), driven by the low proportion (16.5%) of high risk (ASCVD risk ≥7.5%) primary prevention DM patients treated with a high intensity statin. Patients with DM treated with guideline-recommended statin intensity were more likely to believe they were at high CV risk (44.9% vs 38.4%, P = .005) and that statins can reduce this risk (41.1% vs 35.6%, P = .02), compared with patients treated with lower than guideline-recommended statin intensity. Compared with patients with an elevated HgbA1c, patients with well-controlled DM were no more likely to be on a statin (77.9% vs 79.3%, P = .43). CONCLUSIONS: In this nationwide study, the majority of patients with DM were treated with lower than guideline-recommended statin intensity. Patient education and engagement may help providers improve lipid therapy for these high-risk patients.


Assuntos
Atitude Frente a Saúde , Complicações do Diabetes/tratamento farmacológico , Diabetes Mellitus , Fidelidade a Diretrizes , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Idoso , Doenças Cardiovasculares/prevenção & controle , Colesterol/sangue , Diabetes Mellitus/sangue , Feminino , Hemoglobina A Glicada/análise , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Masculino , Pessoa de Meia-Idade , Guias de Prática Clínica como Assunto , Sistema de Registros , Fatores de Risco , Estados Unidos
4.
Life Sci ; 254: 117756, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32389832

RESUMO

Polydatin (PD) is a monocrystalline metabolite from the underground parts of Polygonum cuspidatum Sieb. et Zucc., a member of the Polygonaceae family, which has been traditionally used in Asian countries as both foodstuffs and medicine. PD, also reckoned as pieceid, 3,4',5-trihydroxystilbene-3-ß-D-glucoside, (E)-piceid, (E)-polydatin, and trans-polydatin. It possesses potent biological activities i.e. analgesic, anti-inflammatory, antidiabetic, anticancer, and anti-atherosclerotic properties. The initial part of this report specifically explains distinct sequential mechanisms underlying the initiation and development of atherosclerotic plaques and later part deals with the pharmacological efficacy of PD in the management of major cardiac event i.e. atherosclerotic cardiovascular diseases (ASCVD) via modulation of a set of molecular mechanisms i.e. antioxidant potential, lipid and lipoprotein metabolism including total cholesterol (TC) and low density lipoprotein (LDL) levels, ß-hydroxy-ß-methyl-glutaryl-CoA reductase (HMG-R) expression and functionality, SIRT signalling, LDL-receptor (LDL-R), LDL oxidation status (Ox-LDL), effects on endothelial cells (ECs), smooth muscle cells (SMCs), macrophage, foam cell formation and plaque stabilization, inflammatory signalling pathways and hypertension. In contrast, one of the major insight into the potential cardioprotective molecular mechanism is the PD-mediated targeting of proprotein convertase subtilisin/kexin type-9 (PCSK-9) and LDL-R pathway, both at transcriptional and protein functional level, which makes it a better alternative therapeutic medicinal candidate to treat hypercholesterolemia, especially for the patients facing inadequate lipid lowering with classical HMG-R inhibitors (statins) and statin intolerance. Finally, to sum up the whole, we concluded that PD may be promoted from alternative to mainstream medicine in targeting risk factors mediated ASCVD.


Assuntos
Aterosclerose/tratamento farmacológico , Glucosídeos/farmacologia , Estilbenos/farmacologia , Anticolesterolemiantes/uso terapêutico , LDL-Colesterol/metabolismo , Células Endoteliais/metabolismo , Fallopia japonica/metabolismo , Glucosídeos/uso terapêutico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Hiperlipidemias/tratamento farmacológico , Lipoproteínas LDL , Placa Aterosclerótica/tratamento farmacológico , Receptores de LDL/metabolismo , Fatores de Risco , Estilbenos/uso terapêutico
5.
Clin Immunol ; 215: 108450, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32360516

RESUMO

Acute respiratory distress syndrome (ARDS) is a devastating clinical manifestation of COVID-19 pneumonia and is mainly based on an immune-driven pathology. Mounting evidence suggests that COVID-19 is fueled by a maladaptive host inflammatory response that involves excessive activation of innate immune pathways. While a "cytokine storm" involving IL-6 and other cytokines has been documented, complement C3 activation has been implicated as an initial effector mechanism that exacerbates lung injury in preclinical models of SARS-CoV infection. C3-targeted intervention may provide broader therapeutic control of complement-mediated inflammatory damage in COVID-19 patients. Herein, we report the clinical course of a patient with severe ARDS due to COVID-19 pneumonia who was safely and successfully treated with the compstatin-based complement C3 inhibitor AMY-101.


Assuntos
Betacoronavirus/efeitos dos fármacos , Ativação do Complemento/efeitos dos fármacos , Complemento C3/antagonistas & inibidores , Inativadores do Complemento/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Peptídeos Cíclicos/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Idoso , Antivirais/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/imunologia , Fibrilação Atrial/patologia , Fibrilação Atrial/virologia , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Humanos , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/imunologia , Hipercolesterolemia/patologia , Hipercolesterolemia/virologia , Hipertensão/tratamento farmacológico , Hipertensão/imunologia , Hipertensão/patologia , Hipertensão/virologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Masculino , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Resultado do Tratamento
6.
Rev Med Liege ; 75(4): 260-264, 2020 Apr.
Artigo em Francês | MEDLINE | ID: mdl-32267116

RESUMO

LDL cholesterol targets are increasingly strict in recent international guidelines, especially in patients at very high or high cardiovascular risk. To reach these targets, it is recommended to use a potent statin, with a titration up to the maximal tolerated dose and, if not sufficient, to combine ezetimibe, a medication that blocks the intestinal absorption of cholesterol. This association allows reduce the dose of statin, while keeping an excellent cholesterol-lowering efficacy and favouring a good tolerance profile. This article describes the characteristics of a fixed-dose combination of rosuvastatin, the most potent statin, and ezetimibe, commercialized in Belgium under the trade name Myrosor®.


Assuntos
Anticolesterolemiantes , Ezetimiba , Inibidores de Hidroximetilglutaril-CoA Redutases , Hipercolesterolemia , Rosuvastatina Cálcica , Anticolesterolemiantes/administração & dosagem , Bélgica , LDL-Colesterol , Quimioterapia Combinada , Ezetimiba/administração & dosagem , Humanos , Hipercolesterolemia/tratamento farmacológico , Rosuvastatina Cálcica/administração & dosagem , Resultado do Tratamento
7.
PLoS One ; 15(4): e0231506, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32298312

RESUMO

Hypercholesterolaemia is considered an important cause of atherosclerotic cardiovascular disease. In a previous investigation, we demonstrated that cultured hepatoma cells treated with hypercholesterolaemic sera compared with cells treated with normocholesterolaemic sera show overexpression of mRNAs related to mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase (HMGCS2). In the present work, using an NMR metabolomic analysis, we demonstrate that the hypercholesterolaemic blood sera previously used to treat cultured hepatoma cells are characterized by a metabolomic profile that is significantly different from the normocholesterolaemic sera. Acetate, acetone, 2-hydroxybutyrate, cysteine, valine, and glutamine are the metabolites distinguishing the two groups. Abnormalities in the concentrations of these metabolites reflect alterations in energy-related pathways, such as pantothenate and CoA biosynthesis, pyruvate, glycolysis/gluconeogenesis, the citrate cycle, and ketone bodies. Regarding ketone bodies, the pathway is regulated by HMGCS2; therefore, serum samples previously found to be able to increase HMGCS2 mRNA levels in cultured cells also contain higher amounts of the metabolites of its encoded enzyme protein product.


Assuntos
Hipercolesterolemia/sangue , Metabolômica , Adulto , Carcinoma Hepatocelular/metabolismo , Estudos de Casos e Controles , Linhagem Celular Tumoral , Expressão Gênica/fisiologia , Humanos , Hidroximetilglutaril-CoA Sintase/metabolismo , Hipercolesterolemia/metabolismo , Neoplasias Hepáticas/metabolismo , Espectroscopia de Ressonância Magnética , Masculino , Redes e Vias Metabólicas , Pessoa de Meia-Idade
8.
PLoS One ; 15(4): e0231209, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32251440

RESUMO

As survival of acute lymphoblastic leukemia (ALL) exceeds 90%, limiting therapy-related toxicity has become a key challenge. Cardio-metabolic dysfunction is a challenge during and after childhood ALL therapy. In a single center study, we measured triglycerides (TG), total cholesterol (TC), high (HDL) and low density lipoproteins (LDL) levels at diagnosis and assessed the association with BMI, early therapy response, on-therapy hyperlipidemia and the toxicities; thromboembolism, osteonecrosis and pancreatitis. We included 127 children (1.0-17.9 years) all treated according to the NOPHO ALL2008 protocol. Dyslipidemia was identified at ALL-diagnosis in 99% of the patients, dominated by reduced HDL levels (98%) and mild hypertriglyceridemia (61%). Hypertriglyceridemia was not associated with body mass index (P = 0.71). Five percent of patients had mild hypercholesterolemia, 14% had mild hypocholesterolemia, 13% had decreased and 1% elevated LDL-levels. Increased TG and TC levels at ALL-diagnosis were not associated with any on-therapy lipid levels. Lipid levels and BMI were not associated to MRD after induction therapy; However, BMI and hypercholesterolemia were associated with worse risk group stratification (P<0.045 for all). The cumulative incidence of thromboembolism was increased both for patients with hypo- (20.0%) and hypercholesterolemia (16.7%) compared to patients with normal TC levels (2.2%) at diagnosis (P = 0.0074). In conclusion, dyslipidemic changes were present prior to ALL-therapy in children with ALL but did not seem to affect dysmetabolic traits during therapy and were not predictive of on-therapy toxicities apart from an association between dyscholesterolemia at time of ALL-diagnosis and risk of thromboembolism. However, the latter should be interpreted with caution due to low number in the groups.


Assuntos
Dislipidemias/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Adolescente , Asparaginase/metabolismo , Índice de Massa Corporal , Criança , Pré-Escolar , Dislipidemias/epidemiologia , Feminino , Humanos , Hipercolesterolemia/complicações , Hipercolesterolemia/epidemiologia , Hipertrigliceridemia/complicações , Hipertrigliceridemia/epidemiologia , Lactente , Masculino , Osteonecrose/complicações , Pancreatite/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Estudos Retrospectivos , Risco , Esteroides/metabolismo , Tromboembolia/complicações , Resultado do Tratamento
12.
N Engl J Med ; 382(16): 1507-1519, 2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-32187462

RESUMO

BACKGROUND: Inclisiran inhibits hepatic synthesis of proprotein convertase subtilisin-kexin type 9. Previous studies suggest that inclisiran might provide sustained reductions in low-density lipoprotein (LDL) cholesterol levels with infrequent dosing. METHODS: We enrolled patients with atherosclerotic cardiovascular disease (ORION-10 trial) and patients with atherosclerotic cardiovascular disease or an atherosclerotic cardiovascular disease risk equivalent (ORION-11 trial) who had elevated LDL cholesterol levels despite receiving statin therapy at the maximum tolerated dose. Patients were randomly assigned in a 1:1 ratio to receive either inclisiran (284 mg) or placebo, administered by subcutaneous injection on day 1, day 90, and every 6 months thereafter over a period of 540 days. The coprimary end points in each trial were the placebo-corrected percentage change in LDL cholesterol level from baseline to day 510 and the time-adjusted percentage change in LDL cholesterol level from baseline after day 90 and up to day 540. RESULTS: A total of 1561 and 1617 patients underwent randomization in the ORION-10 and ORION-11 trials, respectively. Mean (±SD) LDL cholesterol levels at baseline were 104.7±38.3 mg per deciliter (2.71±0.99 mmol per liter) and 105.5±39.1 mg per deciliter (2.73±1.01 mmol per liter), respectively. At day 510, inclisiran reduced LDL cholesterol levels by 52.3% (95% confidence interval [CI], 48.8 to 55.7) in the ORION-10 trial and by 49.9% (95% CI, 46.6 to 53.1) in the ORION-11 trial, with corresponding time-adjusted reductions of 53.8% (95% CI, 51.3 to 56.2) and 49.2% (95% CI, 46.8 to 51.6) (P<0.001 for all comparisons vs. placebo). Adverse events were generally similar in the inclisiran and placebo groups in each trial, although injection-site adverse events were more frequent with inclisiran than with placebo (2.6% vs. 0.9% in the ORION-10 trial and 4.7% vs. 0.5% in the ORION-11 trial); such reactions were generally mild, and none were severe or persistent. CONCLUSIONS: Reductions in LDL cholesterol levels of approximately 50% were obtained with inclisiran, administered subcutaneously every 6 months. More injection-site adverse events occurred with inclisiran than with placebo. (Funded by the Medicines Company; ORION-10 and ORION-11 ClinicalTrials.gov numbers, NCT03399370 and NCT03400800.).


Assuntos
Anticolesterolemiantes/uso terapêutico , LDL-Colesterol/sangue , Doença da Artéria Coronariana/tratamento farmacológico , Hipercolesterolemia/tratamento farmacológico , Pró-Proteína Convertase 9/antagonistas & inibidores , RNA Interferente Pequeno/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Anticolesterolemiantes/efeitos adversos , Anticolesterolemiantes/farmacocinética , Doenças Cardiovasculares , Doença da Artéria Coronariana/complicações , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/sangue , Hipercolesterolemia/complicações , Injeções Subcutâneas/efeitos adversos , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , RNA Interferente Pequeno/efeitos adversos , RNA Interferente Pequeno/farmacocinética , Fatores de Risco
13.
Life Sci ; 250: 117514, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32145306

RESUMO

AIMS: Pigs are increasingly used as human metabolic disease models; however, there is insufficient research on breed-related genetic background differences. This study aimed to investigate the differential metabolic responses to high-fat and high-cholesterol (HFC) diet-induced non-alcoholic fatty liver disease (NAFLD) of two miniature pig breeds and explore the molecular mechanisms involved. MAIN METHODS: Male Wuzhishan (WZSP) and Tibetan pigs (TP) were randomly fed either a standard or an HFC diet for 24 weeks. Weight, serum lipids, bile acid, insulin resistance, liver function, liver histology, and hepatic lipid deposition were determined. RNA-Seq was used to detect the hepatic gene expression profiles. Western blot, immunohistochemistry, and qRT-PCR were used to detect the lipid and glucose metabolism-related gene expressions. KEY FINDINGS: The HFC diet caused obesity, hypertension, severe hypercholesterolemia, liver injury, increased hepatocellular steatosis and inflammation, and significantly increased serum insulin levels in both pig breeds. This diet led to higher serum and hepatic cholesterol level concentrations in WZSP and elevated fasting glucose levels in TP. Transcriptome analysis revealed that the genes controlling hepatic cholesterol metabolism and the inflammatory response were consistently regulated; lipid metabolism and insulin signaling related genes were uniquely regulated by the HFC diet in the WZSP and TP, respectively. SIGNIFICANCE: Our study demonstrated that the genetic background affects profoundly pigs' metabolic and hepatic responses to an HFC diet. These results deepened our understanding of the molecular mechanisms of HFC diet-induced NAFLD and provided a foundation for selecting the appropriate pig breeds for metabolic studies in the future.


Assuntos
Ração Animal , Colesterol na Dieta , Dieta Hiperlipídica , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Transcriptoma , Animais , Glicemia/análise , Colesterol/metabolismo , Modelos Animais de Doenças , Biblioteca Gênica , Hipercolesterolemia/etiologia , Hiperlipidemias/etiologia , Hipertensão/etiologia , Inflamação/etiologia , Insulina/metabolismo , Fígado/metabolismo , Hepatopatias/etiologia , Masculino , Obesidade/etiologia , Fenótipo , Distribuição Aleatória , Especificidade da Espécie , Suínos , Porco Miniatura
14.
PLoS One ; 15(3): e0229669, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32163433

RESUMO

Exogenously hypercholesterolemic (ExHC) rats develop diet-induced hypercholesterolemia (DIHC) when fed with dietary cholesterol. Previously, we reported that, under the high-sucrose-diet-feeding condition, a loss-of-function mutation in Smek2 results in low activity of fatty acid synthase (FAS) followed by the shortage of hepatic triacylglycerol content in ExHC rats and the onset of DIHC. However, the relationship between the Smek2 mutation and FAS dysfunction is still unclear. Here, we focused on carbohydrate metabolism, which provides substrates for FAS, and analyzed carbohydrate and lipid metabolisms in ExHC rats to clarify how the deficit of Smek2 causes DIHC. Male ExHC and SD rats were fed high-sucrose or high-starch diets containing 1% cholesterol for 2 weeks. Serum cholesterol levels of the ExHC rats were higher, regardless of the dietary carbohydrate. Hepatic triacylglycerol levels were higher in only the SD rats fed the high-sucrose diet. Moreover, the ExHC rats exhibited a diabetes-like status and accumulation of hepatic glycogen and low hepatic mRNA levels of liver-type phosphofructokinase (Pfkl), which encodes a rate-limiting enzyme for glycolysis. These results suggest that the glucose utilization, particularly glycolysis, is impaired in the liver of ExHC rats. To evaluate how the diet with extremely low glucose affect to DIHC, ExHC.BN-Dihc2BN, a congenic strain that does not develop DIHC, and ExHC rats were fed a high-fructose diet containing 1% cholesterol for 2 weeks. The serum cholesterol and hepatic triacylglycerol levels were similar in the strains. Results of water-soluble metabolite analysis with primary hepatocytes, an increase in fructose-6-phosphate and decreases in succinate, malate and aspartate in ExHC rats, support impaired glycolysis in the ExHC rats. Thus, the Smek2 mutation causes abnormal hepatic glucose utilization via downregulation of Pfkl expression. This abnormal glucose metabolism disrupts hepatic fatty acid synthesis and causes DIHC in the ExHC rats.


Assuntos
Glucose/metabolismo , Hipercolesterolemia/etiologia , Hipercolesterolemia/metabolismo , Fígado/metabolismo , Animais , Animais Congênicos , Colesterol na Dieta/administração & dosagem , Colesterol na Dieta/efeitos adversos , Modelos Animais de Doenças , Regulação para Baixo , Ácido Graxo Sintase Tipo I/metabolismo , Glicólise/genética , Hipercolesterolemia/genética , Mutação com Perda de Função , Masculino , Fosfofrutoquinases/genética , Fosfofrutoquinases/metabolismo , Fosfoproteínas Fosfatases/deficiência , Fosfoproteínas Fosfatases/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos BN , Ratos Sprague-Dawley
15.
Metabolism ; 106: 154205, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32184090

RESUMO

BACKGROUND: Cardiovascular diseases (CVDs), with highest mortality and morbidity rates, are the major cause of death in the world. Due to the limited information on heart tissue changes, mediated by hypercholesterolemia, we planned to investigate molecular mechanisms of endoplasmic reticulum (ER) stress and related cell death in high cholesterol fed rabbit model and possible beneficial effects of α-tocopherol. METHODS: Molecular changes in rabbit heart tissue and cultured cardiomyocytes (H9c2 cells) were measured by western blotting, qRT-PCR, immunflouresence and flow cytometry experiments. Histological modifications were assessed by light and electron microscopes, while degradation of mitochondria was quantified through confocal microscope. RESULTS: Feeding rabbits 2% cholesterol diet for 8 weeks and treatment of cultured cardiomyocytes with 10 µg/mL cholesterol for 3 h induced excessive autophagic activity via IRE1/JNK pathway. While no change in ER-associated degradation (ERAD) and apoptotic cell death were determined, electron and confocal microscopy analyses in cholesterol supplemented rabbits revealed significant parameters of autophagic cell death, including cytoplasmic autophagosomes, autolysosomes and organelle loss in juxtanuclear area as well as mitochondria engulfment by autophagosome. Either inhibition of ER stress or JNK in cultured cardiomyocytes or α-tocopherol supplementation in rabbits could counteract the effects of cholesterol. CONCLUSION: Our findings underline the essential role of hypercholesterolemia in stimulating IRE1/JNK branch of ER stress response which then leads to autophagic cell death in heart tissue. Results also showed α-tocopherol as a promising regulator of autophagic cell death in cardiomyocytes.


Assuntos
Morte Celular Autofágica/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Colesterol/farmacologia , Coração/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Animais , Células Cultivadas , Colesterol/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Coração/fisiologia , Humanos , Hipercolesterolemia/complicações , Hipercolesterolemia/metabolismo , Hipercolesterolemia/patologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Proteínas de Membrana/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/fisiologia , Proteínas Serina-Treonina Quinases/metabolismo , Coelhos , Ratos
17.
G Ital Cardiol (Rome) ; 21(4 Suppl 1): 3S-21S, 2020 04.
Artigo em Italiano | MEDLINE | ID: mdl-32202541

RESUMO

High levels of LDL cholesterol (LDL-C) represent a causal factor for cardiovascular diseases on an atherosclerotic basis, with a direct correlation between these and mortality or cardiovascular events, such that the reduction of both is associated proportionally and linearly with the reduction of LDL-C.Statins and ezetimibe are used for LDL-C lowering but may not be sufficient to achieve the targets defined by the ESC/EAS guidelines, which recommend use of PCSK9 inhibitors for further LDL-C reduction in patients not at goal.This project submitted 86 clinical scenarios to a group of experts, cardiologists, internists and lipidologists, collecting their opinion on the appropriateness of different behaviors and decisions. We used the RAND/UCLA method of assessing the appropriateness of clinical interventions, validated to combine the best scientific evidence available with expert judgment. To this end, the benefit-risk ratio was evaluated in the proposed clinical scenarios. Each indication was classified as "appropriate", "uncertain" or "inappropriate" based on the average score given by the participants.This document presents the results of a consensus process that led to the development of recommendations for the management of clinical scenarios on the treatment of patients with dyslipidemia, which cannot always be solved with scientific evidence alone.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Anticolesterolemiantes/uso terapêutico , Doenças Cardiovasculares , Hipercolesterolemia/tratamento farmacológico , Aterosclerose/tratamento farmacológico , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/prevenção & controle , LDL-Colesterol , Consenso , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Itália , Medição de Risco , Fatores de Risco
18.
Rinsho Ketsueki ; 61(1): 44-46, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32023602

RESUMO

A 68-year-old woman consulted us because of anemia and elevated LDH serum levels >1,000 U/l. No particular disease was observed by various screening tests. Since she was taking atorvastatin despite low cholesterol level, we discontinued the drug, which improved her complaints. We later experienced similar patients with hyperlipidemia induced by other drugs, such as rosuvastatin and pravastatin. These drugs are widely used in patients with hyperlipidemia and more recently in tyrosine kinase inhibitor users. It is important to monitor cholesterol levels and discontinue the drug use when they are unnecessarily administered.


Assuntos
Anemia , Atorvastatina/efeitos adversos , Hipercolesterolemia , Idoso , Anemia/induzido quimicamente , LDL-Colesterol , Feminino , Fluorbenzenos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases , Sinvastatina
19.
Expert Opin Pharmacother ; 21(5): 531-539, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32036729

RESUMO

Introduction: Although statin therapy is a powerful lipid-lowering strategy, only one-fifth of statin users currently reach their lipid goals. In addition, statin treatment alone has relatively low efficacy in reducing other lipid fractions than low-density lipoprotein-cholesterol (LDL-C). In such cases, most guidelines recommend adding the cholesterol absorption inhibitor ezetimibe.Areas covered: This paper summarizes the main pharmacological characteristics of rosuvastatin and ezetimibe (mechanism of action, metabolism), their lipid-lowering and pleiotropic effects, with particular attention to the clinical effects of the combined drugs in hypercholesterolemia and mixed dyslipidemia patients (such as the ones affected by diabetes mellitus and Acquired Immune Deficiency Syndrome (AIDS)).Expert opinion: The additive effect of rosuvastatin and ezetimibe helps to reach lipid goals in a large number of high-risk patients, while avoiding some safety issues related to high dosages of intensive statin therapy. Patients with diabetes receive additional benefits from ezetimibe as they seem to absorb cholesterol more effectively than non-diabetic ones, because of increased NPC1L1 gene expression. Ezetimibe augments rosuvastatin triglyceride-lowering and anti-inflammatory effects, as well. Taking into account its excellent safety profile and lack of clinically relevant drug-drug interactions, the rosuvastatin/ezetimibe association is a valuable alternative to statin dose uptitration.


Assuntos
Anticolesterolemiantes/uso terapêutico , Dislipidemias/tratamento farmacológico , Ezetimiba/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Rosuvastatina Cálcica/uso terapêutico , Anticolesterolemiantes/administração & dosagem , Colesterol/sangue , LDL-Colesterol/sangue , Sinergismo Farmacológico , Quimioterapia Combinada , Ezetimiba/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Rosuvastatina Cálcica/administração & dosagem , Resultado do Tratamento , Triglicerídeos/sangue
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