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1.
Klin Lab Diagn ; 64(7): 388-396, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31408589

RESUMO

Inhibition of hydrolysis of palmitic and oleic triglycedires (TG) in very low density lipoproteins (VLDL), slow formation of active apoВ-100 conformation, blockade of апоЕ/В-100 ligand formation in VLDL and their reduced uptake by insulin-dependent cells cause hypertriglyceridemia (HTG). Palmitic and oleic VLDL (>80% total VLDL) are not converted in low density lipoproteins (LDL). Atherosclerosis is not an alimentary deficiency of polyenic fatty acids (PFA), but results from low in vivo bioavailability of PFA in LDL against the background of high dietary palmitic FA and palmitic LDL. Plasma PFA content and cellular PFA deficiency are as high as LDL cholesterol (CL). Primary prevention of atherosclerosis should be based on a decrease in dietary content of palmitic saturated FA, trans FA and a moderate increase in PFA. It seems highly unlikely that the xeobiotics statins, fibrates and probucol produce pleiotropic biological effects in vivo. These effects are brought about by phylogenetically early humoral mediators eicosanoids: prostacyclins, prostaglandins, thromboxanes, leukotrienes, and resolvins. It is reasonable to suggest that all preparations which act according to the same algorithm activate TG hydrolysis in VLDL and normalize cellular uptake of PFA in linoleic and linolenic LDL via apoВ-100 endocytosis. Atherosclerosis is a syndrome of cellular deficiency of essential polyenic FA.


Assuntos
Dieta , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Hipertrigliceridemia/patologia , Lipólise , Lipoproteínas VLDL/metabolismo , Ácidos Graxos/sangue , Ácidos Fíbricos/farmacologia , Humanos , Triglicerídeos
2.
Medicine (Baltimore) ; 98(34): e16931, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31441882

RESUMO

Several studies have shown that statin users have a lower risk of new-onset dementia (NOD) compared nonusers. However, other studies have shown opposite results. In this study, we investigated the association between the use of statins and the development of NOD.This was a longitudinal cohort study using data from claim forms submitted to the Taiwanese Bureau of National Health Insurance. The study included patients with NOD and non-NOD subjects from January 2002 to December 2013. We estimated the hazard ratios (HRs) of NOD associated with statin use, whereas nonuser subjects were used as a reference group.A total of 19,522 NOD cases were identified in 100,610 hyperlipidemic patients during the study period. The risk of NOD, after adjusting for sex, age, comorbidities, and concurrent medication, was lower among statin users than nonusers (HR 0.95, 95% CI [confidence interval] 0.94-0.96; P < .001). The adjusted HRs for NOD were 1.53 (95% CI, 1.45-1.62), 0.63 (95% CI, 0.57-0.71), and 0.34 (95% CI, 0.30-0.38) when the cumulative defined daily doses ranged from 28 to 365, 366 to 730, and more than 730 relative to nonusers, respectively.We concluded that statin use is associated with a decreased NOD risk. The protective effect of statins for NOD seemed to be related to high exposure to statins. This study also highlights that high exposure to statins has a dose-response effect on lowering NOD risk.


Assuntos
Cognição/efeitos dos fármacos , Demência/prevenção & controle , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Hiperlipidemias/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Comorbidade , Demência/epidemiologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Estimativa de Kaplan-Meier , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taiwan/epidemiologia
3.
Yonsei Med J ; 60(7): 679-686, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31250582

RESUMO

PURPOSE: Statins, metformin, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs) have been suggested for treating age-related macular degeneration (AMD) due to their pleiotropic effects. Therefore, we investigated whether these drugs prevent AMD. MATERIALS AND METHODS: We conducted a nested case-control study using the Korean National Health Insurance Service database. Using risk-set sampling of age, sex, cohort entry date, and follow-up duration, we identified incident patients with AMD and 10 matching controls in cohorts with diabetes mellitus or cardiovascular diseases. Exposure was assessed within one year before the index date using patient prescription records. We conducted conditional logistic regression to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) to evaluate the association between cardiovascular medications and AMD. RESULTS: Our study included 2330 cases and 23278 controls from a cohort of 231274 patients. The ORs (95% CI) for AMD occurrence in users prescribed with statins, metformin, ACE inhibitors, and ARBs were 1.12 (0.94-1.32), 1.15 (0.91-1.45), 0.90 (0.61-1.34), and 1.21 (1.05-1.39), respectively. A duration-response was not observed. CONCLUSION: Statins, metformin, ACE inhibitors, and ARBs did not inhibit AMD in elderly patients. The absence of a duration-response supports the lack of a causal relationship.


Assuntos
Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Degeneração Macular/tratamento farmacológico , Metformina/farmacologia , Idoso , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Modelos Logísticos , Masculino , Metformina/uso terapêutico
4.
Medicine (Baltimore) ; 98(20): e15484, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31096447

RESUMO

INTRODUCTION: The purpose of this study protocol is to provide the methodology for a review to compare the effect of statins vs physical exercise interventions and the effect of different types of physical exercise, on reducing arterial stiffness associated with cardiovascular diseases and mortality. METHODS AND ANALYSIS: The literature search will be conducted in MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Web of Science databases from their inception until July 31, 2019. We will include randomized controlled trials, nonrandomized experimental studies, and controlled pre-post studies assessing the effect in the general population of statins and physical exercise interventions on arterial stiffness measured by pulse wave velocity. The Cochrane Collaboration's tool and the Quality Assessment Tool for Quantitative Studies will be used to assess the risk of bias for studies included in the systematic review. A Bayesian network meta-analysis will be carried out to determine the comparative effect of the different physical exercise interventions and/or statin intervention. ETHICS AND DISSEMINATION: This study will generate evidence about the effectiveness of both statins and exercise on reducing arterial stiffness that potentially can be transferred to patients and practitioners. Moreover, in light of the importance of reducing arterial stiffness for preventing cardiovascular disease, the evidence provided by this study will be potentially suitable to be included in cardiovascular clinical practice guidelines. STRENGTHS AND LIMITATIONS: This protocol describes the methods of a study examining, using network meta-analysis strategies, the efficacy of statins and different types of exercise on improving arterial stiffness, which is an early marker of atherosclerosis. The results of this study could immediately help clinicians to recommend the best evidence-based intervention to their patients to reduce arterial stiffness and, as a consequence, prevent major complications, such as heart failure, stroke, or myocardial infarction. TRIAL REGISTRATION NUMBER: PROSPERO CRD42019123120.


Assuntos
Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/terapia , Exercício/fisiologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Rigidez Vascular/efeitos dos fármacos , Doenças Cardiovasculares/tratamento farmacológico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Meta-Análise em Rede , Ensaios Clínicos Controlados não Aleatórios como Assunto , Avaliação de Resultados (Cuidados de Saúde) , Análise de Onda de Pulso/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa , Rigidez Vascular/fisiologia
5.
PLoS Genet ; 15(4): e1008009, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30951530

RESUMO

Recent and classical work has revealed biologically and medically significant subtypes in complex diseases and traits. However, relevant subtypes are often unknown, unmeasured, or actively debated, making automated statistical approaches to subtype definition valuable. We propose reverse GWAS (RGWAS) to identify and validate subtypes using genetics and multiple traits: while GWAS seeks the genetic basis of a given trait, RGWAS seeks to define trait subtypes with distinct genetic bases. Unlike existing approaches relying on off-the-shelf clustering methods, RGWAS uses a novel decomposition, MFMR, to model covariates, binary traits, and population structure. We use extensive simulations to show that modelling these features can be crucial for power and calibration. We validate RGWAS in practice by recovering a recently discovered stress subtype in major depression. We then show the utility of RGWAS by identifying three novel subtypes of metabolic traits. We biologically validate these metabolic subtypes with SNP-level tests and a novel polygenic test: the former recover known metabolic GxE SNPs; the latter suggests subtypes may explain substantial missing heritability. Crucially, statins, which are widely prescribed and theorized to increase diabetes risk, have opposing effects on blood glucose across metabolic subtypes, suggesting the subtypes have potential translational value.


Assuntos
Estudo de Associação Genômica Ampla/métodos , Modelos Genéticos , Herança Multifatorial , Fenótipo , Algoritmos , Glicemia/efeitos dos fármacos , Glicemia/genética , Análise por Conglomerados , Simulação por Computador , Doença das Coronárias/sangue , Doença das Coronárias/tratamento farmacológico , Doença das Coronárias/genética , Transtorno Depressivo Maior/classificação , Transtorno Depressivo Maior/genética , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Lipídeos/sangue , Polimorfismo de Nucleotídeo Único , Estado Pré-Diabético/genética , Locos de Características Quantitativas
6.
Int J Mol Sci ; 20(6)2019 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-30909654

RESUMO

In this study we attempted to verify the hypothesis that the mevalonate pathway affects amyloid beta precursor protein (AßPP) processing and regulates clusterin protein levels. AßPP expression was monitored by green fluorescence (FL) and Western blot (WB). WB showed soluble amyloid protein precursor alpha (sAßPPα) presence in AßPP-wt cells and Aß expression in AßPP-sw cells. Nerve growth factor (NGF)-differentiated rat neuronal pheochromocytoma PC-12 cells were untreated/treated with statins alone or together with non-sterol isoprenoids. Co-treatment with mevalonate, dolichol, ubiquinol, farnesol, geranylgeraniol, or water-soluble cholesterol demonstrated statin-dependent neurotoxicity resulted from the attenuated activity of mevalonate pathway rather than lower cholesterol level. Atorvastatin (50 µM) or simvastatin (50 µM) as well as cholesterol chelator methyl-ß-cyclodextrin (0.2 mM) diminished cell viability (p < 0.05) and clusterin levels. Interestingly, co-treatment with mevalonate, dolichol, ubiquinol, farnesol, geranylgeraniol, or water-soluble cholesterol stimulated (p < 0.05) clusterin expression. Effects of non-sterol isoprenoids, but not water soluble cholesterol (Chol-PEG), were the most significant in mock-transfected cells. Geranylgeraniol (GGOH) overcame atorvastatin (ATR)-dependent cytotoxicity. This effect does not seem to be dependent on clusterin, as its level became lower after GGOH. The novelty of these findings is that they show that the mevalonate (MEV) pathway rather than cholesterol itself plays an important role in clusterin expression levels. In mock-transfected, rather than in AßPP-overexpressing cells, GGOH/farnesol (FOH) exerted a protective effect. Thus, protein prenylation with GGOH/FOH might play substantial role in neuronal cell survival.


Assuntos
Precursor de Proteína beta-Amiloide/genética , Colesterol/farmacologia , Clusterina/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Mutação , Terpenos/farmacologia , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Colesterol/química , Clusterina/metabolismo , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Redes e Vias Metabólicas/efeitos dos fármacos , Ácido Mevalônico/metabolismo , Células PC12 , Ratos
7.
Can J Gastroenterol Hepatol ; 2019: 6415757, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30854351

RESUMO

Background and Aims: We aimed to assess whether chronic statins used (> 6 months) were protective of the development of esophagitis in patients with gastroesophageal reflux disease. In the presence of esophagitis, complications such as strictures, Barrett's esophagus, and adenocarcinoma were the most common. Statins, lipid lowering drugs with a pleiotropic effect, are recently implicated in various pathologies. Nevertheless, the possible impact of statins in esophagitis development has never been assessed. Methods: We performed a retrospective, cross-sectional, single center study that included 4148 gastroesophageal reflux disease patients from 2014 and 2018 at EMMS Nazareth Hospital. We divided the patients into 5 groups. The groups were split into positive control group, which was the nonesophagitis group, and the other 4 groups were A-D (as per Los Angeles classification). Results: Overall, out of the 4148 patients included, 48% were males and 2840 patients were in the control group. In groups A, B, C, and D there were 818, 402, 72, and 16 patients, respectively. Logistic regression analysis revealed that chronic statins usage is protective by preventing development esophagitis (OR 0.463 [95%CI 0.370-0.579], p < 0.0001). NSAIDS use, Hiatus hernia, and H. pylori were promoting factors (OR, 1.362, 1.779, and 1.811; 95% CI, 1.183-1.569, 1.551-2.040, and 1.428-2.298; P<0.0001, P<0.0001, and P<0.0001, respectively). Conclusion: Using chronic statins was protective to the development of esophagitis among GERD patients. Our findings of potential clinical application mandate further randomized controlled trials to better assess the impact of statins on esophagitis.


Assuntos
Esofagite/epidemiologia , Refluxo Gastroesofágico/complicações , Infecções por Helicobacter/epidemiologia , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Adenocarcinoma/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Esôfago de Barrett/epidemiologia , Estudos Transversais , Neoplasias Esofágicas/epidemiologia , Esofagite/etiologia , Esofagite/prevenção & controle , Feminino , Helicobacter pylori/isolamento & purificação , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Tempo
8.
Neural Plast ; 2019: 7675496, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30911291

RESUMO

Ischemic stroke is usually followed by inflammatory responses mediated by microglia. However, the effect of statins on directly preventing posthypoxia microglia inflammatory factors to prevent injury to surrounding healthy neurons is unclear. Atorvastatin and rosuvastatin, which have different physical properties regarding their lipid and water solubility, are the most common HMG-CoA reductase inhibitors (statins) and might directly block posthypoxia microglia inflammatory factors to prevent injury to surrounding neurons. Neuronal damage and microglial activation of the peri-infarct areas were investigated by Western blotting and immunofluorescence after 24 hours in a middle cerebral artery occlusion (MCAO) rat model. The decrease in neurons was in accordance with the increase in microglia, which could be reversed by both atorvastatin and rosuvastatin. The effects of statins on blocking secretions from posthypoxia microglia and reducing the secondary damage to surrounding normal neurons were studied in a coculture system in vitro. BV2 microglia were cultured under oxygen glucose deprivation (OGD) for 3 hours and then cocultured following reperfusion for 24 hours in the upper wells of transwell plates with primary neurons being cultured in the bottom wells. Inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and cyclooxygenase-2 (COX2), which are activated by the nuclear factor-kappa B (NF-κB) signaling pathway in OGD-induced BV2 microglia, promoted decreased release of the anti-inflammatory cytokine IL-10 and apoptosis of neurons in the coculture systems according to ELISA and Western blotting. However, pretreatment with atorvastatin or rosuvastatin significantly reduced neuronal death, synaptic injury, and amyloid-beta (Aß) accumulation, which might lead to increased low-density lipoprotein receptors (LDLRs) in BV2 microglia. We concluded that the proinflammatory mediators released from postischemia damage could cause damage to surrounding normal neurons, while HMG-CoA reductase inhibitors prevented neuronal apoptosis and synaptic injury by inactivating microglia through blocking the NF-κB signaling pathway.


Assuntos
Sobrevivência Celular/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Infarto da Artéria Cerebral Média/tratamento farmacológico , Microglia/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Animais , Citocinas/metabolismo , Glucose/metabolismo , Infarto da Artéria Cerebral Média/metabolismo , Masculino , Microglia/metabolismo , Neurônios/metabolismo , Oxigênio/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
9.
Pharmacol Rep ; 71(2): 266-271, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30822620

RESUMO

BACKGROUND: Due to anti-inflammatory and anti-thrombotic functions, statins and antiplatelets are widely used for patients with cardiovascular-related or coronary artery diseases. Patients with systemic or complex diseases are commonly prescribed multiple targeted medications; thus, a proper combination of two or more drugs for beneficial efficacy is considered in clinical therapy. Recent studies have suggested that combinational therapy with statins and other medications accelerates their single effect to suppress inflammatory responses. However, the therapeutic efficacy and underlying mechanism of combination treatment with rosuvastatin and cilostazol have been poorly studied. METHODS: Mice were administered rosuvastatin alone, cilostazol alone or rosuvastatin and cilostazol in combination, and then injected with LPS or TNF to induce acute inflammation. The serum TNF level, macrophage infiltration of the lesioned aortas and mice mortality were observed in the acute inflammation model. The phosphorylation of MAPK was analyzed in TNF-stimulated HeLa cells. RESULTS: Compared to the treatment with cilostazol alone, the combination treatment with rosuvastatin and cilostazol significantly reduced not only the levels of TNF in the sera but also macrophage infiltration in aortic lesions. In addition, the combination therapy decreased TNF-mediated phosphorylation of the MAPK signaling pathway and improved the survival rate in the TNF-driven inflammatory mice model. CONCLUSION: Rosuvastatin combined with cilostazol therapy can greatly improve the anti-inflammatory effect of monotherapies, resulting in reduced mortality of mice; thus, we propose the potential of use of this combination therapy as anti-TNF agent.


Assuntos
Anti-Inflamatórios/farmacologia , Cilostazol/farmacologia , Inflamação/tratamento farmacológico , Rosuvastatina Cálcica/farmacologia , Animais , Anti-Inflamatórios/administração & dosagem , Cilostazol/administração & dosagem , Modelos Animais de Doenças , Quimioterapia Combinada , Células HeLa , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Lipopolissacarídeos/administração & dosagem , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Rosuvastatina Cálcica/administração & dosagem , Fator de Necrose Tumoral alfa/administração & dosagem , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/sangue
10.
Neurochem Res ; 44(5): 1065-1078, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30820818

RESUMO

Mounting evidences have demonstrated that diet-induced obesity is associated with cognition impairment via increasing oxidative stress and inflammation in the brain. Atorvastatin (Ator, a HMG-CoA reductase inhibitor) is a cholesterol lowering drug. Studies have reported that Ator can ameliorate the development and progression of cognition impairment. Additionally, silent information regulator 1 (SIRT1) has been demonstrated to be beneficial in cognition impairment. However, the interaction between Ator and SIRT1 activation for cognition impairment remains unclear. This study aimed to identify a relationship between the use of Ator and cognition impairment induced by high-fat diet via Sirt1 activation. A total of 60 healthy male C57BL/6J mice were purchased and then divided into 6 groups, including normal diet group (control), a high-fat diet group (40%HFD, 40% energy from fat), a model group (60%HFD, 60% energy from fat), and model group treated with different doses of Ator (high-dose (80 mg), moderate-dose (40 mg), and low-dose (20 mg) groups). All interventions took place for 7 months. Metabolic phenotypes were characterized for body weight and analysis of serum lipid level. The level of cognition development was examined by Morris water maze (MWM) approach and novel object recognition test (NORT); besides, the expression of Creb1, Gap-43, BDNF, CaMKII, and ERKs of frontal cortex and hippocampus was determined by reverse transcription polymerase chain reaction (RT-PCR). Then, the levels of factors related to inflammation (TNF-a, IL-1ß, HMGB1 and IL-6) and oxidation stress (SOD, MDA, CAT and GSH-Px) were assessed using commercially available kits. Finally, SIRT1 and its downstream molecules (Ac-FoxO1, Ac-p53, Ac-NF-κB, Bcl-2 and Bax) were evaluated by Western blot analysis. Compared with the 60% HFD group, body weight and serum lipid levels were significantly decreased in the Ator treated groups. The results of MWM and NORT, as well as the levels of Creb1, Gap-43, BDNF, CaMKII, and ERKs were markedly reversed in the moderate- and low-dose of Ator treated groups. Meanwhile, the expression of IL-1ß, TNF-a, IL-6, HMGB1, and MDA was notably decreased, whereas the activity of SOD, CAT, and GSH-Px was increased. It was also revealed that the expression of SIRT1 was remarkably unregulated, the level of Bcl-2 was upregulated, and the content of Ac-FoxO1, Ac-p53, Ac-NF-κB, and Bax was downregulated in the moderate- and low-dose of Ator. Furthermore, results showed that the effect of moderate-dose of Ator was significantly greater than the low-dose of Ator. However, these effects were not observed in the high-dose of Ator. Our results showed that moderate- and low-dose of Ator can significantly attenuate cognition impairment induced by HFD through its antioxidant and anti-inflammatory functions related to SIRT1 activation.


Assuntos
Atorvastatina/farmacologia , Disfunção Cognitiva/tratamento farmacológico , Dieta Hiperlipídica/efeitos adversos , Estresse Oxidativo/efeitos dos fármacos , Sirtuína 1/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Peso Corporal/efeitos dos fármacos , Cognição/efeitos dos fármacos , Disfunção Cognitiva/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Obesidade/metabolismo
11.
J Diabetes Res ; 2019: 5245063, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30863781

RESUMO

Increasing evidence shows that statins increase the risk of new-onset diabetes mellitus, but the exact mechanism is not clearly known. Free fatty acid receptor 1 (FFA1) has been recognized to mediate insulin secretion, and pioglitazone has direct effects on glucose-stimulated insulin secretion in addition to the reversion of insulin resistance. In this study, we found that atorvastatin decreased potassium-stimulated insulin secretion and inhibited the expression of FFA1, PDX-1, and BETA2/NeuroD in INS-1 cells. Further study demonstrated that pioglitazone prevented the impairment of insulin secretion induced by atorvastatin and enhanced the expression of FFA1, PDX-1, and BETA2/NeuroD reduced by atorvastatin in INS-1 cells. In addition, the preventive effect of pioglitazone on atorvastatin-induced impairment of insulin secretion and the enhancement of the expression of PDX-1 and BETA2/NeuroD was abolished by knockdown of FFA1 using siRNA or the PLC inhibitor, U-73122, respectively. Ultimately, FFA1 may mediate the atorvastatin-induced pancreatic ß-cell dysfunction and pioglitazone may ameliorate this deleterious effect through the upregulation of FFA1 expression.


Assuntos
Atorvastatina/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Hipoglicemiantes/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Ilhotas Pancreáticas/efeitos dos fármacos , Pioglitazona/farmacologia , Receptores Acoplados a Proteínas-G/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Linhagem Celular , Proteínas de Homeodomínio/metabolismo , Insulina/metabolismo , Resistência à Insulina , Células Secretoras de Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Ratos , Transativadores/metabolismo
12.
Comput Math Methods Med ; 2019: 2123079, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30838048

RESUMO

Background: Mathematical models offer the potential to analyze and compare the effectiveness of very different interventions to prevent future cardiovascular disease. We developed a comprehensive Markov model to assess the impact of three interventions to reduce ischemic heart diseases (IHD) and stroke deaths: (i) improved medical treatments in acute phase, (ii) secondary prevention by increasing the uptake of statins, (iii) primary prevention using health promotion to reduce dietary salt consumption. Methods: We developed and validated a Markov model for the Tunisian population aged 35-94 years old over a 20-year time horizon. We compared the impact of specific treatments for stroke, lifestyle, and primary prevention on both IHD and stroke deaths. We then undertook extensive sensitivity analyses using both a probabilistic multivariate approach and simple linear regression (metamodeling). Results: The model forecast a dramatic mortality rise, with 111,134 IHD and stroke deaths (95% CI 106567 to 115048) predicted in 2025 in Tunisia. The salt reduction offered the potentially most powerful preventive intervention that might reduce IHD and stroke deaths by 27% (-30240 [-30580 to -29900]) compared with 1% for medical strategies and 3% for secondary prevention. The metamodeling highlighted that the initial development of a minor stroke substantially increased the subsequent probability of a fatal stroke or IHD death. Conclusions: The primary prevention of cardiovascular disease via a reduction in dietary salt consumption appeared much more effective than secondary or tertiary prevention approaches. Our simple but comprehensive model offers a potentially attractive methodological approach that might now be extended and replicated in other contexts and populations.


Assuntos
Isquemia Miocárdica/prevenção & controle , Acidente Vascular Cerebral/prevenção & controle , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Simulação por Computador , Feminino , Promoção da Saúde , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Modelos Lineares , Masculino , Cadeias de Markov , Pessoa de Meia-Idade , Modelos Teóricos , Análise Multivariada , Isquemia Miocárdica/epidemiologia , Isquemia Miocárdica/mortalidade , Prevenção Primária , Probabilidade , Prevenção Secundária , Cloreto de Sódio na Dieta , Software , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/mortalidade , Tunísia/epidemiologia
13.
Arch Pharm Res ; 42(3): 195-205, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30877558

RESUMO

Currently, coronary artery disease accounts for a large proportion of deaths occurring worldwide. Damage to the heart muscle over a short period of time leads to myocardial infarction (MI). The biological mechanisms of atherosclerosis, one of the causes of MI, have been well studied. Resistin, a type of adipokine, is closely associated with intravascular level of low-density lipoprotein cholesterol and augmentation of the expression of adhesion molecules in endothelial cells. Therefore, resistin, which is highly associated with inflammation, can progress into coronary artery disease. Adenylyl cyclase associated protein 1, a binding partner of resistin, also plays an important role in inducing pro-inflammatory cytokines. The induction of these cytokines can aggravate atherosclerosis by promoting severe plaque rupture of the lesion site. Recently, drugs, such as statins that can inhibit inflammation have been extensively studied. The development of effective new drugs that can directly or indirectly block pro-inflammatory cytokines may have a great potential in the treatment of coronary artery disease in the future.


Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/metabolismo , Transdução de Sinais/efeitos dos fármacos , Anti-Inflamatórios não Esteroides/farmacologia , Doenças Cardiovasculares/patologia , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia
14.
Int J Oral Maxillofac Implants ; 34(3): 658­664, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30892287

RESUMO

PURPOSE: This histologic study aimed at assessing bone healing after treatment with simvastatin in association with low-level laser therapy (LLLT). METHODS: Twenty-four male rats (Wistar) were submitted to surgery to create a bone defect of 5 mm in diameter in the parietal bone. These rats were randomly and equally divided into four treatment groups (n = 6): control (C), in which no treatment was performed; simvastatin (SIM), in which rats received daily subcutaneous doses of 2.5 mg/kg of simvastatin; LLLT, which was daily applied to the bone defect; and SIM-LLLT, in which both SIM and LLLT were daily applied. All laser irradiations were carried out with a 830-nm infrared diode laser (GaAlAs) with maximum output of 100 mW and a dose of 4 J, totaling 16 J per session. Rats were euthanized on the 12th postoperative day. Formalin-fixed paraffin-embedded bone samples were obtained and stained with hematoxylin-eosin (HE) and toluidine blue for optical microscope analysis. Degree of inflammation, new vascular formation, tissue repair, and osteoblastic activity were assessed. RESULTS: Categorical analysis of the histologic slides revealed newly formed bone reaching the center of the surgical wound in two animals from the SIM group, two from the LLLT group, and three from the SIM-LLLT group. Greater new bone formation and a lower degree of inflammation were observed in the animals that had bone neoformation at the center of the defect, especially in the LLLT and SIM-LLLT groups. SIM and C groups presented greater angiogenesis than LLLT and SIM-LLLT. SIMLLLT therapy showed a statistically significant reduction in the degree of inflammation when compared to the control group (P < .05). CONCLUSION: Within the limitations of this study, the present results suggest that a combination of simvastatin and low-level laser therapy may stimulate better bone formation.


Assuntos
Regeneração Óssea/efeitos dos fármacos , Regeneração Óssea/efeitos da radiação , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Lasers Semicondutores/uso terapêutico , Terapia com Luz de Baixa Intensidade , Sinvastatina/farmacologia , Animais , Terapia com Luz de Baixa Intensidade/métodos , Masculino , Ratos , Ratos Wistar , Cicatrização/efeitos dos fármacos , Cicatrização/efeitos da radiação
15.
N Engl J Med ; 380(11): 1033-1042, 2019 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-30865797

RESUMO

BACKGROUND: ATP citrate lyase is an enzyme in the cholesterol-biosynthesis pathway upstream of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), the target of statins. Whether the genetic inhibition of ATP citrate lyase is associated with deleterious outcomes and whether it has the same effect, per unit decrease in the low-density lipoprotein (LDL) cholesterol level, as the genetic inhibition of HMGCR is unclear. METHODS: We constructed genetic scores composed of independently inherited variants in the genes encoding ATP citrate lyase (ACLY) and HMGCR to create instruments that mimic the effect of ATP citrate lyase inhibitors and HMGCR inhibitors (statins), respectively. We then compared the associations of these genetic scores with plasma lipid levels, lipoprotein levels, and the risk of cardiovascular events and cancer. RESULTS: A total of 654,783 participants, including 105,429 participants who had major cardiovascular events, were included in the study. The ACLY and HMGCR scores were associated with similar patterns of changes in plasma lipid and lipoprotein levels and with similar effects on the risk of cardiovascular events per decrease of 10 mg per deciliter in the LDL cholesterol level: odds ratio for cardiovascular events, 0.823 (95% confidence interval [CI], 0.78 to 0.87; P = 4.0×10-14) for the ACLY score and 0.836 (95% CI, 0.81 to 0.87; P = 3.9×10-19) for the HMGCR score. Neither lifelong genetic inhibition of ATP citrate lyase nor lifelong genetic inhibition of HMGCR was associated with an increased risk of cancer. CONCLUSIONS: Genetic variants that mimic the effect of ATP citrate lyase inhibitors and statins appeared to lower plasma LDL cholesterol levels by the same mechanism of action and were associated with similar effects on the risk of cardiovascular disease per unit decrease in the LDL cholesterol level. (Funded by Esperion Therapeutics and others.).


Assuntos
ATP Citrato (pro-S)-Liase/genética , Doenças Cardiovasculares/genética , LDL-Colesterol/sangue , Predisposição Genética para Doença , Hidroximetilglutaril-CoA Redutases/genética , Análise da Randomização Mendeliana , ATP Citrato (pro-S)-Liase/antagonistas & inibidores , Diabetes Mellitus/genética , Ácidos Dicarboxílicos/farmacologia , Ácidos Dicarboxílicos/uso terapêutico , Ácidos Graxos/farmacologia , Ácidos Graxos/uso terapêutico , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Hipolipemiantes/farmacologia , Hipolipemiantes/uso terapêutico , Lipoproteínas/sangue , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Neoplasias/genética , Razão de Chances , Risco , Triglicerídeos/sangue
16.
Int J Mol Sci ; 20(4)2019 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-30813251

RESUMO

Since none of the multidrug resistance (MDR) modulators tested so far found their way into clinic, a novel approach to overcome the MDR of cancer cells has been proposed. The combined use of two MDR modulators of dissimilar mechanisms of action was suggested to benefit from the synergy between them. The effect of three phenothiazine derivatives that were used as single agents and in combination with simvastatin on cell growth, apoptosis induction, activity, and expression of cyclooxygenase-2 (COX-2) in doxorubicin-resistant colon cancer cells (LoVo/Dx) was investigated. Treatment of LoVo/Dx cells by phenothiazine derivatives combined with simvastatin resulted in an increase of doxorubicin cytotoxicity and its intracellular accumulation as compared to the treatment with phenothiazine derivatives that were used as single agents. Similarly, LoVo/Dx cells treated with two-component mixture of modulators showed the reduced expression of ABCB1 (P-glycoprotein) transporter and COX-2 enzyme, both on mRNA and protein level. Reduced expression of anti-apoptotic Bcl-2 protein and increased expression of pro-apoptotic Bax were also detected. Additionally, COX-2 activity was diminished, and caspase-3 activity was increased to a higher extent by phenothiazine derivative:simvastatin mixtures than by phenothiazine derivatives themselves. Therefore, the introduction of simvastatin strengthened the anti-MDR, anti-inflammatory, and pro-apoptotic properties of phenothiazines in LoVo/Dx cells.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias do Colo/enzimologia , Neoplasias do Colo/patologia , Ciclo-Oxigenase 2/metabolismo , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Fenotiazinas/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Caspase 3/metabolismo , Linhagem Celular Tumoral , Doxorrubicina/química , Sinergismo Farmacológico , Humanos , Fenotiazinas/química , Sinvastatina/química , Sinvastatina/farmacologia , Proteína X Associada a bcl-2/metabolismo
17.
Toxicol Lett ; 307: 49-58, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30853469

RESUMO

Rhabdomyolysis is characterized by elevation of plasma creatine phosphokinase (CPK) level, and multiple organ disorders, especially renal failure, as well as approximately 50% of acquired rhabdomyolysis are caused by pharmaceuticals. Statins are known to cause rhabdomyolysis, and its incidence is ≥10 times higher with coadministration of statin and fibrate. The purpose of this study is to establish a mouse model of drug-induced rhabdomyolysis by coadministration of statin and fibrate to clarify the mechanisms of its myotoxicity. We administered lovastatin (LV) and gemfibrozil (GF) with a glutathione synthesis inhibitor, L-buthionine-(S,R)-sulfoximine (BSO), to C57BL/6 J female mice once daily for 3 days. The plasma levels of CPK and aspartate aminotransferase (AST) were prominently increased, and the increase in plasma miR-206-3p and miR-133-3p levels, not the increase of miR-122-5p and miR-208-3p levels, suggested skeletal muscle-specific toxicity. The caspase 3/7 activity and mRNA levels of oxidative stress-related factors were elevated in skeletal muscle. Pharmacokinetic parameters showed that blood levels of statin were significantly increased by coadministered GF. The possibility of kidney injury was examined as in clinical rhabdomyolysis. In histological examination, vacuoles were observed in renal proximal tubules, and the plasma renal injury marker, lipocalin 2/neutrophil gelatinase-associated lipocalin (Lcn2/Ngal), was markedly increased in the mice coadministered LV and GF, suggesting mild complications of acute kidney injury. A quantitative comparison of the myotoxic potential of various statins was successfully performed using the present method. In this study, a rhabdomyolysis mouse model was established by coadministration of the clinically using statin and fibrate. This mouse model may be useful to identify drugs that have high risk for rhabdomyolysis.


Assuntos
Ácidos Fíbricos/toxicidade , Genfibrozila/toxicidade , Inibidores de Hidroximetilglutaril-CoA Redutases/toxicidade , Lovastatina/toxicidade , Rabdomiólise/induzido quimicamente , Animais , Caspase 3/metabolismo , Caspase 7/metabolismo , Modelos Animais de Doenças , Interações de Medicamentos , Feminino , Ácidos Fíbricos/administração & dosagem , Ácidos Fíbricos/farmacologia , Genfibrozila/administração & dosagem , Genfibrozila/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Lovastatina/administração & dosagem , Lovastatina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/patologia , Reação em Cadeia da Polimerase em Tempo Real , Rabdomiólise/patologia
18.
J Neuroinflammation ; 16(1): 57, 2019 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-30851734

RESUMO

BACKGROUND: Neuromyelitis optica spectrum disorder (herein called NMO) is an inflammatory demyelinating disease that can be initiated by binding of immunoglobulin G autoantibodies (AQP4-IgG) to aquaporin-4 on astrocytes, causing complement-dependent cytotoxicity (CDC) and downstream inflammation. The increased NMO pathology in rodents deficient in complement regulator protein CD59 following passive transfer of AQP4-IgG has suggested the potential therapeutic utility of increasing the expression of complement regulator proteins. METHODS: A cell-based ELISA was developed to screen for pharmacological upregulators of endogenous CD55 and CD59 in a human astrocyte cell line. A statin identified from the screen was characterized in cell culture models and rodents for its action on complement regulator protein expression and its efficacy in models of seropositive NMO. RESULTS: Screening of ~ 11,500 approved and investigational drugs and nutraceuticals identified transcriptional upregulators of CD55 but not of CD59. Several statins, including atorvastatin, simvastatin, lovastatin, and fluvastatin, increased CD55 protein expression in astrocytes, including primary cultures, by three- to four-fold at 24 h, conferring significant protection against AQP4-IgG-induced CDC. Mechanistic studies revealed that CD55 upregulation involves inhibition of the geranylgeranyl transferase pathway rather than inhibition of cholesterol biosynthesis. Oral atorvastatin at 10-20 mg/kg/day for 3 days strongly increased CD55 immunofluorescence in mouse brain and spinal cord and reduced NMO pathology following intracerebral AQP4-IgG injection. CONCLUSION: Atorvastatin or other statins may thus have therapeutic benefit in AQP4-IgG seropositive NMO by increasing CD55 expression, in addition to their previously described anti-inflammatory and immunomodulatory actions.


Assuntos
Aquaporina 4/imunologia , Astrócitos/metabolismo , Antígenos CD55/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Imunoglobulina G/administração & dosagem , Neuromielite Óptica/tratamento farmacológico , Regulação para Cima/efeitos dos fármacos , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Linhagem Celular Transformada , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Interações de Medicamentos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/química , Camundongos , Neuromielite Óptica/metabolismo , Neuromielite Óptica/patologia , RNA Mensageiro/metabolismo , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Ativação Transcricional/efeitos dos fármacos , Receptor fas/metabolismo
19.
Mil Med ; 184(Suppl 1): 644-651, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30901461

RESUMO

Ionizing radiation exposure is a major concern for active military service members, as well as civilian population. Considering that the exposure is not predictable, it is imperative that strategies to counteract radiation damage must be discovered. Recent in vitro studies performed in our laboratory demonstrated that the vitamin E analog gamma-tocotrienol (GT3) in combination with cholesterol-lowering drugs (Statins), synergistically induced endothelial thrombomodulin, an anticoagulant with radio-protective efficacy. It was hypothesized that the combination of treatment with both GT3 along with Statins would provide better radiation protection in vivo than each drug individually. CD2F1 mice were injected subcutaneously with either vehicle or single dose of GT3 (200 mg/kg body weight) 24 hours before irradiation followed by oral or subcutaneous administration of various doses of simvastatin (25, 50, and 100 mg/kg body weight) before exposure to lethal doses (11.5 and 12 Gy) of Cobalt-60 (60Co) gamma-irradiation. The combined treatment group exhibited enhanced radiation lethality protection substantially, accelerated white blood cell recovery, and augmented restoration of bone marrow cellularity when compared to the animals treated with either drug exclusively. This information clearly suggests that combined treatment could be used as a safeguard for military personnel from exposure to harmful ionizing radiation.


Assuntos
Cromanos/farmacologia , Quimioterapia Combinada/normas , Sinvastatina/farmacologia , Vitamina E/análogos & derivados , Animais , Cromanos/uso terapêutico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Quimioterapia Combinada/métodos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Camundongos , Exposição Ocupacional/efeitos adversos , Radiação Ionizante , Sinvastatina/uso terapêutico , Análise de Sobrevida , Vitamina E/farmacologia , Vitamina E/uso terapêutico
20.
Yakugaku Zasshi ; 139(5): 807-815, 2019 May 01.
Artigo em Japonês | MEDLINE | ID: mdl-30773524

RESUMO

It is reported that statins have inconsistent effects on glycemic status and adiponectin concentrations in patients with type 2 diabetes mellitus (T2DM). We aimed to investigate the effect of statins on these variables in patients with T2DM and hypercholesterolemia. A control group comprising 24 patients with T2DM but without hypercholesterolemia was observed for more than 12 weeks, while 24 patients with T2DM and hypercholesterolemia were treated with statins for the same period (statin group). The percentage changes in the glycemic status [blood glucose and glycated hemoglobin (HbA1c)], and levels of plasma adiponectin [total and high molecular weight (HMW)] were compared between the two groups. The statin group had reduced percentage changes in HbA1c, blood glucose, and total and HMW-adiponectin concentration percentage changes that were similar to those in the control group. However, when matched for sex, age (±5 years) and HbA1c (±0.5%) with the control group, the pravastatin group had reduced percentage changes in the plasma HMW-adiponectin concentrations than the matched controls (p=0.023). However, there were no differences in the percentage changes in the plasma total adiponectin (p=0.137), HbA1c (p=0.202), or blood glucose concentrations (p=0.450) between the two groups. Pravastatin treatment had no effect on the glycemic status of patients with T2DM and hypercholesterolemia, but may reduce the percentage changes in the plasma HMW-adiponectin concentrations. Hence, patients with T2DM and hypercholesterolemia receiving long-term treatment with pravastatin might experience increased insulin resistance.


Assuntos
Adiponectina/sangue , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Hemoglobina A Glicada/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Hipercolesterolemia/metabolismo , Pravastatina/farmacologia , Idoso , Diabetes Mellitus Tipo 2/complicações , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Hipercolesterolemia/complicações , Resistência à Insulina , Masculino , Pessoa de Meia-Idade , Peso Molecular , Pravastatina/administração & dosagem
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