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1.
Nat Commun ; 11(1): 4930, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33004804

RESUMO

Inference of causality between gene expression and complex traits using Mendelian randomization (MR) is confounded by pleiotropy and linkage disequilibrium (LD) of gene-expression quantitative trait loci (eQTL). Here, we propose an MR method, MR-link, that accounts for unobserved pleiotropy and LD by leveraging information from individual-level data, even when only one eQTL variant is present. In simulations, MR-link shows false-positive rates close to expectation (median 0.05) and high power (up to 0.89), outperforming all other tested MR methods and coloc. Application of MR-link to low-density lipoprotein cholesterol (LDL-C) measurements in 12,449 individuals with expression and protein QTL summary statistics from blood and liver identifies 25 genes causally linked to LDL-C. These include the known SORT1 and ApoE genes as well as PVRL2, located in the APOE locus, for which a causal role in liver was not known. Our results showcase the strength of MR-link for transcriptome-wide causal inferences.


Assuntos
LDL-Colesterol/sangue , Regulação da Expressão Gênica , Predisposição Genética para Doença , Modelos Genéticos , Locos de Características Quantitativas , Proteínas Adaptadoras de Transporte Vesicular/genética , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , LDL-Colesterol/metabolismo , Simulação por Computador , Conjuntos de Dados como Assunto , Pleiotropia Genética , Humanos , Desequilíbrio de Ligação , Metabolismo dos Lipídeos/genética , Análise da Randomização Mendeliana , Redes e Vias Metabólicas/genética , Herança Multifatorial , Nectinas/genética , Nectinas/metabolismo , Países Baixos , Proteômica , RNA-Seq
2.
Nat Commun ; 11(1): 4727, 2020 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-32948752

RESUMO

The apolipoprotein E (APOE) gene contains both the major common risk variant for late onset Alzheimer's disease (AD), e4, and the major neuroprotective variant, e2. Here we examine the association of APOE e2 with multiple neurodegenerative pathologies, leveraging the NACC v. 10 database of 1557 brains that included 130 e2 carriers and 679 e4 carriers in order to examine potential neuroprotective effects. For AD-related pathologies of amyloid plaques and Braak stage, e2 had large and highly significant protective effects contrasted with e3/e3 and e4 carriers with odds ratios of about 0.50 for e3 contrasts and 0.10 for e4 contrasts. When we separately examined e2/e4 carriers, risk for AD pathologies was similar to that of e4 carriers, not e2 carriers. For multiple fronto-temporal lobar pathologies and tauopathies, e2 was not significantly associated with pathology. In sum, we found that e2 was associated with large but circumscribed protective effects.


Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Apolipoproteína E2/genética , Apolipoproteína E2/metabolismo , Genótipo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Encéfalo/metabolismo , Feminino , Degeneração Lobar Frontotemporal/metabolismo , Humanos , Modelos Logísticos , Masculino , Placa Amiloide/patologia , Tauopatias/metabolismo , alfa-Sinucleína/metabolismo
3.
PLoS One ; 15(8): e0238112, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32857805

RESUMO

This longitudinal study was performed to evaluate the feasibility of detecting the interaction between wall shear stress (WSS) and plaque development. 20 ApoE-/- mice were separated in 12 mice with Western Diet and 8 mice with Chow Diet. Magnetic resonance (MR) scans at 17.6 Tesla and histological analysis were performed after one week, eight and twelve weeks. All in vivo MR measurements were acquired using a flow sensitive phase contrast method for determining vectorial flow. Histological sections were stained with Hematoxylin and Eosin, Elastica van Gieson and CD68 staining. Data analysis was performed using Ensight and a Matlab-based "Flow Tool". The body weight of ApoE-/- mice increased significantly over 12 weeks. WSS values increased in the Western Diet group over the time period; in contrast, in the Chow Diet group the values decreased from the first to the second measurement point. Western Diet mice showed small plaque formations with elastin fragmentations after 8 weeks and big plaque formations after 12 weeks; Chow Diet mice showed a few elastin fragmentations after 8 weeks and small plaque formations after 12 weeks. Favored by high-fat diet, plaque formation results in higher values of WSS. With wall shear stress being a known predictor for atherosclerotic plaque development, ultra highfield MRI can serve as a tool for studying the causes and beginnings of atherosclerosis.


Assuntos
Aorta/diagnóstico por imagem , Imagem por Ressonância Magnética , Placa Aterosclerótica/diagnóstico por imagem , Animais , Aorta/patologia , Aorta/fisiopatologia , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Aterosclerose/diagnóstico por imagem , Aterosclerose/patologia , Aterosclerose/fisiopatologia , Peso Corporal , Dieta Ocidental , Modelos Animais de Doenças , Estudos de Viabilidade , Feminino , Estudos Longitudinais , Imagem por Ressonância Magnética/instrumentação , Imagem por Ressonância Magnética/métodos , Camundongos Knockout , Placa Aterosclerótica/patologia , Placa Aterosclerótica/fisiopatologia , Distribuição Aleatória , Fluxo Sanguíneo Regional , Estresse Mecânico
4.
Cardiovasc Ther ; 2020: 1615826, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32695227

RESUMO

Background: Stress cardiomyopathy (SCM) is a transient reversible left ventricular dysfunction that more often occurs in women. Symptoms of SCM patients are similar to those of acute coronary syndrome (ACS), but little is known about biomarkers. The goals of this study were to identify the potentially crucial genes and pathways associated with SCM. Methods: We analyzed microarray datasets GSE95368 derived from the Gene Expression Omnibus (GEO) database. Firstly, identify the differentially expressed genes (DEGs) between SCM patients in normal patients. Then, the DEGs were used for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Finally, the protein-protein interaction (PPI) network was constructed and Cytoscape was used to find the key genes. Results: In total, 25 DEGs were identified, including 10 upregulated genes and 15 downregulated genes. These DEGs were mainly enriched in ECM-receptor interaction, dilated cardiomyopathy (DCM), human papillomavirus infection, and focal adhesion, whereas in GO function classification, they were mainly enriched in the extracellular region, positive regulation of the multicellular organismal process, establishment of localization, and intracellular vesicle. Conclusion: Seven hub genes contained APOE, MFGE8, ALB, APOB, SAA1, A2M, and C3 identified as hub genes of SCM, which might be used as diagnostic biomarkers or molecular targets for the treatment of SCM.


Assuntos
Antígenos de Superfície/genética , Apolipoproteína B-100/genética , Apolipoproteínas E/genética , Complemento C3/genética , Proteínas do Leite/genética , Albumina Sérica Humana/genética , Proteína Amiloide A Sérica/genética , Cardiomiopatia de Takotsubo/genética , Transcriptoma , Função Ventricular Esquerda/genética , alfa-Macroglobulinas/genética , Bases de Dados Genéticas , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Mapas de Interação de Proteínas , Transdução de Sinais , Cardiomiopatia de Takotsubo/fisiopatologia
5.
Life Sci ; 257: 118086, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32679147

RESUMO

AIMS: To investigate the role of PP2A in calcified aortic valve disease (CAVD). MATERIALS AND METHODS: The expressions of PP2A subunits were detected by real-time polymerase chain reaction (RT-PCR) and western blot in aortic valves from patients with CAVD and normal controls, the activities of PP2A were analyzed by commercial assay kit at the same time. Aortic valve calcification of mice was evaluated through histological and echocardiographic analysis. ApoE-/- mice and ApoE-/- mice injected intraperitoneally with PP2A inhibitor LB100 were fed a high-cholesterol diet for 24 weeks. Immunofluorescent staining was used to locate the cell-type in which PP2A activity was decreased, the PP2A activity of valvular interstitial cells (VICs) treated with osteogenic induction medium was assessed by western blot and commercial assay kit. After changing the activity of VICs through pharmacologic and genetic intervention, the osteoblast differentiation and mineralization were assessed by western blot and Alizarin Red staining. Finally, the mechanism was clarified by using several specific inhibitors. KEY FINDINGS: PP2A activity was decreased both in calcified aortic valves and human VICs under osteogenic induction. The PP2A inhibitor LB100 aggravated the aortic valve calcification of mice. Furthermore, PPP2CA overexpression inhibited osteogenic differentiation of VICs, whereas PPP2CA knockdown promoted the process. Further study revealed that the ERK/p38 MAPKs signaling pathways mediated the osteogenic differentiation of VICs induced by PP2A inactivation. SIGNIFICANCE: This study demonstrated that PP2A plays an important role in CAVD pathophysiology, PP2A activation may provide a novel strategy for the pharmacological treatment of CAVD.


Assuntos
Estenose da Valva Aórtica/fisiopatologia , Valva Aórtica/patologia , Apolipoproteínas E/genética , Calcinose/fisiopatologia , Osteogênese/genética , Proteína Fosfatase 2/genética , Animais , Valva Aórtica/fisiopatologia , Estenose da Valva Aórtica/genética , Calcinose/genética , Diferenciação Celular/genética , Técnicas de Silenciamento de Genes , Humanos , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Piperazinas/farmacologia , Reação em Cadeia da Polimerase em Tempo Real , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
8.
Life Sci ; 257: 117658, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32621921

RESUMO

BACKGROUND: Curcumin (Cur) is a hydrophobic polyphenol compound derived from the rhizome of the herb Curcuma longa. Cur has a wide spectrum of biological and pharmacological activities. It has been shown that human cytomegalovirus (HCMV) infection was an important risk factor for atherosclerosis (AS) and Cur exhibited an outstanding anti-HCMV effect. However, anti-AS effects of Cur remain unclear when HCMV infected endothelial cells. AIMS: This study will investigate the anti-AS activities and mechanism of Cur,when HCMV infected in vivo and in vitro. MATERIALS AND METHODS: Cur (0.5, 1, and 2 µM) was used to explore the anti-AS activities and mechanism after HCMV infected endothelial cells in vitro. ApoE-/- mice were fed a high fat and cholesterol diet (HD) and given 4000,000 copies/mouse MCMV infection by intraperitoneal and treated with ganciclovir (5 mg/kg/d), Cur (25, 15 mg/kg/d) for 10 weeks in vivo. KEY FINDINGS: As our results showed that Cur inhibited CMV replication and proliferation, reduced the intracellular ROS overproduction, decreased the release of inflammatory cytokines, down-regulated the level of HMGB1-TLRS-NF-κB signaling pathway-related proteins in vitro experiments. Cur reduced the serum levels of LDL-C, TC and TG, significantly decreased the formation of atherosclerotic plaque in the aorta, reduced the lipid deposition in liver and inflammatory damage in heart, lung and kidney in vivo experiments. SIGNIFICANCE: This study showed that Cur prevent AS progression by inhibiting CMV activity and CMV-induced HMGB1-TLRS-NF-κB signaling pathway.


Assuntos
Aterosclerose/tratamento farmacológico , Curcumina/farmacologia , Citomegalovirus/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Aterosclerose/metabolismo , Curcuma/metabolismo , Curcumina/metabolismo , Citocinas/metabolismo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Camundongos , Camundongos Transgênicos , NF-kappa B/metabolismo , Extratos Vegetais/farmacologia , Placa Aterosclerótica/metabolismo , Transdução de Sinais/efeitos dos fármacos
9.
PLoS One ; 15(7): e0235553, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32614927

RESUMO

Aortic aneurysm refers to dilatation of the aorta due to loss of elasticity and degenerative weakening of its wall. A preventive role for osteoprotegerin (Opg) in the development of abdominal aortic aneurysm has been reported in the CaCl2-induced aneurysm model, whereas Opg was found to promote suprarenal aortic aneurysm in the AngII-induced ApoE knockout mouse aneurysm model. To determine whether there is a common underlying mechanism to explain the impact of Opg deficiency on the vascular structure of the two aneurysm models, we analyzed suprarenal aortic tissue of 6-month-old ApoE-/-Opg-/- mice after AngII infusion for 28 days. Less aortic dissection and aortic lumen dilatation, more adventitial thickening, and higher expression of collagen I and Trail were observed in ApoE-/-Opg-/- mice relative to ApoE-/-Opg+/+ mice. An accumulation of α-smooth muscle actin and vimentin double-positive myofibroblasts was noted in the thickened adventitia of ApoE-/-Opg-/- mice. Our results suggest that fibrotic remodeling of the aorta induced by myofibroblast accumulation might be an important pathological event which tends to limit AngII-induced aortic dilatation in ApoE -/-Opg-/- mice.


Assuntos
Túnica Adventícia/patologia , Aneurisma da Aorta Abdominal/patologia , Osteoprotegerina/genética , Túnica Adventícia/fisiologia , Angiotensina II/farmacologia , Animais , Aorta Abdominal/patologia , Aorta Abdominal/fisiologia , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Colesterol/sangue , Colágeno Tipo I/metabolismo , Modelos Animais de Doenças , Fibrose , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miofibroblastos/citologia , Miofibroblastos/metabolismo , Osteoprotegerina/deficiência , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Regulação para Cima/efeitos dos fármacos
10.
PLoS One ; 15(6): e0234857, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32559215

RESUMO

The Lipocalin Apolipoprotein D (ApoD) is one of the few genes consistently overexpressed in the aging brain, and in most neurodegenerative and psychiatric diseases. Its functions include metabolism regulation, myelin management, neuroprotection, and longevity regulation. Knowledge of endogenous regulatory mechanisms controlling brain disease-triggered ApoD expression is relevant if we want to boost pharmacologically its neuroprotecting potential. In addition to classical transcriptional control, Lipocalins have a remarkable variability in mRNA 5'UTR-dependent translation efficiency. Using bioinformatic analyses, we uncover strong selective pressures preserving ApoD 5'UTR properties, indicating unexpected functional conservation. PCR amplifications demonstrate the production of five 5'UTR variants (A-E) in mouse ApoD, with diverse expression levels across tissues and developmental stages. Importantly, Variant E is specifically expressed in the oxidative stress-challenged brain. Predictive analyses of 5'UTR secondary structures and enrichment in elements restraining translation, point to Variant E as a tight regulator of ApoD expression. We find two genomic regions conserved in human and mouse ApoD: a canonical (α) promoter region and a previously unknown region upstream of Variant E that could function as an alternative mouse promoter (ß). Luciferase assays demonstrate that both α and ß promoter regions can drive expression in cultured mouse astrocytes, and that Promoter ß activity responds proportionally to incremental doses of the oxidative stress generator Paraquat. We postulate that Promoter ß works in association with Variant E 5'UTR as a regulatory tandem that organizes ApoD gene expression in the nervous system in response to oxidative stress, the most common factor in aging and neurodegeneration.


Assuntos
Regiões 5' não Traduzidas , Apolipoproteínas D/genética , Apolipoproteínas E/genética , Regiões Promotoras Genéticas , Animais , Apolipoproteínas D/metabolismo , Apolipoproteínas E/metabolismo , Astrócitos/metabolismo , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Linhagem Celular , Herbicidas/toxicidade , Lipocalinas/genética , Lipocalinas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Estresse Oxidativo , Paraquat/toxicidade , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
11.
Neuron ; 107(3): 496-508.e6, 2020 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-32526197

RESUMO

Here, we perform a genome-wide screen for variants that regulate the expression of gene co-expression modules in the aging human brain; we discover and replicate such variants in the TMEM106B and RBFOX1 loci. The TMEM106B haplotype is known to influence the accumulation of TAR DNA-binding protein 43 kDa (TDP-43) proteinopathy, and the haplotype's large-scale transcriptomic effects include the dysregulation of lysosomal genes and alterations in synaptic gene splicing that are also seen in the pathophysiology of TDP-43 proteinopathy. Further, a variant near GRN, another TDP-43 proteinopathy susceptibility gene, shows concordant effects with the TMEM106B haplotype. Leveraging neuropathology data from the same participants, we also show that TMEM106B and APOE-amyloid-ß effects converge to alter myelination and lysosomal gene expression, which then contributes to TDP-43 accumulation. These results advance our mechanistic understanding of the TMEM106B TDP-43 risk haplotype and uncover a transcriptional program that mediates the converging effects of APOE-amyloid-ß and TMEM106B on TDP-43 aggregation in older adults.


Assuntos
Envelhecimento/genética , Encéfalo/metabolismo , Regulação da Expressão Gênica/genética , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Progranulinas/genética , Fatores de Processamento de RNA/genética , Proteinopatias TDP-43/genética , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/psicologia , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/metabolismo , Apolipoproteínas E/genética , Encéfalo/patologia , Estudos de Coortes , Proteínas de Ligação a DNA/metabolismo , Feminino , Haplótipos , Humanos , Lisossomos , Masculino , Bainha de Mielina , Locos de Características Quantitativas , Proteinopatias TDP-43/psicologia
12.
Arch Biochem Biophys ; 689: 108453, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32524996

RESUMO

Nitric oxide (NO) deficiency and NADPH oxidase plays key roles in endothelial dysfunction and atherosclerotic plaque formation. Recent evidence demonstrates that nitrate-nitrite-NO pathway in vivo exerts beneficial effects upon the cardiovascular system. We aimed to investigate the effects of dietary nitrate on endothelial function and atherosclerosis in apolipoprotein E knockout (ApoE-/-) mice fed a high-fat diet. It was shown that dietary nitrate significantly attenuated aortic endothelial dysfunction and atherosclerosis in ApoE-/- mice. Mechanistic studies revealed that dietary nitrate significantly improved plasma nitrate/nitrite, inhibited vascular NADPH oxidase activity and oxidative stress in ApoE-/- mice, while xanthine oxidoreductase (XOR) expression and activity was enhanced in ApoE-/- mice in comparison with wide type animals. These beneficial effects of nitrate in ApoE-/- mice were abolished by PTIO (NO scavenger) and significantly prevented by febuxostat (XOR inhibitor). In the presence of nitrate, no further effect of apocynin (NADPH oxidase inhibitor) was observed, suggesting NADPH oxidase as a possible target. In vitro, NO donor significantly inhibited NADPH oxidase activity in vascular endothelial cells via the induction of heme oxygenase-1. Altogether, boosting this nitrate-nitrite-NO signaling pathway resulted in the decreases of vascular NADPH oxidase-derived oxidative stress and endothelial dysfunction, and consequently protected ApoE-/- mice against atherosclerosis. These findings may have novel nutritional implications for the preventive and therapeutic strategies against vascular endothelial dysfunction in atherosclerotic disease.


Assuntos
Aterosclerose/terapia , Endotélio Vascular/patologia , NADPH Oxidases/metabolismo , Nitratos/uso terapêutico , Animais , Apolipoproteínas E/genética , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Dieta Hiperlipídica/efeitos adversos , Suplementos Nutricionais , Modelos Animais de Doenças , Endotélio Vascular/metabolismo , Masculino , Camundongos , Camundongos Knockout , Nitratos/metabolismo , Nitritos/metabolismo , Estresse Oxidativo
13.
Neurology ; 95(2): e166-e178, 2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32580974

RESUMO

OBJECTIVE: To investigate sex differences in late-onset Alzheimer disease (AD) risks by means of multimodality brain biomarkers (ß-amyloid load via 11C-Pittsburgh compound B [PiB] PET, neurodegeneration via 18F-fluorodeoxyglucose [FDG] PET and structural MRI). METHODS: We examined 121 cognitively normal participants (85 women and 36 men) 40 to 65 years of age with clinical, laboratory, neuropsychological, lifestyle, MRI, FDG- and PiB-PET examinations. Several clinical (e.g., age, education, APOE status, family history), medical (e.g., depression, diabetes mellitus, hyperlipidemia), hormonal (e.g., thyroid disease, menopause), and lifestyle AD risk factors (e.g., smoking, diet, exercise, intellectual activity) were assessed. Statistical parametric mapping and least absolute shrinkage and selection operator regressions were used to compare AD biomarkers between men and women and to identify the risk factors associated with sex-related differences. RESULTS: Groups were comparable on clinical and cognitive measures. After adjustment for each modality-specific confounders, the female group showed higher PiB ß-amyloid deposition, lower FDG glucose metabolism, and lower MRI gray and white matter volumes compared to the male group (p < 0.05, family-wise error corrected for multiple comparisons). The male group did not show biomarker abnormalities compared to the female group. Results were independent of age and remained significant with the use of age-matched groups. Second to female sex, menopausal status was the predictor most consistently and strongly associated with the observed brain biomarker differences, followed by hormone therapy, hysterectomy status, and thyroid disease. CONCLUSION: Hormonal risk factors, in particular menopause, predict AD endophenotype in middle-aged women. These findings suggest that the window of opportunity for AD preventive interventions in women is early in the endocrine aging process.


Assuntos
Doença de Alzheimer/epidemiologia , Imagem Multimodal , Neuroimagem , Adulto , Idoso , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/psicologia , Compostos de Anilina , Apolipoproteínas E/genética , Feminino , Fluordesoxiglucose F18 , Hormônios/sangue , Humanos , Estilo de Vida , Imagem por Ressonância Magnética , Masculino , Menopausa/psicologia , Pessoa de Meia-Idade , Testes Neuropsicológicos , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Fatores de Risco , Fatores Sexuais , Tiazóis
14.
BMC Neurol ; 20(1): 231, 2020 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-32503473

RESUMO

BACKGROUND: By 2050, the prevalence of Alzheimer's disease (AD) in the United States is predicted to reach 13.8 million. Despite worldwide research efforts, a cure for AD has not been identified. Thus, it is critical to identify preventive strategies that can reduce the risk of or delay the onset of AD. Physical activity (PA) has potential in this regard. This randomized clinical trial aims to (a) test the causal relationship between PA and AD-associated cognitive function for persons with a family history of AD (FH+), (b) determine the moderating role of apolipoprotein epsilon 4 (APOE4) carrier status on cognition, and (c) assess cerebral structure, cerebral function, and putative biomarkers as mediators of the effects of PA on cognition. METHODS: We are recruiting cognitively normal, middle aged (40-65 years) sedentary adults with FH+. Participants are randomly assigned to a 12-month PA intervention for 3 days/week or to a control group maintaining their normal lifestyle. Saliva samples are taken at pre-test to determine APOE genotype. At pre-, mid-, and post-tests, participants complete a series of cognitive tests to assess information-processing speed, verbal and visual episodic memory, constructional praxis, mnemonic discrimination, and higher-order executive functions. At pre- and post-tests, brain imaging and blood biomarkers are assessed. DISCUSSION: We hypothesize that 1) the PA group will demonstrate improved cognition compared with controls; 2) PA-derived cognitive changes will be moderated by APOE4 status; and 3) PA-induced changes in neural and blood biomarkers will contribute to cognitive changes and differ as a function of APOE4 status. Our results may provide important insights into the potential of PA to preserve neurocognitive function in people with a heightened risk of AD due to FH+ and as moderated by APOE4 status. By using sophisticated analytic techniques to assess APOE as a moderator and neurobiological mechanisms as mediators across trajectories of cognitive change in response to PA, we will advance our understanding of the potential of PA in protecting against AD. TRIAL REGISTRATION: ClinicalTrials.gov NCT03876314. Registered March 15, 2019.


Assuntos
Doença de Alzheimer , Apolipoproteínas E/genética , Cognição/fisiologia , Terapia por Exercício , Exercício Físico/fisiologia , Adulto , Idoso , Doença de Alzheimer/genética , Doença de Alzheimer/terapia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Genótipo , Humanos , Pessoa de Meia-Idade
15.
Int J Nanomedicine ; 15: 2809-2828, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32368056

RESUMO

Introduction: Glioblastoma (GBM) is the most common and lethal of the central nervous system (CNS) malignancies. The initiation, progression, and infiltration ability of GBMs are attributed in part to the dysregulation of microRNAs (miRNAs). Thus, targeting dysregulated miRNAs with RNA oligonucleotides (RNA interference, RNAi) has been proposed for GBM treatment. Despite promising results in the laboratory, RNA oligonucleotides have clinical limitations that include poor RNA stability and off-target effects. RNAi therapies against GBM confront an additional obstacle, as they need to cross the blood-brain barrier (BBB). Methods: Here, we developed gold-liposome nanoparticles conjugated with the brain targeting peptides apolipoprotein E (ApoE) and rabies virus glycoprotein (RVG). First, we functionalized gold nanoparticles with oligonucleotide miRNA inhibitors (OMIs), creating spherical nucleic acids (SNAs). Next, we encapsulated SNAs into ApoE, or RVG-conjugated liposomes, to obtain SNA-Liposome-ApoE and SNA-Liposome-RVG, respectively. We characterized each nanoparticle in terms of their size, charge, encapsulation efficiency, and delivery efficiency into U87 GBM cells in vitro. Then, they were administered intravenously (iv) in GBM syngeneic mice to evaluate their delivery efficiency to brain tumor tissue. Results: SNA-Liposomes of about 30-50 nm in diameter internalized U87 GBM cells and inhibited the expression of miRNA-92b, an aberrantly overexpressed miRNA in GBM cell lines and GBM tumors. Conjugating SNA-Liposomes with ApoE or RVG peptides increased their systemic delivery to the brain tumors of GBM syngeneic mice. SNA-Liposome-ApoE demonstrated to accumulate at higher extension in brain tumor tissues, when compared with non-treated controls, SNA-Liposomes, or SNA-Liposome-RVG. Discussion: SNA-Liposome-ApoE has the potential to advance the translation of miRNA-based therapies for GBM as well as other CNS disorders.


Assuntos
Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Lipossomos/administração & dosagem , Interferência de RNA , Animais , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Técnicas de Transferência de Genes , Glioblastoma/genética , Glioblastoma/patologia , Ouro/química , Humanos , Lipossomos/química , Masculino , Nanopartículas Metálicas/química , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Ácidos Nucleicos/química , Oligonucleotídeos/química , Oligonucleotídeos/genética , Oligonucleotídeos/farmacocinética , Proteínas do Envelope Viral/genética , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Arterioscler Thromb Vasc Biol ; 40(6): e166-e179, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32349534

RESUMO

OBJECTIVE: Recent studies suggest that the P2Y12 (P2Y purinoceptor 12) receptor of vascular smooth muscle cells in atherosclerotic plaques aggravates atherosclerosis, and P2Y12 receptor inhibitors such as CDL (clopidogrel) may effectively treat atherosclerosis. It is imperative to identify an effective biomarker for reflecting the P2Y12 receptor expression on vascular smooth muscle cells in plaques. Approach and Results: We found that there was a positive correlation between the level of circulating sLRP1 (soluble low-density lipoprotein receptor-related protein 1) and the number of LRP1+ α-SMA+ (α-smooth muscle actin), P2Y12+, or P2Y12+ LRP1+ cells in plaques from apoE-/- mice fed a high-fat diet. Furthermore, activation of the P2Y12 receptor increased the expression and shedding of LRP1 in vascular smooth muscle cells by inhibiting cAMP (3'-5'-cyclic adenosine monophosphate)/PKA (protein kinase A)/SREBP-2 (sterol regulatory element binding transcription factor 2). Conversely, genetic knockdown or pharmacological inhibition of the P2Y12 receptor had the opposite effects. Additionally, CDL decreased the number of lesional LRP1+ α-SMA+ cells and the levels of circulating sLRP1 by activating cAMP/PKA/SREBP-2 in apoE-/- mice fed a high-fat diet. CONCLUSIONS: Our study suggests that sLRP1 may be a biomarker that reflects the P2Y12 receptor level in plaques and has the potential to be an indicator for administering P2Y12 receptor inhibitors for patients with atherosclerosis.


Assuntos
Biomarcadores/análise , Expressão Gênica , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/análise , Placa Aterosclerótica/metabolismo , Receptores Purinérgicos P2Y12/genética , Actinas/análise , Animais , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Apolipoproteínas E/fisiologia , Clopidogrel/farmacologia , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Dieta Hiperlipídica , Técnicas de Silenciamento de Genes , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Liso Vascular/química , Músculo Liso Vascular/metabolismo , Placa Aterosclerótica/química , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Receptores Purinérgicos P2Y12/efeitos dos fármacos , Receptores Purinérgicos P2Y12/fisiologia , Transdução de Sinais , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo
17.
Curr Atheroscler Rep ; 22(4): 13, 2020 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-32440785

RESUMO

PURPOSE OF REVIEW: Intracranial atherosclerosis (ICAS) is the most common cause of stroke throughout the world. It also increases the risk of recurrent stroke and dementia. As a complex and multifactorial disease, ICAS is influenced by multiple genetic, biological, and environmental factors. This review summarizes the candidate gene and genome-wide studies aimed at discovering genetic risk factors of ICAS. RECENT FINDINGS: Numerous studies have focused on the association between single-nucleotide polymorphisms (SNPs) of atherosclerosis-related genes and the risk of ICAS. Variants in adiponectin Q (ADIPOQ), ring finger protein 213 (RNF213), apolipoprotein E (APOE), phosphodiesterase 4D (PDE4D), methylenetetrahydrofolate reductase (MTHFR), lipoprotein lipase (LPL), α-adducin (ADD1) genes, angiotensin-converting enzyme (ACE), and other genes related to renin-angiotensin-aldosterone system have been associated with ICAS. We review the available evidences on the candidate genes and SNPs associated with genetic susceptibility to ICAS, and point out future developments of this field. Genetic discoveries could have clinical implications for intracranial atherosclerotic disease.


Assuntos
Predisposição Genética para Doença/genética , Arteriosclerose Intracraniana/genética , Adenosina Trifosfatases/genética , Adiponectina/genética , Apolipoproteínas E/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/genética , Feminino , Humanos , Lipase Lipoproteica/genética , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Pessoa de Meia-Idade , Peptidil Dipeptidase A/genética , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Ubiquitina-Proteína Ligases/genética
18.
Life Sci ; 252: 117601, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32304762

RESUMO

AIM: This work was to investigate the relationship between ApoE and autophagy regulated by AMPK/mTOR pathway in the pathological process of NAFLD. MAIN METHODS: Both WT and ApoE-/- mice were divided into two groups and allocated into either a normal chow (ND) or a high-fat diet (HFD) for 8 weeks. After that, we detected the indicators of lipid accumulation, hepatic injury, mitochondrial function hallmark, autophagy, apoptosis, inflammation, and oxidative stress by commercially available kits, immunohistochemistry, immunofluorescent staining, and western blot. KEY FINDING: We found the lipid levels of serum and liver, and hepatic injury were significantly increased in the ApoE-/--HFD group compared to other groups. ApoE-/- mice exhibited increased deposition of fat in liver tissue. The PGC1α, NRF1, ATP, p-AMPK, AMPK, Beclin1, and LC3 levels were downregulated and ROS, p-mTOR, and mTOR were increased in the ApoE-/--HFD group compared to WT-HFD group. When treated with AMPK and autophagy activators, AICAR and rapamycin, these pathologies and protein levels can be rescued. The expression levels of apoptosis-related proteins, inflammation, and oxidative stress were increased in the ApoE-/--HFD group compared to the WT-HFD group. SIGNIFICANCE: Our results indicated that ApoE deficiency can regulate AMPK/mTOR pathway, which leads to NAFLD most likely by modulating hepatic mitochondrial function.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Apolipoproteínas E/genética , Autofagia/genética , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Serina-Treonina Quinases TOR/metabolismo , Animais , Apoptose/genética , Dieta Hiperlipídica , Modelos Animais de Doenças , Feminino , Inflamação/genética , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Mitocôndrias/metabolismo , Hepatopatia Gordurosa não Alcoólica/genética , Estresse Oxidativo/genética
19.
Metabolism ; 107: 154226, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32277945

RESUMO

BACKGROUND: Aberrant endothelial function is a major contributing factor in cardiovascular disease. Dyslipidemia leads to decreased nitric oxide (NO) bioavailability, an early sign of endothelial failure. Low insulin gene enhancer protein (ISL1) levels decrease healthy NO bioavailability. We hypothesized that the microRNA miR-652-3p negatively regulates endothelial ISL1 expression and that dyslipidemia-induced miR-652-3p upregulation induces aberrant endothelial functioning via ISL1 downregulation. METHODS: Various in vitro experiments were conducted in human umbilical vein endothelial cells (HUVECs). Luciferase assays were performed in HEK293 cells. We constructed a high-fat diet (HFD) Apoe-/- murine model of dyslipidemia and a rat model of low-density lipoprotein (LDL)-induced dyslipidemia to conduct in vivo and ex vivo experiments. RESULTS: Luciferase assays confirmed miR-652-3p's targeting of the ISL1 3'-untranslated region (3'-UTR). Simvastatin blocked oxidized LDL (ox-LDL)-induced increases in miR-652-3p and ox-LDL-induced decreases in ISL1 protein expression, endothelial NO synthase (eNOS) activation, and NO production. Simvastatin's effects were abrogated by miR-652-3p overexpression and phenocopied by miR-652-3p inhibition. The dyslipidemic mouse model exhibited increased miR-652-3p and decreased ISL1 protein levels in the endothelium, effects opposed by simvastatin or miR-652-3p inhibition. The impact of simvastatin in vivo was abolished by overexpressing miR-652-3p or knocking-down ISL1. The rat model of dyslipidemia exhibited a similar pattern of miR-652-3p upregulation, attenuated ISL1 protein levels, decreased eNOS activation, and decreased NO production, effects mitigated by simvastatin. CONCLUSIONS: Dyslipidemia upregulates endothelial miR-652-3p, which decreases ISL1 protein levels, eNOS activation, and NO production. Simvastatin therapy lowers endothelial miR-652-3p expression to protect endothelial function under dyslipidemic conditions.


Assuntos
Dislipidemias/patologia , Dislipidemias/prevenção & controle , Endotélio/patologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Proteínas com Homeodomínio LIM/biossíntese , MicroRNAs/biossíntese , Fatores de Transcrição/biossíntese , Animais , Apolipoproteínas E/genética , Regulação para Baixo/efeitos dos fármacos , Dislipidemias/genética , Ativação Enzimática , Regulação da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/efeitos dos fármacos , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo III/metabolismo , Ratos , Ratos Sprague-Dawley
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