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1.
Zhonghua Yi Xue Za Zhi ; 101(15): 1093-1096, 2021 Apr 20.
Artículo en Chino | MEDLINE | ID: mdl-33878838

RESUMEN

Three cases with age-related cerebral small vessel disease and normal pressure hydrocephalus in the Department of Neurology of Sun Yat-sen University were retrospectively reviewed. All the patients exhibited gait disturbance, cognitive impairment and urinary incontinence. Meanwhile, the Craniocerebral imaging demonstrated cerebral small vessel disease and communicating hydrocephalus. The cerebralspinal fluid (CSF) Aß42 levels decreased, and apolipoprotein E (APOE) genotypes were ε3/ε4,ε3/ε3,ε2/ε3, respectively. After treatment in an all-cause individualized manner, the symptoms of 3 patients were stable or improved.


Asunto(s)
Enfermedades de los Pequeños Vasos Cerebrales , Hidrocéfalo Normotenso , Anciano , Alelos , Apolipoproteínas E/genética , Cognición , Marcha , Genotipo , Humanos , Estudios Retrospectivos
2.
Nat Commun ; 12(1): 2076, 2021 04 06.
Artículo en Inglés | MEDLINE | ID: mdl-33824317

RESUMEN

Knowledge of genomic features specific to the human lineage may provide insights into brain-related diseases. We leverage high-depth whole genome sequencing data to generate a combined annotation identifying regions simultaneously depleted for genetic variation (constrained regions) and poorly conserved across primates. We propose that these constrained, non-conserved regions (CNCRs) have been subject to human-specific purifying selection and are enriched for brain-specific elements. We find that CNCRs are depleted from protein-coding genes but enriched within lncRNAs. We demonstrate that per-SNP heritability of a range of brain-relevant phenotypes are enriched within CNCRs. We find that genes implicated in neurological diseases have high CNCR density, including APOE, highlighting an unannotated intron-3 retention event. Using human brain RNA-sequencing data, we show the intron-3-retaining transcript to be more abundant in Alzheimer's disease with more severe tau and amyloid pathological burden. Thus, we demonstrate potential association of human-lineage-specific sequences in brain development and neurological disease.


Asunto(s)
Apolipoproteínas E/genética , Genoma Humano , Enfermedades Neurodegenerativas/genética , Filogenia , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Encéfalo/patología , Cromosomas Humanos Par 19/genética , Secuencia Conservada/genética , ADN Intergénico/genética , Ontología de Genes , Humanos , Intrones/genética , Desequilibrio de Ligamiento/genética , Anotación de Secuencia Molecular , Fenotipo , Polimorfismo de Nucleótido Simple/genética , ARN Largo no Codificante/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Análisis de Regresión
3.
Molecules ; 26(6)2021 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-33802165

RESUMEN

Dementia is one of the most disabling non-motor symptoms in Parkinson's disease (PD). Unlike in Alzheimer's disease, the vascular pathology in PD is less documented. Due to the uncertain role of commonly investigated metabolic or vascular factors, e.g., hypertension or diabetes, other factors corresponding to PD dementia have been proposed. Associated dysautonomia and dopaminergic treatment seem to have an impact on diurnal blood pressure (BP) variability, which may presumably contribute to white matter hyperintensities (WMH) development and cognitive decline. We aim to review possible vascular and metabolic factors: Renin-angiotensin-aldosterone system, vascular endothelial growth factor (VEGF), hyperhomocysteinemia (HHcy), as well as the dopaminergic treatment, in the etiopathogenesis of PD dementia. Additionally, we focus on the role of polymorphisms within the genes for catechol-O-methyltransferase (COMT), apolipoprotein E (APOE), vascular endothelial growth factor (VEGF), and for renin-angiotensin-aldosterone system components, and their contribution to cognitive decline in PD. Determining vascular risk factors and their contribution to the cognitive impairment in PD may result in screening, as well as preventive measures.


Asunto(s)
Disfunción Cognitiva/fisiopatología , Enfermedad de Parkinson/fisiopatología , Apolipoproteínas E/genética , Presión Arterial/fisiología , Catecol O-Metiltransferasa/genética , Catecol O-Metiltransferasa/metabolismo , Disfunción Cognitiva/sangre , Humanos , Hiperhomocisteinemia/metabolismo , Hiperhomocisteinemia/fisiopatología , Enfermedad de Parkinson/sangre , Sistema Renina-Angiotensina/fisiología , Factores de Riesgo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/fisiología , Sustancia Blanca/patología
4.
Neuron ; 109(6): 907-909, 2021 03 17.
Artículo en Inglés | MEDLINE | ID: mdl-33735610

RESUMEN

In this issue of Neuron, Li et al. (2021) demonstrate that ApoE lipoprotein particles shuttle miRNAs from astrocytes to neurons, leading to inhibition of cholesterol biosynthesis and an increase in histone acetylation in neurons.


Asunto(s)
Astrocitos , MicroARNs , Acetilación , Apolipoproteínas E/genética , Astrocitos/metabolismo , Células Cultivadas , Colesterol , Histonas , MicroARNs/genética , MicroARNs/metabolismo , Neuronas/metabolismo
5.
Nat Commun ; 12(1): 1889, 2021 03 25.
Artículo en Inglés | MEDLINE | ID: mdl-33767172

RESUMEN

Plasma low-density lipoprotein (LDL) is primarily cleared by LDL receptor (LDLR). LDLR can be proteolytically cleaved to release its soluble ectodomain (sLDLR) into extracellular milieu. However, the proteinase responsible for LDLR cleavage is unknown. Here we report that membrane type 1-matrix metalloproteinase (MT1-MMP) co-immunoprecipitates and co-localizes with LDLR and promotes LDLR cleavage. Plasma sLDLR and cholesterol levels are reduced while hepatic LDLR is increased in mice lacking hepatic MT1-MMP. Opposite effects are observed when MT1-MMP is overexpressed. MT1-MMP overexpression significantly increases atherosclerotic lesions, while MT1-MMP knockdown significantly reduces cholesteryl ester accumulation in the aortas of apolipoprotein E (apoE) knockout mice. Furthermore, sLDLR is associated with apoB and apoE-containing lipoproteins in mouse and human plasma. Plasma levels of sLDLR are significantly increased in subjects with high plasma LDL cholesterol levels. Thus, we demonstrate that MT1-MMP promotes ectodomain shedding of hepatic LDLR, thereby regulating plasma cholesterol levels and the development of atherosclerosis.


Asunto(s)
Apolipoproteína B-100/sangre , Apolipoproteínas E/sangre , Aterosclerosis/patología , Lipoproteínas LDL/sangre , Metaloproteinasa 14 de la Matriz/metabolismo , Receptores de LDL/metabolismo , Animales , Apolipoproteínas E/genética , Línea Celular Tumoral , Ésteres del Colesterol/metabolismo , Dependovirus/genética , Femenino , Células HEK293 , Células Hep G2 , Humanos , Masculino , Metaloproteinasa 14 de la Matriz/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados
6.
Mol Med Rep ; 23(6)2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-33786610

RESUMEN

Thoracic radiotherapy is an effective treatment for many types of cancer; however it is also associated with an increased risk of developing cardiovascular disease (CVD), appearing mainly ≥10 years after radiation exposure. The present study investigated acute and early term physiological and molecular changes in the cardiovascular system after ionizing radiation exposure. Female and male ApoE­/­ mice received a single exposure of low or high dose X­ray thoracic irradiation (0.1 and 10 Gy). The level of cholesterol and triglycerides, as well as a large panel of inflammatory markers, were analyzed in serum samples obtained at 24 h and 1 month after irradiation. The secretion of inflammatory markers was further verified in vitro in coronary artery and microvascular endothelial cell lines after exposure to low and high dose of ionizing radiation (0.1 and 5 Gy). Local thoracic irradiation of ApoE­/­ mice increased serum growth differentiation factor­15 (GDF­15) and C­X­C motif chemokine ligand 10 (CXCL10) levels in both female and male mice 24 h after high dose irradiation, which were also secreted from coronary artery and microvascular endothelial cells in vitro. Sex­specific responses were observed for triglyceride and cholesterol levels, and some of the assessed inflammatory markers as detailed below. Male ApoE­/­ mice demonstrated elevated intercellular adhesion molecule­1 and P­selectin at 24 h, and adiponectin and plasminogen activator inhibitor­1 at 1 month after irradiation, while female ApoE­/­ mice exhibited decreased monocyte chemoattractant protein­1 and urokinase­type plasminogen activator receptor at 24 h, and basic fibroblast growth factor 1 month after irradiation. The inflammatory responses were mainly significant following high dose irradiation, but certain markers showed significant changes after low dose exposure. The present study revealed that acute/early inflammatory responses occurred after low and high dose thoracic irradiation. However, further research is required to elucidate early asymptomatic changes in the cardiovascular system post thoracic X­irradiation and to investigate whether GDF­15 and CXCL10 could be considered as potential biomarkers for the early detection of CVD risk in thoracic radiotherapy­treated patients.


Asunto(s)
Apolipoproteínas E/genética , Aterosclerosis/metabolismo , Quimiocina CXCL10/metabolismo , Endotelio Vascular/efectos de la radiación , Factor 15 de Diferenciación de Crecimiento/metabolismo , Rayos X , Animales , Apolipoproteínas E/deficiencia , Aterosclerosis/genética , Molécula 1 de Adhesión Celular/genética , Molécula 1 de Adhesión Celular/metabolismo , Línea Celular , Células Cultivadas , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Quimiocina CXCL10/genética , Células Endoteliales/metabolismo , Células Endoteliales/efectos de la radiación , Endotelio Vascular/citología , Femenino , Factor 1 de Crecimiento de Fibroblastos/genética , Factor 1 de Crecimiento de Fibroblastos/metabolismo , Factor 15 de Diferenciación de Crecimiento/genética , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Selectina-P/genética , Selectina-P/metabolismo , Receptores del Activador de Plasminógeno Tipo Uroquinasa/genética , Receptores del Activador de Plasminógeno Tipo Uroquinasa/metabolismo
7.
Sheng Li Xue Bao ; 73(1): 42-50, 2021 Feb 25.
Artículo en Chino | MEDLINE | ID: mdl-33665659

RESUMEN

This study was designed to evaluate the role of short-chain fatty acid butyrate acid on intestinal morphology and function, and atherosclerotic plaque formation in apolipoprotein E-knockout (ApoE-/-) mice. ApoE-/- mice on high-fat, high-cholesterol diet were treated with butyrate acid (200 mmol/L) or NaCl (control) in the drinking water for 12 weeks, followed by histological evaluations of atherosclerotic lesion in aorta. Real-time PCR analysis and ELISA were used to measure the expression levels of proinflammatory cytokines. Butyrate acid significantly attenuated high-fat, high-cholesterol diet-induced atherosclerotic plaque formation in ApoE-/- mice. Butyrate acid prevented high-fat, high-cholesterol diet-induced inflammation in both the aorta and the circulation, as evidenced by reduced expression of proinflammatory cytokines. These changes were accompanied by a marked attenuation in metabolic endotoxemia lipopolysaccharide (LPS). Butyrate acid induced intestinal expression of the tight junction proteins (Occludin and zona occuldens protein-1), thereby preventing the gut permeability. Butyrate acid dose-dependently upregulated the expression of the tight junction proteins in Caco-2 cells in GPR41-dependent manner. In conclusion, butyrate acid attenuates atherosclerotic lesions by ameliorating metabolic endotoxemia-induced inflammation through restoration of the gut barrier.


Asunto(s)
Aterosclerosis , Placa Aterosclerótica , Animales , Apolipoproteínas E/genética , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/prevención & control , Butiratos/farmacología , Células CACO-2 , Dieta Alta en Grasa/efectos adversos , Ácidos Grasos Volátiles , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados
8.
Nat Metab ; 3(2): 166-181, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33619382

RESUMEN

Stable atherosclerotic plaques are characterized by a thick, extracellular matrix-rich fibrous cap populated by protective ACTA2+ myofibroblast (MF)-like cells, assumed to be almost exclusively derived from smooth muscle cells (SMCs). Herein, we show that in murine and human lesions, 20% to 40% of ACTA2+ fibrous cap cells, respectively, are derived from non-SMC sources, including endothelial cells (ECs) or macrophages that have undergone an endothelial-to-mesenchymal transition (EndoMT) or a macrophage-to-mesenchymal transition (MMT). In addition, we show that SMC-specific knockout of the Pdgfrb gene, which encodes platelet-derived growth factor receptor beta (PDGFRß), in Apoe-/- mice fed a Western diet for 18 weeks resulted in brachiocephalic artery lesions nearly devoid of SMCs but with no changes in lesion size, remodelling or indices of stability, including the percentage of ACTA2+ fibrous cap cells. However, prolonged Western diet feeding of SMC Pdgfrb-knockout mice resulted in reduced indices of stability, indicating that EndoMT- and MMT-derived MFs cannot compensate indefinitely for loss of SMC-derived MFs. Using single-cell and bulk RNA-sequencing analyses of the brachiocephalic artery region and in vitro models, we provide evidence that SMC-to-MF transitions are induced by PDGF and transforming growth factor-ß and dependent on aerobic glycolysis, while EndoMT is induced by interleukin-1ß and transforming growth factor-ß. Together, we provide evidence that the ACTA2+ fibrous cap originates from a tapestry of cell types, which transition to an MF-like state through distinct signalling pathways that are either dependent on or associated with extensive metabolic reprogramming.


Asunto(s)
Metabolismo Energético/genética , Placa Aterosclerótica/patología , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/genética , Actinas/metabolismo , Animales , Apolipoproteínas E/genética , Arteria Braquial/patología , Dieta Occidental , Células Endoteliales/metabolismo , Células Endoteliales/patología , Transición Epitelial-Mesenquimal , Femenino , Fibroblastos/metabolismo , Fibroblastos/patología , Humanos , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Miocitos del Músculo Liso/patología , Placa Aterosclerótica/metabolismo , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismo
9.
Neurology ; 96(11): e1491-e1500, 2021 03 16.
Artículo en Inglés | MEDLINE | ID: mdl-33568538

RESUMEN

OBJECTIVE: To examine whether amyloid PET in cognitively normal (CN) individuals screened for the Anti-Amyloid in Asymptomatic Alzheimer's Disease (A4) study differed across self-identified non-Hispanic White and Black (NHW and NHB) groups. METHODS: We examined 3,689 NHW and 144 NHB participants who passed initial screening for the A4 study and underwent amyloid PET. The effect of race on amyloid PET was examined using logistic (dichotomous groups) and linear (continuous values) regression controlling for age, sex, and number of APOE ε4 and APOE ε2 alleles. Associations between amyloid and genetically determined ancestry (reflecting African, South Asian, East Asian, American, and European populations) were tested within the NHB group. Potential interactions with APOE were assessed. RESULTS: NHB participants had lower rates of amyloid positivity and lower continuous amyloid levels compared to NHW participants. This race effect on amyloid was strongest in the APOE ε4 group. Within NHB participants, those with a lower percentage of African ancestry had higher amyloid. A greater proportion of NHB participants did not pass initial screening compared to NHW participants, suggesting potential sources of bias related to race in the A4 PET data. CONCLUSION: Reduced amyloid was observed in self-identified NHB participants who passed initial eligibility criteria for the A4 study. This work stresses the importance of investigating AD biomarkers in ancestrally diverse samples as well as the need for careful consideration regarding study eligibility criteria in AD prevention trials.


Asunto(s)
Enfermedad de Alzheimer/etnología , Enfermedad de Alzheimer/patología , Proteínas Amiloidogénicas/metabolismo , Encéfalo/patología , Afroamericanos , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico por imagen , Proteínas Amiloidogénicas/análisis , Apolipoproteínas E/genética , Biomarcadores/análisis , Biomarcadores/metabolismo , Encéfalo/diagnóstico por imagen , Femenino , Humanos , Masculino , Tomografía de Emisión de Positrones , Estados Unidos
10.
Neuron ; 109(7): 1100-1117.e10, 2021 04 07.
Artículo en Inglés | MEDLINE | ID: mdl-33606969

RESUMEN

Aging results in gray and white matter degeneration, but the specific microglial responses are unknown. Using single-cell RNA sequencing from white and gray matter separately, we identified white matter-associated microglia (WAMs), which share parts of the disease-associated microglia (DAM) gene signature and are characterized by activation of genes implicated in phagocytic activity and lipid metabolism. WAMs depend on triggering receptor expressed on myeloid cells 2 (TREM2) signaling and are aging dependent. In the aged brain, WAMs form independent of apolipoprotein E (APOE), in contrast to mouse models of Alzheimer's disease, in which microglia with the WAM gene signature are generated prematurely and in an APOE-dependent pathway similar to DAMs. Within the white matter, microglia frequently cluster in nodules, where they are engaged in clearing degenerated myelin. Thus, WAMs may represent a potentially protective response required to clear degenerated myelin accumulating during white matter aging and disease.


Asunto(s)
Microglía/fisiología , Sustancia Blanca/citología , Sustancia Blanca/crecimiento & desarrollo , Envejecimiento/fisiología , Enfermedad de Alzheimer/genética , Animales , Apolipoproteínas E/genética , Enfermedades Desmielinizantes/patología , Regulación de la Expresión Génica , Sustancia Gris/citología , Sustancia Gris/crecimiento & desarrollo , Inmunohistoquímica , Glicoproteínas de Membrana/biosíntesis , Glicoproteínas de Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microglía/ultraestructura , Vaina de Mielina/metabolismo , Receptores Inmunológicos/biosíntesis , Receptores Inmunológicos/genética , Análisis de Secuencia de ARN , Transducción de Señal/fisiología , Análisis de la Célula Individual
11.
Acta Cir Bras ; 36(1): e360105, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33605308

RESUMEN

PURPOSE: To investigate the relationship between atherosclerotic abdominal aortic aneurysm (AAA) and CXC chemokine receptor type 2 (CXCR2). METHODS: Mouse AAA model was established by embedding angiotensin-II pump (1000 ng/kg/min) in ApoE-/- mice. Mice were received SB225002, a selective CXCR2 antagonist, for treatment. Blood pressure was recorded, and CXCR2+ macrophages were examined by flow cytometry analysis. Terminal-deoxynucleotidyl transferase mediated nick end labeling (TUNEL) staining was performed to detect cell apoptosis of abdominal aortic aneurysms. Macrophages were isolated from ApoE-/- mice and treated with Ang II and/or SB225002. Dihydroethidium staining was carried out to determine reactive oxygen species (ROS) activity. Enzyme-linked immunosorbent assay (ELISA) was performed to determine the production of IL-1ß and TNF-α. The corresponding gene expressions were measured using real-time polymerase chain reaction (PCR), western blot, and immunohistochemistry staining. RESULTS: We found that Ang II activated the expression of CXCR2 in monocytes during the formation of AAA. Inhibition of CXCR2 significantly reduced the size of AAA, attenuated inflammation and phenotypic changes in blood vessels. Ang II-induced macrophages exhibited elevated ROS activity, and elevated levels of 1ß and TNF-α, which were then partly abolished by SB225002. CONCLUSIONS: CXCR2 plays an important role in AAA, suggesting that inhibiting CXCR2 may be a new treatment for AAA.


Asunto(s)
Aneurisma de la Aorta Abdominal , Angiotensina II , Animales , Aneurisma de la Aorta Abdominal/tratamiento farmacológico , Aneurisma de la Aorta Abdominal/prevención & control , Apolipoproteínas E/genética , Modelos Animales de Enfermedad , Macrófagos , Ratones , Ratones Endogámicos C57BL , Receptores de Interleucina-8B
12.
Nan Fang Yi Ke Da Xue Xue Bao ; 41(2): 216-222, 2021 Feb 25.
Artículo en Chino | MEDLINE | ID: mdl-33624594

RESUMEN

OBJECTIVE: To explore the feasibility of three-dimensional (3D) vessel wall imaging of carotid atherosclerotic plaques in ApoE-/- mice using 7.0T magnetic resonance imaging (MRI) with delays alternating with nutations for tailored excitation (DANTE)-prepared fast low-angle shot (DANTE-FLASH) technique. OBJECTIVE: Numerical simulations were performed for optimizing imaging parameters to maximize the wall-lumen contrast. Six ApoE-/- and three wild-type mice were scanned using a 7.0T MRI scanner with DANTE-FLASH and multi-slice 2D RARE coupled with inflow outflow saturation bands (2D-IOSBRARE). The wall signal-to-noise ratio (SNRwall), lumen SNR (SNRlumen), wall-lumen contrast-to-noise ratio (CNR), lumen area (LA), and wall area (WA) were compared between DANTE- FLASH and 2D-IOSB-RARE sequences. Linear regression analysis was performed to assess the correlation between the MRI measurements and histopathological measurements of LA and WA. OBJECTIVE: Based on the simulation results, a flip angle of 15° and a train length of 150 were implemented in the live imaging study. Compared with 2D-IOSB-RARE, DANTE-FLASH provided a slightly reduced CNR (P < 0.001) but much improved slice resolution. The LA and WA measurements from the DANTE-FLASH and 2D-IOSB- RARE showed excellent agreement based on ICC analysis (LA: ICC=0.94, P < 0.001; WA: ICC=0.93, P < 0.001) and Bland-Altman plots. Strong correlations were observed between the MRI and histopathological measurements for both LA (P < 0.0001) and WA (P < 0.0001). OBJECTIVE: As a 3D black-blood MR sequence, DANTE-FLASH provides isotropic high spatial resolution to allow reliable visualization and quantitative evaluation of the arteriosclerotic lesions within the carotid artery of ApoE-/- mice using a 7.0T MRI scanner.


Asunto(s)
Apolipoproteínas E , Placa Aterosclerótica , Animales , Apolipoproteínas E/genética , Arterias Carótidas/diagnóstico por imagen , Imagen por Resonancia Magnética , Ratones , Relación Señal-Ruido
13.
Braz J Med Biol Res ; 54(4): e9764, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33624733

RESUMEN

Naringenin (NAR) is a major flavanone in citrus fruits that has multiple pharmacological attributes such as anticancer and antiatherogenic. This study aims to investigate the mechanism of NAR in high-fat-diet (HFD)-induced atherosclerosis (AS) in apolipoprotein E-knockout (ApoE-/-) mice. A HFD-induced AS ApoE-/- mouse model was established. The mice were treated with HFD, different doses of NAR and simvastatin (Simv). After drug treatment, the levels of total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), glutathione peroxidase (GSH-Px), malondialdehyde (MDA), superoxide dismutase (SOD), and alanine aminotransferase (ALT) were determined. The expression of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) was detected using qRT-PCR and enzyme-linked immunosorbent assay. The plaque area of the aorta of AS mice was determined using oil red O staining. Western blot analysis was applied to measure the levels of autophagy-related proteins [protein 1 light chain 3B (LC3B), beclin 1, and p62]. The TC, TG, LDL-C, TNF-α, ALT, and MDA levels were significantly increased while the HDL-C, SOD, and GSH-Px levels were decreased in the HFD-induced AS ApoE-/- mice. NAR treatment reversed the expression of the above indicators in mice. After they were treated with different doses of NAR, the LC3B and beclin 1 levels were improved while the p62 protein level was decreased. This study suggested that NAR could promote cell autophagy to improve HFD-induced AS in ApoE-/- mice.


Asunto(s)
Aterosclerosis , Flavanonas , Animales , Apolipoproteínas E/genética , Aterosclerosis/tratamiento farmacológico , Autofagia , Flavanonas/farmacología , Ratones
14.
Biomed Res Int ; 2021: 6752141, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33521130

RESUMEN

Background: Thyroid cancer is the most common endocrine malignancy, with a recent global increase of 20% in age-related incidence. Ultrasonography and ultrasonography-guided fine-needle aspiration biopsy (FNAB) are the most widely used diagnostic tests for thyroid nodules; however, it is estimated that up to 25% of thyroid biopsies are cytologically inconclusive. Molecular markers can help guide patient-oriented and targeted treatment of thyroid nodules and thyroid cancer. Methods: Datasets related to papillary thyroid cancer (PTC) or thyroid carcinoma (GSE129562, GSE3678, GSE54958, GSE138042, and GSE124653) were downloaded from the GEO database and analysed using the Limma package of R software. For functional enrichment analysis, the Kyoto Encyclopedia of Genes and Genomes pathway analysis and Gene Ontology were applied to differentially expressed genes (DEGs) using the Metascape website. A protein-protein interaction (PPI) network was built from the STRING database. Gene expression, protein expression, immunohistochemistry, and potential functional gene survival were analysed using the GEPIA website, the Human Protein Atlas website, and the UALCAN website. Potential target miRNAs were predicted using the miRDB and Starbase datasets. Results: We found 219 upregulated and 310 downregulated DEGs, with a cut-off of p < 0.01 and ∣log FC | >1.5. The DEGs in papillary thyroid cancer were mainly enriched in extracellular structural organisation. At the intersection of the PPI network and Metascape MCODEs, the hub genes in common were identified as FN1, APOE, CLU, and SDC2. In the targeted regulation network of miRNA-mRNA, the hsa-miR-424-5p was found to synchronously modulate two hub genes. Survival analysis showed that patients with high expression of CLU and APOE had better prognosis. Conclusions: CLU and APOE are involved in the molecular mechanism of papillary thyroid cancer. The hsa-miR-424-5p might have the potential to reverse the processes of papillary thyroid cancer by modulating the hub genes. These are potential targets for the treatment of patients with papillary thyroid cancer.


Asunto(s)
Redes Reguladoras de Genes , MicroARNs/metabolismo , ARN Mensajero/metabolismo , Cáncer Papilar Tiroideo/genética , Neoplasias de la Tiroides/genética , Nódulo Tiroideo/genética , Apolipoproteínas E/genética , Biopsia , Biopsia con Aguja Fina , Análisis por Conglomerados , Clusterina/genética , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , MicroARNs/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Mapeo de Interacción de Proteínas , Cáncer Papilar Tiroideo/patología , Glándula Tiroides/patología , Neoplasias de la Tiroides/patología , Nódulo Tiroideo/patología , Ultrasonografía
15.
J Diabetes Res ; 2021: 8816996, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33490286

RESUMEN

Background: The apolipoprotein E (APOE) gene polymorphisms have been intensively studied in patients with type 2 diabetes mellitus (T2DM) and ischemic stroke (IS) in recent years. However, it is unclear whether APOE gene polymorphisms are correlated with increased risk for developing IS in T2DM patients. Thus, this study was designed to examine the association between APOE gene polymorphisms and risks of IS in Chinese patients with T2DM. Methods: This case-control study enrolled 243 subjects with T2DM as controls, and 210 subjects with T2DM complicated with IS as case patients. The genotypes were determined using real-time PCR while HbA1c and lipid levels were detected using commercially available kits. Results: The systolic blood pressure (SBP), diastolic blood pressure (DBP), and the proportion of patients with a history of hypertension were higher in the case patients than that in the controls. We confirmed that the ε2/ε3 genotype, as well as SBP and history of hypertension, was the independent risk factor for developing IS in T2DM patients. Conclusions: We conclude that the ε2/ε3 genotype might contribute to the increased risk for developing IS in Chinese patients with T2DM.


Asunto(s)
Apolipoproteínas E/genética , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/genética , /genética , Anciano , Grupo de Ascendencia Continental Asiática/genética , Estudios de Casos y Controles , China/epidemiología , Diabetes Mellitus Tipo 2/etnología , Angiopatías Diabéticas/etnología , Angiopatías Diabéticas/genética , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo Genético , Factores de Riesgo
16.
Mol Pharmacol ; 99(3): 175-183, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33384285

RESUMEN

Acyl-CoA:cholesterol acyltransferase (ACAT) mediates cellular cholesterol esterification. In atherosclerotic plaque macrophages, ACAT promotes cholesteryl ester accumulation, resulting in foam cell formation and atherosclerosis progression. Its complete inactivation in mice, however, showed toxic effects because of an excess of free cholesterol (FC) in macrophages, which can cause endoplasmic reticulum stress, cholesterol crystal formation, and inflammasome activation. Our previous studies showed that long-term partial ACAT inhibition, achieved by dietary supplementation with Fujirebio F1394, delays atherosclerosis progression in apoprotein E-deficient (Apoe -/-) mice by reducing plaque foam cell formation without inflammatory or toxic effects. Here, we determined whether short-term partial inhibition of ACAT, in combination with an enhanced systemic FC acceptor capacity, has synergistic benefits. Thus, we crossbred Apoe -/- with human apoprotein A1-transgenic (APOA1 tg/tg) mice, which have elevated cholesterol-effluxing high-density lipoprotein particles, and subjected Apoe -/- and APOA1 tg/tg/Apoe -/- mice to an atherogenic diet to develop advanced plaques. Then mice were either euthanized (baseline) or fed purified standard diet with or without F1394 for 4 more weeks. Plaques of APOA1 tg/tg/Apoe -/- mice fed F1394 showed a 60% reduction of macrophages accompanied by multiple other benefits, such as reduced inflammation and favorable changes in extracellular composition, in comparison with Apoe -/- baseline mice. In addition, there was no accumulation of cholesterol crystals or signs of toxicity. Overall, these results show that short-term partial ACAT inhibition, coupled to increased cholesterol efflux capacity, favorably remodels atherosclerosis lesions, supporting the potential of these combined therapies in the treatment of advanced atherosclerosis. SIGNIFICANCE STATEMENT: Short-term pharmacological inhibition of acyl-CoA:cholesterol acyltransferase-mediated cholesterol esterification, in combination with increased free cholesterol efflux acceptors, has positive effects in mice by 1) reducing the inflammatory state of the plaque macrophages and 2) favoring compositional changes associated with plaque stabilization. These effects occur without toxicity, showing the potential of these combined therapies in the treatment of advanced atherosclerosis.


Asunto(s)
Acetil-CoA C-Acetiltransferasa/antagonistas & inhibidores , Apolipoproteína A-I/genética , Apolipoproteínas E/genética , Aterosclerosis/terapia , Ciclohexanos/administración & dosificación , Dioxanos/administración & dosificación , Animales , Aterosclerosis/genética , Cruzamiento , Ciclohexanos/farmacología , Suplementos Dietéticos , Dioxanos/farmacología , Modelos Animales de Enfermedad , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Marcadores Genéticos/efectos de los fármacos , Humanos , Lipoproteínas HDL/sangre , Masculino , Ratones , Ratones Noqueados , Ratones Transgénicos , Resultado del Tratamiento
17.
Biochem Biophys Res Commun ; 540: 61-66, 2021 02 12.
Artículo en Inglés | MEDLINE | ID: mdl-33450481

RESUMEN

Calorie restriction (CR) reportedly prevents atherosclerotic diseases. Furthermore, CR induces forkhead box protein-O1 (FOXO-1) expression in the skeletal muscle, altering the character of the skeletal muscle. We previously reported that the change in skeletal muscle character, induced by the overexpression of peroxisome proliferator-activated receptor γ coactivator-1α, suppresses atherosclerotic progression in an atherosclerotic apolipoprotein E-knockout (ApoE-KO) mouse model. Thus, we hypothesized that skeletal muscle alternation induced by FOXO-1 may also have an anti-atherosclerotic effect in ApoE-KO mice. In this study, we investigated whether skeletal muscle-specific FOXO-1 overexpression suppresses the progression of atherosclerosis in ApoE-KO mice. We generated ApoE-KO/FOXO-1 mice, in which an ApoE-KO mouse was crossbred with a mouse presenting skeletal muscle-specific FOXO-1 overexpression (FOXO-1Tg). The mice were sacrificed at 20 weeks of age, and atherosclerotic plaque area and protein expression in the plaque were measured. Additionally, we measured the tumor necrosis factor α (TNFα)- induced mRNA expression in human umbilical vein endothelial cells (HUVECs), using serum collected from the FOXO-1Tg mice. Accordingly, ApoE-KO/FOXO-1 mice showed a 65% reduced atherosclerotic plaque area when compared with the ApoE-KO mice, with concomitantly reduced vascular cell adhesion molecule-1 (VCAM-1) and macrophage infiltration. As compared to serum from wild-type mice, the serum collected from the FOXO-1Tg mice significantly suppressed the mRNA expression of VCAM-1, an atherosclerosis initiation factor, in TNFα-treated HUVECs. Therefore, these data suggest that skeletal muscle-specific FOXO-1 overexpression suppresses the progression of atherosclerosis in ApoE-KO mice. In part, the CR-induced anti-atherosclerotic effect could be attributed to FOXO-1 upregulation in the skeletal muscle.


Asunto(s)
Apolipoproteínas E/deficiencia , Aterosclerosis/genética , Aterosclerosis/patología , Progresión de la Enfermedad , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Músculo Esquelético/metabolismo , Animales , Apolipoproteínas E/genética , Células Endoteliales de la Vena Umbilical Humana , Humanos , Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Factor de Necrosis Tumoral alfa/metabolismo , Molécula 1 de Adhesión Celular Vascular/metabolismo
18.
Nat Genet ; 53(2): 143-146, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33510477

RESUMEN

Genome-wide association studies (GWAS) have identified many risk loci for Alzheimer's disease (AD)1,2, but how these loci confer AD risk is unclear. Here, we aimed to identify loci that confer AD risk through their effects on brain protein abundance to provide new insights into AD pathogenesis. To that end, we integrated AD GWAS results with human brain proteomes to perform a proteome-wide association study (PWAS) of AD, followed by Mendelian randomization and colocalization analysis. We identified 11 genes that are consistent with being causal in AD, acting via their cis-regulated brain protein abundance. Nine replicated in a confirmation PWAS and eight represent new AD risk genes not identified before by AD GWAS. Furthermore, we demonstrated that our results were independent of APOE e4. Together, our findings provide new insights into AD pathogenesis and promising targets for further mechanistic and therapeutic studies.


Asunto(s)
Enfermedad de Alzheimer/genética , Encéfalo/metabolismo , Proteoma/genética , Enfermedad de Alzheimer/metabolismo , Apolipoproteínas E/genética , Epóxido Hidrolasas/genética , Estudio de Asociación del Genoma Completo , Humanos , Enfermedad de Parkinson/genética , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo , Receptores Virales/genética , Análisis de Secuencia de ARN , Análisis de la Célula Individual
19.
Expert Opin Investig Drugs ; 30(1): 39-44, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33455481

RESUMEN

Introduction: Four years ago this Autumn, pioneering neurologist Prof. Allen. D. Roses passed away. Hence, we have taken time to reflect on his work and legacy in Alzheimer's disease (AD) research. Prof. Roses rejected the widely accepted amyloid hypothesis, which identifies amyloid beta (Aß) protein accumulation within the brain as the cause of AD. Instead, he proposed that the epsilon type 4 allele of apolipoprotein (APOE- Ɛ4) and translocase of outer mitochondrial membrane 40 homolog (TOMM40) were preeminent factors in the pathogenesis and progression of AD, particularly in late-onset AD (LOAD). This rejection of the amyloid hypothesis has generated new investigations into APOE and TOMM40 as risk factors for AD. Areas covered: We discuss the contributions of Prof. Roses to AD research, describe how APOE-Ɛ4 and TOMM40 have been posited to trigger neuropathological changes leading to AD, and explore paths to future clinical applications built on the foundations of his research. Expert opinion: The unconventional methodology of targeting APOE and TOMM40 offers great potential for the development of effective preventive and disease-modifying AD interventions. Future preclinical and clinical investigations will greatly benefit from the groundbreaking scientific discoveries of Prof. Roses.


Asunto(s)
Enfermedad de Alzheimer/terapia , Apolipoproteínas E/genética , Proteínas de Transporte de Membrana/metabolismo , Alelos , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/fisiopatología , Péptidos beta-Amiloides/metabolismo , Animales , Humanos , Factores de Riesgo
20.
Int J Mol Sci ; 22(2)2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-33467546

RESUMEN

AIMS/HYPOTHESIS: SGLT-2 inhibitors (SGLT-2i) have been studied as potential treatments against NAFLD, showing varying beneficial effects. The molecular mechanisms mediating these effects have not been fully clarified. Herein, we investigated the impact of empagliflozin on NAFLD, focusing particularly on ER stress, autophagy and apoptosis. METHODS: Five-week old ApoE(-/-) mice were switched from normal to a high-fat diet (HFD). After five weeks, mice were randomly allocated into a control group (HFD + vehicle) and Empa group (HFD + empagliflozin 10 mg/kg/day) for five weeks. At the end of treatment, histomorphometric analysis was performed in liver, mRNA levels of Fasn, Screbp-1, Scd-1, Ppar-γ, Pck-1, Mcp-1, Tnf-α, Il-6, F4/80, Atf4, Elf2α, Chop, Grp78, Grp94, Χbp1, Ire1α, Atf6, mTor, Lc3b, Beclin-1, P62, Bcl-2 and Bax were measured by qRT-PCR, and protein levels of p-EIF2α, EIF2a, CHOP, LC3II, P62, BECLIN-1 and cleaved CASPASE-8 were assessed by immunoblotting. RESULTS: Empagliflozin-treated mice exhibited reduced fasting glucose, total cholesterol and triglyceride serum levels, as well as decreased NAFLD activity score, decreased expression of lipogenic enzymes (Fasn, Screbp-1c and Pck-1) and inflammatory molecules (Mcp-1 and F4/80), compared to the Control group. Empagliflozin significantly decreased the expression of ER stress molecules Grp78, Ire1α, Xbp1, Elf2α, Atf4, Atf6, Chop, P62(Sqstm1) and Grp94; whilst activating autophagy via increased AMPK phosphorylation, decreased mTOR and increased LC3B expression. Finally, empagliflozin increased the Bcl2/Bax ratio and inhibited CASPASE-8 cleavage, reducing liver cell apoptosis. Immunoblotting analysis confirmed the qPCR results. CONCLUSION: These novel findings indicate that empagliflozin treatment for five weeks attenuates NAFLD progression in ApoE(-/-) mice by promoting autophagy, reducing ER stress and inhibiting hepatic apoptosis.


Asunto(s)
Apolipoproteínas E/deficiencia , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Compuestos de Bencidrilo/farmacología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Glucósidos/farmacología , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Animales , Apolipoproteínas E/genética , Apoptosis/genética , Autofagia/genética , Compuestos de Bencidrilo/administración & dosificación , Dieta Alta en Grasa/efectos adversos , Estrés del Retículo Endoplásmico/genética , Regulación de la Expresión Génica/efectos de los fármacos , Glucósidos/administración & dosificación , Immunoblotting , Lipogénesis/efectos de los fármacos , Lipogénesis/genética , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Inhibidores del Cotransportador de Sodio-Glucosa 2/administración & dosificación , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología
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