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1.
Yi Chuan ; 44(3): 198-207, 2022 Mar 20.
Artículo en Inglés | MEDLINE | ID: mdl-35307643

RESUMEN

Hypertrophic cardiomyopathy (HCM) is an autosomal dominant genetic disease characterized by left ventricular hypertrophy with prevalence of 1/500-1/200. Up to now, 1500 mutations in more than 30 genes have been found to be related to the disease. Pathogenic gene mutations together with polymorphisms of modifying genes and environmental factors play various roles in the disease processes, resulting in phenotypic heterogeneity of the disease, ranging from no symptoms to sudden cardiac death. The pathological phenotypes of HCM mainly include cardiomyocyte hypertrophy, disordered array, fibrosis, myocardial ischemia, and others. In recent years, many research efforts have been devoted to exploring the influence of HCM genotype on phenotype, and development of treatment methods based on genetics. This article focuses on the correction between HCM genotype and phenotype and summarizes the research progresses on HCM in terms of pathogenic genes, pathogenesis, associated modification factors and treatment methods, thereby providing insights on the future research and development on the genetics of HCM.


Asunto(s)
Cardiomiopatía Hipertrófica , Cardiomiopatía Hipertrófica/genética , Cardiomiopatía Hipertrófica/patología , Genotipo , Humanos , Mutación , Fenotipo
2.
Lipids Health Dis ; 20(1): 101, 2021 Sep 12.
Artículo en Inglés | MEDLINE | ID: mdl-34511120

RESUMEN

BACKGROUND: As an autosomal dominant disorder, familial hypercholesterolemia (FH) is mainly attributed to disease-causing variants in the low-density lipoprotein receptor (LDLR) gene. The aim of this study was to explore the molecular mechanism of LDLR c.501C>A variant in FH and assess the efficacy of proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor treatment for FH patients. METHODS: The whole-exome sequencing was performed on two families to identify disease-causing variants, which were verified by Sanger sequencing. The function of LDLR variant was further explored in HEK293 cells by Western Blot and confocal microscopy. Besides, the therapeutic effects of PCSK9 inhibitor treatment for two probands were assessed for 3 months. RESULTS: All members of the two families with the LDLR c.501C>A variant showed high levels of LDLC. The relationship between the clinical phenotype and LDLR variants was confirmed in the current study. Both in silico and in vitro analyses showed that LDLR c.501C>A variant decreased LDLR expression and LDL uptake. PCSK9 inhibitor treatment lowered the lipid level in proband 1 by 24.91%. However, the treatment was ineffective for proband 2. A follow-up study revealed that the PCSK9 inhibitor treatment had low ability of lipid-lowering effect in the patients. CONCLUSIONS: LDLR c.501C>A variant might be pathogenic for FH. The PCSK9 inhibitor therapy is not a highly effective option for treatment of FH patients with LDLR c.501C>A variant.


Asunto(s)
Hiperlipoproteinemia Tipo II/genética , Mutación Puntual , Proproteína Convertasa 9/genética , Receptores de LDL/genética , Adolescente , Adulto , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Familia , Femenino , Regulación de la Expresión Génica , Células HEK293 , Humanos , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Hiperlipoproteinemia Tipo II/patología , Hipolipemiantes/uso terapéutico , Masculino , Persona de Mediana Edad , Inhibidores de PCSK9/uso terapéutico , Linaje , Proproteína Convertasa 9/metabolismo , Receptores de LDL/deficiencia , Insuficiencia del Tratamiento , Triglicéridos/sangre , Secuenciación del Exoma
3.
Exp Mol Pathol ; 114: 104412, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32113905

RESUMEN

Coronary heart disease (CHD) is the major cause of death in modern society. CHD is characterized by atherosclerosis, which could lead to vascular cavity stenosis or obstruction, resulting in ischemic cardiac conditions such as angina and myocardial infarction. In terms of the mitochondrion, the main function is to produce adenosine triphosphate (ATP) for cells. And the alterations (including mutations, altered copy number and haplogroups) of mitochondrial DNA (mtDNA) are associated with the abnormal expression of oxidative phosphorylation (OXPHOS) system, resulting in mitochondrial dysfunction, then leading to perturbation on the electron transport chain and increased ROS generation and reduction in ATP level, contributing to ATP-producing disorders and oxidative stress, which may further accelerate development or vulnerability of atherosclerosis and myocardial ischemic injury. Therefore, the mtDNA defects may play an important role in making an early diagnosis, identifying disease-specific biomarkers and therapeutic targets, and predicting outcomes for patients with atherosclerosis and CHD. In this review, we aim to summarize the contribution of mtDNA mutations, altered mtDNA copy number and mtDNA haplogroups on the occurrence and development of CHD.


Asunto(s)
Aterosclerosis/genética , Enfermedad Coronaria/genética , ADN Mitocondrial/genética , Estrés Oxidativo/genética , Adenosina Trifosfato/metabolismo , Aterosclerosis/metabolismo , Aterosclerosis/patología , Enfermedad Coronaria/metabolismo , Enfermedad Coronaria/patología , Humanos , Mitocondrias/genética , Mitocondrias/metabolismo , Mutación/genética , Fosforilación Oxidativa , Especies Reactivas de Oxígeno/metabolismo
4.
J Cardiovasc Pharmacol ; 76(5): 506-513, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-33165132

RESUMEN

Familial hypercholesterolemia (FH) is a rare autosomal gene deficiency disease with increased low-density lipoprotein cholesterol, xanthoma, and premature coronary heart disease. Calcified aortic valve disease (CAVD) is prevalent in FH patients, resulting in adverse events and heavy health care burden. Aortic valve calcification is currently considered an active biological process, which shares several common risk factors with atherosclerosis, including aging, hypertension, dyslipidemia, and so on. Unfortunately, the pathogenesis and therapy of CAVD in FH are still controversial. There is no pharmacological intervention recommended to delay the development of CAVD in FH, and the only effective treatment for severe CAVD is aortic valve replacement. In this review, we summarize the detailed description of the pathophysiology, molecular mechanism, risk factors, and treatment of CAVD in FH patients.


Asunto(s)
Antagonistas de Receptores de Angiotensina/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Anticolesterolemiantes/uso terapéutico , Enfermedad de la Válvula Aórtica/terapia , Calcinosis/terapia , Colesterol/sangre , Implantación de Prótesis de Válvulas Cardíacas , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Antagonistas de Receptores de Angiotensina/efectos adversos , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Animales , Anticolesterolemiantes/efectos adversos , Enfermedad de la Válvula Aórtica/epidemiología , Enfermedad de la Válvula Aórtica/fisiopatología , Biomarcadores/sangre , Calcinosis/epidemiología , Calcinosis/fisiopatología , Progresión de la Enfermedad , Implantación de Prótesis de Válvulas Cardíacas/efectos adversos , Humanos , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/epidemiología , Prevalencia , Medición de Riesgo , Factores de Riesgo , Reemplazo de la Válvula Aórtica Transcatéter , Resultado del Tratamiento
5.
Med Sci Monit ; 26: e921742, 2020 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-32350237

RESUMEN

According to the World Health Organization cardiovascular disease risk charts, the mortality rate of cardiovascular diseases in people is still high. The medical expenses caused by cardiovascular diseases are increasing daily, and the medical burden is becoming heavier; as such, it is imperative to prevent and cure cardiovascular diseases. A large number of scholars are analyzing the pathogenesis of cardiovascular diseases from various perspectives. Recent findings suggest that N6-methyladenosine (m6A) plays a multifaceted role in the cardiovascular system. m6A is a methylated modification product on RNA molecules and exists on various RNA molecules. It is one of the most common epigenetic modifications discovered to date. It regulates the expression of genes and subsequent responses. The amount of m6A is determined by methylases (writers) and demethylases (erasers). The third type of proteins, readers, selectively bind to m6A to regulate RNA stability and gene expression. In this paper, the relationship between m6A and related enzymes and cardiovascular structure and function was reviewed based on recent research results regarding the cardiovascular system.


Asunto(s)
Adenosina/análogos & derivados , Sistema Cardiovascular/metabolismo , Adenosina/genética , Adenosina/metabolismo , Adenosina/fisiología , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/fisiopatología , Sistema Cardiovascular/fisiopatología , Epigénesis Genética/genética , Expresión Génica/genética , Humanos , Metabolismo de los Lípidos/fisiología , Lípidos/fisiología , Metilación , Metiltransferasas/metabolismo
6.
Future Oncol ; 14(18): 1825-1834, 2018 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-29969917

RESUMEN

AIM: SMYD3 encodes histone lysine methyltransferase. The goal of our study was to investigate the association between SMYD3 methylation and colorectal cancer (CRC). MATERIALS & METHODS: SMYD3 methylation was measured by quantitative methylation-specific PCR method in 117 pairs of CRC tumor and para-tumor tissues. RESULTS: Significantly lower SMYD3 methylation was observed in CRC tumor tissues than para-tumor tissues (p = 0.002). Further subgroup analysis by clinical features showed that significantly lower SMYD3 methylation were only observed in the CRC patients with tumors of moderately and well differentiation, positive lymph node metastasis, and stage III + IV. CONCLUSION: Our work reported for the first time that SMYD3 promoter hypomethylation was associated with CRC.


Asunto(s)
Neoplasias Colorrectales/genética , Metilación de ADN , Regulación Neoplásica de la Expresión Génica , N-Metiltransferasa de Histona-Lisina/genética , Regiones Promotoras Genéticas/genética , Pueblo Asiatico/genética , Neoplasias Colorrectales/patología , Femenino , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias
7.
J Clin Lab Anal ; 32(5): e22370, 2018 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-29205508

RESUMEN

BACKGROUND: Non-small cell lung cancer (NSCLC) is a common malignant tumor. DNA hypermethylation in the promoter region has been served as a potential molecular marker for several tumors. The goal of the current study was to assess the diagnostic ability of mutL homolog 1 (MLH1) promoter methylation in NSCLC. METHODS: A total of 111 NSCLC patients' paired tissue samples were obtained to explore the association between MLH1 promoter methylation and NSCLC by methylation-specific polymerase chain reaction (MSP) method. Public databases including The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were used to verify our findings. RESULTS: Our results showed a significantly higher MLH1 methylation frequency in tumor tissue samples than their paired adjacent tissues (P = .008). ROC curve indicated that MLH1MSP assay was a sensitive but not a specific method in the diagnosis for NSCLC (sensitivity = 0.964, specificity = 0.135, AUC = 0.550). And the association between the methylation level and clinical characteristics has no statistical significance. TCGA cohort evinced a higher methylation probability in tumor group compared with nontumor group (the mean ß value: -0.449 [-0.467, -0.437] vs -0.466 [-0.472, -0.437], P = .011), which was consistent with our results. Meanwhile, an inverse correlation between MLH1 methylation and MLH1 expression was detected in TCGA and GEO databases. CONCLUSIONS: The MSP method for MLH1 methylation was a sensitive but not a specific diagnostic method for NSCLC.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/genética , Metilación de ADN/genética , Neoplasias Pulmonares/genética , Homólogo 1 de la Proteína MutL/genética , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/epidemiología , Bases de Datos Genéticas/estadística & datos numéricos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Estadística como Asunto
8.
Tumour Biol ; 39(2): 1010428317692230, 2017 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-28222662

RESUMEN

Esophageal squamous cell carcinoma is a commonly malignant tumor of digestive tract with poor prognosis. Previous studies suggested that forkhead box F2 ( FOXF2) could be a candidate gene for assessing and predicting the prognosis of human cancers. However, the relationship between FOXF2 promoter methylation and the prognosis of esophageal squamous cell carcinoma remained unclear. Formalin-fixed, paraffin-embedded esophageal squamous cell carcinoma tissues of 135 esophageal squamous cell carcinoma patients were detected for FOXF2 promoter methylation status by methylation-specific polymerase chain reaction approach. DNA methylation results were evaluated with regard to clinicopathological features and overall survival. Our study confirmed that FOXF2 promoter hypermethylation could independently predict a poorer overall survival of esophageal squamous cell carcinoma patients ( p = 0.002), which was consistent with the data mining results of the data from 82 esophageal squamous cell carcinoma patients in The Cancer Genome Atlas datasets ( p = 0.036). In addition, no correlation was found between FOXF2 promoter methylation and other clinic pathological parameters (age, gender, differentiation, lymph node metastasis, stage, cutting edge, vascular invasion, smoking behavior, and drinking history). In conclusion, FOXF2 methylation might be a useful prognostic biomarker for esophageal squamous cell carcinoma patients.


Asunto(s)
Carcinoma de Células Escamosas/genética , Metilación de ADN , Neoplasias Esofágicas/genética , Factores de Transcripción Forkhead/genética , Secuencia de Bases , Carcinoma de Células Escamosas/cirugía , Neoplasias Esofágicas/cirugía , Carcinoma de Células Escamosas de Esófago , Formaldehído , Células HeLa , Células Hep G2 , Células Endoteliales de la Vena Umbilical Humana , Humanos , Células K562 , Adhesión en Parafina , Valor Predictivo de las Pruebas , Regiones Promotoras Genéticas , Análisis de Supervivencia , Fijación del Tejido , Resultado del Tratamiento
9.
Bioact Mater ; 35: 447-460, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38390527

RESUMEN

Atherosclerosis is featured as chronic low-grade inflammation in the arteries, which leads to the formation of plaques rich in lipids. M2 macrophage-derived extracellular vesicles (M2EV) have significant potential for anti-atherosclerotic therapy. However, their therapeutic effectiveness has been hindered by their limited targeting capability in vivo. The objective of this study was to create the P-M2EV (platelet membrane-modified M2EV) using the membrane fusion technique in order to imitate the interaction between platelets and macrophages. P-M2EV exhibited excellent physicochemical properties, and microRNA (miRNA)-sequencing revealed that the extrusion process had no detrimental effects on miRNAs carried by the nanocarriers. Remarkably, miR-99a-5p was identified as the miRNA with the highest expression level, which targeted the mRNA of Homeobox A1 (HOXA1) and effectively suppressed the formation of foam cells in vitro. In an atherosclerotic low-density lipoprotein receptor-deficient (Ldlr-/-) mouse model, the intravenous injection of P-M2EV showed enhanced targeting and greater infiltration into atherosclerotic plaques compared to regular extracellular vesicles. Crucially, P-M2EV successfully suppressed the progression of atherosclerosis without causing systemic toxicity. The findings demonstrated a biomimetic platelet-mimic system that holds great promise for the treatment of atherosclerosis in clinical settings.

10.
Nat Commun ; 15(1): 557, 2024 Jan 16.
Artículo en Inglés | MEDLINE | ID: mdl-38228638

RESUMEN

Calcific aortic valve disease is a prevalent cardiovascular disease with no available drugs capable of effectively preventing its progression. Hence, an efficient drug delivery system could serve as a valuable tool in drug screening and potentially enhance therapeutic efficacy. However, due to the rapid blood flow rate associated with aortic valve stenosis and the lack of specific markers, achieving targeted drug delivery for calcific aortic valve disease has proved to be challenging. Here we find that protease-activated-receptor 2 (PAR2) expression is up-regulated on the plasma membrane of osteogenically differentiated valvular interstitial cells. Accordingly, we develop a magnetic nanocarrier functionalized with PAR2-targeting hexapeptide for dual-active targeting drug delivery. We show that the nanocarriers effectively deliver XCT790-an anti-calcification drug-to the calcified aortic valve under extra magnetic field navigation. We demonstrate that the nano-cargoes consequently inhibit the osteogenic differentiation of valvular interstitial cells, and alleviate aortic valve calcification and stenosis in a high-fat diet-fed low-density lipoprotein receptor-deficient (Ldlr-/-) mouse model. This work combining PAR2- and magnetic-targeting presents an effective targeted drug delivery system for treating calcific aortic valve disease in a murine model, promising future clinical translation.


Asunto(s)
Estenosis de la Válvula Aórtica , Calcinosis , Ratones , Animales , Válvula Aórtica/metabolismo , Estenosis de la Válvula Aórtica/tratamiento farmacológico , Osteogénesis , Calcinosis/tratamiento farmacológico , Calcinosis/metabolismo , Células Cultivadas , Fenómenos Magnéticos
11.
Animal Model Exp Med ; 2024 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-38372410

RESUMEN

BACKGROUND: Calcific aortic valve stenosis (CAVS) is one of the most challenging heart diseases in clinical with rapidly increasing prevalence. However, study of the mechanism and treatment of CAVS is hampered by the lack of suitable, robust and efficient models that develop hemodynamically significant stenosis and typical calcium deposition. Here, we aim to establish a mouse model to mimic the development and features of CAVS. METHODS: The model was established via aortic valve wire injury (AVWI) combined with vitamin D subcutaneous injected in wild type C57/BL6 mice. Serial transthoracic echocardiography was applied to evaluate aortic jet peak velocity and mean gradient. Histopathological specimens were collected and examined in respect of valve thickening, calcium deposition, collagen accumulation, osteogenic differentiation and inflammation. RESULTS: Serial transthoracic echocardiography revealed that aortic jet peak velocity and mean gradient increased from 7 days post model establishment in a time dependent manner and tended to be stable at 28 days. Compared with the sham group, simple AVWI or the vitamin D group, the hybrid model group showed typical pathological features of CAVS, including hemodynamic alterations, increased aortic valve thickening, calcium deposition, collagen accumulation at 28 days. In addition, osteogenic differentiation, fibrosis and inflammation, which play critical roles in the development of CAVS, were observed in the hybrid model. CONCLUSIONS: We established a novel mouse model of CAVS that could be induced efficiently, robustly and economically, and without genetic intervention. It provides a fast track to explore the underlying mechanisms of CAVS and to identify more effective pharmacological targets.

12.
Cardiovasc Res ; 119(11): 2117-2129, 2023 09 05.
Artículo en Inglés | MEDLINE | ID: mdl-37183487

RESUMEN

AIMS: The incidence of calcific aortic valve disease (CAVD) has risen over the last decade and is expected to continue rising; however, pharmacological approaches have proven ineffective. In this study, we evaluated the role and underlying mechanisms of human antigen R (HuR)-mediated post-transcriptional regulation in CAVD. METHODS AND RESULTS: We found that HuR was significantly upregulated in human calcified aortic valves and primary aortic valvular interstitial cells (VICs) following osteogenic stimulation. Subsequent functional studies revealed that HuR silencing ameliorated calcification both in vitro and in vivo. For the first time, we demonstrated that HuR directly interacted with the transcript of phosphatidylinositol-5-phosphate 4-kinase, type II, alpha (PIP4K2A), which mediates phosphatidylinositol signalling, facilitates autophagy, and acts as an mRNA stabilizer. HuR positively modulated PIP4K2A expression at the post-transcriptional level and consequently influenced the AKT/mTOR/ATG13 pathway to regulate autophagy and CAVD progression. CONCLUSION: Our study provides new insights into the post-transcriptional regulatory role of HuR in modulating autophagy-positive factors to regulate the pathogenesis of CAVD. Our findings highlight the potential of HuR as an innovative therapeutic target in CAVD treatment.


Asunto(s)
Antígenos , Estenosis de la Válvula Aórtica , Calcinosis , Procesamiento Postranscripcional del ARN , Animales , Femenino , Humanos , Masculino , Ratones , Antígenos/fisiología , Antígenos/uso terapéutico , Válvula Aórtica/patología , Estenosis de la Válvula Aórtica/genética , Estenosis de la Válvula Aórtica/metabolismo , Calcinosis/genética , Calcinosis/metabolismo , Células Cultivadas , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Procesamiento Postranscripcional del ARN/fisiología , ARN Mensajero/metabolismo
13.
Sci Rep ; 12(1): 16802, 2022 10 07.
Artículo en Inglés | MEDLINE | ID: mdl-36207371

RESUMEN

An increasing number of researchers are using deep learning technology to classify and process garbage in rural areas, and have achieved certain results. However, the existing garbage detection models still have problems such as high complexity, missed detection of small targets, low detection accuracy and poor real-time performance. To address these issues, we train a model and apply it to garbage classification and detection in rural areas. In general, we propose an attention combination mechanism based on the YOLOv5 algorithm to build a better backbone network structure, add a new small object detection layer in the head network to enhance the model's ability to detect small objects, adopt the CIoU loss function to optimize the output prediction bounding box, and choose the Adam optimization algorithm to train the model. Our proposed YOLOv5s-CSS model detects a single garbage image in 0.021 s with a detection accuracy of 96.4%. Compared with the YOLOv5 algorithm and the classic detection algorithm, the improved algorithm has better detection speed and detection accuracy. At the same time, the complexity of the network model is reduced to a certain extent, which can meet the requirements of real-time detection of rural domestic garbage.


Asunto(s)
Residuos de Alimentos , Algoritmos
14.
Pharmacol Res Perspect ; 9(2): e00751, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33724726

RESUMEN

Clopidogrel is widely used for antiplatelet therapy in patients with coronary artery disease (CAD), but clopidogrel resistance (CR) is relatively common in these patients. The goal of our study was to explore the platelet-derived miRNA expression profile of CR in CAD patients. In this study, 66 CAD patients treated with dual antiplatelet therapy (clopidogrel 75 mg once daily plus aspirin 100 mg once daily) were included. According to inhibition of platelet aggregation (IPA), we divided these patients into CR group (IPA <30%) and control group (IPA ≥30%). The concentrations of clopidogrel and clopidogrel active metabolites in plasma were obtained using UHPLC-Q-Orbitrap HRMS method. The platelet-derived miRNA expression profiles of these subjects were detected by high-throughput sequencing and qRT-PCR. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used for function prediction of differentially expressed miRNAs. Our results suggested no significant difference of clopidogrel and active metabolic derivative concentrations between CR group and control group. Correlation analysis showed no significant association between clopidogrel concentration and IPA; active metabolic derivative and IPA. In addition, 67 platelet-derived miRNAs were differentially expressed between three CR and three control patients. After adjusting, eight miRNAs might be related to CR in CAD. In our validation cohort (30 CR patients and 30 control group), miRNA-142-3p and miRNA-24-3p expression levels were significantly upregulated, and miRNA-411-3p expression was significantly downregulated in the CR group. In conclusion, the miRNA-142-3p, miRNA-24-3p, and miRNA-411-3p might be potential markers for CR in CAD patients.


Asunto(s)
Aspirina/farmacología , Clopidogrel/farmacología , Enfermedad de la Arteria Coronaria/terapia , MicroARNs/metabolismo , Anciano , Aspirina/uso terapéutico , Biomarcadores/sangre , Biomarcadores/metabolismo , Plaquetas/metabolismo , Estudios de Casos y Controles , Clopidogrel/uso terapéutico , Estudios de Cohortes , Enfermedad de la Arteria Coronaria/sangre , Resistencia a Medicamentos/genética , Terapia Antiplaquetaria Doble , Femenino , Perfilación de la Expresión Génica , Humanos , Masculino , MicroARNs/sangre , Persona de Mediana Edad , Intervención Coronaria Percutánea , Agregación Plaquetaria/efectos de los fármacos
15.
Front Genet ; 12: 762587, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34970301

RESUMEN

As an autosomal dominant disorder, familial hypercholesterolemia (FH) is mainly caused by pathogenic mutations in lipid metabolism-related genes. The aim of this study is to investigate the genetic mutations in FH patients and verify their pathogenicity. First of all, a pedigree investigation was conducted in one family diagnosed with FH using the Dutch Lipid Clinic Network criteria. The high-throughput sequencing was performed on three family members to explore genetic mutations. The effects of low-density lipoprotein receptor (LDLR) variants on their expression levels and activity were further validated by silico analysis and functional studies. The results revealed that LDLC levels of the proband and his daughter were abnormally elevated. The whole-exome sequencing and Sanger sequencing were used to confirm that there were two LDLR missense mutations (LDLR c.226 G > C, c.1003 G > T) in this family. Bioinformatic analysis (Mutationtaster) indicated that these two mutations might be disease-causing variants. In vitro experiments suggested that LDLR c.226 G > C and c.1003 G > T could attenuate the uptake of Dil-LDL by LDLR. In conclusion, the LDLR c.226 G > C and c.1003 G > T variants might be pathogenic for FH by causing uptake dysfunction of the LDLR.

16.
Front Cell Dev Biol ; 8: 457, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32582717

RESUMEN

Transcription factor 21 (TCF21) is specific for mesoderm and is expressed in the embryos' mesenchymal derived tissues, such as the epicardium. It plays a vital role in regulating cell differentiation and cell fate specificity through epithelial-mesenchymal transformation during cardiac development. For instance, TCF21 could promote cardiac fibroblast development and inhibit vascular smooth muscle cells (VSMCs) differentiation of epicardial cells. Recent large-scale genome-wide association studies have identified a mass of loci associated with coronary heart disease (CHD). There is mounting evidence that TCF21 polymorphism might confer genetic susceptibility to CHD. However, the molecular mechanisms of TCF21 in heart development and CHD remain fundamentally problematic. In this review, we are committed to providing a detailed introduction of the biological roles of TCF21 in epicardial fate determination and the development of CHD.

17.
Bosn J Basic Med Sci ; 20(1): 31-36, 2020 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-31538912

RESUMEN

The AGTR1 gene encodes angiotensin II receptor type 1, which is involved in cardiovascular diseases such as coronary heart disease (CHD). In the current study, we analyzed AGTR1 methylation level in a Han Chinese population by SYBR green-based quantitative methylation-specific PCR (qMSP). We collected blood samples from 761 CHD patients and 398 non-CHD controls at the Ningbo First Hospital. A data mining analysis was also performed to explore the association between AGTR1 methylation and AGTR1 gene expression, using datasets from the cBioPortal for Cancer Genomics and the Gene Expression Omnibus (GEO) database. Our results showed a significantly higher percentage of methylated reference (PMR) of AGTR1 in male CHD patients compared with male non-CHD controls (median PMR: 2.12% vs. 0.59%, p = 0.037). The data mining analysis showed that AGTR1 expression was significantly increased in human hepatoma HepG2 cells treated with the demethylation agent 5-aza-2'-deoxycytidine (fold = 3.12, p = 0.009). Further data mining analysis using the cholangiocarcinoma (TCGA, PanCancer Atlas) data indicated an inverse association between AGTR1 methylation and AGTR1 expression (r = -0.595, p = 1.29E-04). Overall, our results suggest that AGTR1 methylation is involved in the regulation of AGTR1 gene expression and that AGTR1 hypermethylation is associated with CHD in males. These findings may provide new clues about the pathogenesis of CHD.


Asunto(s)
Pueblo Asiatico/genética , Enfermedad Coronaria/genética , Metilación de ADN/genética , Receptor de Angiotensina Tipo 1/genética , Anciano , Estudios de Casos y Controles , China , Enfermedad Coronaria/diagnóstico , Enfermedad Coronaria/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Receptor de Angiotensina Tipo 1/metabolismo , Factores Sexuales
18.
Bosn J Basic Med Sci ; 20(2): 169-182, 2020 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-31668143

RESUMEN

Currently, statins are the first-line therapies for dyslipidemia and atherosclerotic cardiovascular disease, however, their hypolipidemic effects have not been satisfactory. We performed a meta-analysis to compare lipid-lowering efficacy and safety of ezetimibe and statin combination therapy with double-dose statin monotherapy in patients with high cardiovascular risk. Fourteen studies involving 3105 participants were included in the final analysis; 1558 (50.18%) participants received ezetimibe and statin combination therapy and 1547 (49.82%) received double-dose statin monotherapy. Eight studies reported the percentages of changes in several lipid parameters from baseline to endpoint in both groups. Lipid parameters changed more significantly in patients coadministered with ezetimibe and statin (low-density lipoprotein cholesterol [LDL-C]: MD = -9.39, 95% CI -13.36 to -5.42; non-high-density lipoprotein cholesterol [non-HDL-C]: MD = -10.36, 95% CI -14.23 to -6.50; total cholesterol [TC]: MD = -8.11, 95% CI -10.95 to -5.26; and triglyceride [TG]: MD = -5.96, 95% CI -9.12 to -2.80), with moderate to high heterogeneity among the studies. Two out of fourteen studies investigated several different statins. Our subgroup analysis showed that, compared with double-dose atorvastatin monotherapy, ezetimibe and atorvastatin combination therapy significantly decreased LDL-C, non-HDL-C, TC, and TG levels by 14.16%, 14.01%, 11.06%, and 5.96%, respectively (p < 0.001). No significant difference was found in the incidence of laboratory-related adverse events (AEs) between statin combination therapy and monotherapy. Overall, ezetimibe and statin combination therapy significantly decreased LDL-C, non-HDL-C, and TC levels in patients with high cardiovascular risk, among which ezetimibe combined with atorvastatin had the best therapeutic effect. Compared with ezetimibe and statin combination therapy, double-dose statin monotherapy did not increase the risk of AEs.


Asunto(s)
Enfermedades Cardiovasculares/prevención & control , Ezetimiba/administración & dosificación , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Enfermedades Cardiovasculares/etiología , Quimioterapia Combinada , Humanos
19.
Autoimmunity ; 52(5-6): 192-198, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31476899

RESUMEN

Immunodeficiency, centromeric instability and facial anomalies syndrome (ICF) is a rare autosomal recessive disorder, which is characteristic of a severe impairment of immunity. In the genetic aspect, ICF is featured with mutations primarily located in the specific genes (DNMT3B for ICF1, ZBTB24 for ICF2, CDCA7 for ICF3, and HELLS for ICF4). The subtelomeric region is defined as 500 kb at the terminal of each autosomal arm. And subtelomeric DNA fragments can partially regulate key biological activities, including chromosome movement and localization in the nucleus. In this review, we updated and summarized gene mutations in ICF based on the previous review. In addition, we focused on the correlation between subtelomeric DNA methylation and ICF. The relationship between subtelomeric methylation and telomere length in ICF was also summarized.


Asunto(s)
Centrómero , Inestabilidad Cromosómica , Metilación de ADN , Cara/anomalías , Síndromes de Inmunodeficiencia , Mutación , Centrómero/genética , Centrómero/metabolismo , Centrómero/patología , Humanos , Síndromes de Inmunodeficiencia/genética , Síndromes de Inmunodeficiencia/metabolismo , Síndromes de Inmunodeficiencia/patología
20.
Pathol Res Pract ; 215(7): 152443, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-31085009

RESUMEN

Glutathione peroxidase 3 (GPX3) has an important function of scavenging hydrogen peroxide and preventing cancer. The purpose of this meta-analysis was to analyze the relationship between GPX3 gene methylation and cancer and to further evaluate its diagnostic value for cancer. We screened eligible literatures from the PubMed, Embase, CNKI and Wanfang databases. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to measure the association of GPX3 methylation with cancer. Summary receiver operating characteristics (SROC) analysis was used to assess the diagnostic value of GPX3 methylation for cancer. A total of 17 eligible articles were included in the meta-analysis involving a total of 960 tumor samples and 445 non-tumor samples. The results showed that GPX3 hypermethylation was significantly associated with cancer (OR = 17.32, 95% CI = 8.22-36.51, P < 0.00001). Compared with cancer patients without lymph node metastasis, cancer patients with lymph node metastasis were more associated with GPX3 hypermethylation (OR = 2.97, 95% CI = 1.53-5.76, P = 0.001). SROC analysis showed for GPX3 methylation was a promising biomarker for cancer risk (AUC = 0.89, pooled sensitivity = 0.93, pooled specificity = 0.54, NLR = 0.15, PLR = 2.05, DOR = 17.32). TCGA database bioinformatics analysis of 696 pairs of tumor and non-tumor tissues further validate the association of GPX3 methylation with the risk of cancer [cg21504918: 0.10 (0.08, 0.15) vs. 0.09 (0.08, 0.11), P = 5.8E-28; cg26638444: 0.05 (0.04, 011) vs. 0.04 (0.03, 0.06), P = 8.7E-29]. In summary, our study indicates that GPX3 methylation is associated with cancer and has the potential to become a broad-spectrum tumor screening marker and has a value in predicting tumor lymph node metastasis.


Asunto(s)
Metilación de ADN , Glutatión Peroxidasa/metabolismo , Metástasis Linfática/diagnóstico , Neoplasias/metabolismo , Regiones Promotoras Genéticas , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Glutatión Peroxidasa/genética , Humanos , Metástasis Linfática/genética , Metástasis Linfática/patología , Neoplasias/genética , Neoplasias/patología
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