RESUMEN
Alterations in the vascular smooth muscle cells (VSMC) phenotype play a critical role in the pathogenesis of several cardiovascular diseases, including hypertension, atherosclerosis, and restenosis after angioplasty. MicroRNAs (miRNAs) are a class of endogenous noncoding RNAs (approximately 19-25 nucleotides in length) that function as regulators in various physiological and pathophysiological events. Recent studies have suggested that aberrant miRNAs' expression might underlie VSMC phenotypic transformation, appearing to regulate the phenotypic transformations of VSMCs by targeting specific genes that either participate in the maintenance of the contractile phenotype or contribute to the transformation to alternate phenotypes, and affecting atherosclerosis, hypertension, and coronary artery disease by altering VSMC proliferation, migration, differentiation, inflammation, calcification, oxidative stress, and apoptosis, suggesting an important regulatory role in vascular remodeling for maintaining vascular homeostasis. This review outlines recent progress in the discovery of miRNAs and elucidation of their mechanisms of action and functions in VSMC phenotypic regulation. Importantly, as the literature supports roles for miRNAs in modulating vascular remodeling and for maintaining vascular homeostasis, this area of research will likely provide new insights into clinical diagnosis and prognosis and ultimately facilitate the identification of novel therapeutic targets.
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Hipertensión , MicroARNs , Humanos , MicroARNs/metabolismo , Músculo Liso Vascular , Remodelación Vascular/genética , Proliferación Celular , Hipertensión/metabolismo , Fenotipo , Miocitos del Músculo Liso/metabolismoRESUMEN
BACKGROUND: Chronic inflammation has been shown to promote cancer progression. Rosacea is indeed a long-term inflammatory skin condition and had been reported to link with increased risk for several types of malignancies, but evidence for causality is lacking. OBJECTIVES: To systematically estimate the causal relationship between rosacea and several types of cancer, including cutaneous malignant melanoma (CMM), cutaneous squamous cell carcinoma (cSCC), basal cell carcinoma (BCC), actinic keratosis (AK), thyroid cancer, breast cancer, glioma and hepatic cancer, as well as explore the potential underlying pathogenesis. METHODS: We conducted a bidirectional two-sample Mendelian randomization study to probe the potential causal relationships between rosacea and several types of cancer. Instrumental variables were established using genome-wide significant single nucleotide polymorphisms associated with rosacea and cancers. The assessment of causality was carried out through multiple methods, and the robustness of the results was evaluated via sensitivity analyses. RESULTS: There was no significant indication of causal effects of rosacea on CMM (pivw = 0.71), cSCC (pivw = 0.45), BCC (pivw = 0.90), AK (pivw = 0.73), thyroid cancer (pivw = 0.59), glioma (pivw = 0.15), and hepatic cancer (pivw = 0.07), but the genetic risk of rosacea was associated with an increased susceptibility to human epidermal growth factor receptor (HER)-negative malignant neoplasm of breast (odds ratio [OR], 1.10; 95% confidence interval [CI], 1.02-1.18; pivw = 0.01). TANK (TRAF family member associated nuclear factor kappa B (NFKB) activator) was identified as a common protective gene for both rosacea (OR, 0.90; 95% CI, 0.82-0.99; pivw = 0.048) and HER-negative malignant neoplasm of the breast (OR, 0.86; 95% CI, 0.75-0.98; pivw = 0.032), which was primarily enriched in the negative regulation of NF-κB signal transduction and may contribute to the genetic links between rosacea and this subtype of breast cancer. CONCLUSIONS: Our findings provide suggestive evidence for causal links between rosacea and HER-negative malignant neoplasm of the breast risk.
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Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido Simple , Rosácea , Neoplasias Cutáneas , Humanos , Rosácea/genética , Neoplasias Cutáneas/genética , Femenino , Melanoma/genética , Carcinoma Basocelular/genética , Carcinoma de Células Escamosas/genética , Factores de Riesgo , Predisposición Genética a la Enfermedad/genética , Neoplasias de la Mama/genética , Queratosis Actínica/genética , Neoplasias de la Tiroides/genética , Glioma/genética , Neoplasias Hepáticas/genética , MasculinoRESUMEN
The high toxicity of arsenic (As) can cause irreversible harm to the environment and human health. In this study, the chlorin e6 (Ce6), which emits fluorescence in the infrared region, was introduced as the luminescence center, and the addition of copper ion (Cu2+) and As(V) provoked a regular change in fluorescence at 652 nm, whereas that of As(III) was 665 nm, which was used to optionally detect Cu2+, arsenic (As(III), and As(V)). The limit of detection (LOD) values were 0.212 µM, 0.089 ppm, and 1.375 ppb for Cu2+, As(III), and As(V), respectively. The developed method can be used to determine Cu2+ and arsenic in water and soil with good sensitivity and selectivity. The 1:1 stoichiometry of Ce6 with Cu2+ was obtained from the Job plot that was developed from UV-visible spectra. The binding constants for Cu2+ and As(V) were established to be 1.248 × 105 M-1 and 2.35 × 1012 M-2, respectively, using B-H (Benesi-Hildebrand) plots. Fluorescence lifetimes, B-H plots, FT-IR, and 1H-NMR were used to postulate the mechanism of Cu2+ fluorescence quenching and As(V) fluorescence restoration and the interactions of the two ions with the Ce6 molecule.
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Arsénico , Clorofilidas , Porfirinas , Humanos , Cobre/química , Espectroscopía Infrarroja por Transformada de Fourier , Iones , Espectrometría de Fluorescencia , Colorantes Fluorescentes/químicaRESUMEN
A biomimetic mineralization method was used in the facile and rapid preparation of nanoflowers for immobilizing alcohol dehydrogenase (ADH). The method mainly uses ADH as an organic component and zinc phosphate as an inorganic component to prepare flower-like ADH/Zn3(PO4)2 organic-inorganic hybrid nanoflowers (HNFs) with the high specific surface area through a self-assembly process. The synthesis conditions of the ADH HNFs were optimized and its morphology was characterized. Under the optimum enzymatic reaction conditions, the Michaelis-Menten constant (Km) of ADH HNFs (ß-NAD+ as substrate) was measured to be 3.54 mM, and the half-maximal inhibitory concentration (IC50) of the positive control ranitidine (0.2-0.8 mM) was determined to be 0.49 mM. Subsequently, the inhibitory activity of natural medicine Penthorum chinense Pursh and nine small-molecule compounds on ADH was evaluated using ADH HNFs. The inhibition percentage of the aqueous extract of P. chinense is 57.9%. The vanillic acid, protocatechuic acid, gallic acid, and naringenin have obvious inhibitory effects on ADH, and their percentages of inhibition are 55.1%, 68.3%, 61.9%, and 75.5%, respectively. Moreover, molecular docking analysis was applied to explore the binding modes and sites of the four most active small-molecule compounds to ADH. The results of this study can broaden the application of immobilized enzymes through biomimetic mineralization, and provide a reference for the discovery of ADH inhibitors from natural products.
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Alcohol Deshidrogenasa , Nanoestructuras , Nanoestructuras/química , Biomimética , Simulación del Acoplamiento MolecularRESUMEN
The effects of oenothein B(OEB) on the proliferation, apoptosis, invasion, and migration of breast cancer MCF-7 and MDA-MB-231 cells were investigated by cell culture in vitro, network pharmacology, and molecular docking. In vitro cell experiments revealed that OEB inhibited the proliferation and colony formation ability, and promoted the apoptosis and formation of apoptotic bodies in breast cancer cells, as well as inhibited the invasion and migration of breast cancer cells. The targets of OEB were obtained using SwissTargetPrediction database and breast cancer targets were obtained from GeneCards. The targets of OEB and breast cancer were entered separately in Venny 2.1 software to obtain the Venn diagram of common targets of OEB and breast cancer. The common targets of OEB and breast cancer were input into STRING database to construct a protein-protein interaction(PPI) network, which was entered into Cytoscape 3.7.2 software for network topology analysis. Key targets were screened according to protein association strength, and analyzed for KEGG pathway enrichment. Molecular docking of OEB to key targets using AutoDock software revealed that OEB stably bound to the active pocket of P53, while OEB promoted the expression of P53 protein. MCF-7 and MDA-MB-231 cell viability and migration ability increased after silencing P53, and this change was reversed after treatment with OEB. Therefore, this study showed that OEB inhibited the proliferation, migration, and invasion of breast cancer MCF-7 and MDA-MB-231 cells, and promoted the apoptosis of breast cancer MCF-7 and MDA-MB-231 cells, which may be related to the targeted regulation of P53.
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Neoplasias de la Mama , Humanos , Femenino , Proliferación Celular , Neoplasias de la Mama/tratamiento farmacológico , Proteína p53 Supresora de Tumor/genética , Simulación del Acoplamiento MolecularRESUMEN
The impairment of the angiopoietin-1 (Ang-1)/Tie-2 signaling pathway has been thought to play a critical role in diabetic complications. However, the underlying mechanisms remain unclear. The present study aims to investigate the effects of Tie-2 glycation on Ang-1 signaling activation and Ang-1-induced angiogenesis. We identified that Tie-2 was modified by advanced glycation end products (AGEs) in aortae derived from high fat diet (HFD)-fed mice and in methylglyoxal (MGO)-treated human umbilical vein endothelial cells (HUVECs). MGO-induced Tie-2 glycation significantly inhibited Ang-1-evoked Tie-2 and Akt phosphorylation and Ang-1-regulated endothelial cell migration and tube formation, whereas the blockade of AGE formation by aminoguanidine remarkably rescued Ang-1 signaling activation and Ang-1-induced angiogenesis in vitro. Furthermore, MGO treatment markedly increased AGE cross-linking of Tie-2 in cultured aortae ex vivo and MGO-induced Tie-2 glycation also significantly decreased Ang-1-induced vessel outgrow from aortic rings. Collectively, these data suggest that Tie-2 may be modified by AGEs in diabetes mellitus and that Tie-2 glycation inhibits Ang-1 signaling activation and Ang-1-induced angiogenesis. This may provide a novel mechanism for Ang-1/Tie-2 signal dysfunction and angiogenesis failure in diabetic ischaemic diseases.
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Angiopoyetina 1 , Receptor TIE-2 , Angiopoyetina 1/metabolismo , Angiopoyetina 2/metabolismo , Animales , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Óxido de Magnesio/farmacología , Ratones , Neovascularización Patológica/metabolismo , Receptor TIE-2/metabolismo , Transducción de SeñalRESUMEN
Mitsugumin 53 (MG53), which is expressed predominantly in striated muscle, has been demonstrated to be a myokine/cardiokine secreted from striated muscle under specific conditions. The important roles of MG53 in non-striated muscle tissues have also been examined in multiple disease models. However, no previous study has implicated MG53 in the control of endothelial cell function. In order to explore the effects of MG53 on endothelial cells, human umbilical vein endothelial cells (HUVECs) were stimulated with recombinant human MG53 (rhMG53). Then, rhMG53 uptake, focal adhesion kinase (FAK)/Src/Akt/ERK1/2 signalling pathway activation, cell migration and tube formation were determined in vitro. The efficacy of rhMG53 in regulating angiogenesis was also detected in postnatal mouse retinas. The results demonstrated that rhMG53 directly entered into endothelial cells in a cholesterol-dependent manner. The uptake of rhMG53 directly bound to FAK in endothelial cells, which resulted in a significant decrease in FAK phosphorylation at Y397. Accompanied by the dephosphorylation of FAK, rhMG53 uncoupled FAK-Src interaction and reduced the phosphorylation of Src at Y416. Consequently, the activation of FAK/Src downstream signalling pathways, such as Akt and ERK1/2, was also significantly inhibited by rhMG53. Furthermore, rhMG53 remarkably decreased HUVEC migration and tube formation in vitro and postnatal mouse retinal angiogenesis in vivo. Taken together, these data indicate that rhMG53 inhibits angiogenesis through regulating FAK/Src/Akt/ERK1/2 signalling pathways. This may provide a novel molecular mechanism for the impaired angiogenesis in ischaemic diseases.
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Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Proteínas de la Membrana/farmacología , Neovascularización Fisiológica/efectos de los fármacos , Transducción de Señal , Animales , Células Cultivadas , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Células Endoteliales de la Vena Umbilical Humana/fisiología , Humanos , Ratones , Ratones Endogámicos C57BL , Fosforilación , Unión Proteica , Proteínas Recombinantes/farmacología , Vasos Retinianos/efectos de los fármacos , Vasos Retinianos/metabolismo , Vasos Retinianos/fisiologíaRESUMEN
Angiogenesis is rapidly initiated in response to pathological conditions and is a key target for pharmaceutical intervention in various malignancies. Anti-angiogenic therapy has emerged as a potential and effective therapeutic strategy for treating cancer and cardiovascular-related diseases. Metformin, a first-line oral antidiabetic agent for type 2 diabetes mellitus (T2DM), not only reduces blood glucose levels and improves insulin sensitivity and exerts cardioprotective effects but also shows benefits against cancers, cardiovascular diseases, and other diverse diseases and regulates angiogenesis. MicroRNAs (miRNAs) are endogenous noncoding RNA molecules with a length of approximately 19-25 bases that are widely involved in controlling various human biological processes. A large number of miRNAs are involved in the regulation of cardiovascular cell function and angiogenesis, of which miR-21 not only regulates vascular cell proliferation, migration and apoptosis but also plays an important role in angiogenesis. The relationship between metformin and abnormal miRNA expression has gradually been revealed in the context of numerous diseases and has received increasing attention. This paper reviews the drug-target interactions and drug repositioning events of metformin that influences vascular cells and has benefits on angiogenesis-mediated effects. Furthermore, we use miR-21 as an example to explain the specific molecular mechanism underlying metformin-mediated regulation of the miRNA signaling pathway controlling angiogenesis and vascular protective effects. These findings may provide a new therapeutic target and theoretical basis for the clinical prevention and treatment of cardiovascular diseases.
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Hipoglucemiantes/farmacología , Metformina/farmacología , MicroARNs , Neovascularización Patológica/genética , Animales , Reposicionamiento de Medicamentos , HumanosRESUMEN
Coaxial core/shell electrospun nanofibers consisting of ferroelectric P(VDF-TrFE) and relaxor ferroelectric P(VDF-TrFE-CTFE) are tailor-made with hierarchical structures to modulate their mechanical properties with respect to their constituents. Compared with two single and the other coaxial membranes prepared in the research, the core/shell-TrFE/CTFE membrane shows a more prominent mechanical anisotropy between revolving direction (RD) and cross direction (CD) associated with improved resistance to tensile stress for the crystallite phase stability and good strength-ductility balance. This is due to the better degree of core/shell-TrFE-CTFE nanofiber alignment and the crystalline/amorphous ratio. The coupling between terpolymer P(VDF-TrFE-CTFE) and copolymer P(VDF-TrFE) is responsible for phase stabilization, comparing the core/shell-TrFE/CTFE with the pristine terpolymer. Moreover, an impressive collective deformation mechanism of a two-length scale in the core/shell composite structure is found. We apply in-situ synchrotron X-ray to resolve the two-length scale simultaneously by using the small-angle X-ray scattering to characterize the nanofibers and the wide-angle X-ray diffraction to identify the phase transformations. Our findings may serve as guidelines for the fabrication of the electrospun nanofibers used as membranes-based electroactive polymers.
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Nanofibras/química , Polivinilos/química , Dispersión del Ángulo Pequeño , Sincrotrones/instrumentación , Resistencia a la Tracción , Difracción de Rayos X/métodosRESUMEN
Glycation of extracellular matrix proteins has been demonstrated to contribute to the pathogenesis of vascular complications. However, no previous report has shown the role of glycated fibronectin (FN) in vascular endothelial growth factor (VEGF)-induced angiogenesis. Thus, this study aimed to investigate the effects of glycated FN on VEGF signalling and to clarify the molecular mechanisms involved. FN was incubated with methylglyoxal (MGO) in vitro to synthesize glycated FN, and human umbilical vein endothelial cells (HUVECs) were seeded onto unmodified and MGO-glycated FN. Then, VEGF-induced angiogenesis and VEGF-induced VEGF receptor-2 (VEGFR-2) signalling activation were measured. The results demonstrated that normal FN-positive bands (260 kD) vanished and advanced glycation end products (AGEs) appeared in MGO-glycated FN and glycated FN clearly changed to a higher molecular mass. The glycation of FN inhibited VEGF-induced VEGF receptor-2 (VEGFR-2), Akt and ERK1/2 activation and VEGF-induced cell migration, proliferation and tube formation. The glycation of FN also inhibited the recruitment of c-Src to VEGFR-2 by sequestering c-Src through receptor for AGEs (RAGE) and the anti-RAGE antibody restored VEGF-induced VEGFR-2, Akt and ERK1/2 phosphorylation, endothelial cell migration, proliferation and tube formation. Furthermore, the glycation of FN significantly inhibited VEGF-induced neovascularization in the Matrigel plugs implanted into subcutaneous tissue of mice. Taken together, these data suggest that the glycation of FN may inhibit VEGF signalling and VEGF-induced angiogenesis by uncoupling VEGFR-2-c-Src interaction. This may provide a novel mechanism for the impaired angiogenesis in diabetic ischaemic diseases.
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Fibronectinas/metabolismo , Neovascularización Fisiológica , Factor A de Crecimiento Endotelial Vascular/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Familia-src Quinasas/metabolismo , Animales , Movimiento Celular , Proliferación Celular , Fibronectinas/genética , Productos Finales de Glicación Avanzada , Glicosilación , Células Endoteliales de la Vena Umbilical Humana , Humanos , Ratones , Fosforilación , Transducción de Señal , Factor A de Crecimiento Endotelial Vascular/genética , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genética , Familia-src Quinasas/genéticaRESUMEN
MOTIVATION: With the development and the gradually popularized application of next-generation sequencing technologies (NGS), genome sequencing has been becoming faster and cheaper, creating a massive amount of genome sequence data which still grows at an explosive rate. The time and cost of transmission, storage, processing and analysis of these genetic data have become bottlenecks that hinder the development of genetics and biomedicine. Although there are many common data compression algorithms, they are not effective for genome sequences due to their inability to consider and exploit the inherent characteristics of genome sequence data. Therefore, the development of a fast and efficient compression algorithm specific to genome data is an important and pressing issue. RESULTS: We have developed a referential lossless genome data compression algorithm with better performance than previous algorithms. According to a carefully designed matching strategy selection mechanism, the advantages of local matching and global matching are reasonably combined together to improve the description efficiency of the matched sub-strings. The effects of the length and the position of matched sub-strings to the compression efficiency are jointly taken into consideration. The proposed algorithm can compress the FASTA data of complete human genomes, each of which is about 3 GB, in about 18 min. The compressed file sizes are ranging from a few megabytes to about forty megabytes. The averaged compression ratio is higher than that of the state-of-the-art genome compression algorithms, the time complexity is at the same order of the best-known algorithms. AVAILABILITY AND IMPLEMENTATION: https://github.com/jhchen5/SCCG. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Compresión de Datos , Algoritmos , Genoma Humano , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Análisis de Secuencia de ADN , Programas InformáticosRESUMEN
PURPOSE: The aim of the present study was to explore the efficacy and safety of transurethral needle electrode resection and transurethral holmium laser resection of non-muscular invasive bladder cancer (NMIBC). PATIENTS AND METHODS: In this prospective, case-control study, patients from the Urinary Surgery or Oncology Department who met the inclusion and exclusion criteria received transurethral needle electrode resection (n = 52) or transurethral holmium laser resection (n = 51). RESULTS: A total of 103 patients with NMIBC were included in the present study, with 68 males and 35 females. Their mean age was 57.3 years. Sixty-two patients had Ta, 15 patients had T1, and 26 patients had Tis. Operative time, intraoperative blood loss, postoperative gross hematuria time, bladder irrigation time, and postoperative hospitalization time were all significantly lower in the transurethral holmium laser resection group than the transurethral needle electrode resection group. After resection, transurethral holmium laser resection significantly decreased the value of HGF, TSH, and TNF-α versus the transurethral needle electrode resection group. The incidence of obturator reflex was significantly lower in the transurethral holmium laser resection group than the transurethral needle electrode resection group. There was no significant difference in disease-free survival rate and progression-free survival rate between the two groups. CONCLUSIONS: Transurethral holmium laser resection has clinical advantages in the treatment of NMIBC.
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Terapia por Láser , Láseres de Estado Sólido , Neoplasias de la Vejiga Urinaria , Estudios de Casos y Controles , Electrodos , Femenino , Humanos , Láseres de Estado Sólido/uso terapéutico , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Resultado del Tratamiento , Neoplasias de la Vejiga Urinaria/cirugíaRESUMEN
Platelet (PLT)-endothelial cell (EC) interaction appears to contribute to phenotypic transition of vascular smooth muscle cells (VSMCs), which play an important role in the physiological and pathological process of vascular complications in type 2 diabetes mellitus (DM2). However, the precise mechanisms by which interactions between PLTs and ECs affect VSMC phenotype have largely remained unclear. We determined the effect of diabetic PLT-EC interaction to influence VSMC migration, proliferation, and phenotypic transformation in triple-cell coculture models using the quantitative real-time PCR, Western blot, fluorescence microscopy, wound scratch assays, CCK-8 assays, and gelatin zymography assays. Our results revealed DM2 PLT-EC interaction to be associated with a significant downregulation of VSMC-specific contractile phenotypic genes and proteins, including SM22α, smooth muscle actin, Smoothelin-B, and smooth muscle-myosin heavy chain. Inversely, VSMC-specific proliferative phenotype gene and protein levels, including cyclin D1 and 2, nonmuscle myosin heavy chain B, and PCNA were in upregulation. Furthermore, the DM2-originated PLT-EC interaction promoted the expression level of transforming growth factor-ß1, and the PI3K/Akt and matrix metalloproteinase 9 signaling pathway was activated subsequently. Finally, these reactions contributed to a synthetic phenotype of VSMCs, including the proliferation, migration, and gelatinolytic activities. These findings suggest that PLT-EC interaction modulates the phenotypic transition of VSMCs between a contractile and proliferative/synthetic phenotype under diabetic conditions, conceivably providing important implications regarding the mechanisms controlling the VSMC phenotypic transition and the development of cardiovascular complications.
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Plaquetas/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Endotelio Vascular/metabolismo , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Fenotipo , Animales , Células Cultivadas , Técnicas de Cocultivo , Diabetes Mellitus Tipo 2/etiología , Diabetes Mellitus Tipo 2/patología , Dieta Alta en Grasa/efectos adversos , Endotelio Vascular/citología , Masculino , Ratones , Ratones Endogámicos C57BL , Músculo Liso Vascular/citologíaRESUMEN
Plasminogen activator inhibitor-1 (PAI-1) is increasingly recognized as a mediator in extracellular matrix (ECM) accumulation in diabetic nephropathy. Previous studies have implicated PAI-1 in adipose tissue (AT) expansion, while also contributing to insulin resistance. As inflammation is also known to occur in perirenal AT during obesity, we hypothesized that in a high-fat diet (HFD)-induced obese mouse model, PAI-1 contributes to macrophage-mediated inflammation and diabetic nephropathy. The HFD mice showed increased expression of PAI-1 in perirenal fat and also displayed increased fat weight and macrophage numbers. We found that the macrophage polarization, proinflammatory macrophage-M1-phenotype, including CD11c, IL-6, and monocyte chemoattractant protein-1, were increased by an HFD and decreased by either the genetic depletion of PAI-1 or treatment with the PAI-1 inhibitor, PAI-039. Similarly, an enhanced anti-inflammatory M2-phenotype, including CD206 and IL-10, was accompanied by either the genetic deletion of PAI-1 or PAI-039 treatment. Furthermore, the inhibition of PAI-1 reduced HFD-induced renal histological lesions and abated profibrotic/extracellular-matrix protein. Collectively, our findings provide support that PAI-1 contributes to the development of inflammation in perirenal fat and correlates with the development of diabetic nephropathy in HFD-induced obesity.
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Tejido Adiposo/metabolismo , Nefropatías Diabéticas/genética , Riñón/metabolismo , Obesidad/metabolismo , Serpina E2/genética , Tejido Adiposo/inmunología , Animales , Nefropatías Diabéticas/inmunología , Dieta Alta en Grasa , Tasa de Filtración Glomerular , Ácidos Indolacéticos/farmacología , Inflamación , Riñón/efectos de los fármacos , Riñón/inmunología , Macrófagos/inmunología , Ratones , Ratones Noqueados , Serpina E2/antagonistas & inhibidores , Serpina E2/inmunologíaRESUMEN
BACKGROUND: Current research has shown that microRNAs (miRNAs) play vital roles in plant response to stress caused by heavy metals such as aluminum, arsenic, cadmium (Cd), and mercury. Cd has become one of the most hazardous pollutants in the environment. Maize can be a potential model to study phytoremediation of Cd-contaminated soil owing to its large biomass production. However, little is known about miRNAs as a response to Cd stress in maize. RESULTS: To investigate the role of miRNAs in response to Cd stress, roots of seedlings of the inbred maize lines B73 and Mo17 were collected and treated with 200 mg/L CdCl2·2.5 H2O over different exposure times. Enzyme activities of superoxide dismutase and peroxidase were measured to confirm Cd stress. The expression of six candidate miRNAs and their targets were validated using quantitative real-time PCR (qRT-PCR) technology. In addition, the expression of Zma-miR171b was assessed using in situ hybridization. CONCLUSIONS: Our results showed that miRNAs and their respective target genes were differentially expressed in maize seedling roots exposed to Cd stress. This research produced new insights into the molecular mechanism of miRNAs responsive to Cd stress in plants and sheds light on the latent roles of miRNAs in plants exposed to heavy metal stresses.
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Cadmio/metabolismo , MicroARNs/genética , Raíces de Plantas/genética , Zea mays/genética , Cromosomas de las Plantas/genética , Regulación de la Expresión Génica de las Plantas , Proteínas de Plantas/genética , Plantones/genética , Análisis de Secuencia de ARN , Contaminantes del Suelo/metabolismo , Estrés FisiológicoRESUMEN
An appropriate inflammatory response plays critical roles in eliminating pathogens, whereas an excessive inflammatory response can cause tissue damage. Runt-related transcription factor 1 (RUNX1), a master regulator of hematopoiesis, plays critical roles in T cells; however, its roles in Toll-like receptor 4 (TLR4)-mediated inflammation in macrophages are unclear. Here, we demonstrated that upon TLR4 ligand stimulation by lipopolysaccharide (LPS), macrophages reduced the expression levels of RUNX1 Silencing of Runx1 attenuated the LPS-induced IL-1ß and IL-6 production levels, but the TNF-α levels were not affected. Overexpression of RUNX1 promoted IL-1ß and IL-6 production in response to LPS stimulation. Moreover, RUNX1 interacted with the NF-κB subunit p50, and coexpression of RUNX1 with p50 further enhanced the NF-κB luciferase activity. Importantly, treatment with the RUNX1 inhibitor, Ro 5-3335, protected mice from LPS-induced endotoxic shock and substantially reduced the IL-6 levels. These findings suggest that RUNX1 may be a new potential target for resolving TLR4-associated uncontrolled inflammation and preventing sepsis.
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Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Macrófagos Peritoneales/metabolismo , Subunidad p50 de NF-kappa B/metabolismo , Choque Séptico/metabolismo , Transducción de Señal , Receptor Toll-Like 4/metabolismo , Animales , Benzodiazepinonas/farmacología , Inflamación/inducido químicamente , Inflamación/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Lipopolisacáridos/toxicidad , Ratones , Unión Proteica/efectos de los fármacos , Pirroles/farmacología , Células RAW 264.7 , Choque Séptico/inducido químicamente , Receptor Toll-Like 4/agonistasRESUMEN
Papillary renal cell carcinoma(PRCC) is the second most common and aggressive renal cell carcinoma. Identification of novel microRNA biomarkers could be beneficial for the diagnosis and prognosis of PRCC patients. We aimed to screen differentially expressed miRNAs that can act as prognostic factors and to predict the survival of PRCC patients. High-throughput data of miRNAs of 274 PRCC samples were downloaded from TCGA (The Cancer Genome Atlas) dataset and interested miRNAs were identified. Hierarchical clustering and principal component analysis (PCA) were performed on these miRNAs. Critical genes that can act as prognostic factors were screened by LASSO. What's more, Kaplan-Meier survival analysis and ROC (Receiver Operating Characteristic) growth curve were used to testify the accuracy of the model. Biological processes of putative targets of miRNAs were analyzed by bioinformatics methods such as GO (Go Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis. A total of 105 differentially expressed miRNAs were screened out in PRCC samples compared with healthy controls. Two critical miRNAs, hsa-mir-3199-2, and hsa-mir-1293, were screened out by LASSO (Least Absolute Shrinkage and Selection Operator), including 197 and 189 target genes, respectively. Furthermore, its' accuracy was testified by ROC analysis with the AUC (Area under the curve) value of 0.7774968 and 0.6743466. These miRNAs were significantly enriched in pathways as platelet activating factor biosynthetic process, epithelial cell maturation, and IkappaB kinase complex. In conclusion, hsa-mir-3199-2 and hsa-mir-1293 that can act as prognostic biomarkers of PRCC were screened out, which can provide new insights for the clinical treatment of the disease. J. Cell. Biochem. 118: 3488-3494, 2017. © 2017 Wiley Periodicals, Inc.
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Biomarcadores de Tumor/metabolismo , Carcinoma de Células Renales , Neoplasias Renales , MicroARNs/metabolismo , Modelos Biológicos , ARN Neoplásico/metabolismo , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/mortalidad , Femenino , Humanos , Neoplasias Renales/metabolismo , Neoplasias Renales/mortalidad , Masculino , Modelos de Riesgos ProporcionalesRESUMEN
OBJECTIVE: Plasminogen activator inhibitor-1 (PAI-1), a serine protease inhibitor that promotes and inhibits cell migration, plays a complex and important role in adverse vascular remodeling. Little is known about the effects of pharmacological PAI-1 inhibitors, an emerging drug class, on migration of vascular smooth muscle cells (SMCs) and endothelial cells (ECs), crucial mediators of vascular remodeling. We investigated the effects of PAI-039 (tiplaxtinin), a specific PAI-1 inhibitor, on SMC and EC migration in vitro and vascular remodeling in vivo. APPROACH AND RESULTS: PAI-039 inhibited SMC migration through collagen gels, including those supplemented with vitronectin and other extracellular matrix proteins, but did not inhibit migration of PAI-1-deficient SMCs, suggesting that its antimigratory effects were PAI-1-specific and physiologically relevant. However, PAI-039 did not inhibit EC migration. PAI-039 inhibited phosphorylation and nuclear translocation of signal transducers and activators of transcription-1 in SMCs, but had no discernable effect on signal transducer and activator of transcription-1 signaling in ECs. Expression of low-density lipoprotein receptor-related protein 1, a motogenic PAI-1 receptor that activates Janus kinase/signal transducers and activators of transcription-1 signaling, was markedly lower in ECs than in SMCs. Notably, PAI-039 significantly inhibited intimal hyperplasia and inflammation in murine models of adverse vascular remodeling, but did not adversely affect re-endothelialization after endothelium-denuding mechanical vascular injury. CONCLUSIONS: PAI-039 inhibits SMC migration and intimal hyperplasia, while having no inhibitory effect on ECs, which seems to be because of differences in PAI-1-dependent low-density lipoprotein receptor-related protein 1/Janus kinase/signal transducer and activator of transcription-1 signaling between SMCs and ECs. These findings suggest that PAI-1 may be an important therapeutic target in obstructive vascular diseases characterized by neointimal hyperplasia.
Asunto(s)
Traumatismos de las Arterias Carótidas/tratamiento farmacológico , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Ácidos Indolacéticos/farmacología , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Neointima , Inhibidor 1 de Activador Plasminogénico/metabolismo , Inhibidores de Serina Proteinasa/farmacología , Animales , Traumatismos de las Arterias Carótidas/genética , Traumatismos de las Arterias Carótidas/metabolismo , Traumatismos de las Arterias Carótidas/patología , Células Cultivadas , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Células Endoteliales/patología , Genotipo , Humanos , Hiperplasia , Quinasas Janus/metabolismo , Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Terapia Molecular Dirigida , Músculo Liso/metabolismo , Músculo Liso/patología , Músculo Liso/trasplante , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Músculo Liso Vascular/trasplante , Fenotipo , Fosforilación , Inhibidor 1 de Activador Plasminogénico/deficiencia , Inhibidor 1 de Activador Plasminogénico/genética , Repitelización/efectos de los fármacos , Receptores de LDL/deficiencia , Receptores de LDL/genética , Factor de Transcripción STAT1/metabolismo , Transducción de Señal/efectos de los fármacos , Proteínas Supresoras de Tumor/deficiencia , Proteínas Supresoras de Tumor/genética , Remodelación Vascular/efectos de los fármacos , Vena Cava Inferior/efectos de los fármacos , Vena Cava Inferior/metabolismo , Vena Cava Inferior/patología , Vena Cava Inferior/trasplanteRESUMEN
BACKGROUND: Angiopoietin-2 (Ang-2), a ligand of the Tie-2 receptor, plays an important role in maintaining endothelial cells and in destabilizing blood vessels. Collateral artery growth (arteriogenesis) is a key adaptive response to arterial occlusion. It is unknown whether the destabilization of blood vessels by Ang-2 can affect arteriogenesis and modulate mononuclear cell function. This study aimed to investigate the effects of Ang-2 on collateral artery growth. METHODS: Hindlimb ischaemia model was produced in C57BL/6 mice by femoral artery ligation. Blood flow perfusion was measured using a laser Doppler perfusion imager quantitative RT-PCR analysis was applied to identify the level of angiogenic factors. RESULTS: After the induction of hindlimb ischaemia, blood flow recovery was impaired in mice treated with recombinant Ang-2 protein; this was accompanied by a reduction of peri-collateral macrophage infiltration. In addition, quantitative RT-PCR analysis revealed that Ang-2 treatment decreased monocyte chemotactic protein-1 (MCP-1), platelet-derived growth factor-BB (PDGF-BB) mRNA levels in ischaemic adductor muscles. Ang-2 can lead to macrophage M1/M2 polarization shift inhibition in the ischaemic muscles. Furthermore, Ang-2 reduced the in vitro inflammatory response in macrophages and vascular cells involved in arteriogenesis. CONCLUSIONS: Our results demonstrate that Ang-2 is essential for efficient arteriogenesis, which controls macrophage infiltration.
Asunto(s)
Angiopoyetina 2/uso terapéutico , Arterias/crecimiento & desarrollo , Circulación Colateral , Miembro Posterior/irrigación sanguínea , Miembro Posterior/patología , Isquemia/tratamiento farmacológico , Macrófagos/patología , Angiopoyetina 2/farmacología , Animales , Arterias/efectos de los fármacos , Arterias/patología , Movimiento Celular/efectos de los fármacos , Circulación Colateral/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Inflamación/patología , Isquemia/genética , Isquemia/patología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Ratones Endogámicos C57BL , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Perfusión , Proteínas Recombinantes/farmacología , Proteínas Recombinantes/uso terapéuticoRESUMEN
BACKGROUND: The flowers of Carthamus tinctorius L. are widely used in traditional Chinese medicine to treat cerebrovascular and cardiovascular diseases. Hydroxysafflor yellow A (HSYA), the main constituent of C. tinctorius L. flowers, is known for its multiple biological activities. The present study investigated the effects of HSYA on angiogenesis in vitro and in a mouse hindlimb ischemia model. METHODS: Using human umbilical vein endothelial cells (HUVEC) in vitro and a mouse hindlimb ischemia model in vivo, the angiogenic role of HSYA was evaluated. RESULTS: HSYA significantly increased the capillary-like tube formation and migration of HUVEC. HSYA not only induced a rise in the expression of angiopoietin 1 and Tie-2 but it also increased phosphorylation of Tie-2, Akt, and extracellular signal-regulated kinase 1/2. Furthermore, an anti-Tie-2 neutralizing antibody significantly inhibited HSYA-induced HUVEC tube formation and migration. In vivo, the recovery of perfusion of ischemic hindlimb tissue after femoral artery interruption was significantly increased in HSYA-treated mice compared to vehicle controls. Consistent with these results, the arteriole and capillary densities in ischemic gastrocnemius muscles were significantly increased in HSYA-treated mice. CONCLUSIONS: These results indicate the potential utility of HSYA for the treatment of ischemic diseases.