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BACKGROUND: Although TRIpartite Motif containing 8 (TRIM8) gene plays an important role in a number of biological processes, such as inflammation, its function and mechanism in ulcerative colitis (UC) remain unknown. METHODS: The UC model was established by feeding mice with 3.5% dextran sulfate sodium (DSS). The animals were divided into the following four groups: control group, DSS group, DSS+short hairpin (sh)-NC group, and DSS+sh-TRIM8 group. Changes in body weight and disease activity index (DAI) score of mice in all the groups were recorded for 7 days. The animals were executed at the end of the experiment, and the expression of TRIM8 in colon tissue was detected by polymerase chain reaction and Western blot assays. The length of colon was measured, and the histopathological changes in mice colon were examined by hematoxylin and eosin staining. The expression of pro-inflammatory factors in mice serum and colonic tissue homogenate was detected by enzyme-linked-immunosorbent serologic assay. The expression of nuclear factor kappa B (NF-κB) pathway-related proteins in colonic tissues was detected by Western-blot analysis. RESULTS: TRIM8 was highly expressed in the colonic tissues of UC mice. Knockdown of TRIM8 improved DSS-induced weight loss, increased DAI score, shortened colon length, and alleviated colonic injury and inflammation in mice. Western-blot experiments showed that knockdown of TRIM8 inhibited DSS-induced phosphorylation of p65 and nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) protein but increased IκBα expression. CONCLUSION: Knockdown of TRIM8 inhibits UC injury and inflammatory response caused by DSS. This could be related to the regulation of NF-κB signaling pathway by TRIM8 protein.
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Colitis Ulcerosa , Proteínas del Tejido Nervioso , Ubiquitina-Proteína Ligasas , Animales , Ratones , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/genética , Colitis Ulcerosa/metabolismo , Colon/patología , Sulfato de Dextran , Modelos Animales de Enfermedad , Inflamación/metabolismo , Ratones Endogámicos C57BL , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , FN-kappa B/metabolismo , Inhibidor NF-kappaB alfa/metabolismo , Transducción de Señal , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
HgTe colloidal quantum dots (CQDs) are promising absorber systems for infrared detection due to their widely tunable photoresponse in all infrared regions. Up to now, the best-performing HgTe CQD photodetectors have relied on using aggregated CQDs, limiting the device design, uniformity and performance. Herein, we report a ligand-engineered approach that produces well-separated HgTe CQDs. The present strategy first employs strong-binding alkyl thioalcohol ligands to enable the synthesis of well-dispersed HgTe cores, followed by a second growth process and a final postligand modification step enhancing their colloidal stability. We demonstrate highly monodisperse HgTe CQDs in a wide size range, from 4.2 to 15.0 nm with sharp excitonic absorption fully covering short- and midwave infrared regions, together with a record electron mobility of up to 18.4 cm2 V-1 s-1. The photodetectors show a room-temperature detectivity of 3.9 × 1011 jones at a 1.7 µm cutoff absorption edge.
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M2-type polarization of tumor associated-macrophage (TAM) is involved in the malignancy of gastrointestinal stromal tumor (GIST) progression. ETS variant 1 (ETV1) has been previously validated to regulate GIST pathogenesis. Our study intended to explore the role and mechanism of ETV1 in mediating the M2-polarization of TAM in GIST progression. First, we analyzed the correlation between ETV1 expression and M2-polarization in GIST tissues. IL-4 was used to treat THP-1-derived TAM cells and IL-4-stimulated TAM were co-cultured with GIST-T1 cells to mimic the GIST microenvironment. A loss-of-function assay was performed to explore the role of ETV1. Results showed that ETV1 elevation was positively correlated with M2-polarization. IL-4-induced TAM promoted ETV1 expression, silencing ETV1 inhibited proliferation, invasion and KIT activation in IL-4-treated GIST cells, while cell apoptosis was enhanced. Besides, co-culture of ETV1-silenced GIST cells significantly depressed M2-polarization in TAM, presented as decreased levels of CD206, Agr-1 and cytokines, as well as the proportion of CD206-positive TAM. PDE3A was positively correlated with ETV1 and M2-polarization. Overexpressing PDE3A reversed the inhibitory effects of ETV1 silencing. Generally, ETV1 inhibition depressed M2-polarization of TAM in GIST and its promotion on pathological aggravation via down-regulating PDE3A. This evidence may provide a new target for GIST regulation.
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Although the relationship between tea consumption and the risk of endometrial cancer has been previously analyzed in certain studies, the resulting information is still conflicting, and a previous meta-analysis yielded inconsistent results. Therefore, here, we aimed to perform an updated meta-analysis of studies on this subject in order to elucidate this relationship.We searched the literature on the PubMed, Web of Science, Scopus, and Chinese National Knowledge Infrastructure databases for studies that were published prior to September 25, 2019, and all the relevant references were examined. Ultimately, we included eight studies, and seven of them were on black tea. We used the overall relative risk values (RR) and 95% confidence intervals (CI) to evaluate the risk. The synthetic RR of the eight eligible studies demonstrated that tea consumption was not relevant to the incidence rate of endometrial cancer (RR 1.06, 95% CI 0.96, 1.18). No publication bias was found. We detected significant heterogeneity among the studies (Q = 15.84, p = 0.027, I2 = 55.8%). In conclusion, the results of this meta-analysis indicate that tea consumption is not relevant to the incidence of endometrial cancer. Further research and cohort studies should be conducted to validate our result.
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Camellia sinensis , Neoplasias Endometriales , Neoplasias Endometriales/epidemiología , Neoplasias Endometriales/etiología , Humanos , Incidencia , Riesgo , Factores de Riesgo , TéRESUMEN
Hepatocarcinoma-intestine-pancreas/pancreatitis-associated protein (HIP/PAP), a C-type lectin, exerts anti-oxidative, anti-inflammatory, bactericidal, anti-apoptotic, and mitogenic functions in several cell types and tissues. In this study, we explored the role of HIP/PAP in pulmonary fibrosis (PF). Expression of HIP/PAP and its murine counterpart, Reg3B, was markedly increased in fibrotic human and mouse lung tissues. Adenovirus-mediated HIP/PAP expression markedly alleviated bleomycin (BLM)-induced lung injury, inflammation, and fibrosis in mice. Adenovirus-mediated HIP/PAP expression alleviated oxidative injury and lessened the decrease in pulmonary superoxide dismutase (SOD) activity in BLM-treated mice, increased pulmonary SOD expression in normal mice, and HIP/PAP upregulated SOD expression in cultured human alveolar epithelial cells (A549) and human lung fibroblasts (HLF-1). Moreover, in vitro experiments showed that HIP/PAP suppressed the growth of HLF-1 and ameliorated the H2 O2 -induced apoptosis of human alveolar epithelial cells (A549 and HPAEpiC) and human pulmonary microvascular endothelial cells (HPMVEC). In HLF-1, A549, HPAEpiC, and HPMVEC cells, HIP/PAP did not affect the basal levels, but alleviated the TGF-ß1-induced down-regulation of the epithelial/endothelial markers E-cadherin and vE-cadherin and the over-expression of mesenchymal markers, such as α-SMA and vimentin. In conclusion, HIP/PAP was found to serve as a potent protective factor in lung injury, inflammation, and fibrosis by attenuating oxidative injury, promoting the regeneration of alveolar epithelial cells, and antagonizing the pro-fibrotic actions of the TGF-ß1/Smad signaling pathway.
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Lesión Pulmonar/complicaciones , Lesión Pulmonar/metabolismo , Proteínas Asociadas a Pancreatitis/metabolismo , Neumonía/complicaciones , Sustancias Protectoras/metabolismo , Fibrosis Pulmonar/complicaciones , Células A549 , Adenoviridae , Células Epiteliales Alveolares/efectos de los fármacos , Células Epiteliales Alveolares/metabolismo , Células Epiteliales Alveolares/patología , Animales , Apoptosis/efectos de los fármacos , Bleomicina , Proliferación Celular , Citoprotección/efectos de los fármacos , Células Endoteliales/metabolismo , Transición Epitelial-Mesenquimal/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/patología , Humanos , Peróxido de Hidrógeno/toxicidad , Lesión Pulmonar/inducido químicamente , Masculino , Malondialdehído/metabolismo , Ratones Endogámicos ICR , Peroxidasa/metabolismo , Neumonía/patología , Fibrosis Pulmonar/patología , Superóxido Dismutasa/metabolismo , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
Hepatocarcinoma-intestine-pancreas/pancreatitis-associated protein (HIP/PAP) has antimicrobial, antioxidant, anti-inflammatory, mitogenic, and antiapoptotic effects and thus exerts important functions in the maintenance of integrity and homeostasis of several organs, such as the gastrointestinal tract, pancreas, and liver. Although the potent hepatoprotective effect of HIP/PAP has been validated, its impact on liver fibrosis has not been reported. In this study, we evaluated the role of HIP/PAP on hepatic fibrosis and explored the possible underlying mechanisms. We found that the expression of HIP/PAP and its mouse counterpart, Reg3B, was markedly upregulated in fibrotic human or mouse livers. Intraperitoneal (i.p.) interleukin (IL)-10, IL-6, and TNF-α but not TGF-ß1 significantly induced hepatic overexpression of Reg3B in mice. In both CCl4 and BDL liver fibrosis models, adenovirus-mediated ectopic expression of HIP/PAP markedly alleviated liver injury, inflammation, collagen deposition, hepatic stellate cell activation, and the overexpression of profibrotic cytokines, including transforming growth factor ß1 (TGF-ß1), platelet-derived growth factor (PDGF)-A, B, connective tissue growth factor (CTGF), and plasminogen activator inhibitor-1 (PAI-1), in mice. In vitro experiments demonstrated that, in addition to suppressing hepatic stellate cell proliferation and accelerating hepatocyte proliferation, HIP/PAP mitigated TGF-ß1-induced hepatic stellate cell activation, hepatocyte epithelial-mesenchymal transition (EMT) and upregulated expression of profibrotic cytokines in both hepatic stellate cells and hepatocytes. Moreover, HIP/PAP attenuated the overexpression of TGF-ß receptor II (TGF-ßRII) in fibrotic mouse livers and decreased the basal expression of TGF-ßRII in nonfibrotic mouse livers as well as in cultured hepatocytes and hepatic stellate cells, which is at least partly attributable to the TGF-ß1-antagonizing function of HIP/PAP. This study indicates that increased expression of hepatic HIP/PAP serves as a countermeasure against liver injury and fibrosis. Exogenous supplementation of HIP/PAP might be a promising therapeutic agent for hepatic fibrosis as well as liver injury.
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Cirrosis Hepática/metabolismo , Proteínas Asociadas a Pancreatitis/metabolismo , Receptor Tipo II de Factor de Crecimiento Transformador beta/metabolismo , Animales , Proliferación Celular , Citocinas/metabolismo , Regulación hacia Abajo , Transición Epitelial-Mesenquimal , Células Estrelladas Hepáticas/metabolismo , Humanos , Hígado/química , Cirrosis Hepática/prevención & control , Masculino , Ratones , Ratones Endogámicos ICRRESUMEN
RESEARCH QUESTION: Endometriosis is characterized by the occurrence of endometrial-like tissue outside the uterus. Collagen triple helix repeat containing-1 (CTHRC1) is known as a tumour-promoting factor in several neoplasms. This study aimed to examine the roles of CTHRC1 in the development and progression of endometriosis, and to unravel the underlying mechanisms. DESIGN: Quantitative real-time PCR, western blot analyses and enzyme-linked immunosorbent assay were performed to determine the expression levels of CTHRC1 in tissues and serum. In addition, CTHRC1 expression levels were knocked down by small-interfering RNA in ectopic endometrial stromal cells (EESC). Cell Counting Kit-8, fluorescence-activated cell sorting, Transwell and wound scratch assays were carried out to assess the underlying biological behaviours, and western blot analyses were performed to reveal the molecular mechanisms. RESULTS: mRNA and protein expression levels of CTHRC1 were markedly higher in ectopic endometrial tissues than in eutopic and control endometrial tissues. In addition, the serum concentration of CTHRC1 was apparently higher in the endometriosis group than the control group. Small interfering RNA knockdown of CTHRC1 suppressed the proliferation, migration, invasion and healing abilities of EESC. Furthermore, the protein expressions of key molecules in the Wnt/ß-catenin pathway showed an obvious down-regulated expression after siRNA transfection. CONCLUSIONS: These findings suggest that CTHRC1 may be partly responsible for the development and progression of endometriosis by increasing EESC proliferation, migration and invasion via the Wnt/ß-catenin pathway. CTHRC1 may thus serve as a diagnostic and therapeutic target for endometriosis.
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Movimiento Celular/fisiología , Proliferación Celular/fisiología , Endometrio/metabolismo , Proteínas de la Matriz Extracelular/metabolismo , Células del Estroma/metabolismo , Vía de Señalización Wnt/fisiología , Adulto , Proteínas de la Matriz Extracelular/genética , Femenino , Humanos , beta Catenina/genética , beta Catenina/metabolismoRESUMEN
BACKGROUND: Cyromazine (CYR) and its main degradation product melamine (MEL) are attracting wide attention due to their potential hazards to the environment and humans. In this work, double surfactants-assisted electromembrane extraction (DS-EME) by Tween 20 and alkylated phosphate was firstly used for purification and extraction of CYR and MEL, and the extract was directly analyzed by capillary electrophoresis with capacitively coupled contactless conductivity detection. RESULTS: Under the optimum conditions, two targets could be well separated from the main interferences, including common biogenic amines and inorganic cations within 14 min. This developed method was successfully applied to the analyses of surface water, soil and cucumber samples, and the average recoveries were in the range 93.3-112%. DS-EME provided a synergistic purification and enrichment effect for CYR and MEL by adding Tween 20 and alkylated phosphate into donor phase and supporting liquid membrane, respectively. Satisfactory limits of detection [0.2-1.5 ng mL-1 , signal-to-noise ratio (S/N) = 3] could be obtained in the tested sample matrices, and the corresponding enrichment factors were up to 115â¼123 times. CONCLUSION: This developed method provides an alternative for the simultaneous analysis of CYR and MEL in complex real-world samples. © 2019 Society of Chemical Industry.
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Cucumis sativus/química , Contaminantes del Suelo/aislamiento & purificación , Extracción en Fase Sólida/métodos , Triazinas/aislamiento & purificación , Contaminantes del Agua/aislamiento & purificación , Conductividad Eléctrica , Electroforesis Capilar , Membranas Artificiales , Contaminantes del Suelo/química , Extracción en Fase Sólida/instrumentación , Tensoactivos/química , Triazinas/química , Contaminantes del Agua/químicaRESUMEN
Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is a transcriptional coactivator that has been characterized as master regulators of mitochondrial biogenesis. It has been reported that aberrant regulation of PGC-1α is involved in a variety of human cancers. However, whether PGC-1α is involved in the regulation of tumor growth and metastasis in gastric cancer (GC) remains unknown. In the present study, we found that the expression of PGC-1α was upregulated in GC tissues and GC cell lines. Inhibition of PGC-1α inhibited cell viability, migration, and invasion, and promoted cell apoptosis of GC cells. Furthermore, inhibition of PGC-1α downregulated the SNAI1 expression, whereas upregulated microRNA (miR)-128b expression. The expression of SNAI1 was upregulated and the expression of miR-128b was downregulated in GC tissues. We further found that there was a positive correlation between PGC-1α and SNAI1 expression, and a negative correlation between PGC-1α and miR-128b expression or between SNAI1 and miR-128b expression in GC tissues. Moreover, PGC-1α inhibition-induced increased miR-128b expression, and PGC-1α overexpression-induced decreased miR-128b expression were both markedly suppressed by SNAI1 overexpression. In addition, SNAI1 overexpression or miR-128b inhibition partly reversed the effects of PGC-1α inhibition in GC cells. Furthermore, inhibition of PGC-1α suppressed the tumor growth in a nude mouse model, which may be related with the dysregulation of SNAI1 and miR-128b. In conclusion, these data indicate that the PGC-1α/SNAI1/miR-128b axis plays a vital role in GC via regulating cell viability, migration, invasion, and apoptosis.
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MicroARNs/genética , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Factores de Transcripción de la Familia Snail/genética , Neoplasias Gástricas/genética , Animales , Apoptosis/genética , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Ratones , Metástasis de la Neoplasia/patologíaRESUMEN
The application of real-time precise point positioning (PPP) requires real-time precise orbit and clock products that should be predicted within a short time to compensate for the communication delay or data gap. Unlike orbit correction, clock correction is difficult to model and predict. The widely used linear model hardly fits long periodic trends with a small data set and exhibits significant accuracy degradation in real-time prediction when a large data set is used. This study proposes a new prediction model for maintaining short-term satellite clocks to meet the high-precision requirements of real-time clocks and provide clock extrapolation without interrupting the real-time data stream. Fast Fourier transform (FFT) is used to analyze the linear prediction residuals of real-time clocks. The periodic terms obtained through FFT are adopted in the sliding window prediction to achieve a significant improvement in short-term prediction accuracy. This study also analyzes and compares the accuracy of short-term forecasts (less than 3 h) by using different length observations. Experimental results obtained from International GNSS Service (IGS) final products and our own real-time clocks show that the 3-h prediction accuracy is better than 0.85 ns. The new model can replace IGS ultra-rapid products in the application of real-time PPP. It is also found that there is a positive correlation between the prediction accuracy and the short-term stability of on-board clocks. Compared with the accuracy of the traditional linear model, the accuracy of the static PPP using the new model of the 2-h prediction clock in N, E, and U directions is improved by about 50%. Furthermore, the static PPP accuracy of 2-h clock products is better than 0.1 m. When an interruption occurs in the real-time model, the accuracy of the kinematic PPP solution using 1-h clock prediction product is better than 0.2 m, without significant accuracy degradation. This model is of practical significance because it solves the problems of interruption and delay in data broadcast in real-time clock estimation and can meet the requirements of real-time PPP.
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BACKGROUND: Extracellular high mobility group box 1 (HMGB1) is crucially implicated in the pathogenesis of inflammatory bowel diseases (IBDs). A box domain of HMGB1 has been identified as a specific antagonist of HMGB1. In the present study, we tested the effects of adeno-associated virus (AAV)-mediated colonic secretory expression of HMGB1 A box on murine experimental colitis. METHODS: Self-complementary AAV-2 carrying mouse immunoglobin Gκ leader-human HMGB1 A box (AAV-HMGB1 A box) was constructed. The effects of intracolonically administered AAV-HMGB1 A box on dextran sulfate sodium (DSS)- and 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis were assessed by the disease activity index (DAI), colon length, macroscopic and histological scoring, myeloperoxidase (MPO) activity, and epithelial apoptosis and complementary proliferation. Colonic immune cell infiltrates, mucosal malondialdehyde content and superoxide dismutase activity, colonic tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß and IL-10 levels, serum HMGB1 concentration, and colonic HMGB1 release were determined to investigate the underlying mechanisms. RESULTS: Intracolonically administered AAV-HMGB1 A box efficiently mediated secretory expression of HMGB1 A box and led to significant decreases in DAI, macroscopic and histological scores and colonic epithelial apoptosis in both DSS- and TNBS-treated mice. Modulating inflammation-associated cytokines, such as inhibiting colonic TNF-α and IL-1ß expression, decreasing HMGB1 release, and restoring colonic IL-10 levels, and thereby inhibiting inflammatory cell infiltration and alleviating oxidant damage, might be the underlying mechanism. CONCLUSIONS: Intracolonic application of AAV-HMGB1 A box is effective in alleviating murine colitis and has therapeutic potential in human IBDs.
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Colitis/genética , Colon/metabolismo , Dependovirus/genética , Proteína HMGB1/genética , Animales , Apoptosis/genética , Proliferación Celular/genética , Colitis/inducido químicamente , Colitis/metabolismo , Citocinas/metabolismo , Sulfato de Dextran , Células Epiteliales/metabolismo , Proteína HMGB1/metabolismo , Humanos , Masculino , Ratones Endogámicos BALB C , Peroxidasa/metabolismo , Superóxido Dismutasa/metabolismo , Ácido TrinitrobencenosulfónicoRESUMEN
Connective tissue growth factor (CTGF) is a secreted matricellular protein possessing complex biological functions. CTGF modulates a number of signaling pathways that are involved in cell adhesion, migration, angiogenesis, myofibroblast activation, extracellular matrix deposition and tissue remodeling. Aptamers are oligonucleic acid chains or polypeptides that bind with specific target molecules hence have the potential to be used in the detection and blockade of the targets. In this study, we selected CTGF-targeting DNA aptamers by using systematic evolution of ligands by exponential enrichment (SELEX). After 8 iterative rounds of selection, cloning, DNA sequencing and affinity determination, six aptamers with high affinities to CTGF were obtained. Among them, one (C-ap17P) binds with the N-terminal region (aa 1-190) and the other five (C-ap11, 12, 14, 15 and 18) bind with the C-terminal region (aa 191-350) of hCTGF specifically. The biological stability assay indicated that a representative aptamer, C-ap17P, could keep its integrity at a rather high level for at least 24 h in complete DMEM cell culture medium. These CTGF aptamers might be used as a easy and fast detection tool for CTGF and be developed as CTGF-specific inhibitors for both research works and clinical applications.
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Aptámeros de Nucleótidos/química , Factor de Crecimiento del Tejido Conjuntivo/análisis , Secuencia de Bases , Sitios de Unión , Técnicas Biosensibles , Humanos , Técnica SELEX de Producción de Aptámeros/métodosRESUMEN
Diabetes is a risk factor for stroke; however, its impact on stroke progression at the genomic level is not well understood. To address this gap, we used transcriptome sequencing to explore the relationship between lncRNA and mRNA expression patterns and the reperfusion duration in the cortex of diabetically induced stroke mice. First, focal ischemia was induced in adult male ob/ob mice, which were then subjected to reperfusion periods of one, three, or seven days. Total RNA was extracted from the ischemic cortical tissue for RNA sequencing, and the resulting reads were aligned to the GRCm38 murine reference genome. A total of 672 mRNAs and 301 lncRNAs were identified as differentially expressed one day post-stroke, 1195 mRNAs and 66 lncRNAs at three days post-stroke, and 1069 mRNAs and 75 lncRNAs at seven days post-stroke. Stage-specific differentially expressed mRNAs were bioinformatically analyzed and found significantly enriched in processes such as apoptosis, angiogenesis, and lipid metabolism at one, three, and seven days post-stroke, respectively. Stage-specific DElncRNA-mRNA cis-regulatory relationships were constructed using these biological processes as examples, revealing the potential roles of four pairs of lncRNA-mRNAs (Gm39787-Lcn2, Gm46111-Drd2, D3300500i16Rik-Fosl1, and Gm41689-Egr1) in apoptosis. Additionally, Gm40237-Tie1 and Gm52352-Pdgfrb are associated with angiogenesis and lipid metabolism, respectively. In conclusion, our study demonstrated that lncRNA and mRNA expression in the cortex of transient focal ischemia-induced diabetic mice undergo extensive alterations, providing insights into complex molecular interactions underlying diabetic stroke.
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Isquemia Encefálica , Diabetes Mellitus Experimental , MicroARNs , ARN Largo no Codificante , Accidente Cerebrovascular , Masculino , Ratones , Animales , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Diabetes Mellitus Experimental/genética , Isquemia Encefálica/genética , Accidente Cerebrovascular/genética , Infarto Cerebral , Expresión Génica , ARN Mensajero/metabolismo , Redes Reguladoras de Genes , MicroARNs/metabolismoRESUMEN
After ischemic stroke, microRNAs (miRNAs) participate in various processes, including immune responses, inflammation, and angiogenesis. Diabetes is a key factor increasing the risk of ischemic stroke; however, the regulatory pattern of miRNAs at different stages of diabetic stroke remains unclear. This study comprehensively analyzed the miRNA expression profiles in diabetic mice at 1, 3, and 7 days post-reperfusion following the middle cerebral artery occlusion (MCAO). We identified differentially expressed (DE) miRNAs in diabetic stroke and found significant dysregulation of some novel miRNAs (novel_mir310, novel_mir89, and novel_mir396) post-stroke. These DEmiRNAs were involved in apoptosis and the formation of tight junctions. Finally, we identified three groups of time-dependent DE miRNAs (miR-6240, miR-135b-3p, and miR-672-5p). These have the potential to serve as biomarkers of diabetic stroke. These findings provide a new perspective for future research, emphasizing the dynamic changes in miRNA expression after diabetic stroke and offering potential candidates as biomarkers for future clinical applications.
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Diabetes Mellitus Experimental , Accidente Cerebrovascular Isquémico , MicroARNs , Accidente Cerebrovascular , Animales , Ratones , Diabetes Mellitus Experimental/genética , Regulación de la Expresión Génica de las Plantas , MicroARNs/genética , Plantas Modificadas Genéticamente , Accidente Cerebrovascular/genética , BiomarcadoresRESUMEN
Daptomycin is gaining prominence for the treatment of methicillin-resistant Staphylococcus aureus infections. However, the dosage selection for daptomycin in critically ill patients remains uncertain, especially in Chinese patients. This study aimed to establish the population pharmacokinetics of daptomycin in critically ill patients, optimize clinical administration plans, and recommend appropriate dosage for critically ill patients in China. The study included 64 critically ill patients. Blood samples were collected at the designated times. The blood daptomycin concentration was determined using validated liquid chromatography-tandem mass spectrometry. A nonlinear mixed-effects model was applied for the population pharmacokinetic analysis and Monte Carlo simulations of daptomycin. The results showed a two-compartment population pharmacokinetic model of daptomycin in critically ill adult Han Chinese patients. Monte Carlo simulations revealed that a daily dose of 400 mg of daptomycin was insufficient for the majority of critically ill adult patients to achieve the anti-infective target. For critically ill adult patients with normal renal function (creatinine clearance rate >90 mL/min), the probability of achieving the target only reached 90% when the daily dose was increased to 700 mg. For patients undergoing continuous renal replacement therapy (CRRT), 24 h administration of 500 mg met the pharmacodynamic goals and did not exceed the safety threshold in most patients. Therefore, considering its efficacy and safety, intravenous daptomycin doses are best scaled according to creatinine clearance, and an increased dose is recommended for critically ill patients with hyperrenalism. For patients receiving CRRT, medication is recommended at 24 h intervals.
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Before menopause, females exhibit a lower incidence of cardiovascular disease than age-matched males, possibly owing to the protective effects of sex hormones. 17ß-estradiol (17ß-E2) protects against oxidative stress-induced injury by suppressing thrombospondin-1 (THBS1) expression in endothelial cells. Here, we examined the role of 17ß-E2-mediated THBS1 suppression in preventing cell senescence and apoptosis. Human umbilical vein endothelial cells (HUVECs) were cultivated and treated with siRNA or overexpression plasmids to regulate THBS1. H2O2, estrogen-activity modulating drugs, and LY2109761 (a TGF-ß kinase inhibitor) treatments were applied. THBS1 knockdown repressed, and its overexpression aggravated, H2O2-induced cell injury, affecting cell death, proliferation, senescence, and apoptosis. 17ß-E2 inhibited THBS1 mRNA and protein expression time- and dose-dependently, by targeting ERß. THBS1 overexpression blocked 17ß-E2 from preventing H2O2-induced injury, significantly activating the TGF-ß/Smad pathway. 17ß-E2 inhibited H2O2-induced oxidative stress by downregulating THBS1 expression and TGF-ß/Smad signaling in HUVECs. The THBS1/TGF-ß/Smad axis could thus be a therapeutic target.
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Peróxido de Hidrógeno , Factor de Crecimiento Transformador beta , Femenino , Humanos , Células Endoteliales de la Vena Umbilical Humana , Peróxido de Hidrógeno/toxicidad , Peróxido de Hidrógeno/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Estradiol/farmacología , Estradiol/metabolismo , Estrógenos/metabolismo , ApoptosisRESUMEN
Atherosclerosis is initiated by vascular endothelial dysfunction, and low-shear stress (LSS) of blood flow is a key factor leading to endothelial dysfunction. Growing evidence suggests that endothelial cell pyroptosis plays an important role in the development of atherosclerosis. Studies have shown that low-shear stress can induce endothelial cell pyroptosis, but the exact mechanism remains unclear. Our experiments demonstrated that low-shear stress induced endothelial cell pyroptosis and the phosphorylation of IκB kinase ε (IKKε). IKKε knockdown not only significantly attenuated atherosclerosis lesions of aortic arch areas in ApoE-/- mice fed with high cholesterol diets, but also markedly reduced endothelial cell pyroptosis and NLRP3 expression triggered by low-shear stress. Further mechanism studies showed that IKKε promoted the expression of NLRP3 via activating signal transducer and activator of transcription 1 (STAT1) and the subsequent binding of STAT1 to NLRP3 promoter region. These results suggest that low-shear stress plays a pro-atherosclerotic role by promoting endothelial cell pyroptosis through the IKKε/STAT1/NLRP3 pathway, which provides new insights into the formation of atherosclerosis.
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Aterosclerosis , Células Endoteliales , Quinasa I-kappa B , Proteína con Dominio Pirina 3 de la Familia NLR , Piroptosis , Factor de Transcripción STAT1 , Estrés Mecánico , Piroptosis/fisiología , Aterosclerosis/metabolismo , Aterosclerosis/patología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Animales , Ratones , Quinasa I-kappa B/metabolismo , Factor de Transcripción STAT1/metabolismo , Células Endoteliales/metabolismo , Humanos , Transducción de Señal/fisiología , Ratones Endogámicos C57BL , Células Endoteliales de la Vena Umbilical Humana/metabolismoRESUMEN
Most BTB-containing E3 ligases homodimerize to recognize a single substrate by engaging multiple degrons, represented by E3 ligase KEAP1 dimer and its substrate NRF2. Inactivating KEAP1 to hinder ubiquitination-dependent NRF2 degradation activates NRF2. While various KEAP1 inhibitors have been reported, all reported inhibitors bind to KEAP1 in a monovalent fashion and activate NRF2 in a lagging manner. Herein, we report a unique bivalent KEAP1 inhibitor, biKEAP1 (3), that engages cellular KEAP1 dimer to directly release sequestered NRF2 protein, leading to an instant NRF2 activation. 3 promotes the nuclear translocation of NRF2, directly suppressing proinflammatory cytokine transcription. Data from in vivo experiments showed that 3, with unprecedented potency, reduced acute inflammatory burden in several acute inflammation models in a timely manner. Our findings demonstrate that the bivalent KEAP1 inhibitor can directly enable sequestered substrate NRF2 to suppress inflammatory transcription response and dampen various acute inflammation injuries.
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Inflamación , Proteína 1 Asociada A ECH Tipo Kelch , Factor 2 Relacionado con NF-E2 , Factor 2 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/antagonistas & inhibidores , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/antagonistas & inhibidores , Humanos , Animales , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Ratones , Ratones Endogámicos C57BL , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/antagonistas & inhibidores , MasculinoRESUMEN
Fibrogenesis and hepatocyte degeneration are the main pathological processes in chronic liver diseases. Transforming growth factor-ß1 (TGF-ß1) is the key profibrotic cytokine in hepatic fibrosis. Bone morphogenetic protein-7 (BMP-7) is a potent antagonist of TGF-ß1 and an antifibrotic factor. In this study, we generated a recombinant adeno-associated virus carrying BMP-7 (AAV-BMP-7) and tested its ability to suppress carbon tetrachloride (CCl(4))-induced hepatic fibrosis when orally administered to mice. Our results show that the ectopic expression of BMP-7 in gastrointestinal (GI) mucosa due to the AAV-BMP-7 administration led to the long-term elevation of serum BMP-7 concentrations and resulted in the drastic amelioration of CCl(4)-induced hepatic fibrosis in BALB/c mice. Immunostaining for α-smooth muscle actin (α-SMA) and desmin demonstrated that AAV-BMP-7 inhibited the activation of hepatic stellate cells (HSCs) in the fibrotic mouse liver. Moreover, the ectopic expression of BMP-7 promoted hepatocyte proliferation, as confirmed by an increase in the amount of proliferating cell nuclear antigen (PCNA)-positive hepatocytes in the mice that received AAV-BMP-7. Our results clearly indicate that BMP-7 is capable of inhibiting hepatic fibrosis and promoting hepatocyte regeneration. We suggest that oral AAV-BMP-7 could be developed into a safe, simple, and effective therapy for hepatic fibrosis.
Asunto(s)
Proteína Morfogenética Ósea 7/genética , Dependovirus/genética , Cirrosis Hepática/terapia , Actinas/metabolismo , Administración Oral , Animales , Proteína Morfogenética Ósea 7/biosíntesis , Proteína Morfogenética Ósea 7/sangre , Proliferación Celular , Quimiocina CCL4 , Desmina/metabolismo , Tracto Gastrointestinal/metabolismo , Expresión Génica , Vectores Genéticos/administración & dosificación , Células Estrelladas Hepáticas/metabolismo , Células Estrelladas Hepáticas/fisiología , Ácido Hialurónico/sangre , Hidroxiprolina/metabolismo , Hígado/metabolismo , Hígado/patología , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/sangre , Proteínas Recombinantes/genéticaRESUMEN
According to the World Health Organization, cardiovascular diseases are the leading cause of deaths globally. Electrocardiogram (ECG) is a non-invasive approach for detecting heart diseases and reducing the risk of heart disease-related death. However, there are limited numbers of ECG samples and imbalance distribution for existing ECG databases. It is difficult to train practical and efficient neural networks. Based on the analysis and research of many existing ECG databases, this paper conduct an in-depth study on three fine-labeled ECG databases, to extract heartbeats, unify the sampling frequency, and propose a self-processing method of heartbeats, and finally form a unified ECG arrhythmia classification database, noted as Hercules-3. It is separated into training sets (80%) and testing sets (the remaining 20%). In order to verify its capabilities, we have trained a 16-classification fully connected neural network based on Hercules-3 and it achieves an accuracy rate of up to 98.67%. Compared with other data processing, our proposed method improves classification recall by at least 6%, classification accuracy by at least 4%, and F1-score by at least 7%.