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BACKGROUND: Platelet adhesion and aggregation play a crucial role in arterial thrombosis and ischemic stroke. Here, we identify platelet ERO1α (endoplasmic reticulum oxidoreductase 1α) as a novel regulator of Ca2+ signaling and a potential pharmacological target for treating thrombotic diseases. METHODS: Intravital microscopy, animal disease models, and a wide range of cell biological studies were utilized to demonstrate the pathophysiological role of ERO1α in arteriolar and arterial thrombosis and to prove the importance of platelet ERO1α in platelet activation and aggregation. Mass spectrometry, electron microscopy, and biochemical studies were used to investigate the molecular mechanism. We used novel blocking antibodies and small-molecule inhibitors to study whether ERO1α can be targeted to attenuate thrombotic conditions. RESULTS: Megakaryocyte-specific or global deletion of Ero1α in mice similarly reduced platelet thrombus formation in arteriolar and arterial thrombosis without affecting tail bleeding times and blood loss following vascular injury. We observed that platelet ERO1α localized exclusively in the dense tubular system and promoted Ca2+ mobilization, platelet activation, and aggregation. Platelet ERO1α directly interacted with STIM1 (stromal interaction molecule 1) and SERCA2 (sarco/endoplasmic reticulum Ca2+-ATPase 2) and regulated their functions. Such interactions were impaired in mutant STIM1-Cys49/56Ser and mutant SERCA2-Cys875/887Ser. We found that ERO1α modified an allosteric Cys49-Cys56 disulfide bond in STIM1 and a Cys875-Cys887 disulfide bond in SERCA2, contributing to Ca2+ store content and increasing cytosolic Ca2+ levels during platelet activation. Inhibition of Ero1α with small-molecule inhibitors but not blocking antibodies attenuated arteriolar and arterial thrombosis and reduced infarct volume following focal brain ischemia in mice. CONCLUSIONS: Our results suggest that ERO1α acts as a thiol oxidase for Ca2+ signaling molecules, STIM1 and SERCA2, and enhances cytosolic Ca2+ levels, promoting platelet activation and aggregation. Our study provides evidence that ERO1α may be a potential target to reduce thrombotic events.
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AVC Isquêmico , Trombose , Animais , Camundongos , Plaquetas/metabolismo , Sinalização do Cálcio , Dissulfetos , AVC Isquêmico/metabolismo , Ativação PlaquetáriaRESUMO
BACKGROUND: The efficacy of circulating tumor cells (CTCs) in the selection of stage II colorectal cancer (CRC) patients for adjuvant chemotherapy remains inconclusive. OBJECTIVE: The aim of this study was to validate the necessity of adjuvant chemotherapy for stage II CRC patients with positive postoperative CTCs. METHODS: The clinicopathological features and overall survival (OS) of a cohort of 70 patients with confirmed CRC were collected and analyzed. RESULTS: The total rate of positive CTCs was 55.7%, while the average OS was 70.8 months and the OS rate was 75.7% (53/70). These 70 patients were divided into four subgroups, including a CTC-negative group with non-adjuvant chemotherapy (CHEMO-/CTC-) versus a CTC-positive group with non-adjuvant chemotherapy (CHEMO-/CTC+), CHEMO+/CTC- versus CHEMO+/CTC+, CHEMO-/CTC- versus CHEMO+/CTC-, and CHEMO+/CTC+ versus CHEMO-/CTC+; the total numbers in each subgroup were 25 versus 32, 6 versus 7, 25 versus 6, and 7 versus 32, respectively. The average OS of the CHEMO-/CTC- and CHEMO-/CTC+ groups was 82.0 and 68.1 months, respectively (p = 0.020); the average OS of the CHEMO+/CTC- and CHEMO+/CTC+ groups was 83.6 months and 76.4 months, respectively (p = 0.963); the average OS of the CHEMO-/CTC- and CHEMO+/CTC- groups was 82.0 months and 83.6 months, respectively (p = 0.999); and the average OS of the CHEMO+/CTC+ and CHEMO-/CTC+ groups was 76.4 months and 68.1 months, respectively (p = 0.247). CONCLUSIONS: Positive CTCs are a potential prognostic marker for stage II CRC.
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Neoplasias Colorretais , Células Neoplásicas Circulantes , Humanos , Prognóstico , Estudos Prospectivos , Seguimentos , Células Neoplásicas Circulantes/patologia , Neoplasias Colorretais/patologia , Biomarcadores TumoraisRESUMO
Neutrophil migration requires ß2 integrins and chemoattractant receptor signaling for motility and directionality. G protein subunit Gα13 can facilitate cell migration by mediating RhoA activation induced by G protein-coupled receptors. However, the possible role of Gα13-integrin interaction in migration is unclear. In this study, we show that Gα13 -/- neutrophils are deficient in transendothelial migration and migration on ß2 integrin ligand ICAM-1. However, unlike G protein-coupled receptors and integrin inside-out signaling pathways, Gα13 is important in migration velocity and neutrophil spreading but not in directionality nor cell adhesion. Importantly, neutrophil recruitment in vivo was also inhibited in Gα13 -/- mice, suggesting the importance of Gα13 in transendothelial migration of neutrophils in vitro and in vivo. Furthermore, a synthetic peptide (MB2mP6) derived from the Gα13 binding site of ß2 inhibited Gα13-ß2 interaction and Gα13-mediated transient RhoA inhibition in neutrophils, suggesting that this peptide inhibited integrin outside-in signaling. MB2mP6 inhibited migration of control neutrophils through endothelial cell monolayers or ICAM-1-coated filters, but was without further effect on Gα13 -/- neutrophils. It also inhibited integrin-dependent neutrophil migration velocity without affecting directionality. In vivo, MB2mP6 markedly inhibited neutrophil infiltration into the cardiac tissues induced by ischemia/reperfusion injury. Thus, Gα13-dependent outside-in signaling enables integrin-dependent neutrophil motility without affecting directionality and may be a new therapeutic target for inhibiting neutrophil trafficking but not adhesion.
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Neutrófilos , Migração Transendotelial e Transepitelial , Animais , Antígenos CD18/metabolismo , Adesão Celular/fisiologia , Integrinas/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Camundongos , Neutrófilos/metabolismo , Receptores Acoplados a Proteínas G/metabolismoRESUMO
Objective: Coronary heart disease is incurable and prone to recurrence, and long-term dependence on medication and good nursing management to improve the prognosis. The effect of clopidogrel in the treatment of coronary heart disease is affected by many factors, so paying more attention to details in the process of patient care is conducive to creating more ideal recovery conditions for patients. The purpose of this study is to conduct detailed intervention for coronary heart disease (CHD) after clopidogrel treatment, and to analyze the clinical efficacy of this intervention mode on CHD patients and the relief of angina pectoris. Methods: A total of 120 patients with coronary heart disease who were diagnosed and treated in our hospital from May 2020 to March 2022 were selected as the research objects and divided into a detail group (n=60) and a routine group (n=60) according to the computer randomization method, All research subjects were given clopidogrel intervention, followed by routine intervention in the routine group, and detailed intervention in the detail group. Detailed intervention includes specific measures such as psychological intervention, life intervention, health education, medical assessments, personalized care. The control of angina pectoris of the subjects was analyzed, and the daily life, motor function, quality of life score, negative emotion score and complications were observed. Results: The dimension score of TS [(83.50±5.14) points vs (77.42±4.35) points], DP [(85.59±5.78) points vs (80.14±5.43) points], PL [(79.62±5.19) points vs (74.18±5.04) points], AS [(90.69±6.35) points vs (85.57±6.12) points], AF[(83.54±5.22) points vs (77.51±5.16) points] in the detail group were higher than those of conventional group (P < .001). The differences in daily life, motor function of the subjects before the intervention were not comparable (P > .05), and the scores of daily life [(86.14±5.52) points vs (65.48±5.17) points] and motor function [(88.97±5.34) points vs (70.58±5.46) points] in the detail group at 4 weeks after intervention were higher than those in the routine group (P < .001). The quality of life in the detail group [mental state of (17.56±2.12) points vs (20.13±2.09) points, mental health of (15.62±2.34) points vs (18.09±2.06) points, social function of (15.86±2.41) points vs (18.11±2.14) points, emotional function of (14.36±3.45) points vs (16.78±3.69) points] were lower than those of the conventional group (P < .001). The negative mood scores [SAS score of (41.70±3.14) points vs (67.14±3.25) points, SDS score of (39.59±4.11) points vs (60.58±4.54) points] in the detail group were lower than those of the conventional group (P < .001). In addition, the total incidence of complications (3.33% vs 13.33%) in the detail group was significantly lower than that in the regular group (P < .001). Conclusions: Detailed intervention after clopidogrel treatment in CHD patients can significantly improve the efficacy of patients, reduce angina pectoris, and at the same time can effectively improve various physical functions and relieve their negative emotions, which is worthy of being widely used in clinical practice. Better control of angina pectoris is beneficial to reduce the frequency of hospital admission and save medical resources. The sample size of this study is small, and the sample size will be further expanded in the future to improve the scientific conclusion.
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Selecting training samples is crucial in remote sensing image classification. In this paper, we selected three images-Sentinel-2, GF-1, and Landsat 8-and employed three methods for selecting training samples: grouping selection, entropy-based selection, and direct selection. We then used the selected training samples to train three supervised classification models-random forest (RF), support-vector machine (SVM), and k-nearest neighbor (KNN)-and evaluated the classification results of the three images. According to the experimental results, the three classification models performed similarly. Compared with the entropy-based method, the grouping selection method achieved higher classification accuracy using fewer samples. In addition, the grouping selection method outperformed the direct selection method with the same number of samples. Therefore, the grouping selection method performed the best. When using the grouping selection method, the image classification accuracy increased with the increase in the number of samples within a certain sample size range.
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As a progressive chronic disease, the effective treatment for non-alcoholic fibre liver disease (NAFLD) has not yet been thoroughly explored at the moment. The widespread use of Gynostemma pentaphyllum (Thunb) for its anti-insulin resistance effect indicates that potential therapeutic value may be found in Thunb for NAFLD. Hence, this research aims to discover the latent mechanism of Thunb for NAFLD treatment. To achieve the goal of discovering the latent mechanism of Thunb for NAFLD treatment, molecular docking strategy integrated a network phamacology was adopted in the exploration. We acquire Thunb compounds with activeness from TCMSP database. We collect the putative targets of Thunb and NAFLD to generate the network. Key targets and mechanism are screened by PPI analysis, GO and KEGG pathway enrichment analyses. Molecular docking simulation is introduced into the study as assessment method. Through network analysis and virtual screening based on molecular docking, 2 targets (AKT 1 and GSK3B) are identified as key therapeutic targets with satisfying binding affinity. Main mechanism is believed to be the biological process and pathway related to insulin resistance according to the enrichment analyses outcomes. Particularly, the P13K-AKT signalling pathway is recognized as a key pathway of the mechanism. In conclusion, the study shows that Thunb could be a potential treatment against NAFLD and may suppress insulin resistance through the P13K-AKT signalling pathway. The result of the exploration provides a novel perspective for approaching experimental exploration.
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Medicamentos de Ervas Chinesas , Hepatopatias Alcoólicas , Hepatopatia Gordurosa não Alcoólica , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Gynostemma/química , Hepatopatias Alcoólicas/tratamento farmacológico , Simulação de Acoplamento Molecular , Farmacologia em Rede , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
[Figure: see text].
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Plaquetas/enzimologia , Peróxido de Hidrogênio/metabolismo , Integrina beta3/metabolismo , Mecanotransdução Celular , NADPH Oxidase 2/metabolismo , Ativação Plaquetária , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Animais , Ativação Enzimática , Feminino , Subunidades alfa G12-G13 de Proteínas de Ligação ao GTP/genética , Subunidades alfa G12-G13 de Proteínas de Ligação ao GTP/metabolismo , Integrina beta3/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , NADPH Oxidase 2/genética , NADPH Oxidases/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Fosforilação , Fator Plaquetário 4/genética , Fator Plaquetário 4/metabolismo , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Estresse Mecânico , Quinase Syk/metabolismoRESUMO
OBJECTIVE: Human leukocyte antigen (HLA)-B27 plays a crucial role in the pathogenesis of AS. TNF polymorphisms have been reported to be associated with AS susceptibility, but the results of these previous studies have been inconsistent. The aim of this study was to explore whether TNF polymorphism is associated with AS susceptibility in HLA-27-positive population. METHODS: Our search was done in the Pubmed, Embase, and Cochrane databases (up to March 2020). The pooled and individual odds ratios (ORs) with 95% confidence intervals (CIs) of the minor allele of each locus were presented to assess the associations between TNF polymorphisms and AS in HLA-B27-positive population. RESULTS: Ten studies from 8 articles were included in this meta-analysis. In the population of HLA-B27-positive patients and random healthy controls, there were statistical significance in the evaluation of association between the minor allele of TNF-238, -308, -857, -1031 and -863 and AS susceptibility, respectively. In the population of HLA-B27-positive patients and HLA-B27-positive healthy controls, there were no statistical differences in the comparison of minor allele of with their respective major allele in the fixed model. CONCLUSIONS: There was no association of the TNF polymorphisms with AS in the HLA-B27-positive AS group and HLA-B27-positive control group. Polymorphisms of TNF-238, -308, -857, -1031, -863 were associated with AS susceptibility in the HLA-B27-positive AS patients and random control population. Other gene SNPs except TNF may play an important role in AS susceptibility in HLA-B27-positive population.
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Antígeno HLA-B27 , Espondilite Anquilosante , Alelos , Estudos de Casos e Controles , Frequência do Gene , Predisposição Genética para Doença/genética , Antígeno HLA-B27/genética , Humanos , Polimorfismo de Nucleotídeo Único/genética , Espondilite Anquilosante/genéticaRESUMO
To evaluate the role of microRNA-126 (miR-126) in maintaining the integrity of the blood-retina barrier (BRB), we established a mouse model of oxygen-induced retinopathy (OIR) and measured the retinal levels of miR-126 using recombinant plasmid pCMV-MIR or pCMV-MIR-126 intravitreal injections. We also detected VCAM-1 and BCL2L11 levels. Retinal vaso-obliteration, VCAM-1 localization on retinal endothelial cells, the blood-retina vascular permeability or albumin leakage in retinas, TUNEL histology, Evans blue assays, or Western blotting for detecting albumin or tight junction levels in the retina was performed. We also detected the effect of miR-126 on the survival of Müller cells in a mouse model using vimentin fluorescence staining. Our results suggested that miR-126 may not only regulate the overexpression of VCAM-1 or BCL2L11 and lead to the reduction of retinal endothelial cell apoptosis, retinal vascular leakage, or retinal permeability in the OIR mouse model, but may also protect hypoxic retinal Müller cells via the STAT3 signaling pathway. We believe that miR-126 could also be a potential therapeutic agent to maintain the stability of the BRB in ischemic retinopathy.
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Proteína 11 Semelhante a Bcl-2/metabolismo , Barreira Hematorretiniana/fisiologia , Isquemia/metabolismo , MicroRNAs/fisiologia , Doenças Retinianas/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo , Animais , Animais Recém-Nascidos , Apoptose/fisiologia , Western Blotting , Permeabilidade Capilar/fisiologia , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Retina/citologia , Doenças Retinianas/patologia , Vasos Retinianos/metabolismo , Vasos Retinianos/patologiaRESUMO
MicroRNAs (miRNAs) are a class of non-coding, regulatory small RNAs of â¼22 nt. It was implicated that these small RNAs play critical roles in various important biological processes. During development, some miRNAs are specifically expressed in individual tissues and at particular developmental stages. Many miRNAs show distinct expression patterns in the development of central nervous system, including spinal cord. In this study, we first reported the miRNAs expression in the development of mouse spinal cord. Differentially expressed miRNAs in embryonic (day 13.5) and neonatal mice spinal cords were identified. The predicted target genes of the differentially expressed miRNAs were subject to gene ontology and KEGG pathway analysis, and several nervous development-related pathways were enriched, implying that these miRNAs may be involved in these pathways that regulate mouse spinal cord development.
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MicroRNAs/genética , MicroRNAs/metabolismo , Medula Espinal/embriologia , Medula Espinal/metabolismo , Animais , Animais Recém-Nascidos , Regulação para Baixo , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Ontologia Genética , Camundongos , Camundongos Endogâmicos C57BL , Análise de Sequência com Séries de Oligonucleotídeos , Gravidez , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Regulação para CimaRESUMO
BACKGROUND: Killer cell immunoglobulin-like receptors (KIR) contribute to the pathogenesis of multiple auto-immune diseases via the modulation of NK-, NKT- and T-cells. Thus, we want to know whether the expression pattern of KIR is associated with systemic lupus erythematosus (SLE) susceptibility. METHODS: Here, real-time quantitative PCR and fluorescence-activated cell sorting (FACS) were used to measure the stimulatory KIR (sKIR) and inhibitory KIR (iKIR) mRAN and protein levels on NK-, NKT- and T-cells in both SLE patients and healthy controls. RESULTS: In SLE patients, CD158a/h (KIR2DL1/S1) was highly expressed while CD158b/i/j (KIR2DL2/L3/S2, iKIR/iKIR/sKIR) was lowly expressed in NK- and NKT-cells in patients. The expression levels of KIR2DL1 and KIR2DL2 (iKIRs) were decreased while the expression levels of KIR2DS1 (sKIR) were increased in NK- and NKT-cells in the patients. CONCLUSIONS: We found that SLE patients represent aberrant expression of stimulatory and inhibitory KIRs in NK- and NKT-cells. Consequently, these different expression levels of KIRs may contribute to the abnormal function of these cells, which lead to the risk of SLE.
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Células Matadoras Naturais/metabolismo , Lúpus Eritematoso Sistêmico/imunologia , Células T Matadoras Naturais/metabolismo , Receptores KIR2DL2/metabolismo , Receptores KIR/metabolismo , Adolescente , Adulto , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Humanos , Células Matadoras Naturais/patologia , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/patologia , Masculino , Células T Matadoras Naturais/patologia , Receptores KIR/biossíntese , Receptores KIR/genética , Receptores KIR2DL2/biossíntese , Receptores KIR2DL2/genética , Medição de Risco , Adulto JovemRESUMO
Introduction: Atherosclerosis (AS) is a common cardiovascular disease with a high incidence rate and mortality. Endothelial cell injury and dysfunction are early markers of AS. Oxidative low-density lipoprotein (Ox-LDL) is a key risk factor for the development of AS. Ox-LDL promotes endothelial cell apoptosis and induces inflammation and oxidative stress in endothelial cells. Small non-coding RNAs (sncRNAs) mainly include Piwi-interacting RNAs (piRNAs), small nucleolar RNAs (snoRNAs), small nuclear RNAs (snRNAs), microRNAs (miRNAs) and repeat-associated RNAs. Studies have shown that small non-coding RNAs play an increasingly important role in diseases. Methods: We used ox-LDL to treat rat endothelial cells to simulate endothelial cell injury. The expression changes of sncRNA were analyzed by small RNA high-throughput sequencing, and the expression changes of piRNA, snoRNA, snRNA, miRNA and repeat-associated RNA were verified by quantitative polymerase chain reaction (qPCR). Results: Small RNA sequencing showed that 42 piRNAs were upregulated and 38 piRNAs were downregulated in endothelial cells treated with ox-LDL. PiRNA DQ614630 promoted the apoptosis of endothelial cells. The snoRNA analysis results showed that 80 snoRNAs were upregulated and 68 snoRNAs were downregulated in endothelial cells with ox-LDL treatment, and snoRNA ENSRNOT00000079032.1 inhibited the apoptosis of endothelial cells. For snRNA, we found that 20 snRNAs were upregulated and 26 snRNAs were downregulated in endothelial cells with ox-LDL treatment, and snRNA ENSRNOT00000081005.1 increased the apoptosis of endothelial cells. Analysis of miRNAs indicated that 106 miRNAs were upregulated and 91 miRNAs were downregulated in endothelial cells with ox-LDL treatment, and miRNA rno-novel-136-mature promoted the apoptosis of endothelial cells. The repeat RNA analysis results showed that 4 repeat RNAs were upregulated and 6 repeat RNAs were downregulated in endothelial cells treated with ox-LDL. Discussion: This study first reported the expression changes of sncRNAs in endothelial cells with ox-LDL treatment, which provided new markers for the diagnosis and treatment of endothelial cell injury.
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OBJECTIVE: To identify the factors related to the severity of delayed encephalopathy after acute carbon monoxide poisoning (DEACMP) and establishment of a clinical nomogram assessment model. METHODS: Clinical data of 200 patients with DEACMP admitted to the First Hospital of Yulin from January 2019 to December 2022 were retrospectively analyzed. The patients were classified into severe and non-severe groups according to the severity of the disease. Clinical data was collected from both groups. Logistic regression was applied to analyze the risk factors for disease severity of DEACMP patients. The risk prediction model of the nomogram was constructed by incorporating risk factors, and its effectiveness was verified. Model differentiation performance was evaluated using the Respondent Operating Characteristic (ROC) Curve. Model calibration curve was adopted for fitting the situation of evaluation. The consistency of the model was evaluated by Hosmer-Lemeshow (H-L) analysis. RESULT: Age, coma time out of exposure, creatine kinase (CK), caspase, and red blood cell distribution width (RDW) were the risk factors for the severe DEACMP. A nomogram prediction model was built based on the above indicators. The area under the curve (AUC) of the model in predicting severe DEACMP was 0.961 (95% CI: 0.934-0.988) and 0.929 (95% CI: 0.841-1) in the training and test sets, respectively. The H-L test showed good goodness of fit (χ2 = 4.468, P = 0.813). The calibration curve showed a good agreement between the predicted values of the nomogram and the actual observed values. CONCLUSION: Age, coma time out of exposure, CK, caspase, and RDW were significantly correlated with the severity of DEACMP patients. The nomogram prediction model incorporating the five indicators has certain clinical reference value for predicting the severe DEACMP and could be used as an accurate and rapid clinical assessment tool.
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The aim of our study is to disclose the role and underlying molecular mechanisms of circular RNA ubiquitin protein ligase E3 component n-recognin 4 (circ-UBR4) in atherosclerosis (AS). Our data showed that circ-UBR4 expression was upregulated in AS patients and oxidized low-density lipoprotein (ox-LDL)-induced vascular smooth muscle cells (VSMCs) compared with healthy volunteer and untreated VSMCs. In addition, ox-LDL stimulated proliferation, migration, and inflammation but decreased apoptosis in VSMCs, which were overturned by the inhibition of circ-UBR4. miR-515-5p was sponged by circ-UBR4, and its inhibitor reversed the inhibitory effect of circ-UBR4 knockdown on proliferation, migration, and inflammation in ox-LDL-induced VSMCs. Insulin-like growth factor2 (IGF2) was a functional target of miR-515-5p, and overexpression of IGF2 reversed the suppressive effect of miR-515-5p on ox-LDL-stimulated VSMCs proliferation, migration, and inflammation. Collectively, circ-UBR4 knockdown decreased proliferation, migration, and inflammation but stimulated apoptosis in ox-LDL-induced VSMCs by targeting the miR-515-5p/IGF2 axis.
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OBJECTIVE: B-cell activating factor (BAFF) is a key regulator of primary Sjögren's syndrome (pSS), which is characterized by B-lymphocyte hyperactivity. BAFF, also known as tumor necrosis factor ligand superfamily member 13B, is encoded by TNFSF13B. This study aimed to explore the possible relationships between five single-nucleotide polymorphisms (SNPs) of TNFSF13B (rs9514827, rs1041569, rs9514828, rs1224141, and rs12583006) and pSS susceptibility. METHODS: We searched the following databases for articles on TNFSF13B polymorphism and pSS published up to January 2023: PubMed, Cochrane, Elsevier, Web of Science, CNKI, CQVIP, and WanFang. The odds ratios (with 95% confidence intervals) of genotypes and SNP alleles of TNFSF13B were investigated in patients with pSS to determine their relationships with pSS. RESULTS: This meta-analysis employing the fixed-effect model comprised three studies of pSS patients and randomly selected healthy controls (HCs), revealing statistically significant relationships between pSS susceptibility and two SNPs: rs1041569 and rs12583006. Because rs1041569 was not in Hardy-Weinberg equilibrium in the HC group, it was eliminated from the analysis. CONCLUSIONS: Polymorphisms in the BAFF (TNFSF13B) gene were related to vulnerability to pSS among pSS patients and HCs alike. The SNP rs12583006 was significantly related to pSS susceptibility in pSS patients.
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Fator Ativador de Células B , Síndrome de Sjogren , Humanos , Fator Ativador de Células B/genética , Síndrome de Sjogren/genética , Genótipo , Polimorfismo de Nucleotídeo Único , AlelosRESUMO
The integrins and G protein-coupled receptors are both fundamental in cell biology. The cross talk between these two, however, is unclear. Here we show that ß3 integrins negatively regulate G protein-coupled signaling by directly inhibiting the Gα13-p115RhoGEF interaction. Furthermore, whereas ß3 deficiency or integrin antagonists inhibit integrin-dependent platelet aggregation and exocytosis (granule secretion), they enhance G protein-coupled RhoA activation and integrin-independent secretion. In contrast, a ß3-derived Gα13-binding peptide or Gα13 knockout inhibits G protein-coupled RhoA activation and both integrin-independent and dependent platelet secretion without affecting primary platelet aggregation. In a mouse model of myocardial ischemia/reperfusion injury in vivo, the ß3-derived Gα13-binding peptide inhibits platelet secretion of granule constituents, which exacerbates inflammation and ischemia/reperfusion injury. These data establish crucial integrin-G protein crosstalk, providing a rationale for therapeutic approaches that inhibit exocytosis in platelets and possibly other cells without adverse effects associated with loss of cell adhesion.
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Proteínas de Ligação ao GTP , Transdução de Sinais , Animais , Camundongos , Exocitose , Fatores de Troca de Nucleotídeo Guanina Rho , Integrina beta3RESUMO
Human leukocyte antigen (HLA)-B27 confers a key role in ankylosing spondylitis (AS) susceptibility. Endoplasmic reticulum aminopeptidase 1 (ERAP1) polymorphisms are associated with AS susceptibility in common population. In this study we intended to evaluate the possible association between ERAP1 polymorphisms and AS susceptibility in HLA-27 positive population. Data were collected from Pubmed, Embase, and Cochrane databases. The pooled odds ratios and 95% confidence intervals of the minor allele of each locus were calculated to appraise the associations under ERAP1 polymorphisms and AS in HLA-B27 positive population. Bioinformatics analysis was performed to explore the underlying mechanism. Four studies were included in this meta-analysis. There was a significant association between the minor allele of rs2287987 and reducing the risk of developing AS in HLA-B27 positive population. But there was no significant association between the minor allele of rs30187, rs27044, rs10050860 and rs17482078 and AS susceptibility. According to HaploReg, 5 motifs changed for rs2287987 were found. The eQTL analysis demonstrated that rs2287987 may influence ERAP1 expression. Rs2287987 in ERAP1 may have small influence on AS susceptibility in HLA-B27 positive population. Bioinformatics analysis indicated that the altered motifs and the change of EARP1 expression may influence the AS susceptibility.
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Espondilite Anquilosante , Aminopeptidases/genética , Biologia Computacional , Predisposição Genética para Doença , Antígeno HLA-B27/genética , Humanos , Antígenos de Histocompatibilidade Menor/genética , Polimorfismo de Nucleotídeo Único , Espondilite Anquilosante/genéticaRESUMO
Lubricants performing better in machinery systems would lead to the remarkable reduction of environmental pollution problems and the significant improvement of fuel economy. A new family of supramolecular polymer gel lubricants with urea groups has been successfully prepared via self-assembling noncovalent bonds. These newly designed supramolecular polymer gels were well characterized with field-emission scanning electron microscopy, proton nuclear magnetic resonance, attenuated total reflection-Fourier transform infrared spectroscopy, a rheometer, oscillating reciprocating friction, and a wear tester. Compared to low molecular weight supramolecular gels, the covalent and noncovalent bonds cooperated in the supramolecular polymer gel based on macromolecules. Hence, the mechanical properties and viscoelasticity of gel lubricants are greater than those of the low molecular weight supramolecular gels. Furthermore, owing to the longer chain length of polymer gelators, the thickness of the adsorbed film formed on the surface lubricated by macromolecules is thicker than that on the surface lubricated by low molecular weight supramolecular gels, which positively correlates with the lubricating property, making supramolecular polymer gels based on macromolecules better than low molecular weight supramolecular gels. Excitingly, the supramolecular polymer gels based on macromolecules exhibit more excellent thermal reversibility, creep recovery, and thixotropic properties, which not only achieve the lubricating property but also lead to the remarkable reduction of environmental pollution problems due to oil creeping.
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To investigate the potential transcriptional regulation and signal pathway of a single microRNA in ischemia-induced retinal neovascularization (NV), we used oxygen-induced retinopathy (OIR) in establishing retinal NV model, and quantitative real-time reverse transcriptase PCR analyzing a microRNA (miR-126) alteration. The mice were treated with plasmid pCMV-MIR-126/liposome mixture intravitreal injection, using pCMV-MIR/liposome mixture as control. The expression levels of VEGF, IGF-2 and HIF-1α, and the level changes of total and phosphorylated p38, ERK in retina from OIR mice were determined by western blot analysis. The effects of miR-126 on retinal NV in OIR mice were identified with fluoresecin angiography and H & E staining. No effect of miR-126 intravitreal injection on retinal vessels was performed with CD31 stained retinal sections. Our results showed that miR-126 was significantly decreased in retina from OIR mice. We confirmed that restoration of miR-126 in retina overcame the high levels of VEGF, IGF-2 and HIF-1α through downregulating p38 and ERK signaling molecules in OIR model, and that miR-126 intravitreal injection reduced retinal NV in OIR model. These results suggest that miR-126 might play a potential transcriptional role in the pathogenesis in diabetic retinopathy.
Assuntos
Proteínas Angiogênicas/genética , Isquemia/tratamento farmacológico , MicroRNAs/farmacologia , Neovascularização Retiniana/tratamento farmacológico , Vasos Retinianos/efeitos dos fármacos , Proteínas Angiogênicas/metabolismo , Animais , Animais Recém-Nascidos , Biomarcadores/metabolismo , Proliferação de Células , Modelos Animais de Doenças , Regulação para Baixo , Angiofluoresceinografia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Hiperóxia/metabolismo , Hiperóxia/patologia , Camundongos , Camundongos Endogâmicos C57BL , Oxigênio/toxicidade , Neovascularização Retiniana/metabolismoRESUMO
OBJECTIVE: To find out the reason of three ciguatera fish poisoning cases in Xiamen in 2005 and identify the fish species. METHODS: The grouper implicated in food poisoning and seven other coral reef fishes collected from market were tested by mice bioassay and ciguatoxin-test kit. The mtDNA was extracted from toxic grouper meat, and Cty b gene segment was amplified and the PCR products were sequenced. The sequences were compared with those in the GenBank. RESULTS: The result turned out to be positive by the ciguatoxin-test kit, while the toxicity of the toxic grouper implicated in food poisoning was 0.11 mouse unit (MU)/g by mice bioassay. A 475 bp segments of Cty b gene was amplified by PCR and the sequence was 99% homologous with Epinephelus fuscoguttatus (GenBank: AY950695).No ciguatoxin in six grouper species collected from market was detected. CONCLUSION: All three food poisoning cases were caused by consumption of ciguatoxin-carrying groupers.