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Studies have shown that elevated plasma levels of platelet-derived soluble TREM-like transcript-1 (sTLT-1) are associated with an unfavorable outcome in patients with septic shock. However, the underlying molecular mechanisms are not well defined. This research aimed to study the role of sTLT-1 in mediating immune dysfunction during the development of sepsis. Our study demonstrated that patients with septic shock have significantly higher plasma concentrations of sTLT-1, whereas sTLT-1 is not detectable in healthy subjects. Plasma concentrations of sTLT-1 were correlated with the degree of immunosuppressive parameters in monocytes from patients with septic shock. sTLT-1 can first activate monocytes by binding to the TLR4/MD2 complex but subsequently induce immunosuppressive phenotypes in monocytes. Blocking Abs against TLR4 and MD2 led to a significant decrease in sTLT-1-induced activation. Treatment with an anti-TLT-1 Ab also significantly reduces sTLT-1 binding to monocytes and proinflammatory cytokine secretion in a mouse model of endotoxemia. sTLT-1 acts as an endogenous damage-associated molecular pattern molecule, triggering the activation of monocytes through the TLR4/MD2 complex followed by sustained immune suppression. This process plays a crucial role in the development of sepsis-associated pathophysiology. Our findings outline, to our knowledge, a novel pathway whereby platelets counteract immune dynamics against infection through sTLT-1.
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Sepsis , Choque Séptico , Animales , Ratones , Receptor Toll-Like 4/metabolismo , Alarminas , Receptores Inmunológicos/metabolismoRESUMEN
Neutrophils are the most abundant vertebrate leukocytes and they are essential to host defense. Despite extensive investigation, the molecular network controlling neutrophil differentiation remains incompletely understood. GFI1 is associated with several myeloid disorders, but its role and the role of its co-regulators in granulopoiesis and pathogenesis are far from clear. Here, we demonstrate that zebrafish gfi1aa deficiency induces excessive neutrophil progenitor proliferation, accumulation of immature neutrophils from the embryonic stage, and some phenotypes similar to myelodysplasia syndrome in adulthood. Both genetic and epigenetic analyses demonstrate that immature neutrophil accumulation in gfi1aa-deficient mutants is due to upregulation of cebpa transcription. Increased transcription was associated with Lsd1-altered H3K4 methylation of the cebpa regulatory region. Taken together, our results demonstrate that Gfi1aa, Lsd1 and cebpa form a regulatory network that controls neutrophil development, providing a disease progression-traceable model for myelodysplasia syndrome. Use of this model could provide new insights into the molecular mechanisms underlying GFI1-related myeloid disorders as well as a means by which to develop targeted therapeutic approaches for treatment.
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Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Proteínas de Unión al ADN/metabolismo , Hematopoyesis/genética , Histona Demetilasas/metabolismo , Neutrófilos/citología , Proteínas de Pez Cebra/metabolismo , Animales , Proteínas Potenciadoras de Unión a CCAAT/genética , Diferenciación Celular , Proliferación Celular , Proteínas de Unión al ADN/deficiencia , Embrión no Mamífero , Epigénesis Genética , Células Precursoras de Granulocitos/citología , Células Precursoras de Granulocitos/metabolismo , Histona Demetilasas/genética , Neutrófilos/metabolismo , Pez Cebra , Proteínas de Pez Cebra/deficiencia , Proteínas de Pez Cebra/genéticaRESUMEN
Atherosclerosis is a chronic inflammatory disease of arterial wall. Mitochondrial DNA (mtDNA) and human antimicrobial peptide LL-37 (Cramp in mice) are involved in atherosclerosis. Recently, mtDNA has been found to escape from autophagy and cause inflammation. Normally, mtDNA as an inflammatogenic factor cannot escape from autophagy and degradation by DNase II. In this study, we found elevated amounts of LL37-mtDNA complex in atherosclerotic plasma and plaques. The complex was resistant to DNase II degradation and escaped from autophagic recognition, leading to activation of Toll-like receptor 9 (TLR9)-mediated inflammatory responses. Mouse model studies indicated that Cramp-mtDNA complex aggravated atherosclerotic lesion formation in apolipoprotein E-deficient mice and antibody treatment against the complex alleviated the lesion. These findings suggest that the LL-37-mtDNA complex acts as a key mediator of atherosclerosis formation, and thus represents a promising therapeutic target.
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Aterosclerosis/metabolismo , Autofagia/fisiología , Catelicidinas/metabolismo , ADN Mitocondrial/metabolismo , Placa Aterosclerótica/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Animales , Péptidos Catiónicos Antimicrobianos , Aterosclerosis/patología , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Placa Aterosclerótica/patologíaRESUMEN
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is underdiagnosed with the current gold standard measure pulmonary function test (PFT). A more sensitive and simple option for early detection and severity evaluation of COPD could benefit practitioners and patients. METHODS: In this multicenter retrospective study, frontal chest X-ray (CXR) images and related clinical information of 1055 participants were collected and processed. Different deep learning algorithms and transfer learning models were trained to classify COPD based on clinical data and CXR images from 666 subjects, and validated in internal test set based on 284 participants. External test including 105 participants was also performed to verify the generalization ability of the learning algorithms in diagnosing COPD. Meanwhile, the model was further used to evaluate disease severity of COPD by predicting different grads. RESULTS: The Ensemble model showed an AUC of 0.969 in distinguishing COPD by simultaneously extracting fusion features of clinical parameters and CXR images in internal test, better than models that used clinical parameters (AUC = 0.963) or images (AUC = 0.946) only. For the external test set, the AUC slightly declined to 0.934 in predicting COPD based on clinical parameters and CXR images. When applying the Ensemble model to determine disease severity of COPD, the AUC reached 0.894 for three-classification and 0.852 for five-classification respectively. CONCLUSION: The present study used DL algorithms to screen COPD and predict disease severity based on CXR imaging and clinical parameters. The models showed good performance and the approach might be an effective case-finding tool with low radiation dose for COPD diagnosis and staging.
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Aprendizaje Profundo , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Estudios Retrospectivos , Rayos X , TóraxRESUMEN
As large numbers of people are suffering from gout, an accurate, rapid, and sensitive method for the detection of gout biomarker, uric acid, is important for its effective control, diagnosis, and therapy. Although colorimetric detection methods based on uricase have been considered, they still have limitations as they produce toxic H2O2 and are expensive and not stable. Here, a novel uricase-free colorimetric method was developed for the sensitive and selective detection of uric acid based on the light-induced oxidase-mimicking activity of a new photosensitized covalent organic framework (COF) (2,4,6-trimethylpyridine-3,5-dicarbonitrile-4-[2-(4-formylphenyl)ethynyl]benzaldehyde COF [DCTP-EDA COF]). DCTP-EDA COF has a strong ability to harvest visible light, and it could catalyze the oxidation of 1,4-dioxane, 3,3',5,5'-tetramethylbenzidine under visible light irradiation to produce obvious color changes. With the addition of uric acid, however, the significant inhibition of the oxidase-mimicking activity of DCTP-EDA COF remarkably faded the color, and thus uric acid could be colorimetrically detected in the range of 2.0-150 µM with a limit of detection of 0.62 µM (3σ/K). Moreover, the present colorimetric method exhibited high selectivity; uric acid level in serum samples was successfully determined, and the recoveries ranged from 96.5% to 105.64%, suggesting the high accuracy of the present colorimetric method, which demonstrates great promise in clinical analysis.
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Gota , Estructuras Metalorgánicas , Humanos , Oxidorreductasas , Ácido Úrico , Peróxido de Hidrógeno , Colorimetría/métodos , Urato OxidasaRESUMEN
Renal fibrosis is a common feature of various chronic kidney diseases. However, the underlying mechanism remains poorly understood. The CXC chemokine receptor (CXCR) family plays a role in renal fibrosis; however, the detailed mechanisms have not been elucidated. In this study, we investigated the potential role of CXCR7 in mediating renal fibrosis. CXCR7 expression is decreased in unilateral ischemia-reperfusion injury (UIRI) and unilateral ureteral obstruction mouse models. Furthermore, CXCR7 was specifically expressed primarily in the Lotus Tetragonolobus Lectin-expressing segment of tubules, was slightly expressed in the peanut agglutinin-expressing segment, and was barely expressed in the Dolichos biflorus agglutinin-expressing segment. Administration of pFlag-CXCR7, an overexpression plasmid for CXCR7, significantly inhibited the activation of ß-catenin signaling and protected against the progression of epithelial-to-mesenchymal transition (EMT) and renal fibrosis in a UIRI mouse model. Using cultured HKC-8 cells, we found that CXCR7 significantly downregulated the expression of active ß-catenin and fibrosis-related markers, including fibronectin, Collagen I, and α-SMA. Furthermore, CXCR7 significantly attenuated TGF-ß1-induced changes in ß-catenin signaling, EMT and fibrosis. These results suggest that CXCR7 plays a crucial role in inhibiting the activation of ß-catenin signaling and the progression of EMT and renal fibrosis. Thus, CXCR7 could be a novel therapeutic target for renal fibrosis.
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Enfermedades Renales , Receptores CXCR , Animales , Ratones , beta Catenina , Modelos Animales de Enfermedad , Células Epiteliales , Transición Epitelial-Mesenquimal , Fibrosis , Enfermedades Renales/etiología , Receptores CXCR/genéticaRESUMEN
BACKGROUNDPURPOSE: Immunotherapy is a new treatment option for patients with Lung Cancer (LC). However, relatively limited research has explored about patients' perception of hope and its associated factors during the process. This study aimed to examine level of perceived hope and the factors related to hope, with a particular focus on treatment and physically related factors, in LC patients receiving immunotherapy. METHODS: A cross-sectional study was conducted and patients who had already received at least one immunotherapy cycle were recruited from two hospitals in northern Taiwan. The questionnaire included a background information form, the Herth's Hope Index, and the Symptom Severity Scale. Stepwise regression was applied to identify the most robust factors related to level of hope in the participants. RESULTS: A total of 130 patients were recruited. Overall, patients reported moderate to high levels of hope and mild symptoms. Fatigue, weakness, appearance changes, pruritus, and shortness of breath were identified as the most severe symptoms. Further regression analysis showed that patients with poor performance status, less immunotherapy cycles, higher level of fatigue, and more severe pruritus reported to have lower level of hope which explained 47% of the variances. CONCLUSIONS: This study revealed that lung cancer patients undergoing immunotherapy had moderate level of hope. Patients' performance status, selected symptoms and times of receiving immunotherapy were the robust factors related to hope. Systematic assessment of patients' symptoms and the development of appropriate interventions to reduce distress and enhance hope are strongly recommended for both clinical care and research.
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Airway remodeling is a major feature of asthma. Interleukin (IL)-36γ is significantly upregulated and promotes airway hyper-responsiveness (AHR) in asthma, but its role in airway remodeling is unknown. Here, we aimed to investigate the role of IL-36γ in airway remodeling, and whether IL-38 can alleviate airway remodeling in chronic asthma by blocking the effects of IL-36γ. IL-36γ was quantified in mice inhaled with house dust mite (HDM). Extracellular matrix (ECM) deposition in lung tissues and AHR were assessed following IL-36γ administration to mice. Airway inflammation, AHR, and remodeling were evaluated after IL-38 or blocking IL-36 receptor (IL-36R) treatment in asthmatic mice. The effects of lung fibroblasts stimulated with IL-36γ and IL-38 were quantified in vitro. Increased expression of IL-36γ was detected in lung tissues of HDM-induced asthmatic mice. The intratracheal instillation of IL-36γ to mice significantly enhanced the ECM deposition, AHR, and the number of activated lung fibroblasts around the airways. IL-38 or blocking IL-36R treated asthmatic mice showed a significant alleviation in the airway inflammation, AHR, airway remodeling, and number of activated fibroblasts around airways as compared with the HDM group. In vitro, IL-36γ promoted the activation and migration of human lung fibroblasts (HFL-1). The administration of IL-38 can counteract these biological processes induced by IL-36γ in HFL-1cells. The results indicated that IL-38 can mitigate airway remodeling by blocking the profibrotic effects of IL-36γ in chronic asthma. IL-36γ may be a new therapeutic target, and IL-38 is a potential candidate agent for inhibiting airway remodeling in asthma.
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Remodelación de las Vías Aéreas (Respiratorias) , Asma , Animales , Humanos , Ratones , Asma/metabolismo , Interleucinas/metabolismo , Pulmón/metabolismo , Inflamación/metabolismo , Modelos Animales de Enfermedad , Pyroglyphidae , Ratones Endogámicos BALB CRESUMEN
BACKGROUND: Intercellular communication between macrophages and peritoneal mesothelial cells (PMCs) has been suggested as a key factor regulating peritonitis development. Here, we explored whether PPARγ (peroxisome proliferator-activated receptor gamma) can be packaged into macrophage exosomes to mediate intercellular communication and regulate peritonitis. METHODS: Macrophage exosomes were isolated by ultracentrifugation and identified by nanoparticle tracking analysis and transmission electron microscopy. Proteomic analysis of macrophage-derived exosomes was performed using mass spectrometry. Co-culture models of supernatants or exosomes with PMCs, as well as a mouse peritonitis model induced by lipopolysaccharide (LPS), were employed. RESULTS: In this study, using stable Raw264.7 cells overexpressing GFP-FLAG-PPARγ (OE-PPARγ), we found that PPARγ inhibited LPS-induced inflammatory responses in Raw264.7 cells and that PPARγ was incorporated into macrophage exosomes during this process. Overexpression of PPARγ mainly regulated the secretion of differentially expressed exosomal proteins involved in the biological processes of protein transport, lipid metabolic process, cell cycle, apoptotic process, DNA damage stimulus, as well as the KEGG pathway of salmonella infection. Using co-culture models and mouse peritonitis model, we showed that exosomes from Raw264.7 cells overexpressing PPARγ inhibited LPS-induced inflammation in co-cultured human PMCs and in mice through downregulating CD14 and TLR4, two key regulators of the salmonella infection pathway. Pretreatment of the PPARγ inhibitor GW9662 abolished the anti-inflammatory effect of exosomes from Raw264.7 OE-PPARγ cells on human PMCs. CONCLUSIONS: These results suggested that overexpression of PPARγ largely altered the proteomic profile of macrophage exosomes and that exosomal PPARγ from macrophages acted as a regulator of intercellular communication to suppress LPS-induced inflammatory responses in vitro and in vivo via negatively regulating the CD14/TLR4 axis.
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Fenómenos Biológicos , Peritonitis , Ratones , Humanos , Animales , PPAR gamma/metabolismo , Lipopolisacáridos/farmacología , Receptor Toll-Like 4/metabolismo , Proteómica , Macrófagos/metabolismo , Peritonitis/inducido químicamenteRESUMEN
Blood clot formation induced by dysfunctional coagulation is a frequent complication of coronavirus disease 2019 (COVID-19) and a high-risk factor for severe illness and death. Neutrophil extracellular traps (NETs) are implicated in COVID-19-induced immunothrombosis. Furthermore, human cathelicidin, a NET component, can perturb the interaction between the SARS-CoV-2 spike protein and its ACE2 receptor, which mediates viral entry into cells. At present, however, the levels of cathelicidin antimicrobial peptides after SARS-CoV-2 infection and their role in COVID-19 thrombosis formation remain unclear. In the current study, we analyzed coagulation function and found a decrease in thrombin time but an increase in fibrinogen level, prothrombin time, and activated partial thromboplastin time in COVID-19 patients. In addition, the cathelicidin antimicrobial peptide LL-37 was upregulated by the spike protein and significantly elevated in the plasma of patients. Furthermore, LL-37 levels were negatively correlated with thrombin time but positively correlated with fibrinogen level. In addition to platelet activation, cathelicidin peptides enhanced the activity of coagulation factors, such as factor Xa (FXa) and thrombin, which may induce hypercoagulation in diseases with high cathelicidin peptide levels. Injection of cathelicidin peptides promoted the formation of thrombosis, whereas deletion of cathelicidin inhibited thrombosis in vivo. These results suggest that cathelicidin antimicrobial peptide LL-37 is elevated during SARS-CoV-2 infection, which may induce hypercoagulation in COVID-19 patients by activating coagulation factors.
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Péptidos Catiónicos Antimicrobianos , COVID-19 , Trombosis , Factores de Coagulación Sanguínea , COVID-19/complicaciones , Fibrinógeno , Humanos , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , Trombosis/virología , CatelicidinasRESUMEN
BACKGROUND AND OBJECTIVE: Cancer ratio (CR), which is defined as serum lactate dehydrogenase (LDH) to pleural fluid adenosine deaminase (ADA) ratio, has been reported to be a useful diagnostic marker for malignant pleural effusion (MPE). Whether its diagnostic accuracy is affected by age remains unknown. This study aimed to investigate the effects of age on the diagnostic accuracy of CR. METHODS: The participants in this study were from a prospective cohort (SIMPLE cohort, n = 199) and a retrospective cohort (BUFF cohort, n = 158). All participants were patients with undiagnosed pleural effusion (PE). We used receiver operating characteristic (ROC) curves to evaluate the diagnostic accuracy of CR. The effect of age on the diagnostic accuracy of CR was investigated by adjusting the upper limit of age for participant enrolment. RESULTS: Eighty-eight MPE patients were verified in the SIMPLE cohort, and thirty-five MPE patients were verified in the BUFF cohort. The AUCs of CR in the SIMPLE and BUFF cohorts were 0.60 (95% CI: 0.52-0.68) and 0.63 (95% CI: 0.54-0.71), respectively. In both cohorts, the AUCs of CR decreased with the advancement of age. CONCLUSION: Age can affect the diagnostic accuracy of CR for MPE. CR has limited diagnostic value in older patients. KEY MESSAGE: Cancer ratio is a promising diagnostic marker for malignant pleural effusion. This study revealed that its diagnostic accuracy decreased in older patients. Its diagnostic accuracy is overestimated by previous studies using tuberculosis and pneumonia patients as controls.
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Derrame Pleural Maligno , Derrame Pleural , Humanos , Anciano , Derrame Pleural Maligno/diagnóstico , Derrame Pleural Maligno/patología , Estudios Retrospectivos , Sensibilidad y Especificidad , Estudios Prospectivos , Derrame Pleural/diagnósticoRESUMEN
Tobacco smoke exposure is a major environmental risk factor that facilitates the development and progression of asthma. Our previous study showed that CpG oligodeoxynucleotide (CpG-ODN) inhibits thymic stromal lymphopoietin (TSLP)-dendritic cells (DCs) to reduce Th2/Th17-related inflammatory response in smoke-related asthma. However, the mechanism underlying CpG-ODN -downregulated TSLP remains unclear. A combined house dust mite (HDM)/cigarette smoke extract (CSE) model was used to assess the effects of CpG-ODN on airway inflammation, Th2/Th17 immune response, and amount of IL-33/ST2 and TSLP in mice with smoke-related asthma induced by adoptive transfer of bone-marrow-derived dendritic cells (BMDCs) and in the cultured human bronchial epithelium (HBE) cells administered anti-ST2, HDM, and/or CSE. In vivo, compared to the HDM alone model, the combined HDM/CSE model had aggravated inflammatory responses, while CpG-ODN attenuated airway inflammation, airway collagen deposition, and goblet cell hyperplasia and reduced the levels of IL-33/ST2, TSLP, and Th2/Th17-cytokines in the combined model. In vitro, IL-33/ST2 pathway activation promoted TSLP production in HBE cells, which could be inhibited by CpG-ODN. CpG-ODN administration alleviated Th2/Th17 inflammatory response, decreased the infiltration of inflammatory cells into the airway, and improved the remodeling of smoke-related asthma. The underlying mechanism may be that CpG-ODN inhibits the TSLP-DCs pathway by downregulating the IL-33/ST2 axis.
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Asma , Interleucina-33 , Animales , Humanos , Ratones , Traslado Adoptivo , Alérgenos , Asma/metabolismo , Citocinas/metabolismo , Células Dendríticas , Inflamación , Interleucina-33/metabolismo , Ratones Endogámicos BALB C , Oligodesoxirribonucleótidos/farmacología , Células Th2 , Linfopoyetina del Estroma Tímico , Células Th17RESUMEN
The Australian Cardiovascular Alliance (ACvA), the Cardiac Society of Australia and New Zealand (CSANZ) and the National Heart Foundation of Australia (NHFA) recently joined forces to bring the cardiovascular and stroke community together to convene and document a national discussion and propose a national CVD Implementation and Policy agenda and action plan. This includes prevention and screening, acute care and secondary prevention.
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Enfermedades Cardiovasculares , Humanos , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/prevención & control , Australia/epidemiología , Políticas , Nueva Zelanda/epidemiologíaRESUMEN
Background and Objectives: The identification of possible biomarkers that can predict treatment response among DME eyes is important for the individualization of treatment plans. We investigated optical coherence tomography (OCT)-based biomarkers that may predict the one-year real-life outcomes among diabetic macular edema (DME) eyes following treatment by intravitreal ranibizumab (IVR) injections. Materials and Methods: A total of 65 eyes from 35 treatment-naïve patients with DME treated with ranibizumab injection were recruited. Best-corrected visual acuity (BCVA), central retinal thickness (CRT), intraocular pressure (IOP), and OCT scans were retrospectively recorded at baseline before treatment and at 3 months, 6 months, and 12 months after treatment. The OCT scans were evaluated for biomarkers of interest, which included central retinal thickness (CRT), amount and locations of hyperreflective foci (HRF), subretinal fluid (SRF), intraretinal cysts (IRC), large outer nuclear layer cyst (LONLC), ellipsoid zone disruption (EZD), disorganization of retinal inner layers (DRIL), hard exudates (HE), epiretinal membrane (ERM), and vitreomacular interface (VMI). Correlations between these OCT biomarkers and outcome measures (visual and structural) were statistically analyzed. Results: A total of 65 eyes from 35 patients with DME were enrolled. The mean age was 64.2 ± 10.9 years old. Significant improvement in terms of mean BCVA (p < 0.005) and mean CRT was seen at final follow-up compared to baseline. The biomarkers of DRIL, LONLC, and SRF were found to be predictive for at least 50 µm CRT reduction after treatment (with odds ratio of 8.69, 8.5, and 17.58, respectively). The biomarkers of IRC, LONLC, and SRF were predictive for significant improvement in terms of BCVA and CRT after treatment. Finally, the number of HRF was predictive for both BCVA improvement and a CRT reduction of less than 100 µm after treatment. No serious complications were reported during the study. Conclusion: Our study demonstrated the utility of OCT biomarkers as therapeutic predictors of ranibizumab treatment among DME eyes.
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Diabetes Mellitus , Retinopatía Diabética , Edema Macular , Humanos , Persona de Mediana Edad , Anciano , Ranibizumab/uso terapéutico , Edema Macular/tratamiento farmacológico , Edema Macular/etiología , Tomografía de Coherencia Óptica/métodos , Estudios Retrospectivos , Inhibidores de la Angiogénesis/uso terapéutico , Estudios de Seguimiento , Resultado del Tratamiento , Biomarcadores , Diabetes Mellitus/tratamiento farmacológicoRESUMEN
BACKGROUND: T cell acute lymphoblastic leukemia (T-ALL) defines a group of hematological malignancies with heterogeneous aggressiveness and highly variable outcome, making therapeutic decisions a challenging task. We tried to discover new predictive model for T-ALL before treatment by using a specific pipeline designed to discover aberrantly active gene. RESULTS: The expression of 18 genes was significantly associated with shorter survival, including ACTRT2, GOT1L1, SPATA45, TOPAZ1 and ZPBP (5-GEC), which were used as a basis to design a prognostic classifier for T-ALL patients. The molecular characterization of the 5-GEC positive T-ALL unveiled specific characteristics inherent to the most aggressive T leukemic cells, including a drastic shut-down of genes located on the mitochondrial genome and an upregulation of histone genes, the latter characterizing high risk forms in adult patients. These cases fail to respond to the induction treatment, since 5-GEC either predicted positive minimal residual disease (MRD) or a short-term relapse in MRD negative patients. CONCLUSION: Overall, our investigations led to the discovery of a homogenous group of leukemic cells with profound alterations of their biology. It also resulted in an accurate predictive tool that could significantly improve the management of T-ALL patients.
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Leucemia-Linfoma Linfoblástico de Células Precursoras , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Adulto , Expresión Génica Ectópica , Humanos , Neoplasia Residual/diagnóstico , Neoplasia Residual/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Pronóstico , Linfocitos T/patología , Resultado del TratamientoRESUMEN
Irritable bowel syndrome (IBS) is characterized by visceral hypersensitivity (VH) associated with abnormal serotonin/5-hydroxytryptamine (5-HT) metabolism and neurotrophin-dependent mucosal neurite outgrowth. The underlying mechanisms of VH remain poorly understood. We investigated the role of 5-HT7 receptor in mucosal innervation and intestinal hyperalgesia. A high density of mucosal nerve fibres stained for 5-HT7 was observed in colonoscopic biopsy specimens from IBS patients compared with those from healthy controls. Staining of 5-HT3 and 5-HT4 receptors was observed mainly in colonic epithelia with comparable levels between IBS and controls. Visceromotor responses to colorectal distension were evaluated in two mouse models, one postinfectious with Giardia and subjected to water avoidance stress (GW) and the other postinflammatory with trinitrobenzene sulfonic acid-induced colitis (PT). Increased VH was associated with higher mucosal density of 5-HT7-expressing nerve fibres and elevated neurotrophin and neurotrophin receptor levels in the GW and PT mice. The increased VH was inhibited by intraperitoneal injection of SB-269970 (a selective 5-HT7 antagonist). Peroral multiple doses of CYY1005 (a novel 5-HT7 ligand) decreased VH and reduced mucosal density of 5-HT7-expressing nerve fibres in mouse colon. Human neuroblastoma SH-SY5Y cells incubated with bacteria-free mouse colonic supernatant, 5-HT, nerve growth factor, or brain-derived neurotrophic factor exhibited nerve fibre elongation, which was inhibited by 5-HT7 antagonists. Gene silencing of HTR7 also reduced the nerve fibre length. Activation of 5-HT7 upregulated NGF and BDNF gene expression, while stimulation with neurotrophins increased the levels of tryptophan hydroxylase 2 and 5-HT7 in neurons. A positive-feedback loop was observed between serotonin and neurotrophin pathways via 5-HT7 activation to aggravate fibre elongation, whereby 5-HT3 and 5-HT4 had no roles. In conclusion, 5-HT7-dependent mucosal neurite outgrowth contributed to VH. A novel 5-HT7 antagonist could be used as peroral analgesics for IBS-related pain.
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Síndrome del Colon Irritable , Neuroblastoma , Animales , Humanos , Mucosa Intestinal , Ratones , Proyección Neuronal , SerotoninaRESUMEN
BACKGROUND: Despite the importance of root hydraulics, there is little research on the in situ dynamic responses of embolism formation and embolism repair of roots distributed in different soil depths in response to different water regimes. RESULTS: The vessel diameter, hydraulic conductivity, and vulnerability to cavitation were in the order of deep root > shallow root > branch. The midday PLC of shallow root was the highest in the dry season, while the midday PLC of deep root slightly higher than that of branch with no significant difference in the two seasons. The capacity of embolism repair of roots was significantly greater than that of branch both in dry season and wet season. The xylem pressure was in the order of deep roots > shallow root > branch, and it was negative in most of the time for the latter two in the dry season, but positive for both of the roots during the observation period in the wet season. The NSC and starch content in roots were significantly higher than those in branches, especially in the dry season. In contrast, roots had lower content of soluble sugar. CONCLUSIONS: The relatively stable water condition in soil, especially in the deep layers, is favorable for the development of larger-diameter vessels in root xylem, however it cannot prevent the root from forming embolism. The mechanism of embolism repair may be different in different parts of plants. Deep roots mainly depend on root pressure to refill the embolized vessels, while branches mainly depend on starch hydrolysis to soluble sugars to do the work, with shallow roots shifted between the two mechanisms in different moisture regimes. There is theoretically an obvious trade-off between conducting efficiency and safety over deep roots, shallow roots and branches. But in natural conditions, roots do not necessarily suffer more severe embolism than branches, maybe due to their root pressure-driven embolism repair and relatively good water conditions.
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Sequías , Juglans , Raíces de Plantas/fisiología , Transpiración de Plantas/fisiología , Estaciones del Año , Suelo/química , Almidón , Agua/fisiología , Xilema/fisiologíaRESUMEN
BACKGROUND: Epithelial-mesenchymal transition (EMT) is one of the mechanisms of airway remodeling in chronic asthma. Interleukin (IL)-24 has been implicated in the promotion of tissue fibrosis, and increased IL-24 levels have been observed in the nasal secretions and sputum of asthmatic patients. However, the role of IL-24 in asthmatic airway remodeling, especially in EMT, remains largely unknown. We aimed to explore the effect and mechanism of IL-24 on EMT and to verify whether IL-37 could alleviate IL-24-induced EMT in chronic asthma. METHODS: BEAS-2B cells were exposed to IL-24, and cell migration was assessed by wound healing and Transwell assays. The expression of EMT-related biomarkers (E-cadherin, vimentin, and α-SMA) was evaluated after the cells were stimulated with IL-24 with or without IL-37. A murine asthma model was established by intranasal administration of house dust mite (HDM) extracts for 5 weeks, and the effects of IL-24 and IL-37 on EMT and airway remodeling were investigated by intranasal administration of si-IL-24 and rhIL-37. RESULTS: We observed that IL-24 significantly enhanced the migration of BEAS-2B cells in vitro. IL-24 promoted the expression of the EMT biomarkers vimentin and α-SMA via the STAT3 and ERK1/2 pathways. In addition, we found that IL-37 partially reversed IL-24-induced EMT in BEAS-2B cells by blocking the ERK1/2 and STAT3 pathways. Similarly, the in vivo results showed that IL-24 was overexpressed in the airway epithelium of an HDM-induced chronic asthma model, and IL-24 silencing or IL-37 treatment could reverse EMT biomarker expression. CONCLUSIONS: Overall, these findings indicated that IL-37 mitigated HDM-induced airway remodeling by inhibiting IL-24-mediated EMT via the ERK1/2 and STAT3 pathways, thereby providing experimental evidence for IL-24 as a novel therapeutic target and IL-37 as a promising agent for treating severe asthma.
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Remodelación de las Vías Aéreas (Respiratorias) , Asma , Interleucina-1/farmacología , Animales , Asma/metabolismo , Asma/prevención & control , Bronquios/metabolismo , Transición Epitelial-Mesenquimal , Humanos , Interleucinas/metabolismo , Interleucinas/farmacología , Ratones , Pyroglyphidae/metabolismo , Transducción de Señal , Vimentina/metabolismoRESUMEN
OBJECTIVE: Peritoneal fibrosis (PF) is commonly induced by bioincompatible dialysate exposure during peritoneal dialysis, but the underlying mechanisms remain elusive. This study aimed to investigate the roles of peroxisome proliferator-activated receptor gamma (PPARγ) in PF pathogenesis. METHODS: Rat and cellular PF models were established by high glucose dialysate and lipopolysaccharide treatments. Serum creatinine, urea nitrogen, and glucose contents were detected by ELISA. Histological evaluation was done through H&E and Masson staining. GLUT1, PPARγ, and other protein expression were measured by qRT-PCR, western blotting, and IHC. PPARγ and GLUT1 subcellular distribution were detected using confocal microscopy. Cell proliferation was assessed by MTT and Edu staining. RESULTS: Serum creatinine, urea nitrogen and glucose, and PPARγ and GLUT1 expression in rat PF model were reduced by PPARγ agonists Rosiglitazone or 15d-PGJ2 and elevated by antagonist GW9662. Rosiglitazone or 15d-PGJ2 repressed and GW9662 aggravated peritoneal fibrosis in rat PF model. PPARγ and GLUT1 were mainly localized in nucleus and cytosols of peritoneal mesothelial cells, respectively, which were reduced in cellular PF model, enhanced by Rosiglitazone or 15d-PGJ2, and repressed by GW9662. TGF-ß and a-SMA expression was elevated in cellular PF model, which was inhibited by Rosiglitazone or 15d-PGJ2 and promoted by GW9662. PPARγ silencing reduced GLUT1, elevated a-SMA and TGF-b expression, and promoted peritoneal mesothelial cell proliferation, which were oppositely changed by PPARγ overexpression. CONCLUSION: PPARγ inhibited high glucose-induced peritoneal fibrosis progression through elevating GLUT1 expression and repressing peritoneal mesothelial cell proliferation.
Asunto(s)
Transportador de Glucosa de Tipo 1 , PPAR gamma , Fibrosis Peritoneal , Tiazolidinedionas , Animales , Proliferación Celular , Creatinina , Soluciones para Diálisis/farmacología , Glucosa/farmacología , Transportador de Glucosa de Tipo 1/metabolismo , Nitrógeno/metabolismo , Nitrógeno/farmacología , PPAR gamma/agonistas , PPAR gamma/genética , Fibrosis Peritoneal/inducido químicamente , Fibrosis Peritoneal/genética , Prostaglandina D2 , Ratas , Rosiglitazona/farmacología , Tiazolidinedionas/farmacología , Factor de Crecimiento Transformador beta/metabolismo , UreaRESUMEN
Tyrosine kinase inhibitors (TKIs), which have been developed and approved for cancer treatment in the last few years, are involved in synaptic plasticity of learning and memory. Epigenetic modifications also play crucial roles in the process of learning and memory, but its relationship with TKI-induced learning and memory impairment has not been investigated. We hypothesized that LPM4870108, an effective anti-cancer Trk inhibitor, might affect the learning and memory via epigenetic modifications. In this study, rats were orally administered with LPM4870108 (0, 1.25, 2.5, or 5.0 mg/kg) twice daily for 28 days, after which animals were subjected to a Morris water maze test. LPM4870108 exposure caused learning and memory impairments in this test in a dose-dependent manner and reduced the spine densities. Whole-genome transcriptomic analysis revealed significant differences in the patterns of hippocampal gene expression in LPM4870108-treated rats. These transcriptomic data were combined with next-generation bisulfite sequencing analysis, after which RT-PCR and pyrosequencing were conducted, revealing epigenetic alterations associated with genes (Snx8, Fgfr1, Dusp4, Vav2, and Satb2) known to regulate learning and memory. Increased mRNA and protein expression levels of hippocampal Dnmt1 and Dnmt3a were also observed in these rats. Overall, these data suggest that gene-specific alterations in patterns of DNA methylation can potentially contribute to the incidence of learning and memory deficits associated with exposure to LPM4870108.