RESUMO
A series of MOF-derived ZrO2-supported Pd-Ni bimetallic catalysts (PdNi/UiO-67-CTAB(n)-A500) were prepared by co-impregnation and pyrolysis at 500 °C under air atmosphere using UiO-67-CTAB(n) (CTAB: cetyltrimethylammonium bromide; n: the concentration of CTAB; n = 0, 3, 8, 13, 18) as a sacrificial template. The catalytic activity of PdNi/UiO-66-CTAB(n)-A500 in 1,3-butadiene hydrogenation was found to be dependent on the crystal morphology of the UiO-67 template. The highest activity was observed over the PdNi/UiO-67-CTAB(3)-A500 catalyst which was synthesized using UiO-67-CTAB(3) with uniform octahedral morphology as the template for the 1,3-butadiene selective hydrogenation. The 1,3-butadiene conversion and total butene selectivity were 98.4% and 44.8% at 40 °C within 1 h for the PdNi/UiO-67-CTAB(3)-A500 catalyst, respectively. The catalyst of PdNi/UiO-67-CTAB(3)-A500 can be regenerated in flowing N2 at 200 °C. Carbon deposited on the surface of the catalyst was the main reason for its deactivation. This work is valuable for the high-efficiency bimetallic catalyst's development on the selective hydrogenation of 1,3-butadiene.
RESUMO
Haploidentical transplantation strategies for patients with transfusion-dependent thalassaemia (TD-TM) remain to be investigated. In this study, 54 paediatric patients with TD-TM were treated with a novel approach using post-transplant cyclophosphamide (PTCy) and low-dose methotrexate (LD-MTX), following a myeloablative regimen. The incidence of neutrophil and platelet engraftment was 96.3% ± 2.6% and 94.4% ± 3.1% respectively. The cumulative incidence of grades II-III acute graft-versus-host disease (GVHD) was 13.8% ± 4.8% at 100 days. At three years, the cumulative incidence of chronic GVHD was 28.5% ± 8.5%. With a median follow-up of 520 days (132-1325 days), the overall survival (OS) and event-free survival (EFS) were 98.1% ± 1.8% and 90.7% ± 3.9% respectively. Compared with the low-dose cyclophosphamide (CTX) conditioning regimen (120 mg/kg), the high-CTX regimen (200 mg/kg) achieved a higher incidence of stable engraftment (100% vs 66.7% ± 15.7%, p = 0.003), a comparable incidence of grades II-III acute GVHD, a lower incidence of chronic GVHD (20.2% ± 8.3% vs 66.6% ± 19.2%, p = 0.011), and better overall survival (100% vs 88.9% ± 10.5%, p = 0.025) as well as EFS (95.6% ± 3.1% vs 66.7% ± 15.7%, p = 0.008). Our results using unmanipulated haploidentical grafts and PTCy with LD-MTX in TD-TM are encouraging. (chictr.org.cn ChiCTR1800017969).
Assuntos
Síndrome de Bronquiolite Obliterante , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Pancitopenia , Talassemia , Humanos , Criança , Metotrexato/uso terapêutico , Transplante Haploidêntico/efeitos adversos , Ciclofosfamida/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Doença Enxerto-Hospedeiro/tratamento farmacológico , Pancitopenia/etiologia , Talassemia/complicações , Condicionamento Pré-Transplante/efeitos adversos , China , Transtornos da Insuficiência da Medula Óssea/tratamento farmacológicoRESUMO
As the direct contacting site for pathogens and allergens, the mucosal barrier plays a vital role in the lungs and intestines. Innate lymphoid cells (ILCs) are particularly resident in the mucosal barrier and participate in several pathophysiological processes, such as maintaining or disrupting barrier integrity, preventing various pathogenic invasions. In the pulmonary mucosae, ILCs sometimes aggravate inflammation and mucus hypersecretion but restore airway epithelial integrity and maintain lung tissue homeostasis at other times. In the intestinal mucosae, ILCs can increase epithelial permeability, leading to severe intestinal inflammation on the one hand, and assist mucosal barrier in resisting bacterial invasion on the other hand. In this review, we will illustrate the positive and negative roles of ILCs in mucosal barrier immunity.
Assuntos
Mucosa Intestinal/imunologia , Linfócitos/imunologia , Mucosa Respiratória/imunologia , Animais , Humanos , Imunidade Inata , Linfócitos/citologiaRESUMO
Respiratory syncytial virus (RSV) infection in airway epithelial cells is the main cause of bronchiolitis in children. Excessive mucus secretion is one of the primary symbols in RSV related lower respiratory tract infections (RSV-related LRTI). However, the pathological processes of mucus hypersecretion in RSV-infected airway epithelial cells remains unclear. The current study explores the involvement of miR-34b/miR-34c in mucus hypersecretion in RSV-infected airway epithelial cells by targeting FGFR1. First, miR-34b/miR-34c and FGFR1 mRNA were quantified by qPCR in throat swab samples and cell lines, respectively. Then, the luciferase reporters' assay was designed to verify the direct binding between FGFR1 and miR-34b/miR-34c. Finally, the involvement of AP-1 signalling was assessed by western blot. This study identified that miR-34b/miR-34c was involved in c-Jun-regulated MUC5AC production by targeting FGFR1 in RSV-infected airway epithelial cells. These results provide some useful insights into the molecular mechanisms of mucus hypersecretion which may also bring new potential strategies to improve mucus hypersecretion in RSV disease.
Assuntos
MicroRNAs/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Mucosa Respiratória/metabolismo , Mucosa Respiratória/virologia , Infecções por Vírus Respiratório Sincicial/genética , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sinciciais Respiratórios/fisiologia , Biomarcadores , Linhagem Celular , Suscetibilidade a Doenças , Células Epiteliais/metabolismo , Células Epiteliais/virologia , Expressão Gênica , Perfilação da Expressão Gênica , Interações Hospedeiro-Patógeno/genética , Humanos , Imuno-Histoquímica , Mucina-5AC/genética , Interferência de RNA , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais , Fator de Transcrição AP-1/metabolismoRESUMO
Lung immune responses to respiratory pathogens and allergens are initiated in early life which will further influence the later onset of asthma. The airway epithelia form the first mechanical physical barrier to allergic stimuli and environmental pollutants, which is also the key regulator in the initiation and development of lung immune response. However, the epithelial regulation mechanisms of early-life lung immune responses are far from clear. Our previous study found that integrin ß4 (ITGB4) is decreased in the airway epithelium of asthma patients with specific variant site. ITGB4 deficiency in adult mice aggravated the lung Th2 immune responses and enhanced airway hyper-responsiveness (AHR) with a house dust mite (HDM)-induced asthma model. However, the contribution of ITGB4 to the postnatal lung immune response is still obscure. Here, we further demonstrated that ITGB4 deficiency following birth mediates spontaneous lung inflammation with ILC2 activation and increased infiltration of eosinophils and lymphocytes. Moreover, ITGB4 deficiency regulated thymic stromal lymphopoietin (TSLP) production in airway epithelial cells through EGFR pathways. Neutralization of TSLP inhibited the spontaneous inflammation significantly in ITGB4-deficient mice. Furthermore, we also found that ITGB4 deficiency led to exaggerated lung allergic inflammation response to HDM stress. In all, these findings indicate that ITGB4 deficiency in early life causes spontaneous lung inflammation and induces exaggerated lung inflammation response to HDM aeroallergen.
Assuntos
Células Epiteliais/metabolismo , Hipersensibilidade/complicações , Hipersensibilidade/imunologia , Integrina beta4/metabolismo , Pulmão/patologia , Pneumonia/complicações , Animais , Animais Recém-Nascidos , Hiper-Reatividade Brônquica/complicações , Citocinas/metabolismo , Células Epiteliais/patologia , Receptores ErbB/metabolismo , Hipersensibilidade/parasitologia , Hipersensibilidade/fisiopatologia , Pulmão/parasitologia , Linfócitos/imunologia , Camundongos Transgênicos , Fosforilação , Pyroglyphidae/fisiologia , Linfopoietina do Estroma do TimoRESUMO
Severe RSV infection is the main cause of hospitalization to children under the age of five. The regulation of miRNAs on the severity of RSV infection is unclear. The aim of the study was to identify the critical differential expression miRNAs (DE miRNAs) that can regulate the pathological response in RSV-infected airway epithelial cells. In this study, miRNA and mRNA chips of RSV-infected airway epithelia from Gene Expression Omnibus (GEO) were screened and analysed, separately. DE miRNAs-targeted genes were performed for further pathway and process enrichment analysis. DE miRNA-targeted gene functional network was constructed on the basis of miRNA-mRNA interaction. The screened critical miRNA was also investigated by bioinformatics analysis. Then, RSV-infected human bronchial epithelial cells (HBECs) were constructed to verify the expression of the DE miRNAs. Finally, specific synthetic DE miRNAs mimics were used to confirm the effect of DE miRNAs on the RSV-infected HBECs. 45 DE miRNAs were identified from GEO62306 dataset. Our results showed that hsa-mir-34b-5p and hsa-mir-34c-5p decreased significantly in HBECs after RSV infection. Consistent with the biometric analysis, hsa-mir-34b/c-5p is involved in the regulation of mucin expression gene MUC5AC. In RSV-infected HBECs, the inducement of MUC5AC production by decreased hsa-mir-34b/c-5p was partly mediated through activation of c-Jun. These findings provide new insights into the mechanism of mucus obstruction after RSV infection and represent valuable targets for RSV infection and airway obstruction treatment.
Assuntos
Regulação para Baixo/genética , Células Epiteliais/metabolismo , Células Epiteliais/virologia , Pulmão/patologia , MicroRNAs/genética , Muco/metabolismo , Infecções por Vírus Respiratório Sincicial/genética , Infecções por Vírus Respiratório Sincicial/virologia , Antracenos/farmacologia , Criança , Regulação para Baixo/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Perfilação da Expressão Gênica , Ontologia Genética , Redes Reguladoras de Genes/efeitos dos fármacos , Humanos , MicroRNAs/metabolismo , Mucina-5AC/metabolismo , Proteínas Proto-Oncogênicas c-jun/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
Traumatic brain injury (TBI) is a leading cause of morbidity and mortality in the world, and is tightly associated with microglia-regulated neuroinflammation. However, the activation profile of microglia during the pathophysiological responses is still not fully understood. Micro-RNAs (miRs), as noncoding RNAs, are involved in the progression of TBI. In this study, we attempted to explore the effects of miR-193a on TBI using the in vivo and in vitro studies. Following experimental TBI in mice, we found that miR-193a expression was significantly up-regulated in ipsilateral cortical tissues and in the microglia/macrophages isolated from the ipsilateral cortical tissues, which was accompanied with markedly enhanced expression of pro-inflammatory factors. We then found that miR-193a hairpin inhibitor (antagomir) markedly reduced lesion volume, brain water contents and neuron death in TBI mice induced by the controlled cortical impact (CCI). In addition, cognitive dysfunction in TBI mice was markedly improved after miR-193a antagomir injection. Of note, CCI-induced activation of microglia was repressed by miR-193a inhibition, along with significantly reduced expression of neuroinflammatory markers, which were associated with the blockage of nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome. The anti-neuroinflammation effects of miR-193a suppression were verified in lipopolysaccharide (LPS)-incubated microglial cells transfected with miR-193a inhibitor. In contrast, LPS-induced activation of microglial cells and the expression of pro-inflammatory factors was markedly further accelerated by the transfection of miR-193a mimic. Taken together, TBI resulted in a robust neuroinflammatory response that was closely associated with the up-regulated miR-193a expression mainly in microglia/macrophages; however, miR-193a suppression significantly alleviated post-traumatic neuroinflammation and cognitive dysfunction. Therefore, miR-193a might be a promising therapeutic target for the treatment of TBI-associated neuroinflammation.
Assuntos
Lesões Encefálicas Traumáticas/genética , Lesões Encefálicas Traumáticas/fisiopatologia , MicroRNAs/genética , Animais , Antagomirs/farmacologia , Lesões Encefálicas Traumáticas/tratamento farmacológico , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/patologia , Regulação da Expressão Gênica , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/patologia , Lipopolissacarídeos/toxicidade , Macrófagos/patologia , Masculino , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/patologiaRESUMO
BACKGROUND: Late-onset asthma (LOA) is beginning to account for an increasing proportion of asthma patients, which is often underdiagnosed in the elderly. Studies on the possible relations between aging-related genes and LOA contribute to the diagnosis and treatment of LOA. Forkhead Box O3 (FOXO3) and TP53 are two classic aging-related genes. DNA methylation varies greatly with age which may play an important role in the pathogenesis of LOA. We supposed that the differentially methylated sites of FOXO3 and TP53 associated with clinical phenotypes of LOA may be useful biomarkers for the early screening of LOA. METHODS: The mRNA expression and DNA methylation of FOXO3 and TP53 in peripheral blood of 43 LOA patients (15 mild LOA, 15 moderate LOA and 13 severe LOA) and 60 healthy controls (HCs) were determined. The association of methylated sites with age was assessed by Cox regression to control the potential confounders. Then, the correlation between differentially methylated sites (DMSs; p-value < 0.05) and clinical lung function in LOA patients was evaluated. Next, candidate DMSs combining with age were evaluated to predict LOA by receiver operating characteristic (ROC) analysis and principal components analysis (PCA). Finally, HDM-stressed asthma model was constructed, and DNA methylation inhibitor 5-Aza-2'-deoxycytidine (5-AZA) were used to determine the regulation of DNA methylation on the expression of FOXO3 and TP53. RESULTS: Compared with HCs, the mRNA expression and DNA methylation of FOXO3 and TP53 vary significantly in LOA patients. Besides, 8 DMSs from LOA patients were identified. Two of the DMSs, chr6:108882977 (FOXO3) and chr17:7591672 (TP53), were associated with the severity of LOA. The combination of the two DMSs and age could predict LOA with high accuracy (AUC values = 0.924). In HDM-stressed asthma model, DNA demethylation increased the expression of FOXO3 and P53. CONCLUSIONS: The mRNA expression of FOXO3 and TP53 varies significantly in peripheral blood of LOA patients, which may be due to the regulation of DNA methylation. FOXO3 and TP53 methylation is a suitable blood biomarker to predict LOA, which may be useful targets for the risk diagnosis and clinical management of LOA.
Assuntos
Asma , Metilação de DNA , Idoso , Asma/diagnóstico , Asma/genética , Biomarcadores , Proteína Forkhead Box O3/sangue , Proteína Forkhead Box O3/genética , Humanos , Pulmão/metabolismo , Fenótipo , Proteína Supressora de Tumor p53/sangue , Proteína Supressora de Tumor p53/genéticaRESUMO
BACKGROUND: Integrin ß4 (ITGB4) is a hemi-desmosome protein which is downregulated in the airway epithelial cells of asthma patients. The proximal promoters and exons of ITGB4 contain CpG islands or multiple CpG sites both in human and mice, which indicated the possible methylation regulation of ITGB4 in airway epithelial cells. OBJECTIVE: We sought to unveil that DNA methylation regulates the decreased ITGB4 during the pathogenesis of asthma. METHODS: Mice were exposed to house dust mite (HDM) extracts to construct an asthma model. 5-Aza-2'-deoxycytidine (5-AZA) or dexamethasone (DEX) were added in the last two weeks. Besides, the primary human bronchial epithelial (HBE) cells were incubated for the detection of ITGB4 expression and methylation status after HDM stress. Furthermore, DNA methylation of ITGB4 in peripheral blood was measured in asthma patients. Logistic regression was employed to evaluate the association between methylation sites and asthma patients' ages in the control of potential confounders. Moreover, the correlations between differentially methylated sites (DMSs) and clinical parameters in asthma patients were assessed. Finally, the ability of candidate DMSs to predict asthma was evaluated by receiver operating characteristic (ROC) analysis and principal component analysis (PCA). RESULTS: We found that in HDM-stressed asthma model, DNA methylation regulated the reduced ITGB4 expression in airway epithelial cells. Moreover, alteration in the specific CpG sites (chr17:73717720 and chr17:73717636) of ITGB4 may regulate ITGB4 expression and further may be associated with the clinically phenotypic of asthma. The specific DMSs of ITGB4 in peripheral blood can distinguish asthma patients from healthy controls (HCs) effectively. CONCLUSIONS AND CLINICAL RELEVANCE: This study confirmed that DNA methylation regulates the decreased expression of ITGB4 in the airway epithelial cells of asthma patients. These results supply some useful insights to the mechanism of the decreased ITGB4 in asthmatic airway epithelial and provide possible targets for early prediction and screening of asthma.
Assuntos
Asma/genética , Metilação de DNA , Epigênese Genética , Células Epiteliais/metabolismo , Integrina beta4/genética , Pulmão/metabolismo , Pyroglyphidae/imunologia , Adulto , Animais , Asma/sangue , Asma/imunologia , Asma/fisiopatologia , Biomarcadores/sangue , Estudos de Casos e Controles , Células Cultivadas , Ilhas de CpG , Modelos Animais de Doenças , Regulação para Baixo , Células Epiteliais/imunologia , Feminino , Humanos , Integrina beta4/sangue , Pulmão/imunologia , Pulmão/fisiopatologia , Masculino , Camundongos Knockout , Pessoa de Meia-Idade , Regiões Promotoras GenéticasRESUMO
Airway epithelial cells (AECs) play a key role in asthma susceptibility and severity. Integrin ß4 (ITGB4) is a structural adhesion molecule that is down-regulated in the airway epithelium of asthma patients. Although a few studies hint toward the role of ITGB4 in asthmatic inflammation pathogenesis, their specific resultant effects remain unexplored. In the present study, we determined the role of ITGB4 of AECs in the regulation of Th2 response and identified the underpinning molecular mechanisms. We found that ITGB4 deficiency led to exaggerated lung inflammation and AHR with higher production of CCL17 in house dust mite (HDM)-treated mice. ITGB4 regulated CCL17 production in AECs through EGFR, ERK and NF-κB pathways. EFGR-antagonist treatment or the neutralization of CCL17 both inhibited exaggerated pathological marks in HDM-challenged ITGB4-deficient mice. Together, these results demonstrated the involvement of ITGB4 deficiency in the development of Th2 responses of allergic asthma by down-regulation of EGFR and CCL17 pathway in AECs.
Assuntos
Asma/imunologia , Quimiocina CCL17/imunologia , Células Epiteliais/imunologia , Integrina beta4/imunologia , Pulmão/imunologia , Animais , Asma/genética , Quimiocina CCL17/genética , Receptores ErbB/genética , Receptores ErbB/imunologia , Feminino , Humanos , Integrina beta4/genética , Masculino , Camundongos , Camundongos Knockout , Células Th2/imunologiaRESUMO
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a chronic lung inflammatory disease which has a close relationship with aging. Genome-wide analysis reveals that DNA methylation markers vary obviously with age. DNA methylation variations in peripheral blood have the potential to be biomarkers for COPD. However, the specific DNA methylation of aging-related genes in the peripheral blood of COPD patients remains largely unknown. METHODS: Firstly, 9 aging-related differentially expressed genes (DEGs) in COPD patients were screened out from the 25 aging-related genes profile through a comprehensive screening strategy. Secondly, qPCR and multiple targeted bisulfite enrichment sequencing (MethTarget) were used to detect the mRNA level and DNA methylation level of the 9 differentially expressed genes in the peripheral blood of 60 control subjects and 45 COPD patients. The candidate functional CpG sites were selected on the basis of the regulation ability of the target gene expression. Thirdly, the correlation was evaluated between the DNA methylation level of the key CpG sites and the clinical parameters of COPD patients, including forced expiratory volume in one second (FEV1), forced expiratory volume in one second as percentage of predicted volume (FEV1%), forced expiratory volume/ forced vital capacity (FEV/FVC), modified British medical research council (mMRC) score, acute exacerbation frequency and the situation of frequent of acute aggravation (CAT) score. Lastly, differentially methylated CpG sites unrelated to smoking were also determined in COPD patients. RESULTS: Of the 9 differentially expressed aging-related genes, the mRNA expression of 8 genes were detected to be significantly down-regulated in COPD group, compared with control group. Meanwhile, the methylated level of all aging-related genes was changed in COPD group containing 219 COPD-related CpG sites in total. Notably, 27 CpG sites of FOXO3 gene showed a lower False Discovery Rate (FDR) and higher methylation difference values. Also, some variable DNA methylation is associated with the severity of COPD. Additionally, of the 219 COPD-related CpG sites, 147 CpG sites were not related to smoking. CONCLUSION: These results identified that the mRNA expression and DNA methylation level of aging-related genes were changed in male COPD patients, which provides a molecular link between aging and COPD. The identified CpG markers are associated with the severity of COPD and provide new insights into the prediction and identification of COPD.
Assuntos
Envelhecimento/genética , Metilação de DNA , Doença Pulmonar Obstrutiva Crônica/genética , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/sangue , Estudos de Casos e Controles , Ilhas de CpG , Bases de Dados Genéticas , Feminino , Volume Expiratório Forçado , Fatores de Transcrição Forkhead/genética , Predisposição Genética para Doença , Humanos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/sangue , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Fatores Sexuais , Transcriptoma , Capacidade Vital , Adulto JovemRESUMO
Background: Probiotic supplementary therapy to prevent allergic diseases, including asthma in children, has been widely explored in many randomized controlled trials. However, there is conflicting evidence on the effect of probiotic supplementation during pregnancy and infancy to the incidence of asthma and allergic rhinitis. Method: This study was designed to systematically explore the potential effects of probiotic supplementation on the occurrence and development of asthma, wheeze, and allergic rhinitis. Randomized controlled trials were searched in several medical literature data bases. A meta-analysis was undertaken by using the fixed-effects model or the random effects model to calculate the pooled risk of significant heterogeneity. Two writers were designated to perform the study selection and data extraction. The primary outcome was clinically diagnosed asthma; the secondary outcomes included wheeze, allergic rhinitis, and a positive aeroallergen skin-prick test result. Results: Seventeen randomized controlled trials, which composed a total of 5264 children, were analyzed. The pooled data for risk of developing asthma after probiotic supplementation showed no significant reduction compared with controls (risk ratio [RR] 0.86 [95% confidence interval {CI}, 0.73-1.01]; I² = 0%; p = 0.06). A subgroup of strains indicated that Lactobacillus rhamnosus GG supplementation only had a reduction to the occurrence of asthma (RR 0.75 [95% CI, 0.57-0.99]; I² = 11%; p = 0.04). The supplement in the postnatal group had a similar result, but the incorporated data were limited. Meanwhile, it is failed to identify that probiotic supplementary therapy have a clear benefit to the secondary outcomes: wheeze, allergic rhinitis, positive aeroallergen skin-prick test result. Conclusion: This study showed a significant benefit that supplementation with probiotics in pre- and postnatal periods was likely to play an essential strategic role in the prevention of asthma. However, these effects were based on the type of probiotics used, which also need more large-sample and high-quality RCTs to confirm the reliability of this study.
Assuntos
Asma/dietoterapia , Microbioma Gastrointestinal/fisiologia , Lacticaseibacillus rhamnosus/fisiologia , Exposição Materna/estatística & dados numéricos , Gravidez , Probióticos/uso terapêutico , Rinite Alérgica/dietoterapia , Criança , Suplementos Nutricionais , Feminino , Humanos , Incidência , Ensaios Clínicos Controlados Aleatórios como Assunto , Sons RespiratóriosRESUMO
BACKGROUND: Chronic persistent airway inflammation has been associated with the comorbidity of asthma and bipolar disorder (BD). However, the direct relevance between airway inflammation and BD-like psychiatric comorbidity is almost unknown. Integrin ß4 (ITGB4) is downregulated on the airway epithelial of asthma patients, which might play a critical role in the parthenogenesis of airway inflammation. So this study aimed to examine the role of ITGB4 deficiency in mediating airway inflammation and further leading to the BD-like behaviors. METHODS: ITGB4-/- mice were generated by mating ITGB4fl/fl mice with CCSP-rtTAtg/-/TetO-Cretg/tg mice. Mania-like behavior tests were performed, including hyperlocomotion, D-amphetamine-induced hyperactivity, open-field test, and elevated plus-maze test. Depressive-like behavior tests were carried out, including sucrose preference, forced swimming, and learned helplessness. Inflammatory cells (Th17, Th1, Th2) in the lung were examined by flow cytometry. Futhermore, inflammatory cytokines (IL-4, IL-13) in bronchoalveolar lavage fluid and sera were detected by ELISA. Protein expression of the IL-4Rα on choroid plexus, microglial marker (IBA1), and synapse-associated proteins (synaptophysin, SYP) in the hippocampus and prefrontal cortex were examined by western blotting. Additionally, proinflammatory cytokines (IL-1ß, IL-6, and TNF-α) in the hippocampus and prefrontal cortex were detected by immunohistochemistry. Inflammatory disorder in the lung, hippocampus, and prefrontal cortex was tested by hematoxylin and eosin (H&E) staining. And cell apoptosis in the hippocampus and prefrontal cortex was measured by TUNEL test. RESULTS: ITGB4-/- mice exhibited mania-like behavior, including hyperlocomotion, D-amphetamine-induced hyperactivity, and reduced anxiety-like behavior. While under stressful conditions, ITGB4-/- mice manifested depressive-like behavior, including anhedonia, behavioral despair, and enhanced learned helplessness. At the same time, ITGB4-/- mice mainly exerted Th2-type inflammation in periphery, like the number and major cytokines IL-4 and IL-13 of Th2-type inflammation. ITGB4-/- mice also showed a significant increase of microglia and pro-inflammatory cytokines such as IL-1ß, IL-6, and TNF-α in the hippocampus and prefrontal cortex. Additionally, neuron damage, increased neuron apoptosis, and the decrease of SYP were found in ITGB4-/- mice. CONCLUSIONS: These findings confirmed that airway inflammatory induced by ITGB4 deficiency is the important incentive for the BD-like behavior during asthma pathogenesis. The ITGB4-deficient mice provide a validated animal model for us to study the possible mechanism of BD-like psychiatric comorbidity of asthma patients.
Assuntos
Transtorno Bipolar/genética , Bronquite/genética , Bronquite/patologia , Células Epiteliais/patologia , Integrina beta4/metabolismo , Anfetamina/toxicidade , Animais , Antibacterianos/farmacologia , Modelos Animais de Doenças , Doxiciclina/farmacologia , Comportamento Exploratório/fisiologia , Regulação da Expressão Gênica/genética , Hipercinese/induzido quimicamente , Hipercinese/genética , Integrina beta4/genética , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/patologia , Subpopulações de Linfócitos T/patologia , Uteroglobina/genética , Uteroglobina/metabolismoRESUMO
Cancer immunotherapy has emerged as a promising clinical treatment strategy in recent years. Unfortunately, the satisfactory antitumor therapeutic efficacy of immunotherapy is limited by intricate immunosuppressive tumor microenvironment (ITM). To remodel the ITM and alleviate the immune evasion, we constructed FA-PEG-modified liposomes to deliver plasmid IL-15 (pIL-15) and gemcitabine (GEM) (FPCL@pIL-15 + FPGL), respectively. The FPCL@pIL-15 (150 nm) and FPGL (120 nm) exhibited symmetrically spherical structures as well as desirable penetration and accumulation on tumor tissue depending on folic acid (FA) specialized targeting function. The transfected expression of IL-15 efficiently fosters the proliferation and co-activation of Natural killer (NK) cells and CD8+T cells through binding to IL-15R. FPGL upregulated the expression of Natural killer group 2 member D ligands (NKG2DLs) and reinforced recognition by NK cells to alleviate the immune evasion, and simultaneously promoted activation of CD8+T cells through immunogenic cell death (ICD) effects. More importantly, the combinatorial administration achieved intended anti-tumor efficacy in the subcutaneous 4T1 tumor model. In essence, we demonstrated that combining FPCL@pIL-15 with FPGL synergistically stimulates and mobilizes the immune system to reverse the ITM and trigger an anti-tumor immune response, indicating a tremendous potential for application in immunotherapy.
Assuntos
Gencitabina , Neoplasias , Linhagem Celular Tumoral , Imunoterapia , Interleucina-15/genética , Plasmídeos , Microambiente TumoralRESUMO
Chronic lung disease is the third leading cause of death globally, imposing huge burden of death, disability and healthcare costs. However, traditional pharmacotherapy has relatively limited effects in improving the cure rate and reducing the mortality of chronic lung disease. Thus, new treatments are urgently needed for the prevention and treatment of chronic lung disease. It is particularly noteworthy that, multiple aging-related phenotypes were involved in the occurrence and development of chronic lung disease, such as blocked proliferation, telomere attrition, mitochondrial dysfunction, epigenetic alterations, altered nutrient perception, stem cell exhaustion, chronic inflammation, etc. Consequently, senescent cells induce a series of pathological changes in the lung, such as immune dysfunction, airway remodeling, oxidative stress and regenerative dysfunction, which is a critical issue that needs special attention in chronic lung diseases. Therefore, anti-aging interventions may bring new insights into the treatment of chronic lung diseases. In this review, we elaborate the involvement of aging in chronic lung disease and further discuss the application and prospects of anti-aging therapy.
RESUMO
Acute asthma exacerbation refers to the progressive deterioration of asthma symptoms that is always triggered by virus infection represented by respiratory syncytial virus (RSV). After RSV infection, exaggerated Th2-mediated pulmonary inflammation is the critical pathological response of asthmatic patients with acute exacerbation. Significantly, airway epithelial cells, being the primary targets of RSV infection, play a crucial role in controlling the pulmonary inflammatory response by releasing airway epithelial cell-derived exosomes (AEC-Exos), which potentially influence the development of asthma. However, the specific role of AEC-Exos in acute asthma exacerbation after RSV infection remains obscure. The purpose of this study was to determine the distinct function of AEC-Exos in exacerbating acute asthma following RSV infection. Blockade of exosomes by GW reduce the enhanced pulmonary inflammation significantly. Specifically, the enhanced Th2 inflammation was induced by AEC-Exos thorough transportation of hsa-miR-155-5p-Sirtuin 1 (SIRT1) pathway during acute asthma exacerbation. Targeted inhibition of hsa-miR-155-5p blocks the exaggerated Th2 inflammation effectively in mice with acute asthma exacerbation. In summary, our study showed that during acute asthma exacerbation after RSV infection, AEC-Exos promote the enhanced Th2 inflammation through transportation of increased hsa-miR-155-5p, which was mediated partly through SIRT1-mediated pathway. hsa-miR-155-5p is a potential biomarker for early prediction of acute asthma exacerbation.
RESUMO
Although the possibility of first-line hematopoietic cell transplantation (HCT) from alternative donors in severe aplastic anemia (SAA) patients has been suggested recently, transplantation strategies are still being investigated. We established a novel post-transplantation cyclophosphamide-based HCT protocol for patients with SAA in prior studies. We explores the effectiveness and safety of this HCT approach either as first-line or as salvage treatment in SAA patients. Outcomes of 71 consecutive young patients, who received HCT from unrelated or haploidentical donors, were retrospectively analyzed. According to their treatment before transplantation, the patients were classified into treatment-naive (TN) and relapsed or refractory (R/R) patients. The R/R patients were designated as such when a patient did not respond to previous immunosuppressive therapy or relapsed. We administered an antithymocyte globulin (ATG)-free, total body irradiation (TBI)-free conditioning regimen comprising cyclophosphamide, busulfan, and fludarabine, all in an intravenous formula. We used a thorough post-transplantation prophylaxis regimen for GVHD, including post-transplantation cyclophosphamide (PTCy) and short-term methotrexate and long-term cyclosporine A. The median age of the cohort was 16 (95% confidence interval, 12-20) years at transplantation. Most patients (61 of 71) received HCT from haploidentical donors, and the others received HCT from unrelated donors. TN patients (n = 38) were younger and had a shorter time-to-transplant and lower HCT-specific comorbidity index than patients with R/R diseases (n = 33). The frequencies of graft failure, grade II-IV acute graft-versus-host disease (GVHD), and moderate-severe chronic GVHD were similar, at 5.3% versus 6.5% (P = .057), 8.3% versus 0% (P = .109), and 5.7% versus 0% (P = .199) between R/R and TN patients. With a median 42-month follow-up, the frequencies of overall survival (OS) and event-free survival (EFS) were higher in the TN group than in the R/R group (100% versus 84.8% [P = .013] and 86.8% versus 75.8% [P = .255], respectively). All patients who achieved successful engraftment showed full donor chimerism. Four patients, all in the R/R group, suffered from donor-type aplasia; of these, 2 died, 1 was salvaged with another transplantation, and the final one was still receiving transfusion at the last follow-up. Currently, 93.9% (62 of 66) of the patients are alive more than 12 months after transplantation; of these 93.5% (58 of 62) no longer receive immunosuppression, including 91.7% (33 of 34) of the TN group and 89.3% (25 of 28) in the R/R group. This novel TBI-free and ATG-free HCT protocol using a reduced-intensity conditioning regimen followed by modified PTCy achieved promising engraftment, minimal GVHD risk, and encouraging OS and EFS. Our study suggests that unrelated or haploidentical HCT with PTCy can be used as a first-line treatment for young patients with SAA. Nevertheless, further efforts are needed to explore possibilities for older patients and patients with a poor performance status.
Assuntos
Anemia Aplástica , Doença Enxerto-Hospedeiro , Humanos , Criança , Adolescente , Adulto Jovem , Adulto , Anemia Aplástica/terapia , Estudos Retrospectivos , Condicionamento Pré-Transplante/métodos , Ciclofosfamida/uso terapêutico , Soro Antilinfocitário/uso terapêutico , Doença Enxerto-Hospedeiro/prevenção & controle , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doadores não Relacionados , Proteínas Adaptadoras de Transdução de SinalRESUMO
Airway epithelial cells (AECs) are the first cell barrier of the respiratory system against external stimuli that play a critical role in the development of asthma. It is known that AECs play a key role in asthma susceptibility and severity. ITGB4 is a downregulated adhesion molecule in the airway epithelia of asthma patients, which was involved in the exaggerated lung inflammation after allergy stimulation. Toll-like receptor 4 (TLR4) in AECs has also been shown to play a crucial role in the development of lung inflammation in asthma patients. However, the specific intrinsic regulatory mechanism of TLR4 in AECs are still obscure. In this article, we demonstrated that ITGB4 deficiency in AECs enhances HDM-induced airway inflammation through hyperactivation of the TLR4 signaling pathway, which is mediated by inhibition of FYN phosphorylation. Moreover, TLR4-antagonist treatment or blockade of FYN can inhibit or exaggerate lung inflammation in HDM-stressed ITGB4-deficient mice, separately. Together, these results demonstrated that ITGB4 deficiency in AECs enhances HDM-induced lung inflammatory response through the ITGB4-FYN-TLR4 axis, which may provide new therapeutic approaches for the management of lung inflammation in asthma.
Assuntos
Asma , Integrina beta4 , Pneumonia , Receptor 4 Toll-Like , Animais , Camundongos , Asma/metabolismo , Modelos Animais de Doenças , Inflamação , Pulmão/metabolismo , Pyroglyphidae , Transdução de Sinais , Receptor 4 Toll-Like/antagonistas & inibidores , Receptor 4 Toll-Like/metabolismo , Integrina beta4/metabolismoRESUMO
Respiratory syncytial virus (RSV) infection is the main cause of bronchiolitis in children. Excessive mucus secretion is one of the primary symbols in RSV related lower respiratory tract infections (RSV-related LRTI), which is closely associated with the occurrence and development of asthma in later life. Integrin ß4 (ITGB4) is down-regulated in the airway epithelial cells (AECs) of asthma patients which plays a critical role in the pathogenesis of asthma. However, whether ITGB4 is involved in the pathological processes of RSV infection remains unclear. In this study, we found that decreased expression of ITGB4 was negatively correlated with the level of MUC5AC in childhood AECs following RSV infection. Moreover, ITGB4 deficiency led to mucus hypersecretion and MUC5AC overexpression in the small airway of RSV-infected mice. MUC5AC expression was upregulated by ITGB4 in HBE cells through EGFR, ERK and c-Jun pathways. EGFR inhibitors treatment inhibited mucus hypersecretion and MUC5AC overexpression in ITGB4-deficient mice after RSV infection. Together, these results demonstrated that epithelial ITGB4 deficiency induces mucus hypersecretion by upregulating the expression of MUC5AC through EGFR/ERK/c-Jun pathway, which further associated with RSV-related LRTI.