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1.
Respir Res ; 25(1): 90, 2024 Feb 14.
Artículo en Inglés | MEDLINE | ID: mdl-38355515

RESUMEN

BACKGROUND: Exposure to PM2.5 has been implicated in a range of detrimental health effects, particularly affecting the respiratory system. However, the precise underlying mechanisms remain elusive. METHODS: To address this objective, we collected ambient PM2.5 and administered intranasal challenges to mice, followed by single-cell RNA sequencing (scRNA-seq) to unravel the heterogeneity of neutrophils and unveil their gene expression profiles. Flow cytometry and immunofluorescence staining were subsequently conducted to validate the obtained results. Furthermore, we assessed the phagocytic potential of neutrophils upon PM2.5 exposure using gene analysis of phagocytosis signatures and bacterial uptake assays. Additionally, we utilized a mouse pneumonia model to evaluate the susceptibility of PM2.5-exposed mice to Pseudomonas aeruginosa infection. RESULTS: Our study revealed a significant increase in neutrophil recruitment within the lungs of PM2.5-exposed mice, with subclustering of neutrophils uncovering subsets with distinct gene expression profiles. Notably, exposure to PM2.5 was associated with an expansion of PD-L1high neutrophils, which exhibited impaired phagocytic function dependent upon PD-L1 expression. Furthermore, PM2.5 exposure was found to increase the susceptibility of mice to Pseudomonas aeruginosa, due in part to increased PD-L1 expression on neutrophils. Importantly, monoclonal antibody targeting of PD-L1 significantly reduced bacterial burden, dissemination, and lung inflammation in PM2.5-exposed mice upon Pseudomonas aeruginosa infection. CONCLUSIONS: Our study suggests that PM2.5 exposure promotes expansion of PD-L1high neutrophils with impaired phagocytic function in mouse lungs, contributing to increased vulnerability to bacterial infection, and therefore targeting PD-L1 may be a therapeutic strategy for reducing the harmful effects of PM2.5 exposure on the immune system.


Asunto(s)
Neumonía , Infecciones por Pseudomonas , Animales , Ratones , Neutrófilos/metabolismo , Material Particulado/toxicidad , Infecciones por Pseudomonas/microbiología , Antígeno B7-H1/metabolismo , Pulmón , Neumonía/metabolismo , Pseudomonas aeruginosa
2.
Pharmacol Res ; 200: 107070, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38218353

RESUMEN

Fibrotic hypersensitivity pneumonitis (FHP) is a fatal interstitial pulmonary disease with limited treatment options. Lung macrophages are a heterogeneous cell population that exhibit distinct subsets with divergent functions, playing pivotal roles in the progression of pulmonary fibrosis. However, the specific macrophage subpopulations and underlying mechanisms involved in the disease remain largely unexplored. In this study, a decision tree model showed that matrix metalloproteinase-14 (MMP14) had higher scores for important features in the up-regulated genes in macrophages from mice exposed to the Saccharopolyspora rectivirgula antigen (SR-Ag). Using single-cell RNA sequencing (scRNA-seq) analysis of hypersensitivity pneumonitis (HP) mice profiles, we identified MMP14high macrophage subcluster with a predominant M2 phenotype that exhibited higher activity in promoting fibroblast-to myofibroblast transition (FMT). We demonstrated that suppressing toll-like receptor 2 (TLR2) and nuclear factor kappa-B (NF-κB) could attenuate MMP14 expression and exosome secretion in macrophages stimulation with SR-Ag. The exosomes derived from MMP14-overexpressing macrophages were found to be more effective in regulating the transition of fibroblasts through exosomal MMP14. Importantly, it was observed that the transfer of MMP14-overexpressing macrophages into mice promoted lung inflammation and fibrosis induced by SR-Ag. NSC-405020 binding to the hemopexin domain (PEX) of MMP-14 ameliorated lung inflammation and fibrosis induced by SR-Ag in mice. Thus, MMP14-overexpressing macrophages may be an important mechanism contributing to the exacerbation of allergic reactions. Our results indicated that MMP14 in macrophages has the potential to be a therapeutic target for HP.


Asunto(s)
Alveolitis Alérgica Extrínseca , Neumonía , Fibrosis Pulmonar , Ratones , Animales , Fibrosis Pulmonar/metabolismo , Metaloproteinasa 14 de la Matriz/genética , Metaloproteinasa 14 de la Matriz/metabolismo , Alveolitis Alérgica Extrínseca/metabolismo , Alveolitis Alérgica Extrínseca/patología , Macrófagos/metabolismo , Neumonía/metabolismo , Ratones Endogámicos C57BL
3.
Ecotoxicol Environ Saf ; 272: 116067, 2024 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-38325270

RESUMEN

In order to comprehend the underlying mechanisms contributing to the development and exacerbation of asthma resulting from exposure to fine particulate matter (PM2.5), we established an asthmatic model in fat mass and obesity-associated gene knockdown mice subjected to PM2.5 exposure. Histological analyses using hematoxylin-eosin (HE) and Periodic Acid-Schiff (PAS) staining revealed that the down-regulation of the fat mass and obesity-associated gene (Fto) expression significantly ameliorated the pathophysiological alterations observed in asthmatic mice exposed to PM2.5. Furthermore, the down-regulation of Fto gene expression effectively attenuated damage to the airway epithelial barrier. Additionally, employing in vivo and in vitro models, we elucidated that PM2.5 modulated FTO expression by inducing oxidative stress. Asthmatic mice exposed to PM2.5 exhibited elevated Fto expression, which correlated with increased levels of reactive oxygen species. Similarly, when cells were exposed to PM2.5, FTO expression was up-regulated in a ROS-dependent manner. Notably, the administration of N-acetyl cysteine successfully reversed the PM2.5-induced elevation in FTO expression. Concurrently, we performed transcriptome-wide Methylated RNA immunoprecipitation Sequencing (MeRIP-seq) analysis subsequent to PM2.5 exposure. Through the implementation of Gene Set Enrichment Analysis and m6A-IP-qPCR, we successfully identified inhibitor of nuclear factor kappa B kinase subunit beta (IKBKB) as a target gene regulated by FTO. Interestingly, exposure to PM2.5 led to increased expression of IKBKB, while m6A modification on IKBKB mRNA was reduced. Furthermore, our investigation revealed that PM2.5 also regulated IKBKB through oxidative stress. Significantly, the down-regulation of IKBKB effectively mitigated epithelial barrier damage in cells exposed to PM2.5 by modulating nuclear factor-kappa B (NF-κB) signaling. Importantly, we discovered that decreased m6A modification on IKBKB mRNA facilitated by FTO enhanced its stability, consequently resulting in up-regulation of IKBKB expression. Collectively, our findings propose a novel role for FTO in the regulation of IKBKB through m6A-dependent mRNA stability in the context of PM2.5-induced oxidative stress. Therefore, it is conceivable that the utilization of antioxidants or inhibition of FTO could represent potential therapeutic strategies for the management of asthma exacerbated by PM2.5 exposure.


Asunto(s)
Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato , Asma , Quinasa I-kappa B , Animales , Ratones , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/genética , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/metabolismo , Asma/inducido químicamente , Asma/genética , Quinasa I-kappa B/metabolismo , Obesidad , Estrés Oxidativo/genética , Material Particulado/toxicidad , Estabilidad del ARN , ARN Mensajero/metabolismo
4.
Ecotoxicol Environ Saf ; 277: 116314, 2024 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-38642409

RESUMEN

Fine particulate matter (PM2.5) has been extensively implicated in the pathogenesis of neurodevelopmental disorders, but the underlying mechanism remains unclear. Recent studies have revealed that PM2.5 plays a role in regulating iron metabolism and redox homeostasis in the brain, which is closely associated with ferroptosis. In this study, the role and underlying mechanism of ferroptosis in PM2.5-induced neurotoxicity were investigated in mice, primary hippocampal neurons, and HT22 cells. Our findings demonstrated that exposure to PM2.5 could induce abnormal behaviors, neuroinflammation, and neuronal loss in the hippocampus of mice. These effects may be attributed to ferroptosis induced by PM2.5 exposure in hippocampal neurons. RNA-seq analysis revealed that the upregulation of iron metabolism-related protein Heme Oxygenase 1 (HO-1) and the activation of mitophagy might play key roles in PM2.5-induced ferroptosis in HT22 cells. Subsequent in vitro experiments showed that PM2.5 exposure significantly upregulated HO-1 in primary hippocampal neurons and HT22 cells. Moreover, PM2.5 exposure activated mitophagy in HT22 cells, leading to the loss of mitochondrial membrane potential, alterations in the expression of autophagy-related proteins LC3, P62, and mTOR, as well as an increase in mitophagy-related protein PINK1 and PARKIN. As a heme-degradation enzyme, the upregulation of HO-1 promotes the release of excess iron, genetically inhibiting the upregulation of HO-1 in HT22 cells could prevent both PM2.5-induced mitophagy and ferroptosis. Furthermore, pharmacological inhibition of mitophagy in HT22 cells reduced levels of ferrous ions and lipid peroxides, thereby preventing ferroptosis. Collectively, this study demonstrates that HO-1 mediates PM2.5-induced mitophagy-dependent ferroptosis in hippocampal neurons, and inhibiting mitophagy or ferroptosis may be a key therapeutic target to ameliorate neurotoxicity following PM2.5 exposure.


Asunto(s)
Ferroptosis , Hemo-Oxigenasa 1 , Hipocampo , Mitofagia , Neuronas , Material Particulado , Regulación hacia Arriba , Animales , Material Particulado/toxicidad , Ferroptosis/efectos de los fármacos , Mitofagia/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/patología , Neuronas/efectos de los fármacos , Neuronas/patología , Ratones , Hemo-Oxigenasa 1/metabolismo , Hemo-Oxigenasa 1/genética , Regulación hacia Arriba/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Contaminantes Atmosféricos/toxicidad , Proteínas de la Membrana
5.
Pharmacol Res ; 182: 106286, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35662628

RESUMEN

Pulmonary fibrosis (PF) is the pathological change of end-stage interstitial lung diseases with high mortality and limited therapeutic options. Lung macrophages have distinct subsets with divergent functions, and play critical roles in the pathogenesis of PF. In this study, integrative analysis of lung single-cell and bulk RNA-seq data from patients with fibrotic hypersensitivity pneumonitis and idiopathic pulmonary fibrosis was utilized to identify particular macrophage subsets during the development of PF. We find a specific macrophage subpopulation highly expressing PLA2G7 in fibrotic lungs. We performed additional single-cell RNA-seq analysis to identify analogous macrophage population in bleomycin (BLM)-induced mouse pulmonary fibrosis models. By in vitro and in vivo experiments, we further reveal the pro-fibrotic role for this PLA2G7high macrophage subset in fibroblast-to-myofibroblast transition (FMT) during pulmonary fibrosis. PLA2G7 promotes FMT via LPC/ATX/LPA/LPA2 axis in macrophages. Moreover, PLA2G7 is regulated by STAT1, and pharmacological inhibition of PLA2G7 by Darapladib ameliorates pulmonary fibrosis in BLM-induced mice. The results of this study support the view that PLA2G7high macrophage subpopulation contributes importantly to the pathogenesis of PF, which provides a potential way for targeted therapy.


Asunto(s)
1-Alquil-2-acetilglicerofosfocolina Esterasa , Fibrosis Pulmonar Idiopática , Macrófagos , 1-Alquil-2-acetilglicerofosfocolina Esterasa/efectos adversos , 1-Alquil-2-acetilglicerofosfocolina Esterasa/genética , 1-Alquil-2-acetilglicerofosfocolina Esterasa/metabolismo , Animales , Bleomicina , Fibrosis Pulmonar Idiopática/inducido químicamente , Fibrosis Pulmonar Idiopática/genética , Pulmón , Ratones , Ratones Endogámicos C57BL , Análisis de Secuencia de ARN , Análisis de la Célula Individual
6.
Ecotoxicol Environ Saf ; 220: 112408, 2021 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-34111662

RESUMEN

BACKGROUND: Epidemiologic evidence suggests that PM2.5 exposure aggravates asthma, but the molecular mechanisms are not fully discovered. METHODS: Ovalbumin (OVA)-induced mice exposed to PM2.5 were constructed. Pathological staining and immunofluorescence were performed in in vivo study. Gene set enrichment analysis (GSEA) was performed to identify the pathway involved in asthma severity by using U-BIOPRED data (human bronchial biopsies) and RNA-seq data (Beas-2B cells treated with PM2.5). Lentiviruses transfection, Real-time qPCR, immunofluorescence staining and trans-epithelial electrical resistance (TEER) measurement were performed for mechanism exploration in vitro. RESULTS: PM2.5 exposure aggravated airway inflammation and mucus secretion in OVA-induced mice. Based on transcriptome analysis of mild-to-severe asthma from human bronchial biopsies, gene set enrichment analysis (GSEA) showed that up-regulated reactive oxygen species (ROS) pathway gene set and down-regulated apical junction gene set correlated with asthma severity. Consistent with the analysis of mild-to-severe asthma, after PM2.5 exposure, the ROS pathway in Beas-2B cells was up-regulated with the down-regulation of apical junction. The expression levels of genes involved in the specific gene sets were validated by using qPCR. The mRNA levels of junction genes, ZO-1, E-cadherin and Occludin, were significantly decreased in cells exposed to PM2.5. Moreover, it confirmed that inhibition of ROS recovered the expression levels of E-cadherin, Occludin and ZO-1, and ameliorated inflammation and mucus secretion in airway in OVA-induced mice exposed to PM2.5. Meanwhile, ROS level was elevated by PM2.5. By checking trans-epithelial electrical resistance (TEER) value, we also found that epithelial barrier was damaged after PM2.5 exposure. Importantly, Stanniocalcin 2 (STC2) was identified as a key gene in regulation of epithelial barrier. It showed that STC2 expression was up-regulated by PM2.5, which was recovered by NAC as well. Over-expression of STC2 could decrease the expression levels of ZO-1, Occludin and E-cadherin. Contrarily, suppression of STC2 could increase the expression levels of ZO-1, Occludin and E-cadherin reduced by PM2.5. CONCLUSIONS: By using transcriptome analysis, we revealed that STC2 played a key role in PM2.5 aggravated airway dysfunction through regulation of epithelial barrier in OVA-induced mice.


Asunto(s)
Asma/inducido químicamente , Modelos Animales de Enfermedad , Glicoproteínas/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Material Particulado/efectos adversos , Mucosa Respiratoria/patología , Animales , Asma/genética , Asma/metabolismo , Asma/patología , Perfilación de la Expresión Génica , Glicoproteínas/genética , Humanos , Inflamación , Péptidos y Proteínas de Señalización Intercelular/genética , Ratones , Ovalbúmina/efectos adversos , Especies Reactivas de Oxígeno/metabolismo , Mucosa Respiratoria/efectos de los fármacos , Mucosa Respiratoria/metabolismo , Transcriptoma/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos
7.
Ecotoxicol Environ Saf ; 218: 112272, 2021 May 04.
Artículo en Inglés | MEDLINE | ID: mdl-33962274

RESUMEN

BACKGROUND: Particulate matter of 2.5 µm or less in diameter (PM2.5) is one of the most complex pollutants in the atmospheric environment and harmful to human health. Epidemiologic evidence suggests that asthma exacerbation is associated with PM2.5 exposure. However, the molecular mechanism of PM2.5 in the development of asthma is not fully addressed. METHODS: PM2.5 was collected from Chengdu, China, and the components were analyzed. The relationship between PM2.5 exposure and asthma severity was investigated in an Ovalbumin (OVA)-induced murine model of asthma. U-BIOPRED data from public database and our own RNA-seq data were analyzed to identify the hub genes. Real-time qPCR, immunofluorescence, immunohistochemistry and pathological staining were applied for mechanism dissection in both in vitro and in vivo studies. RESULTS: In PM2.5 samples, a total of 11 elements including major elements and trace elements were identified, 14 of the 16 Polycyclic aromatic hydrocarbons (PAHs) were detected except Acenaphthene and Fluorene. PM2.5 exposure aggravated pulmonary inflammation, mucus secretion, and neutrophils infiltration in asthma model. Based on transcriptome analysis of mild-to-severe asthma dataset, it showed that mucus secretion and neutrophil degranulation correlated with asthma severity. Moreover, NAD(P)H:quinone oxidoreductase 1 (NQO1) was screened out as a hub gene whose expression positively correlated with MUC5AC expression in patient with asthma by performing joint analysis. Furthermore, in OVA-induced asthma model and in vitro assay, it also revealed that PM2.5-induced MU5AC expression was regulated by NQO1 through neutrophil extracellular traps (NETs) caused by oxidative stress. CONCLUSION: Taken together, we discovered a potential relationship between asthma severity and PM2.5 exposure. In addition, neutrophil depletion, NETs inhibition or anti-NQO1 might be novel potential therapeutic options for treatment of PM2.5-induced mucus hyper-secretion.

8.
J Autoimmun ; 112: 102463, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32303424

RESUMEN

It has been reported that SARS-CoV-2 may use ACE2 as a receptor to gain entry into human cells, in a way similar to that of SARS-CoV. Analyzing the distribution and expression level of ACE2 may therefore help reveal underlying mechanisms of viral susceptibility and post-infection modulation. In this study, we utilized previously uploaded information on ACE2 expression in various conditions including SARS-CoA to evaluate the role of ACE2 in SARS-CoV and extrapolate that to COVID-19. We found that the expression of ACE2 in healthy populations and patients with underlying diseases was not significantly different. However, based on the elevated expression of ACE2 in cigarette smokers, we speculate that long-term smoking may be a risk factor for COVID-19. Analysis of ACE2 in SARS-CoV infected cells suggests that ACE2 is not only a receptor but is also involved in post-infection regulation, including immune response, cytokine secretion, and viral genome replication. Moreover, we constructed Protein-protein interaction (PPI) networks and identified hub genes in viral activity and cytokine secretion. Our findings may help clinicians and researchers gain more insight into the pathogenesis of SARS-CoV-2 and design therapeutic strategies for COVID-19.


Asunto(s)
Betacoronavirus/metabolismo , Infecciones por Coronavirus/enzimología , Regulación Enzimológica de la Expresión Génica , Pulmón/enzimología , Peptidil-Dipeptidasa A/biosíntesis , Neumonía Viral/enzimología , Fumar/efectos adversos , Enzima Convertidora de Angiotensina 2 , COVID-19 , Infecciones por Coronavirus/patología , Humanos , Pandemias , Neumonía Viral/patología , Mapas de Interacción de Proteínas , SARS-CoV-2
9.
J Biochem Mol Toxicol ; 34(2): e22429, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31860774

RESUMEN

Alzheimer's disease (AD) is an age-associated neurodegenerative disease, which is developed by oxidative stress and acetylcholine contraction in the synaptic cleft of the neurons. This leads to dementia, memory loss, and decrease in learning ability and orientation. In this research work, we aimed to explore the neuroprotective effect of neferine on AlCl3 -induced AD in rats. The results of our study revealed that the increased reactive oxygen species (ROS) and nitric oxide in the hippocampus leads to the development of AD in the rats. The oral treatment of neferine done the following occurrences such as; it potentially inhibited the ROS formation and acts as a scavenging molecule by preventing the neurodegeneration. It also improved the memory and learning ability to complete the maze activity in the AD rats and significantly increased the antioxidants superoxide dismutase, catalase, and reduced glutathione in neferine treated AD rats. It aggressively declined the activity of acetylcholine esterase and Na+ K+ ATPase in the neurodegenerative rat models. The gene expression pattern of neuroinflammatory cytokines such as tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), and interleukin-1ß (IL-1ß) were decreased in the neferine-treated rats. The neuroinflammatory proteins such as inducible nitric oxide (iNOS), cyclooxygenase-2 (COX-2), and nuclear factor kappa ß (Nf-κß) were decreased and Nf-κß inhibitor IKBα was increased in the neferine-treated AD rats. Finally, the histology study proved that the neferine treatment possibly prevents neurodegeneration in the hippocampus tissue of the AD models. Hence, these all findings concluded that the neferine could be a potential neuropreventive as well as neurodegenerative therapeutic compound in neurological and cognitive dysfunction.


Asunto(s)
Cloruro de Aluminio/farmacología , Enfermedad de Alzheimer/inducido químicamente , Enfermedad de Alzheimer/tratamiento farmacológico , Bencilisoquinolinas/farmacología , Medicamentos Herbarios Chinos/farmacología , Fármacos Neuroprotectores/farmacología , Nootrópicos/farmacología , Administración Oral , Cloruro de Aluminio/efectos adversos , Animales , Conducta Animal/efectos de los fármacos , Bencilisoquinolinas/administración & dosificación , Ciclooxigenasa 2/metabolismo , Citocinas/genética , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/administración & dosificación , Femenino , Expresión Génica/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/patología , Peroxidación de Lípido/efectos de los fármacos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , FN-kappa B/metabolismo , Fármacos Neuroprotectores/administración & dosificación , Óxido Nítrico Sintasa de Tipo II/metabolismo , Nootrópicos/administración & dosificación , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Wistar
10.
ESC Heart Fail ; 2024 Oct 04.
Artículo en Inglés | MEDLINE | ID: mdl-39364781

RESUMEN

AIMS: Heart failure (HF) is characterized by a heightened risk of melanoma, which often metastasizes to the heart. The overlap pathology between HF and melanoma includes chronic low-grade inflammation and dysregulation of inflammatory cancer-associated fibroblasts (iCAFs). The impact of HF on iCAF-driven tumour inflammation remains obscure. METHODS AND RESULTS: To identify critical genes for HF development, transcriptomic data (GSE57338) containing 313 clinical HF samples [136 healthy controls, 95 ischaemia (ISCH) and 82 dilated cardiomyopathy (DCM)] were analysed to screen differentially expressed genes (DEGs) and perform enrichment analysis. Fifty-one DEGs in ISCH and 62 DEGs in DCM were identified with log2|fold change (FC)| ≥ 1 and P value ≤0.05. All these genes are involved in extracellular matrix organization, immune/inflammatory responses and Wnt signalling pathways. Then, the overall survival curves and prognostic models of DEGs in melanoma were evaluated. The correlation of gene expression with lymphocyte infiltration levels was assessed. Only aldehyde oxidase 1 (AOX1) and amphiregulin (AREG) maintained the same trend in melanoma as in HF, negatively affecting prognosis by regulating lymphocyte infiltration (log-rank P value = 0.0017 and 0.0019). The potential drug molecules were screened, and the binding energies were calculated via molecular docking. Eniluracil, a known AOX1 targeting drug, was found to stably bind with AREG (hydrogen bond binding energies: -65.633, -63.592 and -62.813 kcal/mol). CONCLUSIONS: The increased prevalence of melanoma in HF patients and its propensity for cardiac metastasis may be due to AREG-mediated systemic low-grade inflammation. Eniluracil holds promise as a therapeutic agent that may block AREG signalling, inhibiting the activation of iCAF mediated by regulatory T cell (Treg) and neutrophil.

11.
J Nutr Health Aging ; 28(5): 100214, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38489991

RESUMEN

BACKGROUND: Although intrinsic capacity (IC) has been constructed in older populations, whether IC retains the same structure over time has not been formally examined, nor have the factors associated with the changes in IC over time been thoroughly investigated. This study aimed to establish that the structure of IC remains unchanged over time by testing its longitudinal measurement invariance and to investigate factors that influence the longitudinal change of IC over time. METHODS: Data came from 7,271 participants aged 60 and older from the China Health and Retirement Longitudinal Study in 2011 (Wave 1) and 2015 (Wave 3). Bifactor confirmatory factor analysis (CFA) was used to construct IC with its domains, and the longitudinal measurement invariance of IC between Waves was tested. RESULTS: Bifactor CFA fitted the data well at both Waves and showed good construct validity. Partial scalar invariance was supported with non-invariant intercepts for delayed word recall, math, and close vision. Decreases in IC were associated with increasing age, being female (-0.030, 95% CI: -0.045, -0.016), living in rural areas (-0.019, 95% CI: -0.030, -0.009), BMI < 18.5 (-0.019, 95% CI: -0.035, -0.003), and hypertension (-0.012, 95% CI: -0.022, -0.001). Increases in IC were associated with higher education (primary school: 0.012, 95% CI: 0.001, 0.024; lower secondary school: 0.023, 95% CI: 0.005, 0.041) and drinking ≥4/week (0.019, 95% CI: 0.003, 0.034). Stratifying the sample by gender, the protective effect of education was observed only in women. CONCLUSIONS: The bifactor structure of the IC construct was valid and retained its meaning over time. Longitudinal changes in IC were associated with various sociodemographic factors, lifestyle, and health conditions, confirming the need to monitor IC for timely intervention, particularly in those with risk factors for IC decline.


Asunto(s)
Jubilación , Humanos , Estudios Longitudinales , Femenino , Masculino , Anciano , China , Persona de Mediana Edad , Jubilación/estadística & datos numéricos , Análisis Factorial , Envejecimiento/fisiología , Cognición/fisiología , Anciano de 80 o más Años , Pueblos del Este de Asia
12.
Aging (Albany NY) ; 16(10): 9216-9227, 2024 05 24.
Artículo en Inglés | MEDLINE | ID: mdl-38795392

RESUMEN

Oligomeric Aß42 is considered to play a harmful role in the pathophysiology of Alzheimer's disease (AD). Prolonged exposure to oligomeric Aß42 could induce neuronal damage including cellular senescence. Amelioration of Aß42-induced cellular senescence has been considered as a promising strategy for the treatment of AD. Chromofungin, a chromogranin A-derived peptide, has displayed various biological functions in different types of cells and tissues. However, the effects of Chromofungin on oligomeric Aß42-induced cellular senescence have not been previously reported. In the current study, we report a novel function of Chromofungin by showing that treatment with Chromofungin could ameliorate Aß42-induced neurotoxicity in M17 neuronal cells. The Cell Counting Kit-8 (CCK-8) assay and the lactate dehydrogenase (LDH) release experiments revealed that 0.5 and 1 mM are the optimal concentrations of Chromofungin for cell culture in M17 cells. Challenging with oligomeric Aß42 (5 µM) for 7 and 14 days led to a significant decrease in telomerase activity, which was rescued by Chromofungin dose-dependently. Additionally, the senescence-associated ß-galactosidase (SA-ß-gal) staining assay demonstrated that Chromofungin mitigated oligomeric Aß42-induced cellular senescence. Correspondingly, treatment with Chromofungin reversed the gene expression of human telomerase reverse transcriptase (hTERT), telomeric repeat-binding factor 2 (TERF2), and p21 against oligomeric Aß42 in M17 neurons. Interestingly, Chromofungin attenuated oligomeric Aß42-induced oxidative stress (OS) in M17 cells by reducing the production of intracellular reactive oxygen species (ROS) but increasing the levels of intracellular superoxide dismutase (SOD). Importantly, the presence of Chromofungin reduced the expression of cyclooxygenase2 (COX-2) as well as the generation of prostaglandin E2 (PGE2). Transduction with Ad-COX-2 impaired the effects of Chromofungin on telomerase activity and the profile of cellular senescence. Our findings suggest that Chromofungin might act as a potential agent for the treatment of AD.


Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Senescencia Celular , Neuronas , Fragmentos de Péptidos , Péptidos beta-Amiloides/toxicidad , Péptidos beta-Amiloides/metabolismo , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Humanos , Fragmentos de Péptidos/toxicidad , Senescencia Celular/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Especies Reactivas de Oxígeno/metabolismo , Telomerasa/metabolismo , Estrés Oxidativo/efectos de los fármacos , Cromogranina A/metabolismo , Cromogranina A/farmacología
13.
Biochem Biophys Rep ; 39: 101782, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39108621

RESUMEN

Cxcr4a is involved in multiple organ development including coronary vasculature formation and heart left-right (LR) patterning, whether it is involved in heart progenitor determination and cardiac rhythm regulation is not addressed. Here we showed that in cxcr4a mutants, from 2 days post fertilization (dpf) to 4dpf the embryos transiently displayed pericardial edema and increased cardiac rhythm. While from 5dpf, the heart phenotype disappeared. Detailed analysis demonstrated that, at 36hpf and 48hpf, even though there was no distinct difference in the heart size between cxcr4a mutants and controls, the expression of myl7 was decreased. Further data showed that, the heart progenitors were decreased at 18SS(Somite Stage). Mechanically, RNA-seq, RT-qPCR and in situ experiments showed that the retinoic acid (RA) signaling was upregulated, and the up-regulation of RA signaling may mediate the role of cxcr4a in regulating heart progenitor development. In addition, we also identified that low dose of RA treatment accelerated the cardiac rhythm, being similar to that in cxcr4a mutants. Decreasing RA signaling partially restored the rapid cardiac rhythm in cxcr4a mutants, implying the possibility that RA signaling partially mediates the role of cxcr4a in regulating cardiac rhythm. In conclusion, our study identified cxcr4a simultaneously regulates heart progenitor determination and cardiac rhythm.

14.
Front Cell Dev Biol ; 12: 1429782, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39239564

RESUMEN

Cdon and boc are members of the cell adhesion molecule subfamily III Ig/fibronectin. Although they have been reported to be involved in muscle and neural development at late developmental stage, their early roles in embryonic development remain unknown. Here, we discovered that in zebrafish, cdon, but not boc, is expressed in dorsal forerunner cells (DFCs) and the epithelium of Kupffer's vesicle (KV), suggesting a potential role for cdon in organ left-right (LR) patterning. Further data showed that liver and heart LR patterning were disrupted in cdon morphants and cdon mutants. Mechanistically, we found that loss of cdon function led to defect in DFCs clustering, reduced KV lumen, and defective cilia, resulting in randomized Nodal/spaw signaling and subsequent organ LR patterning defects. Additionally, predominant distribution of a cdon morpholino (MO) in DFCs caused defects in DFC clustering, KV morphogenesis, cilia number/length, Nodal/spaw signaling, and organ LR asymmetry, similar to those observed in cdon morphants and cdon -/- embryos, indicating a cell-autonomous role for cdon in regulating KV formation during LR patterning. In conclusion, our data demonstrate that during gastrulation and early somitogenesis, cdon is essential for proper DFC clustering, KV formation, and normal cilia, thereby playing a critical role in establishing organ LR asymmetry.

15.
Nanoscale ; 14(46): 17237-17246, 2022 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-36377706

RESUMEN

In this study, 3-(2,2,2-trifluoroethoxy)-propionitrile (FEON), a fluorinated nitrile compound with high oxidative stability, low volatility and non-flammability, is introduced as an electrolyte solvent for high-energy density Li|NCM batteries. After optimization of the electrolyte as (0.8 M LiTFSI + 0.2 M LiODFB)/FEC : FEON (1 : 3, by vol., abbreviated as FF13), the FEON-based electrolyte exhibits better cycling performance for both the lithium metal anode and 4.4 V high-voltage NCM cathode, compared with those of a commercial carbonate electrolyte of 1 M LiPF6/EC : EMC : DMC (1 : 1 : 1, by vol.). As for the FF13 electrolyte, the maximum coordination number of 3 for FEON molecules in the solvation structure is disclosed through molecular dynamics simulation combined with Fourier transform infrared spectroscopy and nuclear magnetic resonance spectroscopy measurements. Furthermore, the solid electrolyte interphase on the lithium metal anode is enriched with organic components and LiF, which is proposed from FEON decomposition based on density functional theory calculations and X-ray photoelectron spectroscopy analysis. All the above results demonstrate that fluorinated nitrile electrolytes constitute a promising platform for high energy density Li|NCM batteries.

16.
Cell Death Discov ; 8(1): 38, 2022 Jan 28.
Artículo en Inglés | MEDLINE | ID: mdl-35091537

RESUMEN

Fibrotic hypersensitivity pneumonitis (FHP) remains one of fatal interstitial pulmonary disease. Comprehensively dissecting the cellular heterogeneity of FHP paves the way for developing general gene therapeutic solutions for FHP. Here, utilizing an integrated strategy based on scRNA-seq, scTCR-seq, and bulk RNA-seq analysis of FHP profiles, we identified ten major cell types and 19 unique subtypes. FHP exhibited higher features of EMT and inflammation-promoting than normal control. In distinct subsets of lung macrophages in FHP, FN1high, PLA2G7high, and MS4A6Ahigh macrophages with predominant M2 phenotype exhibited higher activity of inflammatory responses and para-inflammation than other macrophages. KRT17high basal-like epithelial cells were significantly increased in FHP, and showed higher ability to induce EMT. We identified roles for ACTA2high, COL1A1high, and PLA2G2Ahigh fibroblasts in FHP, which were significantly related to interstitial fibrosis. NK cells and KLRG1+ effector CD8+ T cells had greater activity in inflammation-promoting. Our results provide a comprehensive portrait of cellular heterogeneity in FHP, and highlight the indispensable role of cell subpopulations in shaping the complexity and heterogeneity of FHP. These subpopulations are potentially key players for FHP pathogenesis.

17.
Langmuir ; 27(6): 2910-6, 2011 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-21299195

RESUMEN

A simple and versatile method for the introduction of redox unites onto the surface of magnetic nanoparticles has been developed based on "click" chemistry. Azide-functionalized Fe2O3 magnetic nanoparticles were synthesized and further reacted with ethynylferrocene via Cu(I)-catalyzed azide alkyne 1,3-dipolar cycloaddition (CuAAC) reaction. The functionalized magnetic nanoparticles were characterized using a powder X-ray diffractometer (XRD), transmission electron microscope (TEM), Fourier transform infrared spectroscope (FTIR), and vibrating sample magnetometer (VSM). The resulting materials have properties of both magnetism and electrochemistry, and the electrochemical properties of the nanoparticles are dependent on the features of ethynylferrocene, while the magnetic properties remain independent of ethynylferrocene. Because of the magnetism of Fe2O3 nanoparticles and the electrocatalytic activity of ferrocene unites, a recyclable, magneto-switchable bioelectrocatalytic system for glucose oxidation in the presence of glucose oxidase is developed by alternate positioning of an external magnet, and the system has a linear response for glucose biosensing over the range of 1.0-10.0 mM.


Asunto(s)
Técnicas Biosensibles , Compuestos Férricos/metabolismo , Compuestos Ferrosos/metabolismo , Glucosa Oxidasa/metabolismo , Glucosa/análisis , Nanopartículas de Magnetita/química , Biocatálisis , Química Clic , Compuestos Férricos/síntesis química , Compuestos Férricos/química , Compuestos Ferrosos/química , Glucosa/metabolismo , Glucosa Oxidasa/química , Fenómenos Magnéticos , Metalocenos , Oxidación-Reducción , Propiedades de Superficie
18.
Phys Chem Chem Phys ; 12(40): 13287-95, 2010 Oct 28.
Artículo en Inglés | MEDLINE | ID: mdl-20830428

RESUMEN

In this paper, catechol, 1,4-dihydroxybenzene and dopamine are investigated as precursors of electrophiles for Michael addition reaction with the self-assembled monolayer (SAM) of 4-thiouracil (4-TU) via electrochemical triggering. All compounds can undergo Michael addition reaction with 4-TU; however, only catechol can react with 4-TU with high efficiency. The catechol-terminated SAMs, via electrochemically triggered Michael addition reaction, exhibit reversible redox response. In addition, we find that catechol-terminated SAMs can complex with Ni(2+) and Cu(2+) with different electrochemical behaviors. Moreover, the mechanism of complexation of Ni(2+)and Cu(2+) with catechol-terminated SAMs is also demonstrated with electrochemical and spectrometric methods. Based on the different electrochemical behaviors of Cu(2+) and Ni(2+) complex, the catechol-terminated SAMs provide a potential platform for metal ions recognition.

19.
Epigenomics ; 12(22): 1969-1981, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-33242255

RESUMEN

Aim: To elucidate the transcriptional characteristics of COVID-19. Materials & methods: We utilized an integrative approach to comprehensively analyze the transcriptional features of both COVID-19 patients and SARS-CoV-2 infected cells. Results: Widespread infiltration of immune cells was observed. We identified 233 genes that were codifferentially expressed in both bronchoalveolar lavage fluid and lung samples of COVID-19 patients. Functional analysis suggested upregulated genes were related to immune response such as neutrophil activation and antivirus response, while downregulated genes were associated with cell adhesion. Finally, we identified LCN2, STAT1 and UBE2L6 as core genes during SARS-CoV-2 infection. Conclusion: The identification of core genes involved in COVID-19 can provide us with more insights into the molecular features of COVID-19.


Asunto(s)
COVID-19/patología , Lipocalina 2/genética , SARS-CoV-2/inmunología , Factor de Transcripción STAT1/genética , Enzimas Ubiquitina-Conjugadoras/genética , Células A549 , Líquido del Lavado Bronquioalveolar/citología , COVID-19/inmunología , Adhesión Celular/genética , Adhesión Celular/fisiología , Línea Celular Tumoral , Citocinas/sangre , Humanos , Pulmón/inmunología , Activación Neutrófila/genética , Activación Neutrófila/inmunología , SARS-CoV-2/genética , Transcripción Genética/genética
20.
Chemphyschem ; 10(17): 3105-11, 2009 Dec 07.
Artículo en Inglés | MEDLINE | ID: mdl-19834930

RESUMEN

Herein, we report a versatile surface chemistry methodology to covalently immobilize ligands and proteins to self-assembled monolayers (SAMs) on gold electrode. The strategy is based on two steps: 1) the coupling of soluble azido-PEG-amimo ligand with an alkynyl-terminated monolayer via click reaction and 2) covalent immobilization hemoglobin (Hb) to the amine-terminated ligand via carbodiimide reaction. Surface-enhanced Raman scattering spectroscopy (SERS), atomic force microscopy (AFM), reflection absorption infrared spectroscopy (RAIR) and cyclic voltammetry are used to characterize the model interfacial reactions. We also demonstrate the excellent biocompatibility of the interface for Hb immobilization and reliable application of the proposed method for H(2)O(2) biosensing. Moreover, the redox thermodynamics of the Fe(3+)/Fe(2+) couple in Hb is also investigated.


Asunto(s)
Electrodos , Oro , Hemoglobinas/química , Técnicas Biosensibles/métodos , Catálisis , Técnicas Electroquímicas , Peróxido de Hidrógeno/análisis , Hierro/química , Oxidación-Reducción , Termodinámica
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