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The photocatalytic reduction of CO2 represents an environmentally friendly and sustainable approach for generating valuable chemicals. In this study, a thiophene-modified highly conjugated asymmetric covalent triazine framework (As-CTF-S) is developed for this purpose. Significantly, single-component intramolecular energy transfer can enhance the photogenerated charge separation, leading to the efficient conversion of CO2 to CO during photocatalysis. As a result, without the need for additional photosensitizers or organic sacrificial agents, As-CTF-S demonstrates the highest photocatalytic ability of 353.2 µmol g-1 and achieves a selectivity of ≈99.95% within a 4 h period under visible light irradiation. This study provides molecular insights into the rational control of charge transfer pathways for high-efficiency CO2 photoreduction using single-component organic semiconductor catalysts.
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In forensic practice, determining the postmortem submersion interval (PMSI) and cause-of-death of cadavers in aquatic ecosystems has always been challenging task. Traditional approaches are not yet able to address these issues effectively and adequately. Our previous study proposed novel models to predict the PMSI and cause-of-death based on metabolites of blood from rats immersed in freshwater. However, with the advance of putrefaction, it is hardly to obtain blood samples beyond 3 days postmortem. To further assess the feasibility of PMSI estimation and drowning diagnosis in the later postmortem phase, gastrocnemius, the more degradation-resistant tissue, was collected from drowned rats and postmortem submersion model in freshwater immediately after death, and at 1 day, 3 days, 5 days, 7 days, and 10 days postmortem respectively. Then the samples were analyzed with liquid chromatography-tandem mass spectrometry (LC-MS/MS) to investigate the dynamic changes of the metabolites. A total of 924 metabolites were identified. Similar chronological changes of gastrocnemius metabolites were observed in the drowning and postmortem submersion groups. The difference in metabolic profiles between drowning and postmortem submersion groups was only evident in the initial 1 day postmortem, which was faded as the PMSI extension. Nineteen metabolites representing temporally-dynamic patterns were selected as biomarkers for PMSI estimation. A regression model was built based on these biomarkers with random forest algorithm, which yielded a mean absolute error (± SE) of 5.856 (± 1.296) h on validation samples from an independent experiment. These findings added to our knowledge of chronological changes in muscle metabolites from submerged vertebrate remains during decomposition, which provided a new perspective for PMSI estimation.
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Afogamento , Água Doce , Imersão , Metabolômica , Modelos Animais , Músculo Esquelético , Mudanças Depois da Morte , Animais , Músculo Esquelético/metabolismo , Afogamento/diagnóstico , Afogamento/metabolismo , Masculino , Cromatografia Líquida , Espectrometria de Massas em Tandem , Ratos , Ratos Sprague-Dawley , Biomarcadores/metabolismoRESUMO
Solar-driven high-efficiency conversion of CO2 with water vapor into high-value-added alcohols is a promising approach for reducing CO2 emissions and achieving carbon neutrality. However, the rapid recombination of photogenerated carriers and low CO2 adsorption capacity of photocatalysts are usually the factors that limit their applicability. Herein, a series of low-cost Z-scheme heterostructures Cu2O/PCN-250-x are constructed by in situ growth of ultrasmall Cu2O nanoparticles on PCN-250. A systematic investigation revealed that there is a strong interaction between Cu2O nanoparticles and PCN-250. The resulting Cu2O/PCN-250-2 exhibits excellent photogenerated carrier separation efficiency and CO2 adsorption capacity, which dramatically promote the conversion of CO2 into alcohols. Notably, the total yield of 268 µmol gcat-1 for the production of CH3OH and CH3H2OH is superior to that of isolated PCN-250 and Cu2O. This study provides a new perspective for the design of a Cu2O nanoparticle/metal-organic framework Z-scheme heterojunction for the reduction of CO2 to alcohols with water vapor.
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BACKGROUND: In Parkinson's disease (PD), inflammation may lead to the degeneration of dopaminergic (DAergic) neurons. Previous studies showed that inflammatory mediators mainly contributed to this phenomenon. On the other hand, invasive neuromodulation methods such as deep brain stimulation (DBS) have better therapeutic effects for PD. One possibility is that DBS improves PD by influencing inflammation. Therefore, we further explored the mechanisms underlying inflammatory mediators and DBS in the pathogenesis of PD. METHODS: We measured serum levels of two inflammatory markers, namely RANTES (regulated on activation, normal T cell expressed and secreted) and tumor necrosis factor-alpha (TNF-α), using Luminex assays in 109 preoperative DBS PD patients, 49 postoperative DBS PD patients, and 113 age- and sex-matched controls. The plasma protein data of the different groups were then statistically analyzed. RESULTS: RANTES (p < 0.001) and TNF-α (p = 0.005) levels differed significantly between the three groups. A strong and significant correlation between RANTES levels and Hoehn-Yahr (H-Y) stage was observed in preoperative PD patients (rs = 0.567, p < 0.001). Significant correlations between RANTES levels and Unified Parkinson's Disease Rating Scale III (UPDRS III) score (rs1 = 0.644, p = 0.033 and rs2 = 0.620, p = 0.042) were observed in matched patients. No correlation was observed for TNF-α levels. CONCLUSION: The results of this study indicate that PD patients have a persistent inflammatory profile, possibly via recruitment of activated monocytes, macrophages, and T lymphocytes to the central nervous system (CNS). DBS was shown to have a significant therapeutic effect on PD, which may arise by improving the inflammatory environment of the central nervous system.
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Estimulação Encefálica Profunda , Doença de Parkinson , Humanos , Doença de Parkinson/patologia , Quimiocina CCL5/uso terapêutico , Estimulação Encefálica Profunda/métodos , Fator de Necrose Tumoral alfa , Resultado do Tratamento , Sistema Nervoso Central/patologia , Inflamação/terapiaRESUMO
The design of white-light phosphor is highly desirable for practical applications in SSL (solid-state lighting) and its related fields. Dye-loaded metal-organic frameworks (MOFs) have been widely demonstrated as one type of promising down conversion materials for WLEDs (white-light-emitting diodes), but two issues (dye leakage and inadequate quantum efficiency) require to be addressed before possible applications. Here, a series of single-phase dyes@In-MOF phosphors have been prepared in two different ways: the in-situ process and soaking method. The study of these dyes@In-MOF phosphors confirms the importance of this in-situ process that could effectively increase dye loading and quantum efficiency and greatly decrease dye leakage. As a result, a perfect WLED, fabricated using the in-situ-synthesized (AF/RhB@In-MOF)-3 (AF: Acriflavine; RhB: Rhodamine B) and 450 nm blue LED chip, exhibited a very high quantum yield (QY, up to 42.27%), a high luminous efficacy (LE) of 50.75 lm/W, a high color rendering index (CRI) of 91.2, and nearly identical Commission International ed'Eclairage (CIE) coordinates (0.33,0.31), indicating the potential application of the dye-loaded MOFs with good color quality in smart white LEDs.
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OBJECTIVES: The metabolomics technique of LC-MS/MS combined with data analysis was used to detect changes and differences in metabolic profiles in the vitreous humor of early rat carcasses found in water, and to explore the feasibility of its use for early postmortem submersion interval (PMSI) estimation and the cause of death determination. METHODS: The experimental model was established in natural lake water with 100 SD rats were randomly divided into a drowning group (n=50) and a postmortem (CO2 suffocation) immediately submersion group (n=50). Vitreous humor was extracted from 10 rats in each group at 0, 6, 12, 18 and 24 h postmortem for metabolomics analyses, of which 8 were used as the training set to build the model, and 2 were used as test set. PCA and PLS multivariate statistical analysis were performed to explore the differences in metabolic profiles among PMSI and causes of death in the training set samples. Then random forest (RF) algorithm was used to screen several biomarkers to establish a model. RESULTS: PCA and PLS analysis showed that the metabolic profiles had time regularity, but no differences were found among different causes of death. Thirteen small molecule biomarkers with good temporal correlation were selected by RF algorithm. A simple PMSI estimation model was constructed based on this indicator set, and the data of the test samples showed the mean absolute error (MAE) of the model was 0.847 h. CONCLUSIONS: The 13 metabolic markers screened in the vitreous humor of rat corpses in water had good correlations with the early PMSI. The simplified PMSI estimation model constructed by RF can be used to estimate the PMSI. Additionally, the metabolic profiles of vitreous humor cannot be used for early identification of cause of death in water carcasses.
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Mudanças Depois da Morte , Corpo Vítreo , Animais , Biomarcadores/metabolismo , Cadáver , Cromatografia Líquida , Imersão , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem , Corpo Vítreo/metabolismo , Água/metabolismoRESUMO
Postmortem submersion interval (PMSI) estimation and cause-of-death discrimination of corpses in water have long been challenges in forensic practice. Recently, many studies have linked postmortem metabolic changes with PMI extension, providing a potential strategy for estimating PMSI using the metabolome. Additionally, there is a lack of potential indicators with high sensitivity and specificity for drowning identification. In the present study, we profiled the untargeted metabolome of blood samples from drowning and postmortem submersion rats at different PMSIs within 24 h by liquid chromatography-tandem mass spectrometry (LC-MS/MS). A total of 601 metabolites were detected. Four different machine learning algorithms, including random forest (RF), partial least squares (PLS), support vector machine (SVM), and neural network (NN), were used to compare the efficiency of the machine learning methods. Nineteen metabolites with obvious temporal regularity were selected as candidate biomarkers according to "IncNodePurity." Robust models were built with these biomarkers, which yielded a mean absolute error of 1.067 h. Additionally, 36 other metabolites were identified to build the classifier model for discriminating drowning and postmortem submersion (AUC = 1, accuracy = 95%). Our results demonstrated the potential application of metabolomics combined with machine learning in PMSI estimation and cause-of-death discrimination.
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Afogamento , Algoritmos , Animais , Biomarcadores , Cromatografia Líquida , Humanos , Imersão , Aprendizado de Máquina , Metabolômica , Mudanças Depois da Morte , Ratos , Espectrometria de Massas em TandemRESUMO
BACKGROUND: Many breast cancer clinical trials with PARPi have been completed or are currently carried out, either by monotherapy or combined with chemotherapy. We aim to assess the efficacy and safety of PARPi in breast cancer patients as compared to chemotherapy. METHODS: A comprehensive literature search of PubMed, EMBASE, CENTRAL, conference meetings and clinical trial registry was performed. The primary outcomes were progression-free survival (PFS), overall survival (OS), overall response rate (ORR). The secondary outcome was safety profile. The comparative effects were measured using hazard ratio (HR) or relative risk (RR) with 95% confidence interval. Subgroup analyses were conducted based on types of intervention and baseline characteristics of patients. RESULTS: Six RCTs (n = 1953) were included. Two RCTs were recognized as high risk. PARPi was associated with an improved PFS (HR, 0.65; 95% CI, 0.56-0.74), OS (HR, 0.86; 95% CI, 0.73-1.01), and a higher ORR (RR, 1.38; 95% CI, 1.05-1.82). PARPi, however, significantly increased risk of grade 3-4 thrombocytopenia (RR, 1.63; 95% CI, 1.06-2.52). Monotherapy was observed with lower risk of disease progression and higher ORR rate than combination therapy, 0.56 to 0.65 and 2.21 to 1.05, respectively. For patients without prior platinum treatment, PARPi significantly improved PFS (HR, 0.64; 95% CI, 0.52-0.79). CONCLUSIONS: PARPi was observed with a significantly improved efficacy in aspects of PFS and ORR, but also higher risk of grade 3-4 thrombocytopenia as compared to chemotherapy. PARPi was a better choice for patients who had not received previous platinum treatment.
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Neoplasias da Mama , Inibidores de Poli(ADP-Ribose) Polimerases , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Terapia Combinada , Feminino , Humanos , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Intervalo Livre de ProgressãoRESUMO
Dysregulation of matrix metalloproteinase- (MMP-) 9 is implicated in the pathogenesis of acute lung injury (ALI). However, it remains controversial whether MMP-9 improves or deteriorates acute lung injury of different etiologies. The receptor for advanced glycation end products (RAGE) plays a critical role in the pathogenesis of acute lung injury. MMPs are known to mediate RAGE shedding and release of soluble RAGE (sRAGE), which can act as a decoy receptor by competitively inhibiting the binding of RAGE ligands to RAGE. Therefore, this study is aimed at clarifying whether and how pulmonary knockdown of MMP-9 affected sepsis-induced acute lung injury as well as the release of sRAGE in a murine cecal ligation and puncture (CLP) model. The analysis of GEO mouse sepsis datasets GSE15379, GSE52474, and GSE60088 revealed that the mRNA expression of MMP-9 was significantly upregulated in septic mouse lung tissues. Elevation of pulmonary MMP-9 mRNA and protein expressions was confirmed in CLP-induced mouse sepsis model. Intratracheal injection of MMP-9 siRNA resulted in an approximately 60% decrease in pulmonary MMP-9 expression. It was found that pulmonary knockdown of MMP-9 significantly increased mortality of sepsis and exacerbated sepsis-associated acute lung injury. Pulmonary MMP-9 knockdown also decreased sRAGE release and enhanced sepsis-induced activation of the RAGE/nuclear factor-κB (NF-κB) signaling pathway, meanwhile aggravating sepsis-induced oxidative stress and inflammation in lung tissues. In addition, administration of recombinant sRAGE protein suppressed the activation of the RAGE/NF-κB signaling pathway and ameliorated pulmonary oxidative stress, inflammation, and lung injury in CLP-induced septic mice. In conclusion, our data indicate that MMP-9-mediated RAGE shedding limits the severity of sepsis-associated pulmonary edema, inflammation, oxidative stress, and lung injury by suppressing the RAGE/NF-κB signaling pathway via the decoy receptor activities of sRAGE. MMP-9-mediated sRAGE production may serve as a self-limiting mechanism to control and resolve excessive inflammation and oxidative stress in the lung during sepsis.
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Lesão Pulmonar Aguda/etiologia , Metaloproteinase 9 da Matriz/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Sepse/complicações , Regulação para Cima , Animais , Ceco , Modelos Animais de Doenças , Técnicas de Silenciamento de Genes , Inflamação/patologia , Ligadura , Pulmão/patologia , Masculino , Camundongos Endogâmicos ICR , NF-kappa B/metabolismo , Punções , Transdução de Sinais , SolubilidadeRESUMO
Integrating the merits of different components to construct heterostructures for energy storage and conversion has attracted intensive attention. Herein, taking advantage of bimetallic MOFs and transition bimetal hydroxide, we have successfully used nanoflower-like Ni1-xCox(OH)2 as both the precursor and template to in situ construct three dimensional (3D) NiCo-MOF@Ni1-xCox(OH)2 (denoted as MOF@TMH) hierarchical heterostructures. Benefiting from the optimized composition with hierarchical heterostructures assembled by ultrathin nanosheets, MOF@TMH-2 possesses rich effective active sites and high electrochemical reactivity, delivering superior pseudocapacitor performance with a specific capacitance of 1855.3 F g-1 at 2 A g-1 and good rate performance. Besides, MOF@TMH-2 also exhibits excellent OER activity with small overpotentials of 193 mV and 310 mV at 10 and 100 mA cm-2, respectively.
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Heat stress (HS) causes significant economic losses in the poultry industry every year. However, the mechanisms for the adverse effects of HS on avian follicular development are largely unknown. The aim of this study was to test whether HS induces apoptosis of follicular cells and impairs egg production by activating the FasL/Fas and tumor necrosis factor (TNF)-α systems. To this end, Hy-Line Brown laying hens, at 32 wk of age, were either exposed to HS of 35°C to 37°C or maintained at 24°C to 26°C (control) for 5 D. At the end of the HS period, follicle numbers, apoptosis, FasL/Fas and TNF-α activation, oxidative stress, and hormone secretion were examined in ovarian follicles. Egg production was observed daily during both the stressed (day S1-S5) and the poststress recovery (day R1-R15) periods. The results demonstrated that HS on hens significantly 1) decreased laying rates from day S3 to R6; 2) reduced numbers of large yellow and hierarchical follicles; 3) triggered apoptosis while increasing the expression of FasL, Fas, TNF-α, and TNF-receptor 1 in small and large yellow follicles; and 4) increased levels of oxidative stress, corticotrophin-releasing hormone, and corticosterone while decreasing the estradiol/progesterone ratio in follicular fluid in small and large yellow follicles. Taken together, the results suggested that hen HS impaired egg production by reducing the number of follicles through inducing apoptosis and that it triggered apoptosis in follicular cells by activating the FasL/Fas and TNF-α systems.
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Apoptose , Galinhas , Proteína Ligante Fas , Resposta ao Choque Térmico , Neuropeptídeos , Folículo Ovariano , Fator de Necrose Tumoral alfa , Animais , Proteína Ligante Fas/genética , Feminino , Neuropeptídeos/genética , Folículo Ovariano/citologia , Ovulação/fisiologia , Ativação Transcricional , Fator de Necrose Tumoral alfa/genéticaRESUMO
Mechanical ventilation (MV) and lipopolysaccharide (LPS) infection are common causes of acute lung injury. The aim of the present study was to identify the key genes and potential mechanisms involved in mechanical ventilation (MV) and lipopolysaccharide (LPS)induced acute lung injury (ALI). Gene expression data of adult C57BL/6 mice with ALI induced by inhaling LPS, MV and LPS + MV were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) associated with MV, LPS and LPS + MV were screened, followed by functional enrichment analysis, proteinprotein interaction network construction, and prediction of transcription factors and small molecule drugs. Finally, the expression of key genes was verified in vivo using reverse transcriptionquantitative PCR. A total of 63, 538 and 1,635 DEGs were associated with MV, LPS and LPS + MV, respectively. MVassociated genes were significantly enriched in the 'purine ribonucleotide metabolic process'. LPS and LPS + MVassociated genes were significantly enriched in 'cellular response to cytokine stimulus' and 'cell chemotaxis'. All three conditions were enriched in 'TNF signaling pathway' and 'IL17 signaling pathway'. Expression levels of CXC motif chemokine ligand (CXCL)2, CXCL3 and CXCL10 were upregulated in the LPS and LPS + MV groups. Adenosine A2b receptor, zinc finger and BTB domaincontaining 16 and hydroxycarboxylic acid receptor 2 were identified as DEGs in the MV group. Compared with the control group, Early growth response 1 and activating TF 3 was upregulated in all three groups. Similarities and differences were observed among the MV and LPSinduced ALI, and MV may enhance the effects of LPS on gene expression. MV may affect urine ribonucleotide metabolicrelated processes, whereas LPS may cause cell chemotaxis and cytokine stimulus responses in ALI progression. The inflammatory response was shared by MV and LPS. The results of the present study may provide insight into a theoretical basis for the study and treatment of ALI.
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Lesão Pulmonar Aguda/genética , Biologia Computacional/métodos , Redes Reguladoras de Genes , Lipopolissacarídeos/efeitos adversos , Respiração Artificial/efeitos adversos , Lesão Pulmonar Aguda/etiologia , Animais , Bases de Dados Genéticas , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mapas de Interação de ProteínasRESUMO
The diagnosis of drowning is one of the major challenges in forensic practice, especially when the corpse is in a state of decomposition. Novel indicators of drowning are desired in the field of forensic medicine. In the past decade, aquatic bacteria have attracted great attention from forensic experts because they can easily enter the blood circulation with drowning medium, and some of them can proliferate in the corpse. Recently, the advent of next-generation sequencing (NGS) has created new opportunities to efficiently analyze whole microbial communities and has catalyzed the development of forensic microbiology. We presumed that NGS could be a potential method for diagnosing drowning. In the present study, we verified this hypothesis by fundamental experiments in drowned and postmortem-submersed rat models. Our study revealed that detecting the bacterial communities with NGS and processing the data in a transparent way with unweighted UniFrac-based principal coordinates analysis (PCoA) could clearly discriminate the skin, lung, blood, and liver specimens of the drowning group and postmortem submersion group. Furthermore, the acquired information could be used to identify new cases. Taken together, these results suggest that we could build a microbial database of drowned and postmortem-submersed victims by NGS and subsequently use a bioinformatic method to diagnose drowning in future forensic practice.
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Organismos Aquáticos/microbiologia , Bactérias/classificação , Afogamento/diagnóstico , Afogamento/microbiologia , Medicina Legal/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Animais , Sangue/microbiologia , Modelos Animais de Doenças , Fígado/microbiologia , Pulmão/microbiologia , Masculino , Ratos , Ratos Sprague-Dawley , Pele/microbiologiaRESUMO
Ventilatorassociated lung injury (VALI) remains a significant medical problem in intensive care units. The present study aimed to investigate the role of sphingosine kinase 1 (SPHK1) in VALI using a twohit model and explore the potential underlying molecular mechanism. Mice were divided into five groups: i) Nonventilated group; ii) nonventilated + lipopolysaccharide (LPS) group; iii) ventilated group; iv) ventilated + LPS group; and v) ventilated + LPS + SPHK1 inhibitor group. Mice were administered LPS (1 mg/kg) via an intraperitoneal injection. After 12 h, the mice were anesthetized and connected to a ventilator (10 ml/kg at 150 breaths/min) for 4 h. SPHK1 inhibitor (50 mg/kg) was injected intraperitoneally 1 h prior to ventilation. Mouse lung vascular endothelial cells were treated with LPS and SPHK1 inhibitor, and then subjected to cyclic stretch for 4 h. The present results suggested that the expression of SPHK1 and sphingosine 1 phosphate was upregulated in the twohit model of VALI; SPHK1 inhibitor could attenuate VALI in the twohit model as observed by hematoxylin and eosin staining, and affected the cell count and the protein content levels in the bronchoalveolar lavage fluid. In addition, treatment with SPHK1 inhibitor reduced the wettodry ratio of the lungs and suppressed Evans blue dye leakage into the lung tissue. Furthermore, SPHK1 inhibitor exhibited protective effects on the twohit model of VALI by inhibiting the Ras homolog family member amediated phosphorylation of myosin phosphatase target subunit 1 (MYPT1) and endothelial hyperpermeability. Additionally, mice were divided into five additional groups: i) Nonventilated group; ii) nonventilated + LPS group; iii) ventilated group; iv) ventilated + LPS group; and v) ventilated + LPS + Rhoassociated coiledcoil forming protein kinase (ROCK)1 inhibitor group. ROCK1 inhibitor (10 mg/kg) was injected intraperitoneally 1 h prior to ventilation. The present results suggested that ROCK1 inhibitor could attenuate mechanical stretchinduced lung endothelial injury and the phosphorylation of MYPT1 in vivo and in vitro. Collectively, the present findings indicated that upregulation of SPHK1 may contribute to VALI in a twohit model.
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Fosfatase de Miosina-de-Cadeia-Leve/genética , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Lesão Pulmonar Induzida por Ventilação Mecânica/genética , Quinases Associadas a rho/genética , Animais , Líquido da Lavagem Broncoalveolar/química , Permeabilidade Capilar/efeitos dos fármacos , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Lipopolissacarídeos/toxicidade , Lisofosfolipídeos/metabolismo , Camundongos , Fosforilação , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Esfingosina/análogos & derivados , Esfingosina/metabolismo , Lesão Pulmonar Induzida por Ventilação Mecânica/induzido quimicamente , Lesão Pulmonar Induzida por Ventilação Mecânica/tratamento farmacológico , Lesão Pulmonar Induzida por Ventilação Mecânica/patologia , Quinases Associadas a rho/antagonistas & inibidoresRESUMO
OBJECTIVES: The R-spondin family attenuates tissue damage via tightening endothelium and preventing vascular leakage. This study aims to investigate whether R-spondins protect against mechanical stretch-induced endothelial dysfunction and lung injury and to reveal the underlying mechanisms. DESIGN: Randomized controlled study. SETTING: University research laboratory. SUBJECTS: Patients scheduled to undergo surgery with mechanical ventilation support. Adult male Institute of Cancer Research mice. Primary cultured mouse lung vascular endothelial cells. INTERVENTIONS: Patients underwent a surgical procedure with mechanical ventilation support of 3 hours or more. Mice were subjected to mechanical ventilation (6 or 30 mL/kg) for 0.5-4 hours. Another group of mice were intraperitoneally injected with 1 mg/kg lipopolysaccharide, and 12 hours later subjected to mechanical ventilation (10 mL/kg) for 4 hours. Mouse lung vascular endothelial cells were subjected to cyclic stretch for 4 hours. MEASUREMENTS AND MAIN RESULTS: R-spondin1 were downregulated in both surgical patients and experimental animals exposed to mechanical ventilation. Intratracheal instillation of R-spondin1 attenuated, whereas knockdown of pulmonary R-spondin1 exacerbated ventilator-induced lung injury and mechanical stretch-induced lung vascular endothelial cell apoptosis. The antiapoptotic effect of R-spondin1 was mediated through the leucine-rich repeat containing G-protein coupled receptor 5 in cyclic stretched mouse lung vascular endothelial cells. We identified apoptosis-stimulating protein of p53 2 as the intracellular signaling protein interacted with leucine-rich repeat containing G-protein coupled receptor 5. R-spondin1 treatment decreased the interaction of apoptosis-stimulating protein of p53 2 with p53 while increased the binding of apoptosis-stimulating protein of p53 2 to leucine-rich repeat containing G-protein coupled receptor 5, therefore resulting in inactivation of p53-mediated proapoptotic pathway in cyclic stretched mouse lung vascular endothelial cells. CONCLUSIONS: Mechanical ventilation leads to down-regulation of R-spondin1. R-spondin1 may enhance the interaction of leucine-rich repeat containing G-protein coupled receptor 5 and apoptosis-stimulating protein of p53 2, thus inactivating p53-mediated proapoptotic pathway in cyclic stretched mouse lung vascular endothelial cells. R-spondin1 may have clinical benefit in alleviating mechanical ventilator-induced lung injury.
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Regulação para Baixo/fisiologia , Pulmão/fisiopatologia , Trombospondinas/sangue , Lesão Pulmonar Induzida por Ventilação Mecânica/prevenção & controle , Animais , Líquido da Lavagem Broncoalveolar/citologia , Células Cultivadas , Modelos Animais de Doenças , Masculino , Camundongos , Distribuição Aleatória , Reação em Cadeia da Polimerase em Tempo Real , Transdução de SinaisRESUMO
BACKGROUND The processes of mechanical ventilation-induced lung injury (VILI) triggers the release of high-mobility group box 1 (HMGB1), a prominent damage-associated molecular pattern (DAMP) family member, which can cause damage to pulmonary vascular endothelial cells. We aimed to determine whether propofol protected against endothelial cell injury induced by HMGB1 in vitro and in vivo. MATERIAL AND METHODS ICR mice (male) were mechanically ventilated for 4 h after anesthetization at both low tidal volume (LVT, 6 ml/kg) and high tidal volume (HVT, 30 ml/kg). A propofol bolus (10 mg/kg) was administered to the animals prior to the onset of ventilation, followed by infusion at 5 mg/(kg·h). We obtained confluent cultures of mouse lung vascular endothelial cells (MLVECs) and then performed cyclic stretching at 20% stretch for 4 h with or without propofol. RESULTS HMGB1 reduced the expression of tight junctions between endothelial cells, including VE-cadherin and ZO-1, and increased endothelial permeability, and both were blocked by propofol. We found that MLVECs exhibited mitochondrial oxidative damage by HMGB1, which was successfully suppressed through administration of MnTBAP as well as propofol. Propofol ameliorated HVT-associated lung vascular hyperpermeability and HMGB1 production in vivo. Propofol also inhibited HMBG1 release caused by cyclic stretching in MLVECs in vitro. CONCLUSIONS Our results prove that the cyto-protective function of propofol protects against lung ventilation-induced dysfunction of the lung endothelial barrier. This function of propofol is mediated through inhibition of HMGB1 release caused by mechanical stretching and mitochondrial oxidative damage triggered by HMGB1.
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Endotélio Vascular/efeitos dos fármacos , Proteína HMGB1/metabolismo , Pulmão/irrigação sanguínea , Pulmão/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Propofol/farmacologia , Lesão Pulmonar Induzida por Ventilação Mecânica/tratamento farmacológico , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Animais , Catálise , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Proteína HMGB1/antagonistas & inibidores , Proteína HMGB1/genética , Proteína HMGB1/farmacologia , Humanos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Mitocôndrias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , RNA/genética , RNA/metabolismo , Proteínas Recombinantes/farmacologia , Respiração Artificial/efeitos adversos , Volume de Ventilação Pulmonar , Lesão Pulmonar Induzida por Ventilação Mecânica/metabolismo , Lesão Pulmonar Induzida por Ventilação Mecânica/patologiaRESUMO
The development of novel strategy to produce new porous carbon materials is extremely important because these materials have wide applications in energy storage/conversion, mixture separation, and catalysis. Herein, for the first time, a novel 3D carbon substrate with hierarchical pores derived from commercially available Cu-MOF (metal-organic framework) (HKUST-1) through carbonization and chemical etching has been employed as the catalysts' support. Highly dispersed Pt nanoparticles and amorphous nickel were evenly dispersed on the surface or embedded within carbon matrix. The corresponding optimal composite catalyst exhibits a high mass-specific peak current of 1195 mA mg-1 Pt and excellent poison resistance capacity ( IF/ IB = 1.58) for methanol oxidation compared to commercial Pt/C (20%). Moreover, both composite catalysts manifest outstanding properties in the reduction of nitrophenol and demonstrate diverse selectivities for 2/3/4-nitrophenol, which can be attributed to different integrated forms between active species and carbon matrix. This attractive route offers broad prospects for the usage of a large number of available MOFs in fabricating functional carbon materials as well as highly active carbon-based electrocatalysts and heterogeneous organic catalysts.
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The integration of terpyridyl and tricarboxylate functionality in a novel ligand allows concerted 3:1 stoichiometric assembly of size-and charge-complementary Zn2+/Tb3+ ions into a water-stable 3D luminescent framework (CTGU-8) capable of highly selective, sensitive, and recyclable of nitrofurans.
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OBJECTIVES: Mechanical ventilation can induce lung fibrosis. This study aimed to investigate whether ventilator-induced lung fibrosis was associated with endothelial-mesenchymal transition and to uncover the underlying mechanisms. DESIGN: Randomized, controlled animal study and cell culture study. SETTING: University research laboratory. SUBJECTS: Adult male Institute of Cancer Research, NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) knockout and wild-type mice. Primary cultured mouse lung vascular endothelial cells. INTERVENTIONS: Institute of Cancer Research, NLRP3 knockout and wild-type mice were subjected to mechanical ventilation (20 mL/kg) for 2 hours. Mouse lung vascular endothelial cells were subjected to cyclic stretch for 24 hours. MEASUREMENTS AND MAIN RESULTS: Mice subjected to mechanical ventilation exhibited increases in collagen deposition, hydroxyproline and type I collagen contents, and transforming growth factor-ß1 in lung tissues. Ventilation-induced lung fibrosis was associated with increased expression of mesenchymal markers (α smooth muscle actin and vimentin), as well as decreased expression of endothelial markers (vascular endothelial-cadherin and CD31). Double immunofluorescence staining showed the colocalization of CD31/α smooth muscle actin, CD31/vimentin, and CD31/fibroblast-specific protein-1 in lung tissues, indicating endothelial-mesenchymal transition formation. Mechanical ventilation also induced NLRP3 inflammasome activation in lung tissues. In vitro direct mechanical stretch of primary mouse lung vascular endothelial cells resulted in similar NLRP3 activation and endothelial-mesenchymal transition formation, which were prevented by NLRP3 knockdown. Furthermore, mechanical stretch-induced endothelial-mesenchymal transition and pulmonary fibrosis were ameliorated in NLRP3-deficient mice as compared to wild-type littermates. CONCLUSIONS: Mechanical stretch may promote endothelial-mesenchymal transition and pulmonary fibrosis through a NLRP3-dependent pathway. The inhibition of endothelial-mesenchymal transition by NLRP3 inactivation may be a viable therapeutic strategy against pulmonary fibrosis associated with mechanical ventilation.
Assuntos
Modelos Animais de Doenças , Endotélio Vascular/fisiopatologia , Inflamassomos/fisiologia , Pulmão/irrigação sanguínea , Mecanotransdução Celular/fisiologia , Mesoderma/fisiopatologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/fisiologia , Fibrose Pulmonar/fisiopatologia , Animais , Células Cultivadas , Células Endoteliais/fisiologia , Camundongos , Camundongos Endogâmicos ICR , Camundongos KnockoutRESUMO
Detecting formaldehyde at low operating temperature and maintaining long-term stability are of great significance. In this work, a hierarchical Co3O4 nanostructure has been fabricated by calcining Co5-based metal-organic framework (MOF) microcrystals. Co3O4-350 particles were used for efficient gas-sensing for the detecting of formaldehyde vapor at lower working temperature (170 °C), low detection limit of 10 ppm, and long-term stability (30 days), which not only is the optimal value among all reported pure Co3O4 sensing materials for the detection of formaldehyde but also is superior to that of majority of Co3O4-based composites. Such extraordinarily efficient properties might be resulted from hierarchically structures, larger surface area and unique pore structure. This strategy is further confirmed that MOFs, especially Co-clusters MOFs, could be used as precursor to synthesize 3D nanostructure metal oxide materials with high-performance, which possess high porosity and more active sites and shorter ionic diffusion lengths.