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We previously demonstrated that normal high-density lipoprotein (nHDL) can promote angiogenesis, whereas HDL from patients with coronary artery disease (dHDL) is dysfunctional and impairs angiogenesis. Autophagy plays a critical role in angiogenesis, and HDL regulates autophagy. However, it is unclear whether nHDL and dHDL regulate angiogenesis by affecting autophagy. Endothelial cells (ECs) were treated with nHDL and dHDL with or without an autophagy inhibitor. Autophagy, endothelial nitric oxide synthase (eNOS) expression, miRNA expression, nitric oxide (NO) production, superoxide anion (O2â¢-) generation, EC migration, and tube formation were evaluated. nHDL suppressed the expression of miR-181a-5p, which promotes autophagy and the expression of eNOS, resulting in NO production and the inhibition of O2â¢- generation, and ultimately increasing in EC migration and tube formation. dHDL showed opposite effects compared to nHDL and ultimately inhibited EC migration and tube formation. We found that autophagy-related protein 5 (ATG5) was a direct target of miR-181a-5p. ATG5 silencing or miR-181a-5p mimic inhibited nHDL-induced autophagy, eNOS expression, NO production, EC migration, tube formation, and enhanced O2â¢- generation, whereas overexpression of ATG5 or miR-181a-5p inhibitor reversed the above effects of dHDL. ATG5 expression and angiogenesis were decreased in the ischemic lower limbs of hypercholesterolemic low-density lipoprotein receptor null (LDLr-/-) mice when compared to C57BL/6 mice. ATG5 overexpression improved angiogenesis in ischemic hypercholesterolemic LDLr-/- mice. Taken together, nHDL was able to stimulate autophagy by suppressing miR-181a-5p, subsequently increasing eNOS expression, which generated NO and promoted angiogenesis. In contrast, dHDL inhibited angiogenesis, at least partially, by increasing miR-181a-5p expression, which decreased autophagy and eNOS expression, resulting in a decrease in NO production and an increase in O2â¢- generation. Our findings reveal a novel mechanism by which HDL affects angiogenesis by regulating autophagy and provide a therapeutic target for dHDL-impaired angiogenesis.
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MicroARNs , Humanos , Ratones , Animales , MicroARNs/metabolismo , Células Endoteliales/metabolismo , Angiogénesis , Ratones Endogámicos C57BL , Autofagia/genéticaRESUMEN
Cardiopulmonary bypass has been speculated to elicit systemic inflammation to initiate acute lung injury (ALI), including acute respiratory distress syndrome (ARDS), in patients after cardiac surgery. We previously found that post-operative patients showed an increase in endothelial cell-derived extracellular vesicles (eEVs) with components of coagulation and acute inflammatory responses. However, the mechanism underlying the onset of ALI owing to the release of eEVs after cardiopulmonary bypass, remains unclear. Plasma plasminogen-activated inhibitor-1 (PAI-1) and eEV levels were measured in patients with cardiopulmonary bypass. Endothelial cells and mice (C57BL/6, Toll-like receptor 4 knockout (TLR4-/-) and inducible nitric oxide synthase knockout (iNOS-/-)) were challenged with eEVs isolated from PAI-1-stimulated endothelial cells. Plasma PAI-1 and eEVs were remarkably enhanced after cardiopulmonary bypass. Plasma PAI-1 elevation was positively correlated with the increase in eEVs. The increase in plasma PAI-1 and eEV levels was associated with post-operative ARDS. The eEVs derived from PAI-1-stimulated endothelial cells could recognize TLR4 to stimulate a downstream signaling cascade identified as the Janus kinase 2/3 (JAK2/3)-signal transducer and activator of transcription 3 (STAT3)-interferon regulatory factor 1 (IRF-1) pathway, along with iNOS induction, and cytokine/chemokine production in vascular endothelial cells and C57BL/6 mice, ultimately contributing to ALI. ALI could be attenuated by JAK2/3 or STAT3 inhibitors (AG490 or S3I-201, respectively), and was relieved in TLR4-/- and iNOS-/- mice. eEVs activate the TLR4/JAK3/STAT3/IRF-1 signaling pathway to induce ALI/ARDS by delivering follistatin-like protein 1 (FSTL1), and FSTL1 knockdown in eEVs alleviates eEV-induced ALI/ARDS. Our data thus demonstrate that cardiopulmonary bypass may increase plasma PAI-1 levels to induce FSTL1-enriched eEVs, which target the TLR4-mediated JAK2/3/STAT3/IRF-1 signaling cascade and form a positive feedback loop, leading to ALI/ARDS after cardiac surgery. Our findings provide new insight into the molecular mechanisms and therapeutic targets for ALI/ARDS after cardiac surgery.
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Lesión Pulmonar Aguda , Vesículas Extracelulares , Proteínas Relacionadas con la Folistatina , Síndrome de Dificultad Respiratoria , Animales , Humanos , Ratones , Lesión Pulmonar Aguda/etiología , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/metabolismo , Células Endoteliales/metabolismo , Vesículas Extracelulares/metabolismo , Proteínas Relacionadas con la Folistatina/metabolismo , Proteínas Relacionadas con la Folistatina/uso terapéutico , Inflamación/metabolismo , Lipopolisacáridos/farmacología , Pulmón/metabolismo , Ratones Endogámicos C57BL , Inhibidor 1 de Activador Plasminogénico/metabolismo , Inhibidor 1 de Activador Plasminogénico/uso terapéutico , Síndrome de Dificultad Respiratoria/etiología , Receptor Toll-Like 4/metabolismo , Receptor Toll-Like 4/uso terapéuticoRESUMEN
BACKGROUND AND OBJECTIVES: Emerging expert consensuses and guidelines recommend that omega-3 fatty acids may have anti-inflammatory effects in hospitalized patients with coronavirus disease (COVID-19). However, these recommendations are based on pathophysiological studies of inflammation rather than direct clinical evidence. We conducted this systematic review and meta-analysis to evaluate the efficacy of omega-3 fatty acid supplementation in hospitalized patients with COVID-19. METHODS AND STUDY DESIGN: We retrieved literature from PubMed, Web of Science, Embase, China National Knowledge Infrastructure (CNKI), WANFANG, Chinese Biomedical Literature Database, and Cochrane Library databases up to May 1, 2023. Data from studies comparing omega-3 fatty acids with a placebo or other pharmaceutical nutrients were analyzed. RESULTS: Of 3032 records, 42 full-text articles were reviewed, five eligible studies were identified, and one study was found in the references. In total of six studies involving 273 patients were included, pooled, and analyzed. Compared to the control group, omega-3 fatty acid intervention reduced the overall mortality of hospitalized patients with COVID-19 (RR=0.76; 95% CI, [0.61, 0.93]; p=0.010). No serious or unexpected drug-related adverse events were observed. No statistical significance was observed in inflammatory markers such as CRP (MD=-9.69; 95% CI, [-22.52, 3.15]; p=0.14; I2=97%) and IL-6; however, the neutrophil/lymphocyte ratio was significantly lower in the omega-3 FAs group on day 7 of intervention (p < 0.001). CONCLUSIONS: Omega-3 fatty acid administration may be associated with reduced mortality in hospitalized patients with COVID-19. Given the small sample size of enrolled studies, more rigorous and large-scale trials are urgently needed in the future to verify its efficacy.
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COVID-19 , Ácidos Grasos Omega-3 , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Ácidos Grasos Omega-3/uso terapéutico , Inflamación/tratamiento farmacológico , ChinaRESUMEN
Based on the offline sampling data of volatile organic compounds (VOCs) and the simultaneous online measurements of conventional gaseous air pollutants and meteorological parameters in urban Huanggang, the volume fractions and component characteristics of VOCs were analyzed. The sources and ozone (O3) formation sensitivity of VOCs during severe ozone pollution episodes were analyzed using the positive matrix factorization (PMF) model and the photochemical box model coupled with master chemical mechanism (PBM-MCM), respectively. The results revealed that the average volume fractions of total volatile organic compounds were (21.57±3.13)×10-9, with higher volume fractions in winter and spring compared to those in summer and autumn. Among these, alkanes (49.9%) and alkenes (16.4%) accounted for the highest proportion. The PMF analysis results showed that fuel combustion (27.8%), vehicle emission (19.9%), solvent use (15.7%), industrial halogenated hydrocarbon emission (12.1%), chemical enterprise emission (10.5%), natural sources (7.8%), and diesel vehicle emission (6.2%) were the main sources of VOC emissions. Anthropogenic VOCs emitted by solvent use, fuel combustion, and chemical enterprises contributed significantly (60.9% in total) to generating O3, which indicates that these three types of anthropogenic sources should be controlled first when it comes to preventing and controlling ozone pollution. Further, the relative incremental reactivity (RIR) and empirical kinetic method approach (EKMA) revealed that O3 formation was in a VOCs-limited regime during the observation period in Huanggang, China. Furthermore, O3 formation was more sensitive to m-xylene, p-xylene, ethylene, 1-butene, and toluene; therefore, reducing these VOCs should be prioritized.
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Normal high-density lipoprotein (nHDL) can induce angiogenesis in healthy individuals. However, HDL from patients with coronary artery disease undergoes various modifications, becomes dysfunctional (dHDL), and loses its ability to promote angiogenesis. Here, we identified a long non-coding RNA, HDRACA, that is involved in the regulation of angiogenesis by HDL. In this study, we showed that nHDL downregulates the expression of HDRACA in endothelial cells by activating WW domain-containing E3 ubiquitin protein ligase 2, which catalyzes the ubiquitination and subsequent degradation of its transcription factor, Kruppel-like factor 5, via sphingosine 1-phosphate (S1P) receptor 1. In contrast, dHDL with lower levels of S1P than nHDL were much less effective in decreasing the expression of HDRACA. HDRACA was able to bind to Ras-interacting protein 1 (RAIN) to hinder the interaction between RAIN and vigilin, which led to an increase in the binding between the vigilin protein and proliferating cell nuclear antigen (PCNA) mRNA, resulting in a decrease in the expression of PCNA and inhibition of angiogenesis. The expression of human HDRACA in a hindlimb ischemia mouse model inhibited the recovery of angiogenesis. Taken together, these findings suggest that HDRACA is involved in the HDL regulation of angiogenesis, which nHDL inhibits the expression of HDRACA to induce angiogenesis, and that dHDL is much less effective in inhibiting HDRACA expression, which provides an explanation for the decreased ability of dHDL to stimulate angiogenesis.
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Lipoproteínas HDL , ARN Largo no Codificante , Ratones , Animales , Humanos , Lipoproteínas HDL/genética , Lipoproteínas HDL/metabolismo , Antígeno Nuclear de Célula en Proliferación , ARN Largo no Codificante/genética , Células Endoteliales/metabolismo , Neovascularización Fisiológica/genéticaRESUMEN
Based on stable isotope technology and a PMF model, the pollution characteristics and sources of carbon and nitrogen components in ambient PM2.5 in Huangshi City were explored. The results showed that the total carbon concentration[ρ(TC)] and the total carbon isotopic composition (δ13CTC) in ambient PM2.5 in Huangshi City both showed seasonal variation characteristics of being high in winter and low in summer, with values of (4.4±1.2) µg·m-3 and (-26.3±0.5) in summer and (9.9±3.5) µg·m-3 and (-25.5±0.5) in winter, respectively. The total nitrogen concentration[ρ(TN)]was significantly lower in summer[(9.1±9.1) µg·m-3]than that in winter[(62.4±26.4) µg·m-3], whereas the total nitrogen isotopic composition (δ15NTN) was obviously enriched in summer[(12.8±1.9)]compared with that in winter[(2.9±4.0)]. In addition to the contribution from local sources, the carbon and nitrogen components were mainly affected by the short-range regional emission in northern Hunan and the long-distance transport in the northwest. The MixSIAR model and the PMF model indicated that the vehicle emission source was the main source of carbon components in PM2.5, with contribution rates of 38.9% and 39.3%, respectively. MixSIAR results showed that NOx emission sources had a greater impact on nitrogen components in PM2.5 of different seasons than NH3 emission sources, and their contribution was higher in summer (80%) than that in winter (66.8%), among which the NOx emissions from coal combustion (summer:36.1%; winter:20.2%) had the largest contribution. By contrast, the PMF model indicated that the main source of nitrogen components was vehicle emissions (59.8%). Combining multiple models to overcome the uncertainty and subjectivity of single-model analysis can provide a theoretical basis for actively controlling and reducing fine particulate matter emissions and effectively dealing with urban aerosol pollution.
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Based on the daily average concentration of PM2.5, social influencing factor data, and meteorological data of 11 cities in Shanxi Province from 2015 to 2019, the concentration period of PM2.5 was determined using wavelet transform. The correlation between PM2.5 and social influencing factors and meteorological factors was explored respectively through Spearman correlation and the wavelet coherence spectrum, and the main influencing factors of long-term and short-term management and control of PM2.5 were determined. The results showed that the concentration of PM2.5 in Shanxi Province showed an upward trend from 2015 to 2017, with an average annual increase rate of 4.3% and a downward trend from 2018 to 2019, with an average annual decrease rate of 4.2%. The average concentration of PM2.5 showed a "U" distribution, with the highest value in January (95 µg·m-3) and the lowest in August (34 µg·m-3); the average value in winter was approximately twice that in summer. The ρ(PM2.5) in southern cities such as Linfen was 62 µg·m-3, and the average value in Datong and other northern cities was 45 µg·m-3, which was high in the south and low in the north. There were significant periodic changes in PM2.5 concentration in the 11 cities, including a long period of approximately 293 d and a short period of approximately 27 d. Among them, the energy consumption level and industrial structure were the strong driving factors affecting the PM2.5 concentration in the long period of Shanxi Province. In the short period, it was greatly affected by the change in atmospheric circulation, and different cities were affected by typical meteorological factors. Linfen, Yuncheng, Datong, Shuozhou, and Xinzhou were vulnerable to wind speed; Jinzhong and Luliang were vulnerable to temperature; and Taiyuan, Jincheng, Yangquan, and Changzhi were uniquely and significantly affected by relative humidity. Therefore, industrial structure adjustment and energy structure adjustment are key to the long-term control of atmospheric PM2.5 and the long-term improvement of air quality in Shanxi Province. The differential impact of different urban meteorological factors on PM2.5 should be considered when carrying out short-term regional joint prevention and control.
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Contaminantes Atmosféricos , Contaminación del Aire , Contaminantes Atmosféricos/análisis , Contaminación del Aire/análisis , China/epidemiología , Ciudades , Monitoreo del Ambiente , Material Particulado/análisis , Estaciones del Año , Análisis de OndículasRESUMEN
Volatile organic compounds (VOCs) were collected at three environmental sampling sites in Yangquan and quantified by gas chromatography-mass selective detector/flame ionization detector(GC-MSD/FID). The VOC sources were identified by diagnostic ratios and positive matrix factorization (PMF), and environmental impact of VOCs on O3 and secondary organic aerosol (SOA) were evaluated. The results showed that the average VOC concentration was (82.1±22.7) µg·m-3, with alkanes being the most abundant group (51.8%), followed by aromatics (17.8%), alkenes (8.0%), and alkynes (3.8%). The diurnal variation of VOCs exhibited a bimodal trend, with twin peaks appearing at 08:00-10:00 and 18:00-20:00, falling to a valley at 12:00-14:00. The results for benzene/toluene (2.1±1.3) and isopentane/n-pentane (1.7±0.6) showed that the ambient VOCs may be influenced by coal combustion and vehicular emissions. Six sources were extracted by PMF:coal combustion (34.9%), vehicle emissions (18.2%), gasoline evaporation (15.2%), industrial emissions (13.6%), biogenic emissions (9.2%), and solvent usage (9.0%). The average concentration of ozone formation potential (OFP) was 156.6 µg·m-3, with the highest contribution from alkenes, while the average concentration of secondary organic aerosol formation potential (SOAp) was 68.7 µg·m-3, mainly from aromatics (93.4%). In summary, coal combustion was the most abundant source of VOCs, and accelerating the management of coal gangue and energy structure readjustment are the key points to address. Meanwhile, restricting the VOCs from vehicle emissions, gasoline evaporation, and industrial emissions is also required.
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The pattern of decreased prefronto-thalamic connectivity and increased sensorimotor-thalamic connectivity has been consistently documented in schizophrenia. However, whether this thalamo-cortical abnormality pattern is of genetic predisposition remains unknown. The present study for the first time aimed to investigate the common and distinct characteristics of this circuit in schizophrenia patients and their unaffected siblings who share half of the patient's genotype. Totally 293 participants were recruited into this study including 94 patients with schizophrenia, 96 their healthy siblings, and 103 healthy controls scanned using gradient-echo echo-planar imaging at rest. By using a fine-grained atlas of thalamus with 16 sub-regions, we mapped the thalamocortical network in three groups. Decreased thalamo-prefronto-cerebellar connectivity was shared between schizophrenia and their healthy siblings, but increased sensorimotor-thalamic connectivity was only found in schizophrenia. The shared thalamo-prefronto-cerebellar dysconnectivity showed an impressively gradient reduction pattern in patients and siblings comparing to controls: higher in the controls, lower in the patients and intermediate in the siblings. Anatomically, the decreased thalamic connectivity mostly centered on the pre-frontal thalamic subregions locating at the mediodorsal nucleus, while the increased functional connectivity with sensorimotor cortices was only observed in the caudal temporal thalamic subregion anchoring at the dorsal and ventral lateral nuclei. Moreover, both decreased thalamo-prefronto-cerebellar connectivity and increased sensorimotor-thalamic connectivity were related to clinical symptoms in patients. Our findings extend the evidence that the decreased thalamo-prefronto-cerebellar connectivity may be related to the high genetic risk in schizophrenia, while increased sensorimotor-thalamic connectivity potentially represents a neural biomarker for this severe mental disorder.