Summary
Background
Autophagy and neutrophil extracellular DNA traps (NETs) are implicated in asthma; however, their roles in asthma pathogenesis have not been elucidated.
Objectives
We compared ...autophagy and NET production levels from peripheral blood neutrophils (PBNs) of patients with severe asthma (SA) and non‐severe asthma (NSA). Additionally, we investigated the inflammatory effects of NETs on human airway epithelial cells (AECs) and peripheral blood eosinophils (PBEs).
Methods
Peripheral blood neutrophils from patients with SA (n = 30) and NSA (n = 38) were treated with interleukin (IL)‐8 (100 ng/mL). Autophagy (light chain 3‐II expression) and NET production levels were evaluated by Western blot, immunofluorescence microscopy, and PicoGreen assay. The effects of NETs on AECs were assessed by investigating cell death, cell detachment, expression of occludin and claudin‐1, and IL‐8 production; the effects of NETs on PBEs were examined by investigating the activation and release of eosinophil cationic protein (ECP) and eosinophil‐derived neurotoxin (EDN).
Results
Untreated and IL‐8‐treated PBNs from the SA group produced higher autophagy and NET levels compared with those from the NSA group (P < 0.01). IL‐8 increased autophagy and NET levels in PBNs from the SA group, but not from the NSA group. NET levels were correlated with autophagy levels in PBNs (P < 0.001). IL‐8‐induced NET production levels negatively were correlated with FEV1/FVC (r = −0.700, P = 0.016). NETs induced cell death, detachment, degradation of occludin and claudin‐1, and IL‐8 production from AECs. Higher levels of NET‐induced ECP and EDN were released from PBEs in SA compared with NSA groups.
Conclusions and Clinical Relevance
Neutrophil autophagy and NETs could enhance asthma severity by damaging airway epithelium and triggering inflammatory responses of AECs and PBEs. Modulating neutrophil autophagy and NET production may be a new target therapy for SA.
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•UV-LED/TNAs could be efficient for photocatalytic degradation of metoprolol (MTP).•Morphology and crystalline composition of TNAs have impact on MTP degradation.•Operational ...parameters affecting UV-LED/TNAs MTP degradation were studied.•Bicarbonate ions were found to be able to quench conduction band electrons.•MTP degradation mechanisms in UV-LED/TNAs treatment was elucidated.
The aim of this study was to evaluate the use of self-organized TiO2 nanotube arrays (TNAs) as immobilized catalyst and UV-LED as light source (UV-LED/TNAs) for photocatalytic degradation of the β-blocker metoprolol (MTP) from aqueous solution. Firstly we employed electrochemical anodization to synthesize self-organized TNAs, and the effect of anodization potential and annealing temperature was examined. Characterization by SEM demonstrated a linear relation between the diameter of TiO2 nanotubes produced and the anodization potential, while Raman measurement revealed the vital role of annealing on crystallographic composition of the anodic produced TiO2 nanotubes. Regarding their performance in photocatalytic MTP degradation, surface morphology and crystallographic composition of the TNAs were found to impose crucial influence: only TNAs with diameter not smaller than 53nm enabled rapid MTP degradation, and highest MTP degradation was obtained when a mixture of anatase and rutile were present in the TNAs. Secondly, the effect of operational parameters, i.e initial MTP concentration, pH, was investigated. Initial MTP concentration at low level had no detrimental effect on the process performance. Rapid MTP degradation and high total removal were achieved in a wide pH range (3–11). To evaluate the applicability of TNAs for water treatment, experiments were first carried out in the presence of three different commonly present water constituents, i.e bicarbonate ions, phosphate ions, and natural organic matters (NOMs). The results show that bicarbonate and phosphate ions have no inhibitory effect at concentration levels up to 200mg/L, and NOMs exhibit detrimental effect when their concentration exceeds 5mg/L. The total removal MTP degradation reduced from 87.09±0.09% to 62.05±0.08% when tap water samples were applied, demonstrating reasonable efficacy for practical applications. Regarding the degradation mechanism, formic acid and tert-butanol were added as scavenger for photo-generated holes (h+) and hydroxyl radicals (·OH), respectively. The obtained results demonstrate that primary degradation process occurred in liquid phase with participation of hydroxyl radicals in the liquid phase (·OH liquid), while smaller portion of MTP were degraded on the catalysis surface via reaction with h+ and hydroxyl radicals adsorbed on the catalyst surface (·OH surface). Other reactive species, e.g photo generated electrons and superoxide radical anions, did also play a minor role in MTP degradation. The mechanistic aspect was further confirmed by identification of degradation products by LC–MS/MS. The TNAs exhibited good stability after repeated use under varied operation conditions.
Chitin deacetylases (CDAs) are enzymes required for one of the pathways of chitin degradation, in which chitosan is produced by the deacetylation of chitin. Bioinformatic investigations with genomic ...and transcriptomic databases identified four genes encoding CDAs in Nilaparvata lugens (NlCDAs). Phylogenetic analysis showed that insect CDAs were clustered into five major groups. Group I, III and IV CDAs are found in all insect species, whereas the pupa‐specific group II and gut‐specific group V CDAs are not found in the plant‐sap/blood‐sucking hemimetabolous species from Hemiptera and Anoplura. The developmental and tissue‐specific expression patterns of four NlCDAs revealed that NlCDA3 was a gut‐specific CDA, with high expression at all developmental stages; NlCDA1, NlCDA2 and NlCDA4 were highly expressed in the integument and peaked periodically during every moulting, which suggests their roles in chitin turnover of the insect old cuticle. Lethal phenotypes of cuticle shedding failure and high mortality after the injection of double‐stranded RNAs (dsRNAs) for NlCDA1, NlCDA2 and NlCDA4 provide further evidence for their functions associated with moulting. No observable morphological and internal structural abnormality was obtained in insects treated with dsRNA for gut‐specific NlCDA3.
The accumulation of myeloid-derived suppressor cells (MDSCs) has been observed in solid tumors and is correlated with tumor progression; however, the underlying mechanism is still poorly understood. ...In this study, we identified a mechanism by which tumor cells induce MDSC accumulation and expansion in the bladder cancer (BC) microenvironment via CXCL2/MIF-CXCR2 signaling. Elevated expression of CXCL2 and MIF and an increased number of CD33
MDSCs were detected in BC tissues, and these increases were significantly associated with advanced disease stage and poor patient prognosis (P<0.01). A positive association was observed between CXCL2 or MIF expression and the number of tumor-infiltrating CD33
MDSCs (P<0.01). Subsequently, we demonstrated that CD45
CD33
CD11b
HLA-DR
MDSCs from fresh BC tissues displayed high levels of suppressive molecules, including Arg1, iNOS, ROS, PDL-1 and P-STAT3, and stronger suppression of T-cell proliferation. Interestingly, these CD45
CD33
CD11b
HLA-DR
MDSCs exhibited increased CXCR2 expression compared with that in peripheral blood from BC patients or healthy controls (P<0.05). Chemotaxis assay revealed that bladder cancer cell line J82 induced MDSC migration via CXCL2/MIF-CXCR2 signaling in vitro. Mechanistic studies demonstrated that J82-induced MDSC trafficking and CXCR2 expression were associated with increased phosphorylation of p38, ERK and p65. Conversely, inhibition of the phosphorylation of p38, ERK or p65 decreased J82-induced MDSC trafficking and CXCR2 expression. CXCL2/MIF-stimulated activation of the mitogen-activated protein kinase and nuclear factor kappa B pathways in MDSCs was MyD88 dependent. Overall, our results identify the CXCL2/MIF-CXCR2 axis as an important mediator in MDSC recruitment and as predictors and potential therapeutic targets in BC patients.
The epithelial-mesenchymal transition (EMT) is crucial to cancer progression and metastasis. Although multiple cellular miRNAs have been identified to regulate the EMT and metastasis in cancers, the ...role of viral miRNAs in cancer progression remains largely unknown. Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-associated malignancy typically characterized by its early metastasis. In the present study, we have discovered the involvement of a viral miRNA, EBV-miR-BART7-3p, in the EMT and metastasis of NPC cells. Initially, we observed that EBV-miR-BART7-3p was highly expressed in NPC and positively correlated with lymph node metastasis and clinical stage of NPC. Subsequently, we demonstrated that EBV-miR-BART7-3p enhanced cell migration/invasion in vitro, cancer metastasis in vivo, and particularly the EMT characterized by loss of epithelial markers and gain of mesenchymal features in NPC cells. Furthermore, mechanistic studies disclosed that EBV-miR-BART7-3p targeted a major human tumor suppressor PTEN, modulating PI3K/Akt/GSK-3β signaling and eventually leading to the high expression and nuclear accumulation of Snail and β-catenin, which favor EMT. Knockdown of PTEN could phenocopy the effect of EBV-miR-BART7-3p, whereas re-expression of PTEN resulted in a phenotypic reversion. Moreover, these findings were supported by an observation of an EBV-positive cell model in which silencing of endogenous EBV-miR-BART7-3p partially attenuated cell migration/invasion and altered EMT protein expression pattern via reverting PI3K/Akt, Snail and β-catenin expression. Thus, this study suggests a novel mechanism by which EBV-miR-BART7-3p modulates the EMT and metastasis of NPC cells, and a clinical implication of EBV-miR-BART7-3p as a potential biomarker or therapeutic target.
The ionized upper layer of Saturn's atmosphere, its ionosphere, provides a closure of currents mediated by the magnetic field to other electrically charged regions (for example, rings) and hosts ...ion-molecule chemistry. In 2017, the Cassini spacecraft passed inside the planet's rings, allowing in situ measurements of the ionosphere. The Radio and Plasma Wave Science instrument detected a cold, dense, and dynamic ionosphere at Saturn that interacts with the rings. Plasma densities reached up to 1000 cubic centimeters, and electron temperatures were below 1160 kelvin near closest approach. The density varied between orbits by up to two orders of magnitude. Saturn's A- and B-rings cast a shadow on the planet that reduced ionization in the upper atmosphere, causing a north-south asymmetry.
Summary
Background
Autophagy and genetic predisposition have been suggested to potentially play roles in the development of asthma. However, little is known about the role of autophagy in the ...pathogenesis of severe asthma.
Objective
We compared autophagy in the sputum granulocytes, peripheral blood cells (PBCs) and peripheral blood eosinophils (PBEs) between patients with severe asthma and those with non‐severe asthma and investigated the functional effects of autophagy.
Methods
We enrolled 36 patients with severe asthma, 14 with non‐severe asthma and 23 normal healthy controls in this study. Sputum granulocytes, PBCs and PBEs were isolated from each subject. Autophagy was evaluated based on the expression of microtubule‐associated protein light chain 3 (LC3) by Western blot, confocal microscopy, transmission electron microscopy and flow cytometry. IL‐8 levels were measured by ELISA. To induce autophagy, HL‐60 cells, human primary small airway epithelial cells (SAECs) and A549 cells were treated with IL‐5, IL‐1β and TNF‐α. To inhibit autophagy, PI3K inhibitors (LY29400 and 3‐methyladenine 3‐MA) and hydroxychloroquine (HCQ) were used. Knockdown of ATG5 and Beclin‐1 was performed in A549 cells, and the therapeutic effects of dexamethasone were evaluated.
Results
Higher autophagy levels were noted in sputum granulocytes, PBCs and PBEs from patients with severe asthma than from patients with non‐severe asthma and healthy controls (P < 0.05 for all). IL‐5 increased autophagy levels in both PBCs and PBEs (P < 0.05). 3‐MA attenuated the increased expression of LC3‐II and eosinophil cationic protein in HL‐60 cells induced by IL‐5 (P = 0.034 for both). Dexamethasone did not affect autophagy levels in PBEs. IL‐1β increased LC3‐II expression and IL‐8 production (P < 0.01) in SAECs, and this was attenuated by LY294002, 3‐MA, HCQ and knockdown of ATG5 and Beclin‐1 (in A549 cells) (P < 0.01).
Conclusions and Clinical Relevance
Autophagy could play a role in the pathogenesis of severe asthma. Autophagy modulation may be a novel therapeutic target for conventional therapy‐resistant severe asthma.
Chitinases are important enzymes required for chitin degradation and reconstruction in insects. Based on a bioinformatics investigation, we identified 12 genes encoding putative chitinase‐like ...proteins, including 10 chitinases (Cht), one imaginal disc growth factor (IDGF) and one endo‐β‐N‐acetylglucosaminidase (ENGase) in the genome of the brown planthopper, Nilaparvata lugens (Hemiptera: Delphacidae). These 12 genes were clustered into nine different groups, with 11 in glycoside hydrolase family 18 groups (groups I‐VIII) and one in the ENGase group. Developmental and tissue‐specific expression pattern analysis revealed that the transcript levels of eight genes peaked periodically during moulting and were mainly expressed in the integument, except NlCht2, NlCht4, NlIDGF and NlENGase. NlCht2, NlIDGF and NlENGase were expressed at all stages with slight periodical changes and mainly expressed in the female reproductive organs in adults, whereas NlCht4 was highly expressed only at the adult stage in the male reproductive organs. Lethal phenotypes were observed in insects challenged by double‐stranded RNAs for NlCht1, NlCht5, NlCht7, NlCht9 and NlCht10 during moulting, suggesting their significant roles in old cuticle degradation. NlCht1 was the most sensitive gene, inducing 50% mortality even at 0.01 ng per insect. Our results illustrate the structural and functional differences of chitinase‐like family genes and provide potential targets for RNA interference‐based rice planthopper management.
Following the Hume–Rothery rules, it is a longstanding notion that atomic size mismatch induces intrinsic residual strains in a common lattice which may cause lattice instability and thus phase ...transition in an alloy. For conventional alloys, such an intrinsic residual strain can be derived with the continuum theory of elasticity; however, lack of distinction between solvent and solute atoms in recently developed high entropy alloys simply defies such an approach. Here, we develop a general self-contained geometric model that enables the calculation of intrinsic residual strains around different sized elements in a multi-component alloy, which links the average lattice constant of the alloy to a few critical geometric variables related to the close atomic packing in that lattice, such as atomic size, atomic fraction and packing density. When applied to glass-forming high entropy alloys and bulk metallic glasses, our model unravels that amorphization occurs when the root-mean-square (R.M.S.) residual strain rises above ∼10%, in good agreement with the Lindemann’s lattice instability criterion. By comparison, the transition from a single- to multi-phase solid solution takes place in crystalline high entropy alloys when the R.M.S. residual strain approaches ∼5%. Our current findings provide a quantitative insight into phase stability in multicomponent alloys, which should be useful in the design of high entropy alloys with desired phases.
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