BackgroundAirway remodeling is a repair process that occurs after injury resulting in increased airway hyper-responsiveness in asthma. Thymic stromal lymphopoietin (TSLP), a vital cytokine, plays a critical role in orchestrating, perpetuating and amplifying the inflammatory response in asthma. TSLP is also a critical factor in airway remodeling in asthma.ObjectivesTo examine the role of TSLP-induced cellular senescence in airway remodeling of asthma in vitro and in vivo.MethodsCellular senescence and airway remodeling were examined in lung specimens from patients with asthma using immunohischemical analysis. Both small molecule and shRNA approaches that target the senescent signaling pathways were used to explore the role of cellular senescence in TSLP-induced airway remodeling in vitro. Senescence-Associated β-galactosidase (SA-β-Gal) staining, and BrdU assays were used to detect cellular senescence. In addition, the Stat3-targeted inhibitor, WP1066, was evaluated in an asthma mouse model to determine if inhibiting cellular senescence influences airway remodeling in asthma.ResultsActivation of cellular senescence as evidenced by checkpoint activation and cell cycle arrest was detected in airway epithelia samples from patients with asthma. Furthermore, TSLP-induced cellular senescence was required for airway remodeling in vitro. In addition, a mouse asthma model indicates that inhibiting cellular senescence blocks airway remodeling and relieves airway resistance.ConclusionTSLP stimulation can induce cellular senescence during airway remodeling in asthma. Inhibiting the signaling pathways of cellular senescence overcomes TSLP-induced airway remodeling.
Background Macrophage-inducible C-type lectin [Mincle] signalling plays a proinflammatory role in different organs such as the brain and liver, but its role in intestinal inflammation, including Crohn’s disease [CD], remains unknown. Methods The characteristics of Mincle signalling expression in CD patients and experimental colitis were examined. The functional role of Mincle signalling in the intestine was addressed in experimental colitis models in vivo by using Mincle knock-out [Mincle-/-] mice. In addition, neutralising anti-Mincle antibody, downstream spleen tyrosine kinase [Syk] inhibitor, and Mincle pharmacological agonist were used to study the Mincle signalling in intestine. Bone marrow-derived macrophages were collected from mice and used to further verify the effect of Mincle signalling in macrophages. Results This study has shown that Mincle signalling was significantly elevated in active human CD and experimental colitis, and macrophages were the principal leukocyte subset that upregulate Mincle signalling. Mincle deficiency and Syk pharmacological inhibition ameliorated the colitis by reducing induced macrophage pyroptosis, and activation of Mincle with the agonist aggravated the intestinal inflammation. The ex vivo studies demonstrated that activation of Mincle signalling promoted the release of proinflammatory cytokines, whereas its absence restricted release of proinflammatory cytokines from pyroptosis of macrophages. In addition, Mincle/Syk signalling in macrophages could promote the production of chemokines to recruit neutrophils by activating mitogen-activated protein kinase [MAPK] during intestinal inflammation. Conclusions Mincle signalling promotes intestinal mucosal inflammation by inducing macrophage pyroptosis. Modulation of the Mincle/Syk axis emerges as a potential therapeutic strategy to target inflammation and treat CD.
Esophagojejunal anastomotic leakage (EJAL) is considered to be one of the most serious complications after total gastrectomy (TG), despite improvements in surgical instruments and technique. The occurrence of EJAL would cause poorer quality of life, prolonged hospital stay, and increased surgery-related costs and mortality. Although there is ever-increasing knowledge about EJAL, the optimal management is controversial. In the present review, we aim to demonstrate the effective management by focus on the possible risk factors, potentially useful preventive strategies, and several kinds of treatments in esophagojejunal anastomotic leakage after total gastrectomy for gastric cancer.
Long–non‐coding RNAs (lncRNA) AWPPH promotes the progression of liver and bladder cancer, indicating its oncogenic role. The current study aimed to explore the involvement of AWPPH in triple‐negative breast cancer (TNBC). In the current study, we found that plasma levels of lncRNA AWPPH and microRNA‐21 (miRNA‐21) were upregulated in patients with TNBC than in healthy controls, and the upregulation of plasma lncRNA AWPPH and miRNA‐21 distinguished early‐stage patients with TNBC from healthy controls. Plasma levels of lncRNA AWPPH and miRNA‐21 were significantly and positively correlated in both patients with TNBC and healthy controls. LncRNA AWPPH and miRNA‐21 overexpression led to promoted cancer cells proliferation and improved cancer cell viability under carboplatin treatment, while lncRNA AWPPH small interfering RNA (siRNA) silencing played an opposite role. In addition, miRNA‐21 overexpression attenuated the effects of lncRNA AWPPH siRNA silencing on of cancer cell behaviors. LncRNA AWPPH overexpression led to upregulated miRNA‐21 in TNBC cells, while miRNA‐21 overexpression also led to significantly upregulated lncRNA AWPPH expression. Therefore, lncRNA AWPPH and miRNA‐21 may regulate cancer cell proliferation and chemosensitivity in TNBC by interacting with each other.
BackgroundTo evaluate the diagnostic efficacy of prothrombin induced by the absence of vitamin K or antagonist-II (PIVKA-II) for early stage hepatitis virus B (HBV) related hepatocellular carcinoma (HCC).MethodsSerums levels of PIVKA-II and a-Fetoprotein (AFP) was detected and compared in 113 patients with clinical confirmed Barcelona Clinic Liver Cancer (BCLC) stage 0-A HBV-related HCC and 161 chronic hepatitis B (CHB) patients. Diagnostic efficiencies as well as cut-off values of PIVKA-II, AFP and combination of the two markers were calculated using receiver operator curve (ROC) analysis.ResultsThe mean level of PIVKA-II among HCC patients were 79.64 ± 149.88, significantly higher than control group (P < 0.001). ROC results showed that among those AFP-negative HCC patients, the area under ROC curve (AUROC) of PIVKA-II was 0.73 (95%CI 0.640–0.815, P < 0.001). Among HCC patients diagnosed with small HCC (tumor size ≤2 cm), the AUROC of PIVKA- II was 0.692 (95%CI 0.597–0.788, P < 0.001). To evaluate the diagnostic value of PIVKA-II in HCC patient, all CHB cases were pooled together as control for analysis. The AUROC of PIVKA-II was 0.756 (95%CI 0.698–0.814, P < 0.001), and the optimal cutoff value of PIVKA-II was 32.09 mAU/ml with sensitivity of 52.21% and specificity of 81.49%. When serum levels of PIVKA-II and AFP were combined to obtain a new marker for HCC diagnosis, PIVKA-II + AFP further increased diagnostic efficiency, with AUROC of 0.868 (95%CI 0.822–0.913), higher than that of AFP (P < 0.01) or PIVKA-II (P < 0.001) alone. In addition, we found that HCC patients in poorly differentiated- undifferentiated group and in microvascular invasion group had higher levels of PIVKA-II. Multivariate analysis showed that high serum PIVKA-II level (OR = 1.003, 95%CI 1.001–1.007, P = 0.047) was an independent risk factor for microvascular invasion in HCC patients.ConclusionSerum PIVKA-II level is a potential marker for early diagnosis of HCC and microvascular invasion. The use of PIVKA-II may improve assessment of tumor prognosis and guide development of therapeutic strategy.
The aim of the present study was to investigate the regulatory mechanism of nuclear factor (NF)-κB on polymorphonuclear neutrophil (PMN) accumulation and the inflammatory response in lung tissues with acute respiratory distress syndrome (ARDS), as well as the therapeutic effect of pyrrolidine dithiocarbamate (PDTC). Mouse models of ARDS were established by intraperitoneal injection of lipopolysaccharide (LPS). BALB/c mice were divided into control, LPS and PDTC + LPS groups. The expression of PMN adhesion molecules, CD11b/CD18 and intercellular adhesion molecule-1 (ICAM-1), were detected by immunohistochemistry, while the protein expression levels of NF-κB p65 in the lung tissue were analyzed by western blot analysis. In addition, flow cytometry was used to investigate the apoptosis rate of PMNs in the bronchoalveolar fluid, and the expression levels of interleukin (IL)-1β, IL-8 and tumor necrosis factor (TNF)-α and myeloperoxidase (MPO) activity were also determined. Following an intraperitoneal injection of LPS, alveolar septum rupture, pulmonary interstitial hyperemia and PMN infiltration in the alveolar was observed. The protein expression of p65 in the pulmonary cytoplasm decreased, while the expression of p65 in the nucleus increased. The levels of IL-8, IL-1β and TNF-α increased and the high expression status was maintained for 24 h. As the time increased, CD11b/CD18 and ICAM-1 expression increased, as well as MPO activity, while the apoptosis of PMNs was delayed. Compared with the LPS group, the expression of p65 in the pulmonary cytoplasm and the PMN apoptosis rate increased following PDTC intervention, while the expression of p65 in the nucleus decreased, as well as the expression levels of the cytokines and MPO activity. Therefore, PDTC reduced the production of inflammatory cytokines via the NF-κB pathway, which reduced the activation of PMNs in the lung tissue and promoted PMN apoptosis.
Crohn’s disease (CD) is an intestinal immune-dysfunctional disease. Extracellular vesicles (EVs) are membrane-enclosed particles full of functional molecules, e.g., nuclear acids. Recently, EVs have been shown to participate in the development of CD by realizing intercellular communication among intestinal cells. However, the role of EVs carrying double-strand DNA (dsDNA) shed from sites of intestinal inflammation in CD has not been investigated. Here we isolated EVs from the plasma or colon lavage of murine colitis and CD patients. The level of exosomal dsDNA, including mtDNA and nDNA, significantly increased in murine colitis and active human CD, and was positively correlated with the disease activity. Moreover, the activation of the STING pathway was verified in CD. EVs from the plasma of active human CD triggered STING activation in macrophages in vitro. EVs from LPS-damaged colon epithelial cells were also shown to raise inflammation in macrophages via activating the STING pathway, but the effect disappeared after the removal of exosomal dsDNA. These findings were further confirmed in STING-deficient mice and macrophages. STING deficiency significantly ameliorated colitis. Besides, potential therapeutic effects of GW4869, an inhibitor of EVs release were assessed. The application of GW4869 successfully ameliorated murine colitis by inhibiting STING activation. In conclusion, exosomal dsDNA was found to promote intestinal inflammation via activating the STING pathway in macrophages and act as a potential mechanistic biomarker and therapeutic target of CD.
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