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• A modified plasticity-creep superposition model was developed to predict the lifetime. • The effects of creep-ratcheting evolution, anelastic recovery and PCR were discussed. • The proposed model can well simulate the evolution of stress–strain during the whole lifetime. The creep-ratcheting behavior of advanced 9–12 % Cr ferritic steel at 600 °C under peak holding time of 0 min, 2 min, 5 min, 10 min, 20 min and 30 min were investigated and a creep-ratcheting constitutive model was developed. Results present that the anelastic strain during the whole creep-fatigue life for various holding time approximately keep constant. However, it decreases rapidly during the last several cycles. Moreover, the primary creep regeneration (PCR) behavior during repeated loading and unloading process was observed. It keeps almost the same with increasing number of cycles and changes slightly for different peak holding time under the same stress amplitude and stress ratio. Additionally, a modified plasticity-creep superposition model was established considering the combination effects of creep damage, ratcheting evolution, anelastic recovery and PCR. The comparison between tested and predicted data shows that the proposed model has high accuracy for the prediction of both creep-ratcheting strain and creep-fatigue lifetime. It is of interest that the proposed model can also well simulate the evolution of stress–strain during the whole lifetime, especially for the reproduction of anelastic creep recovery and PCR along the load history. [ABSTRACT FROM AUTHOR]

Abstract: Toll-like receptor 2 (TLR2) is involved in phagocytosis and autophagy to enhance host innate immune response to bacterial infection. TLR2 has been reported to participate in the recognition of Staphylococcus aureus (S. aureus). However, the role of TLR2 in phagocytosis and autophagy in S. aureus-stimulated macrophages and the underlying mechanisms as yet remain unclear. In the present study, stimulation of mouse macrophage cell line RAW264.7 with S. aureus activated multiple signaling pathways including mitogen-activated protein kinases (MAPKs), myeloid differentiation factor 88 (MyD88), phosphatidylinositide 3-kinase (PI3K) and Rac1 and triggered autophagy process. Knockdown of TLR2 by siRNA significantly reduced phagocytosis and autophagy of macrophages upon S. aureus infection. Interestingly, TLR2 siRNA markedly attenuated S. aureus-induced phosphorylation of c-Jun N-terminal kinase (JNK) but not p38 or extracellular regulated protein kinase (ERK) in macrophages. Similarly, SP600125, a JNK inhibitor, also down-regulated phagocytosis and autophagy in S. aureus-stimulated macrophages. Furthermore, TLR2 siRNA and SP600125 simultaneous treatment showed similar phagocytosis and autophagy compared to that in TLR2 siRNA treatment alone. Collectively, our results indicate that TLR2 may be critical for phagocytosis and autophagy through JNK signaling pathway, and provide an underlying mechanistic link between innate immune receptor and induction of phagocytosis and autophagy in S. aureus-stimulated macrophages. [Copyright &y& Elsevier]

Activation of toll-like receptor (TLR) signaling that initiates an innate immune response to pathogens must be strictly regulated to prevent excessive inflammatory damage in the host. Here, we demonstrate that Mer receptor tyrosine kinase (MerTK) is a negative regulatory molecule in the lipoteichoic acid (LTA)-induced inflammatory response. LTA that activated TLR2 signaling concomitantly induced activation of MerTK signaling in RAW264.7 macrophages, including phosphoinositide 3-kinase (PI3K)/Akt and suppressor of cytokine signaling 3 (SOCS3). Moreover, LTA induced MerTK activation in a time-dependent manner, and LTA-induced MerTK activation was dependent on the ligand Gas6. Additionally, pretreatment with a specific Mer-blocking antibody significantly inhibited LTA-induced phosphorylation of MerTK, while further enhancing LTA-induced phosphorylation of IκB-α and NF-κBp65 as well as production of TNF-α and IL-6. Meanwhile, the antibody blockade of MerTK markedly prevented LTA-induced Akt phosphorylation and SOCS3 expression, both of which were crucial for the inhibition of TLR2-mediated immune response. Collectively, these results suggest, for the first time, that MerTK is an intracellular negative feedback regulator that inhibits the inflammatory response of LTA-stimulated macrophages through the PI3K/Akt pathway and SOCS3 protein. [ABSTRACT FROM AUTHOR]

Background and objective Repeated inhalation of sevoflurane ( SVF) can benefit asthmatic patients by bronchodilation. However, the impact of repeated inhalation of SVF on allergic airway inflammation has not been clarified. This study was aimed at investigating the effects of repeated inhalation of SVF on airway inflammation in mice. Methods Female C57BL/6 mice were sensitized with ovalbumin ( OVA) and treated by inhalation with SVF or vehicle daily for seven consecutive days, immediately followed by OVA challenge. Airway inflammation was evaluated by counting the numbers of different types of inflammatory infiltrates in bronchoalveolar lavage fluid ( BALF), histology, cytokine measurements and mucus production in individual mice. Results In comparison with the OVA group, repeated inhalation of SVF significantly reduced the numbers of total cells, eosinophils, lymphocytes, macrophages and neutrophils ( P < 0.05 to P < 0.01), and the levels of BALF tumour necrosis factor-α and lung high-mobility group box 1 ( P < 0.01), accompanied by elevated levels of BALF interleukin-10 in allergic mice ( P < 0.05). Repeat inhalation of SVF decreased the levels of serum OVA-specific immunoglobulin E ( IgE) and mitigated allergic airway epithelial goblet cell hyperplasia and mucus hypersecretion in allergic mice ( P < 0.01). Conclusions Repeated inhalation of SVF inhibits allergic airway inflammation by reducing inflammatory infiltrates, improving the imbalance of cytokine responses and mitigating allergen-specific IgE responses and goblet cell hyperplasia in mice. [ABSTRACT FROM AUTHOR]

Hypoxia which commonly exists in solid tumors, leads to cancer cells chemoresistance via provoking adaptive responses including autophagy. Therefore, we sought to evaluate the role of autophagy and hypoxia as well as the underlying mechanism in the cisplatin resistance of lung cancer cells. Our study demonstrated that hypoxia significantly protected A549 and SPC-A1 cells from cisplatin-induced cell death in a Hif-1α- and Hif-2α- dependent manner. Moreover, compared with normoxia, cisplatin-induced apoptosis under hypoxia was markedly reduced. However, when autophagy was inhibited by 3-MA or siRNA targeted ATG5, this reduction was effectively attenuated, which means autophagy mediates cisplatin resisitance under hypoxia. In parallel, we showed that hypoxia robustly augmented cisplatin-induced autophagy activation, accompanying by suppressing cisplatin-induced BNIP3 death pathways, which was due to the more efficient autophagic process under hypoxia. Consequently, we proposed that autophagy was a protective mechanism after cisplatin incubation under both normoxia and hypoxia. However, under normoxia, autophagy activation 'was unable to counteract the stress induced by cisplatin, therefore resulting in cell death, whereas under hypoxia, autophagy induction was augmented that solved the cisplatin-induced stress, allowing the cells to survival. In conclusion, augmented induction of autophagy by hypoxia decreased lung cancer cells susceptibility to cisplatin-induced apoptosis. [ABSTRACT FROM AUTHOR]

Abstract: Aims: Glucocorticoids (GCs) are frequently used to treat various pulmonary diseases, which are typically accompanied by hypoxia. Whether hypoxia influences the effects of GCs on human airway cells remains unclear. The aim of the present study was to characterize changes in the expression levels of two isoforms of the glucocorticoid receptor (GR) and to evaluate the anti-inflammatory actions of GCs under hypoxic conditions in A549 cells. Main methods: A549 cells were exposed to normoxic or hypoxic conditions for 24, 48 and 72 h. Morphological alterations of cells were captured using a differential interference contrast microscope (DIC), and cell cycle distribution was estimated by flow cytometry. Real-time quantitative polymerase chain reaction and western blot were used to determine the mRNA and protein expression levels of GRα and GRβ. Radioimmunoassay (RIA) for interleukin (IL)-8 was used to assess the anti-inflammatory actions of GCs after cells were stimulated with lipopolysaccharide (LPS). Key findings: After cells were exposed to hypoxic conditions for 48 h, visible morphological alterations in the cells were observed. Cell cycle analysis showed that the number of cells in G1 phase increased significantly under hypoxia compared to the normoxic conditions. Hypoxia caused a time-dependent decrease in both mRNA and protein expression levels for GRα, but not GRβ. Furthermore, when exposed to hypoxia for 48 h, the inhibitory effects of dexamethasone on LPS-stimulated IL-8 release were attenuated. Significance: These results indicate that hypoxia impairs the anti-inflammatory actions of GCs in A549 cells, which could be attributed to down-regulation of GRα expression under hypoxic conditions. [Copyright &y& Elsevier]