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Bronchial asthma poses a considerable burden on both individual patients and public health. Sesamin is a natural lignan that relieves asthma. However, the potential regulatory mechanism has not been fully validated. In this study, we revealed the mechanism of sesamin in inhibiting airway inflammation of asthma. In cockroach extract (CRE)-induced asthmatic mice, sesamin efficiently inhibited inflammatory cell infiltration, expressions of total and CRE-specific IgE in serum, and inflammatory cytokines (including IL-4, 5, 13) in bronchoalveolar lavage fluid. Further study revealed that sesamin inhibited Th2 cells in the mediastinal lymph nodes and spleen, the expression of PTEN-induced putative kinase 1 (PINK1) and Parkin, and apoptosis of lung airway epithelial cells.

The aim of this study is to investigate the protective effects of glaucocalyxin A (GLA) on airways in mouse models of asthma, concerning the inflammatory mediators, Th1/Th2 subgroup imbalance, and Toll-like receptor 4 (TLR4)/NF-κB signaling pathway. Hematoxylin and eosin/periodic acid–Schiff staining was used to observe the pathological changes in lung tissues. Inflammatory cytokine contents in the bronchoalveolar lavage fluid were detected by enzyme-linked immunosorbent assay. Protein expression levels were detected with Western blot, immunohistochemistry, and immunofluorescence. In vivo studies showed that, in ovalbumin (OVA)-induced asthmatic mouse models, the GLA treatments reduced the airway hyperresponsiveness and the secretion of inflammatory cells, declined the proliferation of goblet cells, decreased the levels of IL-4, IL-5, and IL-13, and increased the contents of interferon-γ and IL-12. Moreover, GLA inhibited the protein expression levels of TLR4, MyD88, TRAF6, and NF-κB in OVA-induced asthmatic mouse models. Further in vitro studies showed that GLA inhibited the expression of NF-κB, p-IκBα, tumor necrosis factor-α, IL-6, and IL-1β and blocked the nuclear transfer of NF-κB in lipopolysaccharide-stimulated RAW264.7 macrophages. Conclusively, GLA can inhibit the inflammatory responses in OVA-induced asthmatic mice and inhibit the release of inflammatory factors in LPS-induced RAW264.7 macrophages, which may be related to the inhibition of TLR4/NF-κB signaling pathway.

Introduction Pterostilbene (Pts) may be used for allergic asthma treatment. The AMPK/Sirt1 and Nrf2/HO‐1 pathways are potential targets for asthma treatement. However, the relationship between Pts and AMPK/Sirt1 and Nrf2/HO‐1 pathways in asthma is unclear. Herein, we aim to explore the pharmacological effects of Pts on oxidative stress and allergic inflammatory response as well as the mechanism involving AMPK/Sirt1 and Nrf2/HO‐1 pathways. Methods Asthma model was established in mice with ovalbumin (OVA). The model mice were treated by different concentrations of Pts. Lung pathological changes were observed through histological staining. In vitro, lipopolysaccharide (LPS)‐stimulated 16HBE cells were treated with Pts. The siAMPKα2, siSirt1 and siNrf2 knockdown, and treatment with compound C, EX‐527 or ML385 were also performed in 16HBE cells. Enzyme‐linked immunosorbent assay was used to detect interleukin‐4 (IL‐4), IL‐13, IL‐5, total and OVA specific immunoglobulin E (IgE), and interferon γ (IFN‐γ). Pneumonography was used to measure the airway hyperreactivity (AHR). Superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA) levels were also detected. Immunohistochemistry, Western blot and immunofluorescence were used to measure protein levels. Results Pts significantly attenuated lung inflammatory cell infiltration and goblet cell proliferation. Meanwhile, Pts treatment could reduce IL‐4, IL‐13, IL‐5, and IgE (total and OVA specific) levels in the asthma model mice. However, IFN‐γ in bronchoalveolar lavage fluid was elevated. In addition, Pts reduced AHR. We also found that Pts treatment promoted serum SOD and CAT, and reduced MDA. In vitro results showed that Pts treatment promoted iNOS, TNF‐α, COX‐2, IL‐1β, and IL‐6 expressions in 16HBE cells, prolonged G0/G1 phase of the cell cycle, and resulted in a shortened G2M phase. Moreover, we found that Pts promoted the phosphorylation of AMPK in 16HBE, and meanwhile inhibited the increase of ROS induced by LPS. Additionally, Pts treatment inhibited p‐AMPK, Sirt1, Nrf2 and HO‐1, which in turn leads to the alleviation of AMPK/Sirt1 and Nrf2/HO‐1 pathways. Conclusion Pts alleviated oxidative stress and allergic airway inflammation via regulation of AMPK/Sirt1and Nrf2/HO‐1 signaling pathways., Pts can relieve asthma by suppressing oxidative stress through the AMPK/Sirt1 and Nrf2/HO‐1 signaling pathways. Thus, Pts might be a potential anti‐inflammatory drug for the treatment of asthma.

Glaucocalyxin A (GLA) has various pharmacological effects like antioxidation, immune regulation, and antiatherosclerosis. Here, in this study, the effect and mechanism of GLA on mast cell degranulation were studied. The results of the anti-DNP IgE-mediated passive cutaneous anaphylaxis (PCA) showed that GLA dramatically inhibited PCA in vivo, as evidenced by reduced Evans blue extravasation and decreased ear thickness. In addition, GLA significantly reduced the release of histamine and β-hexosaminidase, calcium influx, cytokine (IL-4, TNF-α, IL-1β, IL-13, and IL-8) production in the RBL-2H3 (rat basophilic leukemia cells), and RPMCs (peritoneal mast cells) in vitro. Moreover, we further investigated the regulatory mechanism of GLA on antigen-induced mast cells by Western blot, which showed that GLA inhibited FcεRI-mediated signal transduction and invalidated the phosphorylation of Syk, Fyn, Lyn, Gab2, and PLC-γ1. In addition, GLA inhibited the recombinant mouse high mobility group protein B1- (HMGB1-) induced mast cell degranulation through limiting nuclear translocation of NF-κBp65. Treatment of mast cells with siRNA-HMGB1 significantly inhibited HMGB1 levels, as well as MyD88 and TLR4, decreased intracellular calcium levels, and suppressed the release of β-hexosaminidase. Meanwhile, GLA increased NrF2 and HO-1 levels by activating p38MAPK phosphorylation. Consequently, these data suggest that GLA regulates the NrF2/HO-1 signaling pathway through p38MAPK phosphorylation and inhibits HMGB1/TLR4/NF-κB signaling pathway to reduce mast cell degranulation and allergic inflammation. Our findings could be used as a promising therapeutic drug against allergic inflammatory disease.

This study is to investigate the inhibitory effects and mechanisms of DEK‐targeting aptamer (DTA‐64) on epithelial mesenchymaltransition (EMT)‐mediated airway remodelling in mice and human bronchial epithelial cell line BEAS‐2B. In the ovalbumin (OVA)‐induced asthmatic mice, DTA‐64 significantly reduced the infiltration of eosinophils and neutrophils in lung tissue, attenuated the airway resistance and the proliferation of goblet cells. In addition, DTA‐64 reduced collagen deposition, transforming growth factor 1 (TGF‐β1) level in BALF and IgE levels in serum, balanced Th1/Th2/Th17 ratio, and decreased mesenchymal proteins (vimentin and α‐SMA), as well as weekend matrix metalloproteinases (MMP‐2 and MMP‐9) and NF‐κB p65 activity. In the in vitro experiments, we used TGF‐β1 to induce EMT in the human epithelial cell line BEAS‐2B. DEK overexpression (ovDEK) or silencing (shDEK) up‐regulated or down‐regulated TGF‐β1 expression, respectively, on the contrary, TGF‐β1 exposure had no effect on DEK expression. Furthermore, ovDEK and TGF‐β1 synergistically promoted EMT, whereas shDEK significantly reduced mesenchymal markers and increased epithelial markers, thus inhibiting EMT. Additionally, shDEK inhibited key proteins in TGF‐β1‐mediated signalling pathways, including Smad2/3, Smad4, p38 MAPK, ERK1/2, JNK and PI3K/AKT/mTOR. In conclusion, the effects of DTA‐64 against EMT of asthmatic mice and BEAS‐2B might partially be achieved through suppressing TGF‐β1/Smad, MAPK and PI3K signalling pathways. DTA‐64 may be a new therapeutic option for the management of airway remodelling in asthma patients.

Background: The phase 3 studies, VOYAGE 1 and 2, were conducted to assess guselkumab in the treatment of patients with moderate-to-severe psoriasis.Objectives: To investigate the efficacy and safety of guselkumab in Korean patients.Methods: The Korean sub-population of VOYAGE 1 and 2 study patients were included in this analysis. Efficacy and safety were evaluated through Weeks 24 and 28, respectively.Results: Of 126 randomized Korean patients, 30, 63, and 33 received placebo, guselkumab, and adalimumab, respectively. At Week 16, guselkumab was superior to placebo in achieving an Investigator's Global Assessment (IGA) score of 0 or 1 (cleared or minimal; 90.5 vs. 20.0%, p

Background: Macrophages substantially shape the development, progression, and complications of inflammation-driven diseases. Although numerous researches support a critical role for Notch signaling in most inflammatory diseases, there is limited data on the role of Notch signaling in TLR4-induced macrophage activation and the interaction of Notch signaling with other signaling pathways(e.g., the NF-kB pathway during inflammation) in macrophages. Methods and Results: In this study, we confirmed that stimulation with TLR4 ligand LPS up-regulates Notch1 expression in RAW264.7 monocyte/macrophage-like cell line. LPS also induced the expression of Notch target genes Notch1 and Hes1 mRNA in macrophages, suggesting that TLR4 signaling enhances Notch pathway activation. The upregulation of Notch1, NICD, and Hes1 protein by LPS treatment was inhibited by the Notch1 inhibitor of DAPT. The increase of TNF-a, IL-6, and IL-1b induced by LPS was inhibited by DAPT while jagged1, the Notch1 ligand, rescued them. Furthermore, the suppression of Notch signaling by DAPT up-regulated CYLD expression but down-regulated TRAF6, IKKa/bphosphorylation, and subsequently phosphorylation and degradation of IκB-α, indicating the inhibition of TLR4-triggered NF-kB activation by DAPT. Interestingly, DAPT showed no inhibitory effect on the increase of MyD88 expression induced by LPS in our study. Conclusions: Our study shows that the stimulation of macrophages via the TLR4 signaling cascade triggers the activation of Notch1 signaling, which regulates the expression patterns of genes involved in pro-inflammatory responses through by activating NF-kB. It may be dependent on the CYLD-TRAF6-IKK pathway. The Notch1 signaling may be considered as a potential therapeutic target against infectious and inflammatory driven diseases.

We investigated the regulatory role of miR-181b-5p in neutrophilic asthma and its mechanisms by targeting DEK. DEK, matrix metalloproteinase (MMP)-2, and MMP-9 were overexpressed and the miR-181b-5p was decreased in mice with neutrophilic asthma. DEK was a direct target of miR-181b-5p. In mouse model, miR-181b-5p agomir had an inhibitory effect on airway inflammation and remodeling. miR-181b-5p inhibited DEK/p-GSK-3β

MicroRNAs (miRNAs) can participate in airway remodeling by regulating immune molecule expression. Here, we aimed to identify the differential miRNAs involved in airway remodeling. Airway remodeling was induced by ovalbumin in female BALB/C mice. The differentially expressed miRNAs were screened with microarray. GO (Gene Ontology) and KEGG enrichment analysis was performed. The miRNA target gene network and miRNA target pathway network were constructed. Verification with real-time PCR and Western blot was performed. We identified 63 differentially expressed miRNAs (50 up-regulated and 13 down-regulated) in the lungs of ovalbumin-induced airway remodeling mice. Real-time PCR confirmed that 3 miRNAs (mmu-miR-1931, mmu-miR-712-5p, and mmu-miR-770-5p) were significantly up-regulated, and 4 miRNAs (mmu-miR-128-3p, mmu-miR-182-5p, mmu-miR-130b-3p, and mmu-miR-20b-5p) were significantly down-regulated. The miRNA target gene network analysis identified key mRNAs in the airway remodeling, such as Tnrc6b (trinucleotide repeat containing adaptor 6B), Sesn3 (sestrin 3), Baz2a(bromodomain adjacent to zinc finger domain 2a), and Cux1 (cut like homeobox 1). The miRNA target pathway network showed that the signal pathways such as MAPK (mitogen-activated protein kinase), PI3K/Akt (phosphoinositide 3-Kinase/protein kinase B), p53 (protein 53), and mTOR (mammalian target of rapamycin) were closely related to airway remodeling in asthma. Collectively, differential miRNAs involved in airway remodeling (such as mmu-miR-1931, mmu-miR-712-5p, mmu-miR-770-5p, mmu-miR-128-3p mmu-miR-182-5p, and mmu-miR-130b-3p) as well as their target genes (such as Tnrc6b, Sesn3, Baz2a, and Cux1) and pathways (such as MAPK, PI3K/Akt, p53, mTOR pathways) have been identified. Our findings may help to further understand the pathogenesis of airway remodeling.

We investigated whether Panax notoginseng saponin (PNS-R1) attenuates allergic rhinitis (AR) through AMPK/Drp1-mediated mitochondrial fission. AR model was established in mice by Ovalbumin (OVA). In vitro, human nasal epithelial cells (HNEpCs) were stimulated using recombinant human interleukin 13 (IL-13). PNS-R1 was administrated in vivo and in vitro. Then, HE staining of nasal tissue, ELISA detection of immunoglobulin E (IgE) and proinflammatory cytokine levels in serum and nasal lavage fluid, flow cytometry analysis of Th1/Th2 ratio and apoptosis, TUNEL staining, Western blot, detection of reactive oxygen species (ROS) and mitochondrial ROS, immunofluorescence analysis of Tom20 and mitochondrial fission protein Drp1 co-localization, and mitochondrial membrane potential detection, were performed. PNS-R1 attenuated allergic symptoms in AR mice, decreased OVA-specific IgE, IL-4, IL-6, IL-8, IL-13, and TNF-α levels, and restored the Th1/Th2 imbalance. Meanwhile, we found that PNS-R1 treatment significantly reduced apoptosis, ROS production, and co-localization of Tom20 and Drp1 in the nasal epithelium of AR mice. In vitro, we found that PNS-R1 upregulated mitochondrial membrane potential and reduced ROS and mitochondrial ROS production as well as Cleaved-caspase-3/9, Bax, Cyt-c, Apaf-1 expression and mitochondrial fission. Mechanistically, we found that PNS-R1 downregulated Drp1 phosphorylation (Ser 616) and Drp1 translocation in an AMPK-dependent manner, promoted MFN2 expression, and reduced TXNIP, NLRP3, Caspase-1, and IL-1β expression. PNS-R1 may protect mitochondrial integrity by inhibiting AMPK/Drp1 and TXNIP/NLRP3 signaling pathway, thereby alleviating AR symptoms in mice. PNS-R1 may have great potential as a therapeutic agent for AR.

Objectives: Guselkumab, an interleukin-23 antagonist, is approved for self-administration with the UltraSafe Plus™ syringe to treat moderate-to-severe plaque-type psoriasis. We evaluated the effica...

This study is to investigate the effects of imperatorin (IMP) on allergic responses mediated by mast cells, both in vitro and in vivo. Passive cutaneous anaphylaxis (PCA) model was established. Histological detection was performed to assess the ear histology. ELISA and Western blot analysis were used to detect the levels of corresponding cytokines and signalling pathway proteins. IMP decreased the leakage of Evans blue and the ear thickness in the PCA models, in a dose-dependent manner, and alleviated the degranulation of mast cells. Moreover, IMP reduced the expression of TNF-α, IL-4, IL-1β, IL-8, and IL-13. Furthermore, IMP inhibited the phosphorylation levels of Syk, Lyn, PLC-γ1, and Gab2, as well as the downstream MAPK, PI3K/AKT, and NF-κB signaling pathways. In addition, IMP inhibited the mast cell-mediated allergic responses through the Nrf2/HO-1 pathway. IMP attenuates the allergic responses through inhibiting the degranulation and decreasing the expression levels of proinflammatory cytokines in the mast cells, involving the PI3K/Akt, MAPK, NF-κB, and Nrf2/HO-1 pathways.

Introduction: This study aimed to explore the effects and mechanisms of salidroside (SAL) in airway inflammation in asthmatic mice. Methods: Mice were sensitized with ovalbumin (OVA) to establish an asthma model. They were divided into the control group, OVA group, SAL low-dose group (SAL-L), SAL high-dose group (SAL-H), and dexamethasone (DXM) group. The airway reactivity of the mice was measured, and the total cells, neutrophils, eosinophils, and lymphocytes were counted, respectively. The levels of IL-4, IL-5, IL-13, and IFN-γ in bronchoalveolar lavage fluid (BALF) were detected by ELISA. Immunohistochemistry was used to detect the expression levels of p-AMPK, p-Akt, and p-GSK3β. Western blot was used to detect cytokine levels in lung tissue and p-AMPK, p-Akt, and p-GSK3β levels in LPS-induced 16HBE cells. Results: The airway hyperresponsiveness of asthmatic mice in the SAL-H group decreased (p < 0.05), and the total number of cells, neutrophils, eosinophils, and lymphocytes decreased significantly (p < 0.05). In addition, the airways of mice showed airway inflammatory infiltration and goblet cell proliferation, and the corresponding cellular inflammatory factors IL-4, IL-5, and IL-13 were significantly decreased. However, the expression of IFN-γ in BALF and lung tissues was increased (p < 0.05). Moreover, after the mice were treated with SAL, the phosphorylation level of AMPK was significantly increased, which further reduced the phosphorylation levels of Akt and GSK3β (p < 0.05). Both SAL and AMPK inhibitors exerted effects on LPS-induced 16HBE cells, consistent with in vivo results. Conclusion: SAL can inhibit bronchial hyperresponsiveness and reduce tracheal inflammation by increasing AMPK phosphorylation and inhibiting Akt and GSK3β signaling pathways.

Glaucocalyxin A (GLA) has various pharmacological effects like antioxidation, immune regulation, and antiatherosclerosis. Here, in this study, the effect and mechanism of GLA on mast cell degranulation were studied. The results of the anti-DNP IgE-mediated passive cutaneous anaphylaxis (PCA) showed that GLA dramatically inhibited PCA in vivo, as evidenced by reduced Evans blue extravasation and decreased ear thickness. In addition, GLA significantly reduced the release of histamine and β-hexosaminidase, calcium influx, cytokine (IL-4, TNF-α, IL-1β, IL-13, and IL-8) production in the RBL-2H3 (rat basophilic leukemia cells), and RPMCs (peritoneal mast cells) in vitro. Moreover, we further investigated the regulatory mechanism of GLA on antigen-induced mast cells by Western blot, which showed that GLA inhibited FcεRI-mediated signal transduction and invalidated the phosphorylation of Syk, Fyn, Lyn, Gab2, and PLC-γ1. In addition, GLA inhibited the recombinant mouse high mobility group protein B1- (HMGB1-) induced mast cell degranulation through limiting nuclear translocation of NF-κBp65. Treatment of mast cells with siRNA-HMGB1 significantly inhibited HMGB1 levels, as well as MyD88 and TLR4, decreased intracellular calcium levels, and suppressed the release of β-hexosaminidase. Meanwhile, GLA increased NrF2 and HO-1 levels by activating p38MAPK phosphorylation. Consequently, these data suggest that GLA regulates the NrF2/HO-1 signaling pathway through p38MAPK phosphorylation and inhibits HMGB1/TLR4/NF-κB signaling pathway to reduce mast cell degranulation and allergic inflammation. Our findings could be used as a promising therapeutic drug against allergic inflammatory disease.

The phase 3 studies, VOYAGE 1 and 2, were conducted to assess guselkumab in the treatment of patients with moderate-to-severe psoriasis.To investigate the efficacy and safety of guselkumab in Korean patients.The Korean sub-population of VOYAGE 1 and 2 study patients were included in this analysis. Efficacy and safety were evaluated through Weeks 24 and 28, respectively.Of 126 randomized Korean patients, 30, 63, and 33 received placebo, guselkumab, and adalimumab, respectively. At Week 16, guselkumab was superior to placebo in achieving an Investigator's Global Assessment (IGA) score of 0 or 1 (cleared or minimal; 90.5 vs. 20.0%,The efficacy and safety of guselkumab in Korean psoriasis patients through 28 weeks were consistent with findings for the overall VOYAGE 1 and 2 study population.

Objective To investigate whether the recombinant pyrin domain protein can alleviate the airway inflammation and airway remodeling of OVA-induced mice with chronic asthma by inhibiting transforming growth factor β1(TGF-β1)/SMAD and Jagged1/Notch1 signaling pathways. Methods Thirty-two male BALB/c mice were selected and divided into 4 groups with 8 mice in each group. The four groups were the control group, OVA model group, recombinant pyrin domain protein treatment group (100 μg/kg), and the dexamethasone treatment group (1 mg/kg). Enzyme-linked immunosorbent assay (ELISA) was used to determine the expression of inflammatory factors in bronchoalveolar lavage fluid (BALF) of mice in each group. hematoxylin-eosin staining (HE) was used to observe the inflammatory infiltration of bronchus in mice. The changes of goblet cells were observed by periodic acid-Schiff (PAS) staining and collagen fibers by Masson staining. Immunohistochemical staining (IHC) was performed to observe the expression distribution of α smooth muscle actin (α-SMA), TGF-β1 and Notch1 proteins in lung tissues. Western blotting was used to detect the protein levels of α-SMA, E-cadherin, TGF-β1, SMAD2/3, SMAD7, Jagged1, Notch1 and Hes1 in lung tissues. Results The recombinant pyrin domain protein not only improved the airway inflammatory response of the OVA-induced mice with bronchial asthma, but also inhibited the hyperplasia of goblet cells and collagen fiber deposition, reduced the tumor necrosis factor α (TNF-α) in BALF, interleukin 1β (IL-1β), IL-4, IL-13 levels, and inhibited the protein expression of TGF-β1, SMAD2/3, Jagged1, Notch1, Hes1 and α-SMA in lung tissues. Conclusion The recombinant pyrin domain protein can reduce the airway inflammation and airway remodeling of asthmatic mice by inhibiting TGF-β1/SMAD and Jagged1/Notch1 signaling pathways.

Background The effect of ginsenoside Rh2 (G-Rh2) on mast cell-mediated anaphylaxis remains unclear. Herein, we investigated the effects of G-Rh2 on OVA-induced asthmatic mice and on mast cell-mediated anaphylaxis. Methods Asthma model was established for evaluating airway changes and ear allergy. RPMCs and RBL-2H3 were used for in vitro experiments. Calcium uptake, histamine release and degranulation were detected. ELISA and Western blot measured cytokine and protein levels, respectively. Results G-Rh2 inhibited OVA-induced airway remodeling, the production of TNF-α, IL-4, IL-8, IL-1β and the degranulation of mast cells of asthmatic mice. G-Rh2 inhibited the activation of Syk and Lyn in lung tissue of OVA-induced asthmatic mice. G-Rh2 inhibited serum IgE production in OVA induced asthmatic mice. Furthermore, G-Rh2 reduced the ear allergy in IgE-sensitized mice. G-Rh2 decreased the ear thickness. In vitro experiments G-Rh2 significantly reduced calcium uptake and inhibited histamine release and degranulation in RPMCs. In addition, G-Rh2 reduced the production of IL-1β, TNF-α, IL-8, and IL-4 in IgE-sensitized RBL-2H3 cells. Interestingly, G-Rh2 was involved in the FceRI pathway activation of mast cells and the transduction of the Lyn/Syk signaling pathway. G-Rh2 inhibited PI3K activity in a dose-dependent manner. By blocking the antigen-induced phosphorylation of Lyn, Syk, LAT, PLCγ2, PI3K ERK1/2 and Raf-1 expression, G-Rh2 inhibited the NF-κB, AKT-Nrf2, and p38MAPK-Nrf2 pathways. However, G-Rh2 up-regulated Keap-1 expression. Meanwhile, G-Rh2 reduced the levels of p-AKT, p38MAPK and Nrf2 in RBL-2H3 sensitized IgE cells and inhibited NF-κB signaling pathway activation by activating the AKT-Nrf2 and p38MAPK-Nrf2 pathways. Conclusion G-Rh2 inhibits mast cell-induced allergic inflammation, which might be mediated by the AKT-Nrf2/NF-κB and p38MAPK-Nrf2/NF-κB signaling pathways.

In this study, we investigated the role and mechanism of imperatorin (IMP) in chronic inflammation and airway remodeling. The levels of TNF-α, IL-1β, IL-6, IL-8, VEGF, α-SMA, and ROS were detected by ELISA, immunohistochemistry (IHC), immunofluorescence, and Western blot. In addition, we evaluated the effect of IMP on MAPK, PI3K/Akt, NF-κB, and Nrf2/HO-1 signaling pathways. IMP treatment obviously attenuated the production of inflammatory cytokines and inflammatory cells in bronchoalveolar lavage fluid of OVA-induced airway remodeling model. Meanwhile, it significantly inhibited inflammatory cell infiltration, goblet cell hyperplasia, collagen deposition, VEGF production, α-SMA, and ROS expression. Our study has shown that IMP could regulate the signaling pathways including MAPK, PI3K/Akt, NF-κB, and Nrf2/HO-1 to release the inflammatory responses. IMP might attenuate airway remodeling by the down-regulation of Nrf2/HO-1/ROS/PI3K/Akt, Nrf2/HO-1/ROS/MAPK, and Nrf2/HO-1/ROS/NF-κB signaling pathways. Schematic picture of the role of Imperatorin in alleviating ROS-mediated airway remodeling by targeting the Nrf2/HO-1 signaling pathway.

This study is to determine the role and mechanism of cryptotanshinone (CTS) in allergic airway inflammation. Asthma induced by OVA was established in BALB/c mice. We found increased airway hyperresponsiveness (AHR), increased inflammatory cell infiltration, elevated levels of TNF-α, interleukin-1β (IL-1β), IL-4, IL-5, IL-6 and IL-13, decreased interferon gamma (IFN-γ) in lung tissue, increased content of total immunoglobulin E (IgE), OVA specific IgE, Eotaxin, ICAM-1, VCAM-1, nuclear factor-kappaB (NF-κB) and phosphorylation of p38 MAPK in lung tissue. However, the administration of CTS significantly decreased AHR in asthmatic mice, reduced inflammation around the bronchioles and inflammatory cells around airway, regulated cytokine production, reduced the total IgE and OVA-specific IgE levels, and inhibited NF-κB activation and p38 MAPK phosphorylation. In vitro experiments in 16 HBE cells revealed that CTS attenuated CAM-1 and IL-6 expression. These results indicate that CTS alleviates allergic airway inflammation by modulating p38 MAPK phosphorylation and NF-κB activation.

Polydatin(PD) shows anti-allergic inflammatory effect, and this study investigated its underlying mechanisms in in vitro and in vivo models. IgE-mediated passive cutaneous anaphylaxis (PCA) and passive systemic anaphylaxis (PSA) models were used to confirm PD effect in vivo. Various signaling pathway proteins in mast cell were examined. RT-PCR, ELISA and western blotting were applied when appropriate. Activity of Lyn and Fyn kinases in vitro was measured using the Kinase Enzyme System. PD dose-dependently reduced the pigmentation of Evans blue in the PCA model and decreased the concentration of serum histamine in PSA model, and attenuated the degranulation of mast cells without generating cytotoxicity. PD decreased pro-inflammatory cytokine expression (TNF-α, IL-4, IL-1β, and IL-8). PD directly inhibited activity of Lyn and Syk kinases and down-regulated downstream signaling pathway including MAPK, PI3K/AKT and NF-kB. In addition, PD also targets Nrf2/HO-1 pathway to inhibit mast cell-derived allergic inflammatory reactions. In conclusion, the study demonstrates that PD is a possible therapeutic candidate for allergic inflammatory diseases. It directly inhibited activity of Lyn and Syk kinases and down-regulates the signaling pathway of MAPK, PI3K/AKT and NF-κB, and up-regulates the signaling pathway of Nrf2/HO-1 to inhibit the degranulation of mast cells.

Guselkumab, an interleukin-23 blocker, was superior to placebo and adalimumab and well-tolerated in phase 3 psoriasis studies (VOYAGE 1 and VOYAGE 2). This analysis evaluated the consistency of response in the Asian subpopulation in VOYAGE 1 and VOYAGE 2. Study designs were identical through week 24; patients were randomized to guselkumab, placebo, or adalimumab. Investigator's Global Assessment (IGA), Psoriasis Area and Severity Index (PASI), safety, and pharmacokinetic and immunogenicity data from VOYAGE 1 and VOYAGE 2 were pooled and compared by race (Asian, n = 199; non-Asian, n = 1630). At week 16, treatment differences between guselkumab and placebo were 78.2 (95% confidence interval [CI], 66.9-89.6) and 76.4 (95% CI, 72.7-80.2) percentage points for IGA 0/1 (score of 0 or 1) and 70.1 (95% CI, 60.0-80.1) and 68.5 (95% CI, 64.9-72.2) percentage points for PASI 90 (≥90% improvement) in the Asian and non-Asian populations, respectively. Treatment differences between guselkumab and adalimumab were 31.1 (95% CI, 17.7-44.6) and 16.1 (95% CI, 11.2-21.0) percentage points for IGA 0/1 and 24.9 (95% CI, 9.4-40.5) and 23.2 (95% CI, 17.7-28.6) percentage points for PASI 90 in the Asian and non-Asian populations, respectively. Similar results were observed at week 24. Safety was generally similar between populations and among treatment groups. Median serum guselkumab concentrations over time were comparable between the populations. Comparable responses between the Asian and non-Asian populations in this analysis suggest that the overall efficacy, safety, and the resulting benefit/risk analyses from VOYAGE 1 and VOYAGE 2 are applicable to Asian populations.

Based on the problems of heat storage in the process of solar energy utilization and the advantages of finned tube heat exchanger, the finned tube is applied into the solar phase change heat accumulator and the heat storage process of the phase change material is simulated numerically. The results show that the use of finned tube instead of smooth tube in solar phase change heat accumulator can effectively improve the heat transfer intensity of the outside of the tube during phase change heat storage, thus enhancing the heat transfer capacity of the whole heat accumulator and shortening the heat storage time. In the simulation range of this paper, the optimum structure parameter of finned tube is: finned outer diameter of D2=28mm, fins thickness of t=1mm, fins number of c=13, spacing between fins of h=25mm.

At present, in many fields such as petrochemical industry, in order to make better use of heat energy and reduce energy consumption in the process of equipment operation, heat transfer enhancement of heat exchange equipment has attracted more and more attention. Corrugated tube has many advantages compared with other smooth tubes, which are enhancing heat transfer, strong anti-fouling ability and easy to clean. In this paper, a heat exchanger with corrugated tube is studied. The geometry is meshed with the software GAMBIT. It is used with Fluent software and the initial and boundary conditions are set. Heat transfer performance between smooth tube and corrugated tube at the same inner wall temperature and velocity. Then, the influence from inlet velocity on heat transfer performance is investigated. The variation of temperature field, pressure field and velocity field in corrugated tube heat exchanger with different inlet velocity is discussed. The results show that the enhanced heat transfer effect of corrugated tube is much better than that of smooth tubes. At three different inlet velocities (0.5m/s, 1m/s, 3m/s), the enhanced heat transfer effects of the corrugated tube heat exchanger are different. With the increase of inlet velocity, the heat transfer effects of corrugated tube heat exchanger are enhanced, but the extent of enhancement decreases. In the range of this paper, the optimal inlet velocity is 0.5m/s in order to obtain the more heat transfer quantity and lower operation cost.

Toreforant is a selective histamine H4 receptor antagonist. H4 receptor activation may play a role in immune-mediated inflammation in psoriasis.To evaluate Toreforant efficacy and safety in patients with moderate-to-severe psoriasis.Biologic-naïve patients were to be treated (30, 60, or 3 mg Toreforant or placebo) for 12 weeks and followed through week 16. In this adaptive-design study, assignments were guided by interim analyses. Primary and major secondary efficacy endpoints, evaluated using Bayesian analyses, were the proportions of patients achieving ≥75% improvement in Psoriasis Area and Severity Index (PASI) from baseline and achieving Investigator's Global Assessment (IGA) of cleared (0) or minimal (1), respectively, at week 12.Per interim analyses results, patients were randomized to 30 (n = 30) or 60 mg (n = 26) Toreforant or placebo (n = 6). The estimated mean difference in the PASI 75 response rate at week 12 from the posterior distributions compared to placebo was 14.1% (95% credible interval [CI], -0.1% to 30.9%) and 8.9% (95% CI, -5.0% to 24.3%) with 30 and 60 mg Toreforant, respectively. The posterior probabilities of 30 and 60 mg Toreforant inducing a greater response rate than placebo were 97.4% and 90.3%, respectively; neither met the 97.5% predefined success criterion. Results for the IGA 0/1 endpoint were similar. Toreforant was generally safe and well tolerated. No deaths, serious or opportunistic infections, active tuberculosis, or malignancies were reported.Toreforant efficacy at 30 and 60 mg was greater than placebo but did not meet predefined success criterion. J Drugs Dermatol. 2018;17(8):873-879.

SummaryBackground Guselkumab, an anti-interleukin-23 monoclonal antibody, has demonstrated significant efficacy in phase III psoriasis trials. Objectives To evaluate the efficacy and safety of guselkumab in patients with moderate-to-severe plaque psoriasis who had an inadequate response to ustekinumab. Methods In this phase III, randomized, double-blind study, 871 patients received open-label ustekinumab (45 mg or 90 mg) at weeks 0 and 4. At week 16, 268 patients with an inadequate response to ustekinumab [Investigator's Global Assessment (IGA) ≥ 2] were randomized (double-blind) to guselkumab 100 mg or to continue ustekinumab; 585 of 871 patients (67%) with IGA 0/1 at week 16 continued open-label ustekinumab. The primary end point was the number of visits at which randomized patients achieved IGA 0/1 and at least a two-grade improvement (from week 16) from week 28 to week 40. Improvement ≥ 90% or 100% in Psoriasis Area and Severity Index (PASI 90/100) and Dermatology Life Quality Index (DLQI) of 0/1 were also assessed. Results The mean number of visits at which patients achieved IGA 0/1 and at least a two-grade improvemen (week 28–40) was significantly greater in the guselkumab group vs. the randomized ustekinumab group (1·5 vs. 0·7; P

The molecular mechanism of fear memory is poorly understood. Therefore, the pathogenesis of post-traumatic stress disorder (PTSD), whose symptom presentation can enhance fear memory, remains largely unclear. Recent studies with knockout animals have reported that Rin1 and stathmin regulate fear memory. Rin1 inhibits acquisition and promotes memory extinction, whereas stathmin regulates innate and basal fear. The aim of our study was to examine changes in the expression of Rin1 and stathmin in different animal models of stress, particluarly traumatic stress. We used three animal traumatic stresses: single prolonged stress (SPS, which is a rodent model of PTSD), an immobilization-stress (IM) and a Loud sound stress (LSS), to examine the change and uniqueness in Rin1/stathmin expression. Behavioral tests of SPS rats demonstrated increased anxiety and contextual fear-conditioning. They showed decreased long-term potentiation (LTP), as well as decreased stathmin and increased Rin1 expression in the hippocampus and the amygdala. Expression of the stathmin effector, tubulin, and downstream molecules Rin1, Rab5, and Abl, appeared to increase. Rin1 and EphA4 were endogenously coexpressed in primary neurons after SPS stimulation. IM rats exhibited increased anxiety behavior and enhanced fear-conditioning to contextual and auditory stimuli. Similar changes in expression of Rin1/stathmin were observed in IM rats whereas no changes were observed in rats exposed to a loud sound. These data suggest that changes in expression of the Rin1 and stathmin genes may be involved in rodents with SPS and IM stresses, which provide valuable insight into fear memories under abnormal conditions, particularly in PTSD.

Time is an important aspect of information and is very useful for information utilization. The goal of this study was to analyze the challenges of temporal expression (TE) extraction and normalization in Chinese clinical notes by assessing the performance of a rule-based system developed by us on a manually annotated corpus (including 1,778 clinical notes of 281 hospitalized patients). In order to develop system conveniently, we divided TEs into three categories: direct, indirect and uncertain TEs, and designed different rules for each category of them. Evaluation on the independent test set shows that our system achieves an F-score of93.40% on TE extraction, and an accuracy of 92.58% on TE normalization under “exact-match” criterion. Compared with HeidelTime for Chinese newswire text, our system is much better, indicating that it is necessary to develop a specific TE extraction and normalization system for Chinese clinical notes because of domain difference.

Pyrin domain (PYD), a subclass of protein motif known as the death fold, is frequently involved in inflammation and immune responses. PYD modulates nuclear factor-kappa B (NF-κB) signalling pathway upon various stimuli. Herein, a novel recombinant pyrin domain protein (RPYD) was generated. Its role and mechanism in inflammatory response in an ovalbumin (OVA) induced asthma model was investigated. After OVA challenge, there was inflammatory cell infiltration in the lung, as well as airway hyper-responsiveness (AHR) to inhaled methacholine. In addition, eosinophils increased in the bronchoalveolar lavage fluids, alone with the elevated levels of Th-2 type cytokines [interleukin (IL)-4, IL-5 and IL-13], eotaxin, and adhesion molecules. However, the transnasal administration of RPYD before the OVA challenge significantly inhibited these asthmatic reactions. Moreover, RPYD markedly suppressed NF-κB translocation, reduced phosphorylation of p38 MAPK, and thus attenuated the expression of intercellular adhesion molecule 1 and IL-6 in the BEAS-2B cells stimulated by proinflammatory cytokines in vitro. These findings indicate that RPYD can protect asthma host from OVA-induced airway inflammation and AHR via down-regulation of NF-κB and p38 MAPK activities. RPYD may be used as a potential medicine for the treatment of asthma in clinic.

Aims The present study is to investigate the effect of cornuside on mast cell-mediated allergic response, as well as its possible mechanisms of action. Methods To test the anti-allergic effects of cornuside in vivo, local extravasation was induced by local injection of anti-dinitrophenyl immunoglobulin E (IgE) followed by intravenous antigenic challenge in passive cutaneous anaphylaxis model rats. Mast cell viability was determined using MTT assay. Histamine content from rat peritoneal mast cells was measured by the radioenzymatic method. To investigate the mechanisms by which cornuside affects the reduction of histamine release, the levels of calcium uptake were measured. To examine whether cornuside affects the expression of pro-inflammatory cytokines, Western blotting and ELISA were carried out. Results Oral administration of cornuside inhibited passive cutaneous anaphylaxis in rats. Presence of cornuside attenuated IgE-induced histamine release from rat peritoneal mast cells. The inhibitory effect of cornuside on histamine release was mediated by the modulation of intracellular calcium. In addition, cornuside decreased phorbol 12-myristate 13-acetate (PMA) and calcium ionophore A23187-stimulated production and secretion of pro-inflammatory cytokines such as TNF-α and IL-6 in human mast cells. The inhibitory effect of cornuside on pro-inflammatory cytokines was dependent on nuclear factor-κB and p38 mitogen-activated protein kinase. Conclusions The present study provides evidence that cornuside inhibits mast cell-derived inflammatory allergic reactions by blocking histamine release and pro-inflammatory cytokine expression. Furthermore, in vivo and in vitro anti-allergic effects of cornuside suggest a possible therapeutic application of this agent in inflammatory allergic diseases.

Microporous poly(vinyl butyral) (PVB) membranes were successfully prepared by supercritical CO 2 -induced phase separation. The obtained membrane structures were characterized by scanning electron microscope. The results indicated that the process parameters, such as PVB concentration in casting solution, CO 2 pressure, temperature and depressurization time, had significant effects on the membrane structure. The increase of PVB concentration led to a decrease of the mean pore size. With the increase of temperature and CO 2 pressure, the top surface of the membrane became dense, the pore size of cross-section increased and the asymmetry became more pronounced. With the increase of the depressurization time, the top surface became porous and the pore size of cross-section increased. Macrovoids occurred at a certain distance from the skin layer of the membrane prepared under the pressure of 15 MPa or at the PVB concentration of 19% (w/w). The crystallinity and thermal stability of membranes were characterized by wide-angle X-ray diffraction, differential scanning calorimeter and thermogravimetric analysis. The relations between the membrane characteristics and the process parameters were extensively discussed.

The supercritical fluid expansion depressurization (SFED) process is a novel technique proposed recently to prepare microparticles with narrow size distribution. In this work, Erythromycin microparticles were precipitated successfully from ethanol by SFED process. The spherical or approximately spherical particles with diameters less than 3 μm were obtained. The influences of the operation parameters, including the pressure and the temperature in the mixing vessel, the solution concentration, the solution feed rate and the temperature in the precipitator, on the particle morphology, size and size distribution were investigated in detail. The results show that the pressure in the mixing vessel and the solution feed rate are two most effective operation parameters while the solution concentration is the next. The temperatures in the mixing vessel and the precipitator have little effect on the particles, but they have great influence on the yield of the final product. The erythromycin microparticles with narrow size distribution can be prepared by SFED process and the particle morphology, size and size distribution can be controlled by adjusting operation parameters. The optimal operation parameters obtained in this work for preparing erythromycin microparticles are: the pressure of 10 MPa and the temperature of 70 °C in the mixing vessel, the solution feed rate of 9 ml/min, the solution concentration of 15 mg/ml and the precipitator temperature of 70 °C.