The AKT inhibitor MK2206 suppresses airway inflammation and the pro­remodeling pathway in a TDI­induced asthma mouse model.

The cellular and molecular mechanisms via which MK2206, an AKT inhibitor, prevents the activation of AKT in toluene diisocyanate (TDI)­induced asthma remain unclear. Thus, the present study aimed to evaluate the potential effects of MK2206 on airway AKT activation, inflammation and remodeling in a TDI­induced mouse model of asthma. A total of 24 BALB/c mice were selected and randomly divided into untreated (AOO), asthma (TDI), MK2206 (TDI + MK2206), and dexamethasone (TDI + DEX) groups. Phosphorylated AKT (p­AKT), total AKT, airway remodeling indices, α­smooth muscle actin (α­SMA) and collagen I levels in pulmonary tissue were measured using western blotting. Airway inflammation factors, including interleukin (IL)­4, ­5, ­6, and ­13 in bronchoalveolar lavage fluid (BALF) and IgE in serum, were determined using ELISA. Additionally, the airway hyperresponsiveness (AHR) and pulmonary pathology of all groups were evaluated. The results of the present study demonstrated that p­AKT levels in lung protein lysate were upregulated, and neutrophil, eosinophil and lymphocyte counts were increased in the lungs obtained from the asthma group compared with the AOO group. Both MK2206 and DEX treatment in TDI­induced mice resulted not only in the attenuation of AKT phosphorylation, but also reductions in neutrophil, eosinophil and lymphocyte counts in the lungs of mice in the asthma group. Consistently, increases in the levels of the inflammatory cytokines IL­4, ­5, ­6 and ­13 analyzed in BALF, and serum IgE in the TDI group were demonstrated to be attenuated in the TDI + MK2206 and TDI + DEX groups. Furthermore, α­SMA and AHR were significantly attenuated in the TDI + MK2206 group compared with the TDI group. These results revealed that MK2206 not only inhibited AKT activation, but also served a role in downregulating airway inflammation and airway remodeling in chemical­induced asthma. Therefore, the findings of the present study may provide important insight into further combination therapy.

Dabigatran ameliorates airway smooth muscle remodeling in asthma by modulating Yes-associated protein.

Accumulating evidence indicates that thrombin, the major effector of the coagulation cascade, plays an important role in the pathogenesis of asthma. Interestingly, dabigatran, a drug used in clinical anticoagulation, directly inhibits thrombin activity. The aim of this study was to investigate the effects and mechanisms of dabigatran on airway smooth muscle remodeling in vivo and in vitro. Here, we found that dabigatran attenuated inflammatory pathology, mucus production, and collagen deposition in the lungs of asthmatic mice. Additionally, dabigatran suppressed Yes-associated protein (YAP) activation in airway smooth muscle of asthmatic mice. In human airway smooth muscle cells (HASMCs), dabigatran not only alleviated thrombin-induced proliferation, migration and up-regulation of collagen I, α-SMA, CTGF and cyclin D1, but also inhibited thrombin-induced YAP activation, while YAP activation mediated thrombin-induced HASMCs remodeling. Mechanistically, thrombin promoted actin stress fibre polymerization through the PAR1/RhoA/ROCK/MLC2 axis to activate YAP and then interacted with SMAD2 in the nucleus to induce downstream target genes, ultimately aggravating HASMCs remodeling. Our study provides experimental evidence that dabigatran ameliorates airway smooth muscle remodeling in asthma by inhibiting YAP signalling, and dabigatran may have therapeutic potential for the treatment of asthma.

Enhanced NO2 Sensing at Room Temperature with Graphene via Monodisperse Polystyrene Bead Decoration.

Graphene is a single layer of carbon atoms with a large surface-to-volume ratio, providing a large capacity gas molecule adsorption and a strong surface sensitivity. Chemical vapor deposition-grown graphene-based NO2 gas sensors typically have detection limits from 100 parts per billion (ppb) to a few parts per million (ppm), with response times over 1000 s. Numerous methods have been proposed to enhance the NO2 sensing ability of graphenes. Among them, surface decoration with metal particles and metal-oxide particles has demonstrated the potential to enhance the gas-sensing properties. Here, we show that the NO2 sensing of graphene can be also enhanced via decoration with monodisperse polymer beads. In dark conditions, the detection limit is improved from 1000 to 45 ppb after the application of polystyrene (PS) beads. With laser illumination, a detection limit of 0.5 ppb is determined. The enhanced gas sensing is due to surface plasmon polaritons excited by interference and charge transfer between the PS beads. This method opens an interesting route for the application of graphene in gas sensing.

High Selectivity Gas Sensing and Charge Transfer of SnSe2.

SnSe2 is an anisotropic binary-layered material with rich physics, which could see it used for a variety of potential applications. Here, we investigate the gas-sensing properties of SnSe2 using first-principles calculations and verify predictions using a gas sensor made of few-layer SnSe2 grown by chemical vapor deposition. Theoretical simulations indicate that electrons transfer from SnSe2 to NO2, whereas the direction of charge transfer is the opposite for NH3. Notably, a flat molecular band appears around the Fermi energy after NO2 adsorption and the induced molecular band is close to the conduction band minimum. Moreover, compared with NH3, NO2 molecules adsorbed on SnSe2 have a lower adsorption energy and a higher charge transfer value. The dynamic-sensing responses of SnSe2 sensors confirm the theoretical predictions. The good match between the theoretical prediction and experimental demonstration suggests that the underlying sensing mechanism is related to the charge transfer and induced flat band. Our results provide a guideline for designing high-performance gas sensors based on SnSe2.

Inhibitory effects of methamphetamine on mast cell activation and cytokine/chemokine production stimulated by lipopolysaccharide in C57BL/6J mice.

Previous studies have demonstrated that methamphetamine (MA) influences host immunity; however, the effect of MA on lipopolysaccharide (LPS)-induced immune responses remains unknown. Mast cells (MCs) are considered to serve an important role in the innate and acquired immune response, but it remains unknown whether MA modulates MC activation and LPS-stimulated cytokine production. The present study aimed to investigate the effect of MA on LPS-induced MC activation and the production of MC-derived cytokines in mice. Markers for MC activation, including cluster of differentiation 117 and the type I high affinity immunoglobulin E receptor, were assessed in mouse intestines. Levels of MC-derived cytokines in the lungs and thymus were also examined. The results demonstrated that cytokines were produced in the bone marrow-derived mast cells (BMMCs) of mice. The present study demonstrated that MA suppressed the LPS-mediated MC activation in mouse intestines. MA also altered the release of MC cytokines in the lung and thymus following LPS stimulation. In addition, LPS-stimulated cytokines were decreased in the BMMCs of mice following treatment with MA. The present study demonstrated that MA may regulate LPS-stimulated MC activation and cytokine production.

The effects of D3R on TLR4 signaling involved in the regulation of METH-mediated mast cells activation.

Accumulating studies have revealed that the dopamine D3 receptor (D3R) plays an important role in methamphetamine (METH) addiction. However, the action of D3R on METH-mediated immune response and the underlying mechanism remain unclear. Mast cells (MCs) are currently identified as effector cells in many processes of immune responses, and MC activation is induced by various stimuli such as lipopolysaccharide (LPS). Moreover, CD117 and FcεRI are known as MC markers due to their specific expression in MCs. To investigate the effects of D3R on METH-mediated alteration of LPS-induced MCs activation and the underlying mechanism, in this study, we examined the expression of CD117 and FcεRI in the intestines of wild-type (D3R(+/+)) and D3R-deficient (D3R(-/-)) mice. We also measured the production of MC-derived cytokines, including TNF-α, IL-6, IL-4, IL-13 and CCL-5, in the bone marrow-derived mast cells (BMMCs) of WT and D3R(-/-) mice. Furthermore, we explored the effects of D3R on METH-mediated TLR4 and downstream MAPK and NF-κB signaling induced by LPS in mouse BMMCs. We found that METH suppressed MC activation induced by LPS in the intestines of D3R(+/)mice. In contrast, LPS-induced MC activation was less affected by METH in D3R(-/-) mice. Furthermore, METH altered LPS-induced cytokine production in BMMCs of D3R(+/+) mice but not D3R(-/-) mice. D3R was also involved in METH-mediated modulation of LPS-induced expression of TLR4 and downstream MAPK and NF-κB signaling molecules in mouse BMMCs. Taken together, our findings demonstrate that the effect of D3R on TLR4 signaling may be implicated in the regulation of METH-mediated MCs activation induced by LPS.

The dopamine D3 receptor regulates the effects of methamphetamine on LPS-induced cytokine production in murine mast cells.

Previous studies have demonstrated that methamphetamine (METH) alter inflammatory and anti-inflammatory cytokine production in the periphery. However, the effect of METH on lipopolysaccharide (LPS)-induced immune responses and its underlying mechanism of action remains unclear. The dopamine D3 receptor (D3R) plays an important role in METH addiction, indicating that the D3R may regulate METH-mediated immune responses. In this study, we examined the effect of METH on mast cell released cytokines in the lungs and thymi of mice stimulated by LPS, and on LPS-induced murine bone marrow-derived mast cells (BMMCs). Moreover, we used D3R-deficient mice to investigate the effect of this receptor on LPS-stimulated mast cell released cytokine production after METH treatment in the lungs and thymi. The effects of a D3R agonist and antagonist on LPS-induced cytokine production after METH treatment in murine BMMCs were also evaluated. METH suppressed LPS-induced cytokine production in the lungs and thymi of wild-type (WT) mice and BMMCs. However, METH did not alter LPS-induced cytokine production in the lungs and thymi of D3R-deficient mice. When BMMCs were treated with the D3R receptor antagonist, NGB2904 hydrochloride (NGB-2904), METH did not alter LPS-induced cytokine production. However, treatment with the D3R agonist, 7-hydroxy-(di-n-propylamino) tetralin (7-OH-DPAT), significantly enhanced the effects of METH on LPS-induced cytokine production. Our results suggest that METH regulates mast cell released cytokines production in an LPS-induced mouse model via the D3R.

Numerical investigation of turbulent diffusion in push-pull and exhaust fume cupboards.

The aim of this study is to investigate airflow motions and associated pollutant distributions in fume hoods. Currently, most exhaust fume hoods are designed to use an airflow induced by a fan at the top to remove pollutants. Ambient fluids are drawn, flowing toward the opening and subsequently turning to the outlet at the roof. Pollutants are supposedly captured by the airflow and brought out from the cupboard. The present numerical study based on the finite-volume method and the standard k-epsilon turbulence model simulates flow patterns and pollutant distributions in an exhaust fume hood with and without a manikin present. Subsequently, a push-pull air curtain technique is applied to a fume cupboard. To investigate the capturing performance of a push-pull fume cupboard, numerical approaches are used to simulate flow and concentration variations. Numerical results reveal that four characteristic flow modes exist for a variety of speed ratios of push-pull flows and openings. A concave curtain mode which has a fast pull flow and a weak push flow is suggested for the operation of a push-pull fume cupboard. According to ANSI-ASHRAE Standard 110-1995, the local concentration at the specified point is <0.1 parts per million (p.p.m.). Meanwhile, we also examine concentration variations at 12 selected points in front of the sash, and all where the concentration is <0.1 p.p.m. A manikin is put in front of the sash to observe its effect. As a result, the flow and the concentration contours in a push-pull fume cupboard are not affected by a manikin. In terms of those predicted results, it turns out that a push-pull fume cupboard successfully captures pollutants and prevents an operator from breathing pollutants.