Drop to Gate Nasal Drops Attenuates Sepsis-Induced Cognitive Dysfunction.

Nasal administration can bypass the blood-brain barrier and directly deliver drugs to the brain, providing a non-invasive route for central nervous system (CNS) diseases. Inspired by the appearance that a gate can block the outside world and the characteristics of the sol-gel transition can form a "gate" in the nasal cavity, a Drop to Gate nasal drop (DGND) is designed to set a gate in nose, which achieves protecting role from the influence of nasal environment. The DGND demonstrates the efficiency and application prospect of delivering drugs to the brain through the N-to-B. The effective concentration of single administration is increased through the hydrophobic interaction between C8-GelMA and SRT1720 (SA), and then cross-linked under UV to form nanogel, which can respond to MMP in the inflammatory microenvironment of sepsis-induced cognitive dysfunction. Finally, the SA/nanogel is compounded into the thermogel, which can respond to the nasal cavity temperature to form DGND in situ, increasing the residence time and delivery efficiency of drugs in the nasal cavity. In vitro, the DGND alleviates lipopolysaccharides (LPS)-induced BV2 inflammation. In vivo, DGND effectively targets the nasal mucosa and deliver drugs to the brain, which activate Sirt1 to alleviate inflammation mediated by microglia and improve cognitive dysfunction in sepsis mice.

Swimming short fibrous nasal drops achieving intraventricular administration.

Adequate drug delivery across the blood-brain barrier (BBB) is a critical factor in treating central nervous system (CNS) disorders. Inspired by swimming fish and the microstructure of the nasal cavity, this study is the first to develop swimming short fibrous nasal drops that can directly target the nasal mucosa and swim in the nasal cavity, which can effectively deliver drugs to the brain. Briefly, swimming short fibrous nasal drops with charged controlled drug release were fabricated by electrospinning, homogenization, the π-π conjugation between indole group of fibers, the benzene ring of leucine-rich repeat kinase 2 (LRRK2) inhibitor along with charge-dipole interaction between positively charged poly-lysine (PLL) and negatively charged surface of fibers; this enabled these fibers to stick to nasal mucosa, prolonged the residence time on mucosa, and prevented rapid mucociliary clearance. In vitro, swimming short fibrous nasal drops were biocompatible and inhibited microglial activation by releasing an LRRK2 inhibitor. In vivo, luciferase-labelled swimming short fibrous nasal drops delivered an LRRK2 inhibitor to the brain through the nasal mucosa, alleviating cognitive dysfunction caused by sepsis-associated encephalopathy by inhibiting microglial inflammation and improving synaptic plasticity. Thus, swimming short fibrous nasal drops is a promising strategy for the treatment of CNS diseases.

Dexmedetomidine Protects against Airway Inflammation and Airway Remodeling in a Murine Model of Chronic Asthma through TLR4/NF-κB Signaling Pathway.

Asthma is a common respiratory disease characterized by chronic airway inflammation. Dexmedetomidine (DEX), a highly selective α2 adrenergic receptor agonist, has been shown to participate in regulating inflammatory states and thus exert organ protective actions. However, the potential of DEX in asthma is still unknown. This study is aimed at investigating the role of DEX in a mouse model of house dust mite- (HDM-) induced asthma and exploring its underlying mechanism. Here, we found that DEX treatment significantly ameliorated airway hyperresponsiveness, airway inflammation, and airway remodeling in the asthmatic mice, which were similar to the efficacy of the reference anti-inflammatory drug dexamethasone. In addition, DEX reversed the increased expression of toll-like receptor 4 (TLR4) and its downstream signaling adaptor molecule nuclear factor-κB (NF-κB) in the lung tissue of asthmatic mice. Furthermore, these protective effects of DEX were abolished by yohimbine, an α2 adrenergic receptor antagonist. These results indicate that DEX is capable of ameliorating airway inflammation and remodeling in asthmatic mice, and this protective effect is associated with the inhibition of the TLR4/NF-κB signaling pathway.

Dexmedetomidine reduces IL-4 and IgE expression through downregulation of theTLR4/NF-κB signaling pathway to alleviate airway hyperresponsiveness in OVA mice.

BACKGROUND: Airway hyperresponsiveness (AHR) is a clinical manifestation of airflow limitation due to abnormal tracheal and bronchial sensitivity and is the main basis for the diagnosis of asthma. Patients with AHR are at high risk of perioperative tracheal and bronchospasm, which can lead to hypoxaemia and haemodynamic instability and, in severe cases, to a life-threatening 'silent lung'. It is therefore important to reduce the incidence or intensity of AHR episodes in the perioperative period. The inflammatory response is key to the development and progression of AHR. HYPOTHESIS/PURPOSE: Based on the modulatory role of dexmedetomidine (DEX) in the inflammatory response, we hypothesised that dexmedetomidine (DEX) attenuates inflammatory properties by inhibiting the toll-like receptor 4 (TLR4)/nuclear factor (NF-κB) signalling pathway and can reduce the respiratory parameters of mechanical ventilation in ovalbumin-induced allergic airway hyperresponsiveness. STUDY DESIGN: BABL/C mice were divided into control and OVA groups (ovalbumin-induced allergy. Ten mice in all OVA models were randomly selected for in vivo invasive lung function monitoring to analyse airway resistance parameters and demonstrate successful model establishment. The remaining OVA mice were treated with dexmedetomidine 25 µg/kg for 5 days (OVA + DEX group) or dexmedetomidine 25 µg/kg + yohimbine 1 mg/kg for 5 days (OVA + DEX + yohimbine). After treatment, bronchoalveolar lavage fluid (BAL) and peripheral blood (ELISA) and lung tissue (H&E and PAS) were collected for analysis of inflammatory factors, and lung tissue was verified by PCR for genes and proteins that do correlate with inflammatory mediators. RESULTS: All airway resistance parameters were increased in OVA mice by invasive lung function monitoring. Proximal airway resistance (parameter Rn) and total respiratory resistance (parameter Rrs) were attenuated after dexmedetomidine intervention treatment. Dexmedetomidine reduced total inflammatory cell count and inflammatory infiltration of lung tissue in BALF and down-regulated IL-4 and IgE levels in BALF and peripheral blood, as shown by Giemsa, H&E, PAS staining and ELISA; this mechanism of action was found to be related to the TLR4/NFκB pathway, but not to TLR4/NFκB, as measured by PCR. CONCLUSION: Dexmedetomidine reduces hyperresponsiveness and airway inflammatory responses. This mechanism of action may be related to the TLR4/NFκB signalling pathway. Overall conclusions are presented in.

Research progress in the mechanism of calcium ion on contraction and relaxation of airway smooth muscle cells.

lntracellular calcium ion is the key secondary messenger system of the cellular processes in airway smooth muscle cells(ASMc). The treatment and regulation of Ca2+ in airway smooth muscle (ASM) is, in part, to associated with many airway diseases such as asthma, COPD and pulmonary fibrosis. The mechanism of contraction and relaxation of ASM is a concerned aspect in airway diseases. This review emphasizes established and recent discoveries whice show the research progress of Ca2+ on cell contraction and relaxation in ASM in recent years, to provide theoretical support and new targets for clinical prevention and treatment of perioperative bronchospasm and variousrespiratory related diseases.

Association between retinol-binding protein 4 concentrations and gestational diabetes mellitus (A1GDM and A2GDM) in different pregnancy and postpartum periods.

BACKGROUND: Gestational diabetes mellitus (GDM) can cause severe adverse effects on fetal and neonatal outcomes. The following study investigates the relationship between retinol-binding protein 4 (RBP4) and GDM in pregnant women with different grades (A1 and A2) and different gestational weeks. METHODS: In this retrospective study, 194 GDM patients (GDM group) and 67 normal glucose tolerance pregnant women (control group) were enrolled from 2014 to 2017. Elbow venous blood samples were collected from all subjects. Enzyme electrode method and enzyme linked immunosorbent assay (ELISA) were used for fasting plasma glucose (FPG) and RBP4/insulin levels (FINS) analysis, respectively. RESULTS: At middle pregnancy and late stage, FINS, insulin resistance index (HOMA-IR) and RBP4 were all significantly higher in the GDM group compared to control group (P<0.05). Higher HOMA-IR and RBP4 levels, and lower levels of FPG were observed at late stage than those middle pregnancy in the GDM group (P<0.05). Moreover, FINS and RBP4 gradually decreased from middle pregnancy and late stage after delivery in the GDM group. Levels of FINS and RBP4 in postpartum GDM group were higher than those in normal control group (P<0.05). The optimal cut-off value of RBP4 at middle pregnancy diagnostic GDM was 34.84 µg/mL with sensitivity of 79.4% and specificity of 79.1%. The OGTT0h, 2h in A2GDM group was higher than that in A1GDM group, but there was no difference in OGTT1h, age and FINS, RBP4 in both A1GDM and A2GDM group. CONCLUSIONS: RBP4 is closely related to GDM, and its levels increases with the increase of gestational weeks, which may reflect the development of insulin resistance in GDM. RBP4 suggests that the impaired insulin function of GDM in pregnant women is still difficult to recover in the short term after delivery. Compared with OGTT1h, the increase in OGTT0h and 2h levels during middle pregnancy is more helpful for predicting the risk of developing A2GDM at late stage.

Synchronizing terahertz wave generation with attosecond bursts.

We perform a joint measurement of terahertz waves and high-harmonics generated from argon atoms driven by a fundamental laser pulse and its second harmonic. By correlating their dependence on the phase delay between the two pulses, we determine the generation of THz waves in tens of attoseconds precision. Compared with simulations and models, we find that the laser-assisted soft collision of the electron wave packet with the atomic core plays a key role. It is demonstrated that the rescattering process, being indispensable in high-harmonic generation processes, dominates THz wave generation as well in a more elaborate way. The new finding might be helpful for the full characterization of the rescattering dynamics.