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Background Severe steroid-insensitive asthma is a substantial clinical problem. Effective treatments are urgently required, however, their development is hampered by a lack of understanding of the mechanisms of disease pathogenesis. Steroid-insensitive asthma is associated with respiratory tract infections and noneosinophilic endotypes, including neutrophilic forms of disease. However, steroid-insensitive patients with eosinophil-enriched inflammation have also been described. The mechanisms that underpin infection-induced, severe steroid-insensitive asthma can be elucidated by using mouse models of disease. Objective We sought to develop representative mouse models of severe, steroid-insensitive asthma and to use them to identify pathogenic mechanisms and investigate new treatment approaches. Methods Novel mouse models of Chlamydia , Haemophilus influenzae , influenza, and respiratory syncytial virus respiratory tract infections and ovalbumin-induced, severe, steroid-insensitive allergic airway disease (SSIAAD) in BALB/c mice were developed and interrogated. Results Infection induced increases in the levels of microRNA (miRNA)-21 (miR-21) expression in the lung during SSIAAD, whereas expression of the miR-21 target phosphatase and tensin homolog was reduced. This was associated with an increase in levels of phosphorylated Akt, an indicator of phosphoinositide 3-kinase (PI3K) activity, and decreased nuclear histone deacetylase (HDAC)2 levels. Treatment with an miR-21–specific antagomir (Ant-21) increased phosphatase and tensin homolog levels. Treatment with Ant-21, or the pan-PI3K inhibitor LY294002, reduced PI3K activity and restored HDAC2 levels. This led to suppression of airway hyperresponsiveness and restored steroid sensitivity to allergic airway disease. These observations were replicated with SSIAAD associated with 4 different pathogens. Conclusion We identify a previously unrecognized role for an miR-21/PI3K/HDAC2 axis in SSIAAD. Our data highlight miR-21 as a novel therapeutic target for the treatment of this form of asthma. [ABSTRACT FROM AUTHOR]

[Display omitted] • Heparin modified mesoporous silica nanoparticle (MSN-Hep) was successfully prepared for platin-based drugs delivery. • Pt drug was carried via complexation with carboxylic groups on heparin. • High Pt drug loading content was recorded, which increases double after heparin conjugation. • MSN-Hep exhibited pH-responsive release of Pt drug. • MSN-Hep is a biocompatible nanocarrier with no obvious cytotoxicity. Although Platinum-based drugs such as cisplatin, carboplatin, oxaliplatin play vital roles in chemotherapy treatment of various malignant tumors, their application and clinical efficiency are limited due to the toxicity and resistance. In this study, a drug delivery system based on mesoporous silica nanoparticles modified with heparin, a polymer consists of excessive amounts of carboxylic groups being able to coordinate with platin atoms, was fabricated to ensure a sustainable and pH-responsive release of Platinum-based drug. Heparin modified MSNs (MSN-Hep) were synthesized by Stober method, conjugated via primary amine group on particles' surface, and then characterized. SEM images showed high uniform spherical particles with 89.03 ± 4.49 nm in diameter. After modification, loading capacity of MSN-Hep was 131 mg cisplatin (a model Platinum-based drug) per 1 g MSN-Hep, twice as the bare MSNs' figure. The amount of drug released in pH 5.8 (tumor microenvironment) was significantly higher compared to that of drug released in pH 7.4 (physiological environment). Finally, Resazurin assay indicated that MSN-Hep was a biocompatible nanocarrier which had no toxicity on MCF-7 cells. These results demonstrated that MSN-Hep could be a great potential nanocarrier in chemotherapy with effectively loading ability and sustained release of Platinum-based drugs with pH response. [ABSTRACT FROM AUTHOR]

Fibronectin (FN), a dimeric adhesive glycoprotein, which is present both in plasma and the extracellular matrix can interact with platelets and thus contribute to platelet adhesion and aggregation. It has been shown that FN can decrease platelet aggregation but enhance platelet adhesion, suggesting a dual role of FN in haemostasis. The prevalent function(s) of FN may be determined by its fibril form. To explore the suggested dual role of this adhesive protein for haemostasis in further detail, we now tested for any differences of adherent and suspended platelets with regard to their effect to unfold and assemble FN upon interaction. Platelet aggregation and adhesion assays were performed using washed platelets in the presence of exogenous FN. Addition of plasma FN reduced platelet aggregation in response to collagen or PMA by 50% or 25% but enhanced platelet adhesion onto immobilized collagen, as compared to control experiments. Analyses by fluorescence resonance energy transfer (FRET) demonstrated that adherent platelets but not suspended platelets were capable of unfolding FN during 3 h incubation. Fluorescence microscopy and deoxycholate (DOC) solubility assays demonstrated that FN fibrils formed only on the surfaces of adherent platelets. In addition, platelets adherent onto FN revealed a significantly higher activity of specific Src phosphorylation (pY418) than platelets in suspension. These data suggest (1) that the function of FN in haemostasis is prevalent to its assembly, unfolding and subsequent fibril formation on the surface of adherent platelets and (2) that outside-in signaling contributes to the interaction of platelets and FN. [ABSTRACT FROM AUTHOR]

This study aims to investigate the mutual effect of integrating alginate (Alg) into N,O-carboxymethyl chitosan (NOCC) – aldehyde hyaluronic acid (AHA) network regarding degradation behavior and biocompatibility of the hybrid hydrogel. The introduction of Alg not only generated the synergistic effect between electrostatic interaction and Schiff-base crosslinking, which was proved to significantly enhance the system stability and prolong degradation time, but also circumvented the limitation of bio-inert property of Alg-based composites. This approach is versatile and does not required extra effort to modify chemical compositions of the hydrogel components. Fourier Transform Infrared Spectroscopy (FT-IR) analysis was used to study the crosslinking mechanism of obtained fast gelling hybrid. The variation of volume ratios between three constituent components was found to modulate the gel-forming ability, biodegradation and biocompatibility of acquired hydrogel networks. Among investigated formulations, 6:4(1:1) NOCC-Alg-AHA sample possessed desired interconnected porous structure as shown by SEM technique, appropriate water uptake capacity, extended degradation time and excellent cell attachment and proliferation through in vitro studies, which is a promising injectable scaffold and/or encapsulating substrate for tissue engineering applications. Image 1 • Prolong degradation rate of NOCC - AHA hydrogel without chemical modification by adding Alg. • Investigate the effect of hybrid crosslink at different volume ratio of NOCC, AHA and Alg. • Resolve the bio-inert of Alg to enhance cell adhesion and proliferation by endogenous interactions within the system. • Be used as an in-situ base to load inorganic phases, cells or drugs for further application in tissue engineering. [ABSTRACT FROM AUTHOR]

This study aimed to fabricate the potential therapeutic scaffold to efficiently and safely fastening skin wound healing. A biocompatible grafting polymer-based thermal sensitive hybrid hydrogel (Chitosan-P123, CP) containing gelatin and curcumin was designed to be suitable stiffness for tissue regeneration. A detailed in the rheological study found that the encapsulated agents induced the change in the stiffness of the hydrogel from the hard to the soft. Especial, the thermally induced phase transition of CP hydrogel was governed by the participant of gelatin rather than curcumin. For example, at 25 wt% gelatin, CP hydrogel exhibited a unique gel–sol-gel transition following the function of temperature. Moreover, in vitro investigation revealed that the hybrid hydrogel provides the capacity of especially induced curcumin release with a sustainable rate as well as the excellent biocompatibility scaffold. Altogether with in vivo study, the hybrid hydrogel highlighted the advance of the dual synergistic of curcumin and gelatin in development of smart scaffold system, which promoted the efficacy in the regeneration of the structure and the barrier's function of damaged skin such as wound or skin cancer. [ABSTRACT FROM AUTHOR]