Effects of Blocking NLRP3 Inflammasome on Type II Innate Lymphoid Cell Response in Allergic Rhinitis.

Background: Type 2 innate lymphoid cells (ILC2s) and NLRP3 inflammasome are related to allergic and inflammatory responses. NLRP3 inflammasome inhibitor MCC950 was demonstrated to ameliorate allergic rhinitis (AR) in animal models.

Objective: To elucidate the effect of MCC950 on ILC2 responses in AR.

Inhibition of IL-4/STAT6/IRF4 signaling reduces the epithelial-mesenchymal transition in eosinophilic chronic rhinosinusitis with nasal polyps.

Background: Previous studies have shown that epithelial-to-mesenchymal transition (EMT) in nasal epithelial cells is critical for tissue remodeling of chronic rhinosinusitis with nasal polyps (CRSwNP). However, the precise mechanism underlying the EMT remains poorly understood. This study aimed to investigate the role of interleukin-4 (IL-4)/signal transducer and activator of transcription 6 (STAT6)/interferon regulatory factor 4 (IRF4) signaling pathway on EMT in eosinophilic CRSwNP.

Design and performance study of grease spool-less relief valve.

The high resistance characteristic of the grease delivery process makes the centralized lubrication system easy to cause pipeline blockage during the grease supply process. The main objective of the present article is to design a non-spool relief valve device based on the round pipe. The plug shape characteristics of the grease flow in the tube are established by combining the hydrodynamic equation and the grease rheological model.

Anti-inflammatory Effect of a Limonin Derivative In Vivo and Its Mechanisms in RAW264.7 Cells.

A potential new limonoid derivative, (12S,12aS)-6,6,8a,12a-tetramethyl-12-(5-(4-(piperidin-1-yl)butanoyl)furan-3-yl)decahydro-1H,3H-oxireno[2,3-d]pyrano[4',3':3,3a]isobenzofuro[5,4-f]isochromene-3,8,10(6H,9aH)-trione (I-C-1), has been screened for its anti-inflammatory activity. This study aimed to demonstrate the anti-inflammatory activities of I-C-1 and to further explore the underlying mechanisms of these activities in RAW264.7 macrophages.

Discovery of the First Selective IDO2 Inhibitor As Novel Immunotherapeutic Avenues for Rheumatoid Arthritis.

Indoleamine 2,3-dioxygenase 2 (IDO2), a closely related homologue of well-studied immunomodulatory enzyme IDO1, has been identified as a pathogenic mediator of inflammatory autoimmunity in preclinical models. Therapeutic targeting IDO2 in autoimmune diseases has been challenging due to the lack of small-molecule IDO2 inhibitors. Here, based on our previously developed IDO1/IDO2 dual inhibitor, guided by the homology model of the IDO2 structure, we discovered compound , the most potent inhibitor targeting IDO2 with good inhibitory activity (IDO2 IC = 112 nM).

Dropouts From Sublingual Immunotherapy and the Transition to Subcutaneous Immunotherapy in House Dust Mite-Sensitized Allergic Rhinitis Patients.

Both subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) are effective in reducing symptoms and medication scores and inducing long-term efficacy in patients with allergic rhinitis (AR). However, SLIT has been associated with poor patient adherence. This study investigates the factors impacting dropout rates from SLIT in house dust mite (HDM)-sensitized AR patients.

Dual-target synergistic antithrombotic mechanism of a dabigatran etexilate analogue (HY023016).

Thrombin has long been considered a desirable antithrombotic target, but anti-thrombin therapy without anti-platelet therapy has never achieved the ideal effect. HY023016, derived from dabigatran etexilate, exhibited a potent antithrombotic efficacy. In the present study, mechanisms underlying this effect were explored.

Optimization of P2Y Antagonist Ethyl 6-(4-((Benzylsulfonyl)carbamoyl)piperidin-1-yl)-5-cyano-2-methylnicotinate (AZD1283) Led to the Discovery of an Oral Antiplatelet Agent with Improved Druglike Properties.

P2Y antagonists are widely used as antiplatelet agents for the prevention and treatment of arterial thrombosis. Based on the scaffold of a known P2Y antagonist AZD1283, a series of novel bicyclic pyridine derivatives were designed and synthesized. The cyclization of the ester substituent on the pyridine ring to the ortho-methyl group led to lactone analogues of AZD1283 that showed significantly enhanced metabolic stability in subsequent structure-pharmacokinetic relationship studies.

Discovery of novel limonin derivatives as potent anti-inflammatory and analgesic agents.

Novel series of limonin derivatives (V-A-1-V-A-8, V-B-1-V-B-8) were synthesized by adding various tertiary amines onto the C (7)-position of limonin. The synthesized compounds possessed favorable physicochemical property, and the intrinsic solubility of the novel compounds were significantly improved, compared with limonin. Different pharmacological models were used to evaluate the analgesic and anti-inflammatory activities of the target compounds.

A novel limonin derivate modulates inflammatory response by suppressing the TLR4/NF-κB signalling pathway.

In our previous studies, we have demonstrated that a novel water-soluble derivative of limonin, (12S,12aS,Z)-8-((2-(diethylamino)ethoxy)imino)-12-(furan-3-yl)-6,6,8a,12a-tetramethyldodecahydro-1H,3H-oxireno[2,3-d]pyrano[4',3':3,3a]isobenzofuro[5,4-f]isochromene-3,10(9aH)-dione (V-A-4), exhibited strong anti-inflammatory activity both in vitro and in vivo. The purpose of this study was to further explore the underlying mechanisms of such activity demonstrated by V-A-4. The protective effect of V-A-4 on the alleviation of xylene-induced ear swelling and carrageenan-induced subcutaneous air pouch model was detected in vivo.

Dual inhibition of HY023016 based on binding properties of platelet membrane receptor subunit glycoprotein Ibα and thrombin exosites.

Thrombin has long been suggested as a desirable antithrombotic target, but anti-thrombin therapy without anti-platelet thereby has never achieved the ideal effect. HY023016 is a novel compound, in our previous study, it exerted better anti-thrombotic than dabigatran etexilate. The present study aims to illustrate the excess anti-thrombotic molecular mechanisms of HY023016 through thrombin anion exosites and the platelet membrane receptor subunit glycoprotein Ibα (GPIbα).

Autophagy regulates the degeneration of the auditory cortex through the AMPK-mTOR-ULK1 signaling pathway.

Presbycusis is the most common sensory impairment associated with aging; however, the underlying molecular mechanism remains unclear. Autophagy has been demonstrated to serve a key role in diverse diseases; however, no studies have examined its function in central presbycusis. The aim of the present study was to investigate the changes of autophagy in the physiological processes of the auditory cortex and its role in the degeneration of the auditory cortex, as well as the related mechanisms using naturally aging rats and a D‑galactose (D‑gal)‑induced mimetic rat model of aging.

Expression of IL-17 and syndecan-1 in nasal polyps and their correlation with nasal polyps.

Nasal polyp (NP) is a common chronic inflammatory disease of the nasal cavity and sinuses. Although some authors have suggested that NP is related to inflammatory factors such as interleukin (IL)-1β, IL-5, IL-8, granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor (TNF)-α, and IL-17, the mechanisms underlying the pathogenesis and progression of NP remain obscure. This study investigated the expression and distribution of IL-17 and syndecan-1 in NP, and explored the roles of these two molecules in the pathogenesis of eosinophilic chronic rhinosinusitis with nasal polyps (Eos CRSwNP) and non-Eos CRSwNP.

Design, synthesis and antithrombotic evaluation of novel non-peptide thrombin inhibitors.

Ten derivatives of 4-((1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-1-yl)methyl)benzimida-mide (I-1∼I-2, II-1∼II-8) were designed, synthesized and evaluated for their inhibitory effect on human thrombin. Compound II-7 (IC=82.8nM), which showed the strongest thrombin inhibitory activity among the tested compounds, was chosen as the lead compound, and ten carbamate derivatives (II-9a∼II-13a, II-9b∼II-12b, II-14) were prepared and evaluated for their anticoagulant activity.

Evaluating antithrombotic activity of HY023016 on rat hypercoagulable model.

The generation of thrombus is not considered as an isolated progression without other pathologic processes, which may also enhance procoagulant state. The purpose of this study was to assess whether HY023016, a novel dabigatran prodrug and an oral direct thrombin inhibitor, or dabigatran etexilate, another thrombin inhibitor can improve the state of whole blood hypercoagulability in vitro/vivo. By using whole blood flow cytometry we explored the effects of HY023016 and dabigatran etexilate on thrombin and ADP-induced human platelet-leukocyte aggregation generated in vitro.

Design, synthesis and antithrombotic evaluation of novel dabigatran etexilate analogs, a new series of non-peptides thrombin inhibitors.

Thrombin is a serine protease that plays a key role in blood clotting, which makes it a promising target for the treatment of thrombotic diseases. Dabigatran is direct potent thrombin inhibitor. Based on bioisosteric and scaffold hopping principle, two dabigatran mimics (I-1 and II-1) in which the benzamidine moiety of dabigatran was replaced by a tricyclic fused scaffold were designed, synthesized and evaluated for their in vitro activities for inhibiting thrombin.

Discovery and SAR study of 2-(1-propylpiperidin-4-yl)-3H-imidazo[4,5-c]pyridine-7-carboxamide: A potent inhibitor of poly(ADP-ribose) polymerase-1 (PARP-1) for the treatment of cancer.

A series of imidazo[4,5-c]pyridine-7-carboxamide derivatives as poly(ADP-ribose) polymerase (PARP) inhibitors have been developed. All target compounds were evaluated for their PARP-1 inhibitory activity and some were further assessed for cellular potency. These efforts led to identification of a novel PARP-1 inhibitor 2-(1-propylpiperidin-4-yl)-3H-imidazo[4,5-c]pyridine-7-carboxamide 11a (XZ-120312).

Design, Synthesis, and Biological Evaluation of Dabigatran Etexilate Mimics, a Novel Class of Thrombin Inhibitors.

Human α-thrombin is a particularly promising target for anticoagulant therapy, and identification of oral small-molecular inhibitors of thrombin remains a research focus. On the basis of the X-ray crystal structure of human α-thrombin and its inhibitor dabigatran, we designed and synthesized a series of dabigatran etexilate mimics containing a novel tricyclic fused scaffold. The biological evaluations reveal that all of the compounds possess moderate activity of antiplatelet aggregation induced by thrombin in vitro.

Ethyl pyruvate attenuates murine allergic rhinitis partly by decreasing high mobility group box 1 release.

High-mobility group box 1 (HMGB1) protein, a pro-inflammatory DNA-binding protein, meditates inflammatory responses through Toll-like receptor-4 signals and amplifies allergic inflammation by interacting with the receptor for advanced glycation end products. Previous studies have shown that HMGB1 is elevated in the nasal lavage fluids (NLF) of children suffering from allergic rhinitis (AR) and is associated with the severity of this disease. Furthermore, HMGB1 has been implicated in the pathogenesis of lower airway allergic diseases, such as asthma.

NLRP3 inflammasome sequential changes in Staphylococcus aureus-induced mouse model of acute rhinosinusitis.

The NLR pyrin domain containing 3 (NLRP3) inflammasome plays a crucial role in lung disease and may have a similar role in upper respiratory tract inflammation. We therefore constructed a C57BL/6 mouse model of acute rhinosinusitis induced by Staphylococcus aureus and investigated the role of the NLRP3 inflammasome in this model. Mice were classified as non-inoculated group (group A) and inoculated groups (groups B, C, D and E, sacrificed 1, 3, 7 and 14 days after inoculation, respectively).

House dust mite allergen levels in households and correlation with allergic rhinitis symptoms.

Background: House dust mite (HDM) allergen is a risk factor for the development of allergic rhinitis (AR).

Objectives: To determine the levels of indoor allergens in the households of patients with AR in Wuhan city, identify the environmental risk factors for high allergen exposure, and investigate the correlations between allergen exposure and specific immunoglobulin E levels and symptoms.

Methods: The study examined 50 patients with AR.

Design, synthesis, and structure-activity and structure-pharmacokinetic relationship studies of novel [6,6,5] tricyclic fused oxazolidinones leading to the discovery of a potent, selective, and orally bioavailable FXa inhibitor.

The blood coagulation enzyme factor Xa (FXa) is a particularly promising target for anticoagulant therapy, and identification of oral small-molecule inhibitors of FXa remains a research focus. On the basis of the X-ray crystal structure of FXa and its inhibitor rivaroxaban, we designed and synthesized a series of conformationally restricted mimics containing a novel [6,6,5] tricyclic fused oxazolidinone scaffold. Intensive structure-activity relationship (SAR) and structure-pharmacokinetic relationship (SPR) studies on this new series led to the discovery of compound 11a: a highly potent, selective, direct, and orally bioavailable FXa inhibitor with excellent in vivo antithrombotic efficacy and preferable pharmacokinetic profiles.

Effects of IL-17 on expression of GRO-α and IL-8 in fibroblasts from nasal polyps.

Recent studies indicated that interleukin (IL)-17, growth-related oncogene (GRO)-α and IL-8 play an important role in the pathogenesis of nasal polyps. However, the effects of the increased amount of IL-17 and the production of GRO-α and IL-8 in human nasal polyp fibroblasts are not completely understood. This study aimed to determine the effects of the increased IL-17 on the changes of GRO-α and IL-8 expression in human nasal polyp fibroblasts and further investigate the mechanism of neutrophil infiltration in nasal polyps.