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1.
Eur Heart J ; 45(18): 1662-1680, 2024 May 13.
Article in English | MEDLINE | ID: mdl-38666340

ABSTRACT

BACKGROUND AND AIMS: The Glu504Lys polymorphism in the aldehyde dehydrogenase 2 (ALDH2) gene is closely associated with myocardial ischaemia/reperfusion injury (I/RI). The effects of ALDH2 on neutrophil extracellular trap (NET) formation (i.e. NETosis) during I/RI remain unknown. This study aimed to investigate the role of ALDH2 in NETosis in the pathogenesis of myocardial I/RI. METHODS: The mouse model of myocardial I/RI was constructed on wild-type, ALDH2 knockout, peptidylarginine deiminase 4 (Pad4) knockout, and ALDH2/PAD4 double knockout mice. Overall, 308 ST-elevation myocardial infarction patients after primary percutaneous coronary intervention were enrolled in the study. RESULTS: Enhanced NETosis was observed in human neutrophils carrying the ALDH2 genetic mutation and ischaemic myocardium of ALDH2 knockout mice compared with controls. PAD4 knockout or treatment with NETosis-targeting drugs (GSK484, DNase1) substantially attenuated the extent of myocardial damage, particularly in ALDH2 knockout. Mechanistically, ALDH2 deficiency increased damage-associated molecular pattern release and susceptibility to NET-induced damage during myocardial I/RI. ALDH2 deficiency induced NOX2-dependent NETosis via upregulating the endoplasmic reticulum stress/microsomal glutathione S-transferase 2/leukotriene C4 (LTC4) pathway. The Food and Drug Administration-approved LTC4 receptor antagonist pranlukast ameliorated I/RI by inhibiting NETosis in both wild-type and ALDH2 knockout mice. Serum myeloperoxidase-DNA complex and LTC4 levels exhibited the predictive effect on adverse left ventricular remodelling at 6 months after primary percutaneous coronary intervention in ST-elevation myocardial infarction patients. CONCLUSIONS: ALDH2 deficiency exacerbates myocardial I/RI by promoting NETosis via the endoplasmic reticulum stress/microsomal glutathione S-transferase 2/LTC4/NOX2 pathway. This study hints at the role of NETosis in the pathogenesis of myocardial I/RI, and pranlukast might be a potential therapeutic option for attenuating I/RI, particularly in individuals with the ALDH2 mutation.


Subject(s)
Aldehyde Dehydrogenase, Mitochondrial , Extracellular Traps , Leukotriene C4 , Myocardial Reperfusion Injury , Animals , Female , Humans , Male , Mice , Middle Aged , Aldehyde Dehydrogenase, Mitochondrial/genetics , Aldehyde Dehydrogenase, Mitochondrial/metabolism , Benzamides , Benzodioxoles , Disease Models, Animal , Extracellular Traps/metabolism , Leukotriene Antagonists/pharmacology , Leukotriene Antagonists/therapeutic use , Leukotriene C4/antagonists & inhibitors , Leukotriene C4/metabolism , Mice, Knockout , Myocardial Reperfusion Injury/prevention & control , Myocardial Reperfusion Injury/genetics , Myocardial Reperfusion Injury/metabolism , Neutrophils/metabolism , Protein-Arginine Deiminase Type 4/metabolism , ST Elevation Myocardial Infarction/metabolism
2.
Proc Natl Acad Sci U S A ; 120(11): e2220012120, 2023 03 14.
Article in English | MEDLINE | ID: mdl-36893260

ABSTRACT

Adenosine triphosphate-binding cassette (ABC) transporters, such as multidrug resistance protein 1 (MRP1), protect against cellular toxicity by exporting xenobiotic compounds across the plasma membrane. However, constitutive MRP1 function hinders drug delivery across the blood-brain barrier, and MRP1 overexpression in certain cancers leads to acquired multidrug resistance and chemotherapy failure. Small-molecule inhibitors have the potential to block substrate transport, but few show specificity for MRP1. Here we identify a macrocyclic peptide, named CPI1, which inhibits MRP1 with nanomolar potency but shows minimal inhibition of a related multidrug transporter P-glycoprotein. A cryoelectron microscopy (cryo-EM) structure at 3.27 Å resolution shows that CPI1 binds MRP1 at the same location as the physiological substrate leukotriene C4 (LTC4). Residues that interact with both ligands contain large, flexible sidechains that can form a variety of interactions, revealing how MRP1 recognizes multiple structurally unrelated molecules. CPI1 binding prevents the conformational changes necessary for adenosine triphosphate (ATP) hydrolysis and substrate transport, suggesting it may have potential as a therapeutic candidate.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1 , Multidrug Resistance-Associated Proteins , Adenosine Triphosphate/metabolism , ATP Binding Cassette Transporter, Subfamily B/metabolism , ATP Binding Cassette Transporter, Subfamily B, Member 1/chemistry , ATP-Binding Cassette Transporters/metabolism , Biological Transport , Cryoelectron Microscopy , Leukotriene C4/metabolism , Multidrug Resistance-Associated Proteins/metabolism , Peptides/metabolism , Peptides, Cyclic/pharmacology
3.
BMC Complement Med Ther ; 22(1): 242, 2022 Sep 17.
Article in English | MEDLINE | ID: mdl-36115955

ABSTRACT

BACKGROUND: Ecklonia cava is an edible marine brown alga harvested from the ocean that is widely consumed in Asian countries as a health-promoting medicinal food The objective of the present study is to evaluate the anti-asthma mechanism of a new functional food produced by bioprocessing edible algae Ecklonia cava and shiitake Lentinula edodes mushroom mycelia and isolated fractions. METHODS: We used as series of methods, including high performance liquid chromatography, gas chromatography, cell assays, and an in vivo mouse assay to evaluate the asthma-inhibitory effect of Ecklonia cava bioprocessed (fermented) with Lentinula edodes shiitake mushroom mycelium and its isolated fractions in mast cells and in orally fed mice. RESULTS: The treatments inhibited the degranulation of RBL-2H3 cells and immunoglobulin E (IgE) production, suggesting anti-asthma effects in vitro. The in vitro anti-asthma effects in cells were confirmed in mice following the induction of asthma by alumina and chicken egg ovalbumin (OVA). Oral administration of the bioprocessed Ecklonia cava and purified fractions suppressed the induction of asthma and was accompanied by the inhibition of inflammation- and immune-related substances, including eotaxin; thymic stromal lymphopoietin (TSLP); OVA-specific IgE; leukotriene C4 (LTC4); prostaglandin D2 (PGD2); and vascular cell adhesion molecule-1 (VCAM-1) in bronchoalveolar lavage fluid (BALF) and other fluids and organs. Th2 cytokines were reduced and Th1 cytokines were restored in serum, suggesting the asthma-induced inhibitory effect is regulated by the balance of the Th1/Th2 immune response. Serum levels of IL-10, a regulatory T cell (Treg) cytokine, were increased, further favoring reduced inflammation. Histology of lung tissues revealed that the treatment also reversed the thickening of the airway wall and the contraction and infiltration of bronchial and blood vessels and perialveolar inflammatory cells. The bioprocessed Ecklonia cava/mushroom mycelia new functional food showed the highest inhibition as compared with commercial algae and the fractions isolated from the bioprocessed product. CONCLUSIONS: The in vitro cell and in vivo mouse assays demonstrate the potential value of the new bioprocessed formulation as an anti-inflammatory and anti-allergic combination of natural compounds against allergic asthma and might also ameliorate allergic manifestations of foods, drugs, and viral infections.


Subject(s)
Agaricales , Anti-Allergic Agents , Anti-Asthmatic Agents , Asthma , Phaeophyceae , Shiitake Mushrooms , Aluminum Oxide/adverse effects , Animals , Anti-Allergic Agents/adverse effects , Anti-Asthmatic Agents/pharmacology , Anti-Inflammatory Agents/pharmacology , Asthma/drug therapy , Cytokines/metabolism , Immunoglobulin E , Inflammation/drug therapy , Interleukin-10 , Leukotriene C4/adverse effects , Mice , Mice, Inbred BALB C , Mycelium , Ovalbumin/adverse effects , Phaeophyceae/metabolism , Prostaglandin D2/adverse effects , Shiitake Mushrooms/metabolism , Vascular Cell Adhesion Molecule-1/adverse effects
4.
Comput Math Methods Med ; 2022: 2657994, 2022.
Article in English | MEDLINE | ID: mdl-35720028

ABSTRACT

Objective: To study the effect of Hanchuan Zupa granule combined with conventional western medicine in the treatment of children with bronchial asthma. Methods: 98 cases in Fengrun District People's Hospital of Tangshan City from June 2018 to February 2021 were selected. The control group was given oxygen therapy, antibiotics, and aerosol inhalation of quick acting ß 2 receptor agonist, glucocorticoid, and other conventional western medicine treatment, while the observation group was treated with Bairui granule on the basis of the control group. The course of treatment of the two groups was 1 week. Results: After treatment, the levels of sputum IL-4, IL-17, neu, and ECP in the two groups decreased, and the observation group was lower than the control group (P < 0.05). The levels of EOS, CXCR4, LTB4, and SDF-1 in peripheral blood of the two groups were lower than those in the control group (P < 0.05). The daytime cough, night cough, and TCM syndrome scores of the two groups were decreased, and the observation group was lower than the control group (P < 0.05). Conclusion: Bairui granule combined with conventional western medicine in the treatment of children with bronchial asthma, the curative effect is worthy of affirmation, can effectively improve cough symptoms, reduce EOS, CXCR, LTB4, SDF-1 levels, inhibit airway inflammation, and has good clinical application value.


Subject(s)
Asthma , Sputum , Asthma/drug therapy , Child , Cough/drug therapy , Eosinophils , Humans , Inflammation Mediators , Leukotriene B4/therapeutic use , Leukotriene C4/therapeutic use
5.
Front Immunol ; 13: 880412, 2022.
Article in English | MEDLINE | ID: mdl-35711458

ABSTRACT

IgE-mediated release of proinflammatory mediators and cytokines from basophils and mast cells is a central event in allergic disorders. Several groups of investigators have demonstrated the presence of autoantibodies against IgE and/or FcεRI in patients with chronic spontaneous urticaria. By contrast, the prevalence and functional activity of anti-IgE autoantibodies in atopic dermatitis (AD) are largely unknown. We evaluated the ability of IgG anti-IgE from patients with AD to induce the in vitro IgE-dependent activation of human basophils and skin and lung mast cells. Different preparations of IgG anti-IgE purified from patients with AD and rabbit IgG anti-IgE were compared for their triggering effects on the in vitro release of histamine and type 2 cytokines (IL-4, IL-13) from basophils and of histamine and lipid mediators (prostaglandin D2 and cysteinyl leukotriene C4) from human skin and lung mast cells. One preparation of human IgG anti-IgE out of six patients with AD induced histamine release from basophils, skin and lung mast cells. This preparation of human IgG anti-IgE induced the secretion of cytokines and eicosanoids from basophils and mast cells, respectively. Human monoclonal IgE was a competitive antagonist of both human and rabbit IgG anti-IgE. Human anti-IgE was more potent than rabbit anti-IgE for IL-4 and IL-13 production by basophils and histamine, prostaglandin D2 and leukotriene C4 release from mast cells. Functional anti-IgE autoantibodies rarely occur in patients with AD. When present, they induce the release of proinflammatory mediators and cytokines from basophils and mast cells, thereby possibly contributing to sustained IgE-dependent inflammation in at least a subset of patients with this disorder.


Subject(s)
Basophils , Dermatitis, Atopic , Animals , Autoantibodies/pharmacology , Cytokines/pharmacology , Eicosanoids , Histamine , Humans , Immunoglobulin E , Immunoglobulin G/pharmacology , Interleukin-13/pharmacology , Interleukin-4/pharmacology , Leukotriene C4 , Mast Cells , Prostaglandins , Rabbits
6.
Iran J Allergy Asthma Immunol ; 21(2): 141-150, 2022 Apr 11.
Article in English | MEDLINE | ID: mdl-35490268

ABSTRACT

Current medications to treat allergic rhinitis (AR) include antihistamines, corticosteroids, and anti-leukotrienes. In the present study, we investigated the effects of combination therapy; using these drugs, and evaluates the AR-related markers and parameters in an animal model. After inducing BALB/c mice AR models, the animals were treated with either pranlukast, loratadine, fluticasone, loratadine + fluticasone, loratadine + pranlukast, fluticasone + pranlukast, or loratadine + fluticasone + pranlukast. Clinical symptoms, Immunoglobulin (Ig)G1, ovalbumin (OVA)-specific and total IgE, leukotriene (LT)B4, LTC4, histamine, thymic stromal lymphopoietin (TSLP) serum levels, and interleukin 4 level in the nasal lavage fluid were determined. The expressions of HRH1, CysLT1R, NLR3, Caspase-1, and MUC5a were studied. Allergic symptoms (nasal rubbing and sneezing), serum Igs (IgG1, total and OVA-specific IgE), eicosanoids (LTB4 and LTC4), histamine, TSLP, and IL-4 as well as gene expressions of MUC5a, Caspase-1, NLR3, HRH1, and CysLT1R were reduced in the animals receiving each of the therapeutic regimens; however, more pronounced effects were seen in the group treated with the triple combined protocol (loratadine + fluticasone + pranlukast). The combination of the loratadine, fluticasone, and pranlukast can effectively control the symptoms of AR probably via modulating several related mechanisms at early and late phases of allergic responses.


Subject(s)
Loratadine , Rhinitis, Allergic , Allergens/therapeutic use , Animals , Caspase 1 , Fluticasone/therapeutic use , Histamine , Immunoglobulin E , Leukotriene C4/therapeutic use , Loratadine/therapeutic use , Mice , Rhinitis, Allergic/drug therapy , Rhinitis, Allergic/metabolism
7.
J Investig Med ; 70(8): 1753-1758, 2022 12.
Article in English | MEDLINE | ID: mdl-35410888

ABSTRACT

Asthma is a complex airway disease that affects more than 350 million humans worldwide. Allergic asthma symptoms are induced by Th2 immune response with the release of cytokines and allegro-inflammatory mediators that amplify the inflammatory response, airway hyper-responsiveness (AHR) and hyperproduction of mucus. Higenamine, as a chemical compound, is a ß2 adrenoreceptor agonist and can be used as bronchodilator in allergic asthma.BALB/c mice were allocated in four groups and then allergic asthma was induced in three groups. One of the asthmatic groups was treated with albuterol and other one was treated with higenamine. At least, methacholine challenge to determine the AHR, measurement of cytokines, total immunoglobulin E (IgE), LTB4 and LTC4 levels, evaluation of gene expression of Muc5ac, Muc5b, Agr2 and Arg1, and histopathological study were done.Higenamine treatment reduced AHR, interleukin (IL)-4, IL-13 levels, mRNA expression of MUC5ac, MUC5b, Arg1 and Agr2, goblet cell hyperplasia and mucus hypersecretion. Higenamine had no significant effect on IL-5, interferon-γ (INF-γ), IgE, LTB4, LTC4 levels and eosinophilic inflammation in lung tissue.Higenamine treatment controls asthma acute attack and breathlessness and can be used as asthma treatment with control of AHR and decrease of airflow obstruction and mucus hypersecretion and had allegro-immune-regulatory effect. But higenamine treatment had no notable effect on the inflammation and inflammatory factors.


Subject(s)
Anti-Allergic Agents , Asthma , Respiratory Hypersensitivity , Animals , Mice , Asthma/drug therapy , Cytokines/metabolism , Disease Models, Animal , Immunoglobulin E/metabolism , Immunoglobulin E/pharmacology , Inflammation/pathology , Leukotriene B4/metabolism , Leukotriene B4/pharmacology , Leukotriene B4/therapeutic use , Leukotriene C4/metabolism , Lung/pathology , Mice, Inbred BALB C , Mucoproteins/metabolism , Mucoproteins/pharmacology , Mucoproteins/therapeutic use , Respiratory Hypersensitivity/drug therapy
8.
Eur J Med Chem ; 231: 114167, 2022 Mar 05.
Article in English | MEDLINE | ID: mdl-35152061

ABSTRACT

Microsomal prostaglandin E2 synthase-1 (mPGES-1) is recognized as a promising therapeutic target for next-generation anti-inflammatory drugs to treat inflammatory diseases. In this study, we report the identification of new, potent and selective inhibitors of human mPGES-1 such as compounds 10, 31 and 49 with IC50 of 0.03-0.09 µM in a cell-free assay of PGE2 production. Compound 10 and 49 also inhibited leukotriene C4 synthase (LTC4S) at sub-µM concentrations (IC50 = 0.7 and 0.4 µM, respectively), affording compounds dually targeting inflammatory PGE2 and cysteinyl leukotriene (cys-LT) biosynthesis. However, compound 31 showed substantial selectivity towards mPGES-1 (IC50 = 0.03 µM) with a decreased inhibitory activity on LTC4S (IC50 = 2.8 µM), and also on other related targets such as FLAP and 5-LO. These oxadiazole thione-benzimidazole derivatives warrant further exploration of new and alternative analogs that may lead to the identification of novel derivatives with potent anti-inflammatory properties.


Subject(s)
Leukotriene C4 , Microsomes , Anti-Inflammatory Agents/pharmacology , Benzimidazoles/pharmacology , Dinoprostone , Humans , Prostaglandin-E Synthases
9.
Biochim Biophys Acta Mol Cell Res ; 1869(3): 119203, 2022 03.
Article in English | MEDLINE | ID: mdl-34968576

ABSTRACT

Leukotriene (LT) C4 synthase (LTC4S) catalyzes the conversion from LTA4 to LTC4, which is a proinflammatory lipid mediator in asthma and other inflammatory diseases. LTC4 is metabolized to LTD4 and LTE4, all of which are known as cysteinyl (Cys) LTs and exert physiological functions through CysLT receptors. LTC4S is expressed in adipocytes. However, the function of CysLTs and the regulatory mechanism in adipocytes remain unclear. In this study, we investigated the expression of LTC4S and production of CysLTs in murine adipocyte 3T3-L1 cells and their underlying regulatory mechanisms. Expression of LTC4S and production of LTC4 and CysLTs increased during adipogenesis, whereas siRNA-mediated suppression of LTC4S expression repressed adipogenesis by reducing adipogenic gene expression. The CysLT1 receptor, one of the two LTC4 receptors, was expressed in adipocytes. LTC4 and LTD4 increased the intracellular triglyceride levels and adipogenic gene expression, and their enhancement was suppressed by co-treatment with pranlukast, a CysLT1 receptor antagonist. Moreover, the expression profiles of LTC4S gene/protein during adipogenesis resembled those of peroxisome proliferator-activated receptor (PPAR) γ. LTC4S expression was further upregulated by treatment with troglitazone, a PPARγ agonist. Promoter-luciferase and chromatin immunoprecipitation assays showed that PPARγ directly bound to the PPAR response element of the LTC4S gene promoter in adipocytes. These results indicate that the LTC4S gene expression was enhanced by PPARγ, and LTC4 and LTD4 activated adipogenesis through CysLT1 receptors in 3T3-L1 cells. Thus, LTC4S and CysLT1 receptors are novel potential targets for the treatment of obesity.


Subject(s)
Adipocytes/cytology , Adipogenesis , Glutathione Transferase/genetics , Leukotriene C4/pharmacology , Leukotriene D4/pharmacology , PPAR gamma/metabolism , Receptors, Leukotriene/metabolism , 3T3-L1 Cells , Adipocytes/drug effects , Adipocytes/metabolism , Animals , Gene Expression Regulation , Glutathione Transferase/metabolism , Mice , PPAR gamma/genetics , Promoter Regions, Genetic , Receptors, Leukotriene/genetics
10.
Iran J Allergy Asthma Immunol ; 21(6): 704-710, 2022 Dec 24.
Article in English | MEDLINE | ID: mdl-36640061

ABSTRACT

Allergic rhinitis (AR) is an allergic disease induced by the T helper 2 (TH2) lymphocyte immune response, where its mediators are the primary cause of clinical symptoms. Environmental factors are the primary determinants of the allergic response in genetically susceptible individuals. This study investigates the effects of climate conditions (warm, cold, humid, and dry) on allergic rhinitis. AR models were created in mice under 4 different conditions. We investigated AR-related behavior (sneezing and nose rubbing), as well as total immunoglobulin E (IgE), histamine, interleukin-4 (IL-4), leukotriene (LT) B4 and LTC4 levels, and gene expression of CysLT1R, HRH1, and MUC5a. Nose rubbing, histamine levels, and the expression of MUC5a and HRH1 were increased in AR models in cold conditions, and sneezing was increased in AR models kept in dry conditions. LTB4 and LTC4 levels and the expression of CysLT1R in AR models kept in a wet environment also significantly increased compared with the control group. The levels of total IgE and IL-4 showed no significant changes. Air temperature and humidity affect AR pathophysiology, and weather conditions can be essential in controlling AR.


Subject(s)
Interleukin-4 , Rhinitis, Allergic , Animals , Mice , Disease Models, Animal , Histamine , Humidity , Immunoglobulin E , Leukotriene C4/adverse effects , Mice, Inbred BALB C , Nasal Mucosa , Ovalbumin , Sneezing , Temperature
11.
J Environ Pathol Toxicol Oncol ; 40(3): 63-73, 2021.
Article in English | MEDLINE | ID: mdl-34587405

ABSTRACT

Allergic rhinitis (AR) is a common type of inflammatory disease with symptoms including rhinorrhea, fatigue, sneezing, and disturbed sleep. AR affects nearly 40% of peoples worldwide with the increased numbers of new cases. In this work, the study was conducted to disclose the anti-inflammatory and antiallergic properties of cirsilineol against the ovalbumin (OVA)-sensitized AR in mice. AR was provoked in BALB/c mice through the OVA challenge 30 days along with 10 and 20 mg/kg of cirsilineol treatment. The nasal symptoms, i.e., rubbing and sneezing was monitored after the final OVA challenge. The status of OVA-specific IgE, PGD2, and LTC4 was investigated using assay kits. The status of pro-inflammatory markers also examined using assay kits. The levels of oxidative markers, SOD activity, and pro-inflammatory markers in the spleen mononuclear cells (SMEs) were studied by using respective assay kits. The mRNA expression of TXNIP was assessed using RT-PCR study. The 10 and 20 mg/kg of cirsilineol treatment effectively decreased the sneezing and nasal rubbings in OVA-provoked mice. Cirsilineol also decreased the IgE, PGD2, and LTC4 status in the AR animals. The status of pro-inflammatory markers, i.e., IL-4, IL-5, IL-6, IL-33 and TNF-α was found to be decreased in the cirsilineol administered AR mice. Cirsilineol effectively reduced the ROS and MDA and improved SOD in the OVA-challenged SMCs. The mRNA expression of TXNIP was appreciably suppressed by the cirsilineol treatment. Altogether, these findings proved the beneficial actions of cirsilineol against the OVA-triggered AR in mice. The additional studies on the cirsilineol could lead to the development of new drug for AR management.


Subject(s)
Anti-Allergic Agents/pharmacology , Flavones/pharmacology , Rhinitis, Allergic/prevention & control , Animals , Biomarkers/metabolism , Carrier Proteins/genetics , Cells, Cultured , Disease Models, Animal , Eosinophils/drug effects , Histamine/blood , Immunoglobulin E/blood , Immunoglobulin E/metabolism , Leukotriene C4/metabolism , Mice, Inbred BALB C , Nasal Lavage Fluid , Ovalbumin/toxicity , Oxidative Stress/drug effects , Prostaglandin D2/metabolism , Rhinitis, Allergic/chemically induced , Rhinitis, Allergic/immunology , Spleen/cytology , Thioredoxins/genetics
12.
J Pharmacol Sci ; 147(1): 126-131, 2021 Sep.
Article in English | MEDLINE | ID: mdl-34294363

ABSTRACT

Type I hypersensitivity is an immediate immune reaction that involves IgE-mediated activation of mast cells. Activated mast cells release chemical mediators, such as histamine and lipid mediators, which cause allergic reactions. Recent developments in detection devices have revealed that mast cells simultaneously release a wide variety of lipid mediators. Mounting evidence has revealed that mast cell-derived mediators exert both pro- and anti-inflammatory functions and positively and negatively regulate the development of allergic inflammation. This review presents the roles of major lipid mediators released from mast cells. Author believes this review will be helpful for a better understanding of the pathogenesis of allergic diseases and provide a new strategy for the diagnosis and treatment of allergic reactions.


Subject(s)
Hypersensitivity, Immediate/etiology , Lipid Metabolism/physiology , Fatty Acids, Unsaturated , Histamine Release , Humans , Hydroxyeicosatetraenoic Acids , Hypersensitivity, Immediate/diagnosis , Hypersensitivity, Immediate/therapy , Immunoglobulin E , Inflammation , Leukotriene B4 , Leukotriene C4 , Mast Cells/metabolism , Prostaglandin D2
13.
Prostaglandins Other Lipid Mediat ; 155: 106563, 2021 08.
Article in English | MEDLINE | ID: mdl-34029712

ABSTRACT

Aspirin-exacerbated respiratory disease and some cases of chronic idiopathic urticaria are disorders in which increased baseline urinary excretion of leukotriene(LT)E4 further increases following aspirin administration. Increased urinary excretion of the metabolites of prostaglandin D2, 11ß-prostaglandin(PG)F2α and (2,3-dinor)-11ß-PGF2α, have been documented in systemic mastocytosis (SM) and in mast cell activation syndrome (MCAS). Symptoms due to increased baseline and/or episodic release of PGD2 can be prevented with aspirin, an inhibitor of cyclooxygenase (COX)1 and COX2. Here by retrospective chart review we discovered 8 of 10 patients with SM in whom normalization of an elevated urinary (2,3-dinor)-11ß-PGF2α occurred with aspirin therapy also had a parallel increased excretion of LTE4 by an average of nearly 13-fold. How widespread this phenomenon occurs in SM is unknown; however, this occurrence needs to be considered when interpreting changes in these urinary mast cell mediator metabolites during aspirin therapy.


Subject(s)
Leukotriene C4
14.
Allergol Immunopathol (Madr) ; 49(3): 42-49, 2021.
Article in English | MEDLINE | ID: mdl-33938187

ABSTRACT

BACKGROUND: The aim of this study was to evaluate the inhibitory effect of tamarixetin on the production of inflammatory mediators in IgE/antigen-induced mouse bone marrow-derived mast cells (BMMCs). MATERIALS AND METHODS: The effects of tamarixetin on mast cell activation were investigated with regard to degranulation, eicosanoid generation, Ca2+ influx, and immunoblotting of various signaling molecules. RESULTS: Tamarixetin effectively decreased degranulation and the eicosanoid generation such as leukotriene C4 and prostaglandin D2 in BMMCs. To elucidate the mechanism involved, we investigated the effect of tamarixetin on the phosphorylation of signal molecules. Tamarixetin inhibited the phosphorylation of Akt and its downstream signal molecules including IKK and nuclear factor κB. In addition, tamarixetin downregulated the phosphorylation of cytosolic phospholipase A2 (cPLA2) and p38 mitogen-activated protein kinase. CONCLUSIONS: Taken together, this study suggests that tamarixetin inhibits degranulation and eicosanoid generation through the PLCγ1 as well as Akt pathways in BMMCs, which would be potential for the prevention of allergic inflammatory diseases.


Subject(s)
Cell Degranulation/drug effects , Disaccharides/pharmacology , Eicosanoids/biosynthesis , Inflammation Mediators/metabolism , Inula/chemistry , Mast Cells/drug effects , Quercetin/analogs & derivatives , Animals , Bone Marrow Cells/drug effects , Bone Marrow Cells/metabolism , Calcium/metabolism , Leukotriene C4/biosynthesis , Mast Cells/metabolism , Mast Cells/physiology , Mice , Mice, Inbred BALB C , NF-kappa B/metabolism , Phospholipase C gamma/metabolism , Phospholipases A2/metabolism , Phosphorylation/drug effects , Prostaglandin D2/biosynthesis , Protein Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Quercetin/pharmacology , beta-N-Acetylhexosaminidases/metabolism , p38 Mitogen-Activated Protein Kinases/metabolism
15.
Proc Natl Acad Sci U S A ; 118(13)2021 03 30.
Article in English | MEDLINE | ID: mdl-33753496

ABSTRACT

Acute and chronic itch are burdensome manifestations of skin pathologies including allergic skin diseases and atopic dermatitis, but the underlying molecular mechanisms are not well understood. Cysteinyl leukotrienes (CysLTs), comprising LTC4, LTD4, and LTE4, are produced by immune cells during type 2 inflammation. Here, we uncover a role for LTC4 and its signaling through the CysLT receptor 2 (CysLT2R) in itch. Cysltr2 transcript is highly expressed in dorsal root ganglia (DRG) neurons linked to itch in mice. We also detected CYSLTR2 in a broad population of human DRG neurons. Injection of leukotriene C4 (LTC4) or its nonhydrolyzable form NMLTC4, but neither LTD4 nor LTE4, induced dose-dependent itch but not pain behaviors in mice. LTC4-mediated itch differed in bout duration and kinetics from pruritogens histamine, compound 48/80, and chloroquine. NMLTC4-induced itch was abrogated in mice deficient for Cysltr2 or when deficiency was restricted to radioresistant cells. Itch was unaffected in mice deficient for Cysltr1, Trpv1, or mast cells (WSh mice). CysLT2R played a role in itch in the MC903 mouse model of chronic itch and dermatitis, but not in models of dry skin or compound 48/80- or Alternaria-induced itch. In MC903-treated mice, CysLT levels increased in skin over time, and Cysltr2-/- mice showed decreased itch in the chronic phase of inflammation. Collectively, our study reveals that LTC4 acts through CysLT2R as its physiological receptor to induce itch, and CysLT2R contributes to itch in a model of dermatitis. Therefore, targeting CysLT signaling may be a promising approach to treat inflammatory itch.


Subject(s)
Dermatitis, Atopic/immunology , Leukotriene C4/metabolism , Pruritus/immunology , Receptors, Leukotriene/metabolism , Skin/innervation , Animals , Chronic Disease , Dermatitis, Atopic/chemically induced , Dermatitis, Atopic/complications , Dermatitis, Atopic/pathology , Disease Models, Animal , Ganglia, Spinal/cytology , Ganglia, Spinal/metabolism , Humans , Mice , Mice, Knockout , Pruritus/pathology , Receptors, Leukotriene/genetics , Sensory Receptor Cells/metabolism , Signal Transduction/immunology , Skin/pathology
16.
Nat Commun ; 12(1): 1728, 2021 03 19.
Article in English | MEDLINE | ID: mdl-33741927

ABSTRACT

Microsomal glutathione S-transferase 2 (MGST2) produces leukotriene C4, key for intracrine signaling of endoplasmic reticulum (ER) stress, oxidative DNA damage and cell death. MGST2 trimer restricts catalysis to only one out of three active sites at a time, but the molecular basis is unknown. Here, we present crystal structures of human MGST2 combined with biochemical and computational evidence for a concerted mechanism, involving local unfolding coupled to global conformational changes that regulate catalysis. Furthermore, synchronized changes in the biconical central pore modulate the hydrophobicity and control solvent influx to optimize reaction conditions at the active site. These unique mechanistic insights pertain to other, structurally related, drug targets.


Subject(s)
Glutathione Transferase/chemistry , Glutathione Transferase/genetics , Glutathione Transferase/metabolism , Binding Sites , Catalysis , Catalytic Domain , Crystallography, X-Ray , Endoplasmic Reticulum/metabolism , Humans , Leukotriene C4/metabolism , Molecular Dynamics Simulation , Mutagenesis, Site-Directed , Oxidative Stress , Protein Conformation
17.
Proteins ; 89(6): 659-670, 2021 06.
Article in English | MEDLINE | ID: mdl-33469960

ABSTRACT

Human multidrug resistance protein 1 (hMRP1) is an important member of the ATP-binding cassette (ABC) transporter superfamily. It can extrude a variety of anticancer drugs and physiological organic anions across the plasma membrane, which is activated by substrate binding, and is accompanied by large-scale cooperative movements between different domains. Currently, it remains unclear completely about how the specific interactions between hMRP1 and its substrate are and which critical residues are responsible for allosteric signal transduction. To the end, we first construct an inward-facing state of hMRP1 using homology modeling method, and then dock substrate proinflammatory agent leukotriene C4 (LTC4) to hMRP1 pocket. The result manifests LTC4 interacts with two parts of hMRP1 pocket, namely the positively charged pocket (P pocket) and hydrophobic pocket (H pocket), similar to its binding mode with bMRP1 (bovine MRP1). Additionally, we use the Gaussian network model (GNM)-based thermodynamic method proposed by us to identify the key residues whose perturbations markedly alter their binding free energy. Here the conventional GNM is improved with covalent/non-covalent interactions and secondary structure information considered (denoted as sscGNM). In the result, sscGNM improves the flexibility prediction, especially for the nucleotide binding domains with rich kinds of secondary structures. The 46 key residue clusters located in different subdomains are identified which are highly consistent with experimental observations. Furtherly, we explore the long-range cooperation within the transporter. This study is helpful for strengthening the understanding of the work mechanism in ABC exporters and can provide important information to scientists in drug design studies.


Subject(s)
Adenosine Triphosphate/chemistry , Leukotriene C4/chemistry , Multidrug Resistance-Associated Proteins/chemistry , Adenosine Triphosphate/metabolism , Allosteric Site , Animals , Cattle , Humans , Hydrophobic and Hydrophilic Interactions , Kinetics , Leukotriene C4/metabolism , Molecular Docking Simulation , Multidrug Resistance-Associated Proteins/metabolism , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , Protein Isoforms/chemistry , Protein Isoforms/metabolism , Signal Transduction , Static Electricity , Structural Homology, Protein , Substrate Specificity , Thermodynamics
18.
J Allergy Clin Immunol ; 148(1): 195-208.e5, 2021 07.
Article in English | MEDLINE | ID: mdl-33285161

ABSTRACT

BACKGROUND: The 3 cysteinyl leukotrienes (cysLTs), leukotriene (LT) C4 (LTC4), LTD4, and LTE4, have different biologic half-lives, cellular targets, and receptor specificities. CysLT2R binds LTC4 and LTD4in vitro with similar affinities, but it displays a marked selectivity for LTC4in vivo. LTC4, but not LTD4, strongly potentiates allergen-induced pulmonary eosinophilia in mice through a CysLT2R-mediated, platelet- and IL-33-dependent pathway. OBJECTIVE: We sought to determine whether LTD4 functionally antagonizes LTC4 signaling at CysLT2R. METHODS: We used 2 different in vivo models of CysLT2R-dependent immunopathology, as well as ex vivo activation of mouse and human platelets. RESULTS: LTC4-induced CD62P expression; HMGB1 release; and secretions of thromboxane A2, CXCL7, and IL-33 by mouse platelets were all were blocked by a selective CysLT2R antagonist and inhibited by LTD4. These effects did not depend on CysLT1R. Inhaled LTD4 blocked LTC4-mediated potentiation of ovalbumin-induced eosinophilic inflammation; recruitment of platelet-adherent eosinophils; and increases in IL-33, IL-4, IL-5, and IL-13 levels in lung tissue. In contrast, the effect of administration of LTE4, the preferred ligand for CysLT3R, was additive with LTC4. The administration of LTD4 to Ptges-/- mice, which display enhanced LTC4 synthesis similar to that in aspirin-exacerbated respiratory disease, completely blocked the physiologic response to subsequent lysine-aspirin inhalation challenges, as well as increases in levels of IL-33, type 2 cytokines, and biochemical markers of mast cell and platelet activation. CONCLUSION: The conversion of LTC4 to LTD4 may limit the duration and extent of potentially deleterious signaling through CysLT2R, and it may contribute to the therapeutic properties of desensitization to aspirin in aspirin-exacerbated respiratory disease.


Subject(s)
Blood Platelets/immunology , Leukotriene C4/immunology , Leukotriene D4/immunology , Lung/immunology , Platelet Activation/immunology , Animals , Asthma/immunology , Cysteine/immunology , Cytokines/immunology , Leukotriene E4/immunology , Leukotrienes/immunology , Male , Mice , Mice, Inbred C57BL , Pulmonary Eosinophilia/immunology , Receptors, Leukotriene/immunology
19.
Eur J Pharmacol ; 884: 173353, 2020 Oct 05.
Article in English | MEDLINE | ID: mdl-32707189

ABSTRACT

Phosphatidylinositol-specific phospholipase C (PI-PLC) and cytosolic phospholipase A2 (cPLA2) regulate both eosinophil degranulation and leukotriene (LT) synthesis via PI-PLC-mediated calcium influx and cPLA2 activation. Phosphatidylcholine-specific phospholipase C (PC-PLC) likely plays a key role in cellular signaling, including the eosinophilic allergic inflammatory response. This study examined the role of PC-PLC in eosinophil LT synthesis and degranulation using tricyclodecan-9-yl-xanthogenate (D609), a PC-specific PLC inhibitor. D609 inhibited N-formyl-met-leu-phe + cytochalasin B (fMLP/B)-induced arachidonic acid (AA) release and leukotriene C4 (LTC4) secretion. However, at concentrations that blocked both AA release and LTC4 secretion, D609 had no significant inhibitory effect on stimulated cPLA2 activity. D609 also partially blocked fMLP/B-induced calcium influx, indicating that inhibition of AA release and LTC4 secretion by D609 is due to inhibition of calcium-mediated cPLA2 translocation to intracellular membranes, not inhibition of cPLA2 activity. In addition, D609 inhibited fMLP/B-stimulated eosinophil peroxidase release, indicating that PC-PLC regulates fMLP/B-induced eosinophil degranulation by increasing the intracellular calcium concentration ([Ca2+]i). Overall, our results showed that PC-PLC is critical for fMLP/B-stimulated eosinophil LT synthesis and degranulation. In addition, degranulation requires calcium influx, while PC-PLC regulates LTC4 synthesis through calcium-mediated cPLA2 activation.


Subject(s)
Cell Degranulation , Eosinophils/enzymology , Leukotrienes/metabolism , Type C Phospholipases/metabolism , Arachidonic Acid/metabolism , Calcium Signaling , Cell Degranulation/drug effects , Cytochalasin B/pharmacology , Enzyme Activation , Eosinophils/drug effects , Group IV Phospholipases A2/metabolism , Humans , Leukotriene C4/metabolism , N-Formylmethionine Leucyl-Phenylalanine/pharmacology , Norbornanes/pharmacology , Phosphodiesterase Inhibitors/pharmacology , Signal Transduction , Thiocarbamates/pharmacology , Type C Phospholipases/antagonists & inhibitors
20.
Virulence ; 11(1): 730-738, 2020 01 01.
Article in English | MEDLINE | ID: mdl-32441188

ABSTRACT

Outbreaks of multiple respiratory diseases with high morbidity and mortality have been frequently reported in poultry industry. Metabolic profiling has showed widespread usage in metabolic and infectious disease for identifying biomarkers and understanding of complex mechanisms. In this study, the non-targeted metabolomics were used on Mycoplasma gallisepticum (MG) and Escherichia coli (E.coli) co-infection model in serum, which showed that Leukotriene C4 (LTC4), Leukotriene D4 (LTD4), Chenodeoxycholate, Linoleate and numerous energy metabolites were varied significantly. KEGG enrichment analysis revealed that the metabolic pathways of linoleic acid, taurine and arachidonic acid (AA) were upregulated. To further characterize the consequences of co-infection, we performed an AA metabolic network pathway with metabolic products and enzyme genes. The results showed that the expression of LTC4 increased extremely significant and accompanied with different degree of infection. Meanwhile, the AA network performed the changes and differences of various metabolites in the pathway when multiple respiratory diseases occurred. Taken together, co-infection induces distinct alterations in the serum metabolome owing to the activation of AA metabolism. Furthermore, LTC4 in serum could be used as the biomarker for detecting poultry respiratory disease. ABBREVIATIONS: MG: Mycoplasma gallisepticum; E.coli: Escherichia coli; AA: Arachidonic acid; LTC4: Leukotriene C4; CRD: chronic respiratory diseases; KEGG: Kyoto Encyclopedia of Genes and Genomes; LTs: leukotrienes; PGs: prostaglandins; NO: nitric oxide; HIS: histamine; PCA: Principal Component Analysis; PLS-DA: Partial Least Squares Discriminant Analysis; CCU: color change unit; UPLC: ultra-performance liquid chromatography; MS: mass spectrometry; DEMs: differentially expressed metabolites; ELISA: enzyme-linked immunosorbent assay; SD: standard deviation; VIP: Variable importance in the projection.


Subject(s)
Arachidonic Acid/metabolism , Coinfection/veterinary , Leukotriene C4/blood , Mycoplasma gallisepticum/metabolism , Poultry/microbiology , Respiratory Tract Infections/veterinary , Animals , Biomarkers/blood , Chromatography, Liquid , Coinfection/microbiology , Escherichia coli , Mass Spectrometry , Metabolic Networks and Pathways , Metabolome , Metabolomics , Respiratory Tract Infections/diagnosis
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