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Mite allergens
Published in Richard F. Lockey, Dennis K. Ledford, Allergens and Allergen Immunotherapy, 2020
Enrique Fernández-Caldas, Leonardo Puerta, Luis Caraballo, Victor Iraola, Richard F. Lockey
As the complex nature of IgE synthesis became more evident, the discovery of “beyond MHC” immune response genes influencing IgE was more frequent. Polymorphisms in Th2 genes, for instance, those in the gene encoding interleukin 4 at the 5q31 locus [257,258] and the signal transducer and activator of transcription 6 (STAT6) [259], have been replicated in different populations. Associations with mite sensitization also have been reported with polymorphisms in the genes encoding interleukin-18 (IL-18) [260,261], leukotriene C4 synthase (LTC4S) [262], nitric oxide synthase 1 (NOS1) [263], interleukin-4 receptor alpha (ILR4A) [257], dendritic cell associated nuclear protein 1 (DCNP1) [264], interferon regulatory factor 1 (IRF-1) [265], CD14 [266,267], Janus kinase 2 (JAK2), GATA binding protein 3 (GATA3), CD40, and interleukin-5 receptor alpha (IL5RA) [268], all of them participating in any of the multiple steps of IgE synthesis. The significant associations with polymorphisms in innate immune genes suggest that genetic effects exert their influences at very early phases of the response. These loci include the complement component 3 (C3) associated with the specific IgE levels to D. pteronyssinus [269], the myeloid differentiation factor 2 (MD2) associated with the specific IgE levels to D. pteronyssinus and Der p 2 [270], and the nucleotide-binding oligomerization domain containing 1 (NOD1) associated with mite sensitization [268].
Phytochemical, Pharmacological and Therapeutic Profile of Bacopa monnieri
Published in Dilip Ghosh, Pulok K. Mukherjee, Natural Medicines, 2019
Muhammad Shahid, Fazal Subhan, Nazar Ul Islam, Ihsan Ullah, Javaid Alam, Nisar Ahmad, Gowhar Ali
Bacopa monnieri has strong anti-inflammatory activity (Vidya et al. 2011) that is mediated through decreased release of tumour necrosis factor-α and interleukin-6 from mononuclear cells (Viji and Helen 2011), inhibition of activities of cyclooxygenase-2, lipooxygenase-5 and lipooxygenase-15 (Viji and Helen 2008), inhibition of prostaglandin-E2 production (Channa et al. 2006), and stabilisation of lysosomal membranes (Jain et al. 1994) and mast cells (Samiulla et al. 2001). The presence of bacoside A in Bacopa monnieri inhibits bacteria-derived proteases and is responsible for its wound-healing effect (Sharath et al. 2010). Bacopa monnieri reduces airway inflammation and inhibits the activities of leukotriene-C4-synthase, leukotriene-A4-hydrolase and/or cyclooxygenase-2. Moreover, it also downregulates the expression of mRNA of leukotriene-C4-synthase (Soni et al. 2014)]. Additionally, Bacopa monnieri and its active constituent, bacoside A, inhibit the release of inflammatory cytokines (TNF-α and IL-6) from microglial cells and inhibit enzymes (caspase 1 and 3, and matrix metalloproteinase-3) associated with inflammation in the brain (Nemetchek et al. 2017).
Post-viral atopic airway disease: pathogenesis and potential avenues for intervention
Published in Expert Review of Clinical Immunology, 2019
Syed-Rehan A. Hussain, Asuncion Mejias, Octavio Ramilo, Mark. E. Peeples, Mitchell H. Grayson
Leukotriene C4 synthase (LTC4S) is an enzyme that conjugates LTA4 and glutathione to form LTC4, which subsequently is converted to LTD4 and LTE4 [48]. Polymorphism in the LTC4S gene (−444A>C SNP) promotor causes dysregulation of CysLT levels and may be associated with severe asthma in Caucasian populations based on meta-analyses [49,50]. Further studies are needed to validate this potential link between asthma severity and the LTC4S polymorphism.
Drug discovery strategies for novel leukotriene A4 hydrolase inhibitors
Published in Expert Opinion on Drug Discovery, 2021
Till A Röhn, Shin Numao, Heike Otto, Christian Loesche, Gebhard Thoma
Leukotrienes are highly potent lipid mediators with numerous immunomodulatory properties [1]. Two classes of leukotrienes exist: the dihydroxy fatty acid, LTB4, and the glutathione conjugated peptide-leukotrienes, referred to as the cysteinyl-leukotrienes (CysLTs), consisting of LTC4, LTD4, and LTE4. Leukotrienes, as indicated by the name, are mainly produced by leukocytes and in particular, by neutrophils, eosinophils, basophils, mast cells, monocytes, macrophages, and dendritic cells [2]. They belong to the class of eicosanoids as they are derived from the C:20 omega-6 polyunsaturated fatty acid arachidonic acid (AA), which is released into the cytoplasm from phospholipid membranes by phospholipases such as cytosolic phospholipase A2 [3] (Figure 1). The central enzyme in leukotriene biosynthesis is the iron containing oxidoreductase 5-lipoxygenase (5-LO) which, supported by 5-lipoxygenase activating protein (FLAP) and coactosin-like protein (CLP), converts AA to the unstable allylic epoxide intermediate LTA4 [4]. LTA4 can be further metabolized by LTA4H into LTB4 [5]; by leukotriene C4 synthase (LTC4S) into LTC4 [6]; or by 12/15 Lipoxygenases into anti-inflammatory Lipoxin A4 (LXA4) [7]. Since their initial discovery in the late 1970s, the numerous functions of the leukotrienes on the immune system have become increasingly clear, and drug discovery approaches have been conducted on all biosynthetic enzymes of the 5-LO pathway and the different leukotriene receptors (BLT1 and BLT2 for LTB4 and CysLTR1, and CysLTR2 for the CysLTs) [1,2,8,9]. Despite major efforts by numerous pharmaceutical companies, only the low potency 5-LO inhibitor Zileuton, and several CysLTR1 selective antagonists (e.g. Montelukast, Zafirlukast, Pranlukast) have reached the market for the treatment of asthma [10–13]. Drug discovery efforts to identify more potent inhibitors that completely block the leukotriene pathway have remained active and there are on-going development programs in several pharmaceutical and biotech companies. These approaches have been reviewed recently in great detail and will not be subject to this article, which focuses exclusively on drug discovery strategies aimed at LTA4H [8,9,14,15].
Cysteinyl leukotriene induces eosinophil extracellular trap formation via cysteinyl leukotriene 1 receptor in a murine model of asthma
Published in Experimental Lung Research, 2021
Aline Andrea da Cunha, Josiane Silva Silveira, Géssica Luana Antunes, Keila Abreu da Silveira, Rodrigo Benedetti Gassen, Ricardo Vaz Breda, Paulo Márcio Pitrez
Therapeutic strategies to reduce eosinophilic inflammation in the lung have been related to a decrease in asthma symptoms.4 Eosinophils are able to release inflammatory cytokines, reactive oxygen species (ROS), cytotoxic granule, eosinophil extracellular trap (EET), and lipid mediators such as leukotrienes.5–8 Leukotrienes are synthesized from arachidonic acid through the 5-lipoxygenase pathway and play multiple roles in inflammatory disorders, such as asthma.9,10 There are two classes of leukotrienes, leukotriene B4 (LTB4) and cysteinyl leukotriene (cysLT). The LTB4 is involved in neutrophilic inflammation11,12; and cysLT induce eosinophilic inflammation.13 The stimulation of leukocytes by allergens induces the liberation of arachidonic acid from the phospholipids membrane by phospholipase A2. The 5-lipoxygenase, with the aid of the 5-lipoxygenase-activating protein (FLAP), catalyzes the conversion of arachidonic acid to 5-hydroperoxyeicosatetraenoic acid (5-HPETE) followed by the generation of leukotriene A4 (LTA4). The LTA4 can be metabolized by LTA4 hydrolase into LTB4 or it can be conjugated to glutathione by leukotriene C4 synthase (LTC4S) to LTC4, which may then be sequentially metabolized into leukotriene D4 (LTD4) and, finally, in leukotriene E4 (LTE4).9 The LTC4, LTD4, and LTE4 are cysLTs due to the presence of cysteine in their structure.14 The major cellular sources of cysLT production are eosinophils.13 In eosinophils, synthesis of cysLT occurs in perinuclear membranes and lipid bodies in the cytoplasm. There are three types of cysLT receptors: cysteinyl leukotriene receptor 1 (cysLT1), cysteinyl leukotriene receptor 2 (cysLT2), and cysteinyl leukotriene receptor 3 (cysLT3).15 The CysLT1 receptor is expressed on airway smooth muscle cells, eosinophils, B cells, mast cells, monocytes, and macrophages.16 Activation of cysLT1 receptor induces bronchoconstriction, mucus secretion, and airway edema in asthma.17 Moreover, there are two main therapeutic strategies to antagonize cysLT in patients with asthma. The first strategy is decreasing cysLT production by inhibiting 5-lipoxygenase or FLAP.18 The second strategy is the inhibition of cysLT1 receptor with antagonists leading to the reduction of cysLT binding on target cells.18 Thus, cysLT plays an important role in asthma pathophysiology. However, cysLT participation in the mechanism of eosinophil extracellular trap (EET) formation in asthma is not completely understood.