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The Role of Plant-Based Natural Compounds in Inflammation
Published in Namrita Lall, Medicinal Plants for Cosmetics, Health and Diseases, 2022
Marcela Dvorakova, Premysl Landa, Lenka Langhansova
Lipoxygenases are non-heme, iron-containing, lipid-peroxidizing enzymes. There are six human lipoxygenases, of which 5-LOX is the one primarily associated with inflammation. 5-LOX is activated by 5-lipoxygenase-activating protein (FLAP) and converts AA to 5-HPETE, which subsequently undergoes dehydration to form non-cysteinyl leukotriene A4 (LTA4). LTA4 is unstable and thus is rapidly converted either in mast cells or eosinophils to cysteinyl-LTs (LTC4, LTD4, and LTE4) or in neutrophils or monocytes to non-cysteine–containing dihydroxy-leukotriene B4 (LTB4). The cysteinyl-LTs are formed via successive action of LTC4 synthase (forms LTC4), transpeptidase (forms LTD4) and, finally, dipeptidase (forms LTE4), while LTB4 is formed directly by LTA4 hydrolase (Ghosh et al., 2016; Garscha et al., 2017; Pein et al., 2018; Rahman et al., 2019). The other human LOX enzymes, like 12- and 15-LOX, are expressed in various cell types and organs, and their metabolites exhibit both pro- and anti-inflammatory effects (Singh and Rao, 2019).
Eosinophils in Immunological Reactions
Published in Gerald J. Gleich, A. Barry Kay, Eosinophils in Allergy and Inflammation, 2019
In all cells, substrate arachidonate is not present to any large degree as free fatty acid (3), but rather is esterified within glycerolipids and is mobilized principally from classes of phospholipids by the actions of phospholipases in order to initiate the cascades that eventuate in eicosanoid formation. Since eicosanoid precursors containing arachidonyl-phospholipids are widely assumed to reside within cell membranes, it is cellular membranes in eosinophils as in other cells that are assumed to constitute the sole sites of eicosanoid formation. Prostaglandin H2 (PGH) synthase (cyclooxygenase) is believed to reside within membranes (4,5), perhaps, as interpreted by some (6) but not all (7), to have a conventional hydrophobic transmembrane spanning region. In other cell types, PGH synthase has been localized to the endoplasmic reticulum, to the nuclear membrane, and infrequently to the plasma membrane (5). The key proximal enzyme in the synthesis of leukotrienes, 5-lipoxygenase, is cytosolic but can undergo translocation to membranes where it acts to form 5-HPETE and LTA4 (8). In neutrophils, a membrane-bound protein, 5-lipoxygenase activating protein (FLAP), is involved in the translocation of cytosolic 5-lipoxygenase to membranes (9,10). Another enzyme in the eosinophil involved in the synthesis of LTC4, LTC4 synthase, is believed to reside at microsomal membranes, based on studies in other cells.
Research progress of natural products and their derivatives against Alzheimer’s disease
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Jin-Ying Liu, Hong-Yan Guo, Zhe-Shan Quan, Qing-Kun Shen, Hong Cui, Xiaoting Li
Both liquiritigenin and isoliquiritigenin are dihydro- flavonoid monomer compounds extracted from the natural plant liquorice. As these two compounds have similar structures, their pharmacological activities are also similar. In recent years, researchers have found that liquiritigenin and isoliquiritigenin are promising agents for the treatment of AD. Studies have shown that liquiritigenin can be a potent inhibitor of tau amyloid fibril formation by preventing structural transitions in its structure and exposure of hydrophobic groups. Therefore, reducing tau aggregation-mediated neurotoxicity42. Aβ levels can also be reduced by modulating the M1/M2 phenotype transition in microglia, thereby reducing memory decline during AD43. Isoliquiritigenin attenuated Aβ25-35 induced neuronal damage in rat cortical neurons by interfering with [Ca2+]i and ROS production44. Isoliquiritigenin reduces neuronal damage by inhibiting 5-lipoxygenase (5-LO). The activity of 5-LO is regulated by 5-lipoxygenase-activating protein (FLAP), and targeting the 5-LO/FLAP pathway is considered an effective strategy for the treatment of AD. 5-LO is involved in AD pathological changes, and its activity is significantly enhanced. Studies have shown that activation of 5-LO promotes Aβ amyloid deposition and tau hyperphosphorylation45 (Figure 5, Table 2).
Nanosized silver, but not titanium dioxide or zinc oxide, enhances oxidative stress and inflammatory response by inducing 5-HETE activation in THP-1 cells
Published in Nanotoxicology, 2020
Wing-Lam Poon, Jetty Chung-Yung Lee, Kin Sum Leung, Harri Alenius, Hani El-Nezami, Piia Karisola
Gene expression of several enzymes involved in oxidation of PUFA were also found to be disrupted by n-Ag in the microarray analyses especially at 24 h. Phospholipase A2 isozymes are responsible for the hydrolytic release of sn-2 fatty acid (including AA) from membrane phospholipids and some of them were upregulated (PLA2G4C) by n/b-ZnO and especially by n-Ag, when compared to unexposed controls (Figure 4(A)). ALOX5 (arachidonate 5-Lipoxygenase, also known as 5-LOX, Figure 4(B)), which catalyzes the conversion of AA to 5-HpETE (the precursor of 5-HETE), and its activating protein, ALOX5AP (arachidonate 5-lipoxygenase-activating protein, also known as FLAP, Figure 4(C)) were down-regulated, whereas expression of the COX-2 gene (called also PTGS2) was found to be increased exclusively by n-Ag (Figure 4(D)).
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].