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Lipoxins
A lipoxin (LX or Lx), an acronym for lipoxygenase interaction product, is a bioactive autacoid metabolite of arachidonic acid made by various cell types. They are categorized as nonclassic eicosanoids and members of the specialized pro-resolving mediator (SPM) family of polyunsaturated fatty acid (PUFA) metabolites. Like other SPMs, LXs form during an inflammatory response and act to resolve it. The first lipoxins identified were lipoxin A4 (LXA4) and lipoxin B4 (LXB4), followed by their respective epimers, the epi-lipoxins 15-epi-LXA4 and 15-epi-LXB4. History LXA4 and LXB4 were first described by Charles Serhan, Mats Hamberg, and Bengt Samuelsson in 1984. They reported that human blood neutrophils, when stimulated, make these two lipoxins and that neutrophils, when stimulated by either of the LXs, mounted superoxide anion (O2−) generation and degranulation responses. Both responses are considered to be pro-inflammatory in that, while aimed at neutralizing invading pathog ...
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Epi-lipoxin
Epi-lipoxins are trihydroxy (i.e. containing 3 hydroxyl residues) metabolites of arachidonic acid. They are 15''R''-epimers of their lipoxin counterparts; that is, the epi-lipoxins, 15-epi-lipoxin A4 (15-epi-LxA4) and 15-epi-lipoxin B4 (15-epi-LXB4), differ from their respective lipoxin A4 (LxA4) and lipoxin B4 (LxB4) epimers in that their 15-hydroxy residue has ''R'' rather than ''S'' chirality. Formulae for these lipoxins (Lx) are: *LxA4: 5''S'',6''R'',15''S''-trihydroxy-7''E'',9''E'',11''Z'',13''E''-eicosatetraenoic acid *LxB4: 5''S'',14''R'',15''S''-trihydroxy-6''E'',8''Z'',10''E'',12''E''-eicosatetraenoic acid *15-epi-LxA4: 5''S'',6''R'',15''R''-trihydroxy-7''E'',9''E'',11''Z'',13''E''-eicosatetraenoic acid *15-epi-LxB4: 5''S'',14''R'',15''R''-trihydroxy-6''E'',8''Z'',10''E'',12''E''-eicosatetraenoic acid The two-epi-Lx's as well as the two lx's are nonclassic eicosanoids that, like other members of the specialized pro-resolving mediators class of autocoids, form du ...
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Cyclooxygenase 2
Cyclooxygenase-2 (COX-2), also known as prostaglandin-endoperoxide synthase 2 ( HUGO PTGS2), is an enzyme that in humans is encoded by the ''PTGS2'' gene. In humans it is one of three cyclooxygenases. It is involved in the conversion of arachidonic acid to prostaglandin H2, an important precursor of prostacyclin, which is expressed in inflammation. Function PTGS2 (COX-2), converts arachidonic acid (AA) to prostaglandin endoperoxide H2. PTGSs are targets for NSAIDs and PTGS2 (COX-2) specific inhibitors called coxibs. PTGS-2 is a sequence homodimer. Each monomer of the enzyme has a peroxidase and a PTGS (COX) active site. The PTGS (COX) enzymes catalyze the conversion of AA to prostaglandins in two steps. First, hydrogen is abstracted from carbon 13 of arachidonic acid, and then two molecules of oxygen are added by the PTGS2 (COX-2), giving PGG2. Second, PGG2 is reduced to PGH2 in the peroxidase active site. The synthesized PGH2 is converted to prostaglandins ( PGD2, PG ...
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ALOX15
ALOX15 (also termed arachidonate 15-lipoxygenase, 15-lipoxygenase-1, 15-LO-1, 15-LOX-1) is, like other lipoxygenases, a seminal enzyme in the metabolism of polyunsaturated fatty acids to a wide range of physiologically and pathologically important products. ▼ Gene Function Kelavkar and Badr (1999) stated that the ALOX15 gene product is implicated in antiinflammation, membrane remodeling, and cancer development/metastasis. Kelavkar and Badr (1999) described experiments yielding data that supported the hypothesis that loss of the TP53 gene, or gain-of-function activities resulting from the expression of its mutant forms, regulates ALOX15 promoter activity in human and in mouse, albeit in directionally opposite manners. These studies defined a direct link between ALOX15 gene activity and an established tumor-suppressor gene located in close chromosomal proximity. Kelavkar and Badr (1999) referred to this as evidence that 15-lipoxygenase is a mutator gene. ▼ Mapping By PCR ana ...
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15-lipoxygenase
ALOX15 (also termed arachidonate 15-lipoxygenase, 15-lipoxygenase-1, 15-LO-1, 15-LOX-1) is, like other lipoxygenases, a seminal enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ... in the metabolism of polyunsaturated fatty acids to a wide range of physiologically and pathologically important products. ▼ Gene Function Kelavkar and Badr (1999) stated that the ALOX15 gene product is implicated in antiinflammation, membrane remodeling, and cancer development/metastasis. Kelavkar and Badr (1999) described experiments yielding data that supported the hypothesis that loss of the TP53 gene, or gain-of-function activities resulting from the expression of its mutant forms, regulates ALOX15 promoter activity in human and in mouse, albeit in directionally opposite manners. These stud ...
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Arachidonic Acid
Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega−6 fatty acid 20:4(ω−6), or 20:4(5,8,11,14). It is a precursor in the formation of leukotrienes, prostaglandins, and thromboxanes. Together with omega−3 fatty acids and other omega−6 fatty acids, arachidonic acid provides energy for body functions, contributes to cell membrane structure, and participates in the synthesis of eicosanoids, which have numerous roles in physiology as signaling molecules. Its name derives from the ancient Greek neologism ''arachis'' 'peanut', although peanut oil does not contain any arachidonic acid. Arachidonate is the name of the derived carboxylate anion ( conjugate base of the acid), salts, and some esters. Chemistry In chemical structure, arachidonic acid is a carboxylic acid with a 20-carbon chain and four '' cis''- double bonds; the first double bond is located at the sixth carbon from the omega end. Some chemistry sources define 'arachidonic acid' to designa ...
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5-lipoxygenase
Arachidonate 5-lipoxygenase, also known as ALOX5, 5-lipoxygenase, 5-LOX, or 5-LO, is a non-heme iron-containing enzyme (EC 1.13.11.34) that in humans is encoded by the ''ALOX5'' gene. Arachidonate 5-lipoxygenase is a member of the lipoxygenase family of enzymes. It transforms essential fatty acids (Essential fatty acid, EFA) substrates into leukotrienes as well as a wide range of other biologically active products. ALOX5 is a current target for pharmaceutical intervention in a number of diseases. Gene The ''ALOX5'' gene, which occupies 71.9 kilobase pairs (kb) on chromosome 10 (all other human lipoxygenases are clustered together on chromosome 17), is composed of 14 exons divided by 13 introns encoding the mature 78 kilodalton (kDa) ALOX5 protein consisting of 673 amino acids. The gene promoter region of ALOX5 contains 8 GC boxes but lacks TATA boxes or CAT boxes and thus resembles the gene promoters of typical housekeeping genes. Five of the 8 GC boxes are arranged in tandem ...
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ALOX12
ALOX12 (), also known as arachidonate 12-lipoxygenase, 12-lipoxygenase, 12''S''-Lipoxygenase, 12-LOX, and 12''S''-LOX is a lipoxygenase-type enzyme that in humans is encoded by the ''ALOX12'' gene which is located along with other lipoyxgenases on chromosome 17p13.3. ALOX12 is 75 kilodalton protein composed of 663 amino acids. Nomenclature Other systematic names for ALOX12 include 12S-Lipoxygenase, platelet-type 12-lipoxygenase, arachidonate:oxygen 12-oxidoreductase, Delta12-lipoxygenase, 12Delta-lipoxygenase, and C-12 lipoxygenase. ALOX12, often termed plate platelet-type 12-lipoxygenase, is distinguished from leukocyte-type 12-lipoxygenase which is found in mice, rats, cows, and pigs but not humans. Leukocyte-type 12-lipoxygenase in these animal species shares 73-86% amino acid identity with human ALOX15 but only 57-66% identity with human platelet-type 12-lipoxygenase and, like ALOX15, metabolizes arachidonic acid primarily to 15(''S'')-hydroperoxy-5''Z'',8''Z'',11''Z'',13' ...
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Lipoxygenase
Lipoxygenases () (LOX) are a family of (non- heme) iron-containing enzymes, more specifically oxidative enzymes, most of which catalyze the dioxygenation of polyunsaturated fatty acids in lipids containing a cis,cis-1,4- pentadiene into cell signaling agents that serve diverse roles as autocrine signals that regulate the function of their parent cells, paracrine signals that regulate the function of nearby cells, and endocrine signals that regulate the function of distant cells. The lipoxygenases are related to each other based upon their similar genetic structure and dioxygenation activity. However, one lipoxygenase, ALOXE3, while having a lipoxygenase genetic structure, possesses relatively little dioxygenation activity; rather its primary activity appears to be as an isomerase that catalyzes the conversion of hydroperoxy unsaturated fatty acids to their 1,5- epoxide, hydroxyl derivatives. Lipoxygenases are found in eukaryotes (plants, fungi, animals, protists); whi ...
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Resolvin
Resolvins are specialized pro-resolving mediators (SPMs) derived from omega-3 fatty acids, primarily eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), as well as from two isomers of docosapentaenoic acid (DPA), one omega-3 and one omega-6 fatty acid. As autacoids similar to hormones acting on local tissues, resolvins are under preliminary research for their involvement in promoting restoration of normal cellular function following the inflammation that occurs after tissue injury. Resolvins belong to a class of polyunsaturated fatty acid (PUFA) metabolites termed specialized proresolving mediators (SPMs). Biochemistry and production Resolvins (Rvs) fall into several sub-classes based on the straight chain PUFA from which they are formed and derive their unique structure. The resolvins Ds (RvDs) are metabolites of the 22-carbon PUFA, DHA (i.e. 4''Z'',7''Z'',10''Z'',13''Z'',16''Z'',19''Z''-docosahexaenoic acid); the resolvins Es (RvEs) are metabolites of the 20-ca ...
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Maresin
Maresin 1 (MaR1 or 7''R'',14''S''-dihydroxy-4''Z'',8''E'',10''E'',12''Z'',16''Z'',19''Z''-docosahexaenoic acid) is a macrophage-derived mediator of inflammation resolution coined from macrophage mediator in resolving inflammation. Maresin 1, and more recently defined maresins, are 12-lipoxygenase-derived metabolites of the omega-3 fatty acid, docosahexaenoic acid (DHA), that possess potent anti-inflammatory, pro-resolving, protective, and pro-healing properties similar to a variety of other members of the specialized proresolving mediators (SPM) class of polyunsaturated fatty acid (PUFA) metabolites. SPM are dihydroxy, trihydroxy, and epoxy-hydroxy metabolites of long chain PUFA made by certain dioxygenase enzymes viz., cyclooxygenases and lipoxygenases. In addition to the maresins, this class of mediators includes: the 15-lipoxygenase (i.e. ALOX15 and/or possibly ALOX15B)-derived lipoxin A4 and B4 metabolites of the omega 6 fatty acid, arachidonic acid; the cyclooxygenase 2-de ...
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Leukotriene A4
Leukotriene A4 (LTA4) is a leukotriene Leukotrienes are a family of eicosanoid inflammation, inflammatory mediators produced in leukocytes by the redox, oxidation of arachidonic acid (AA) and the essential fatty acid eicosapentaenoic acid (EPA) by the enzyme arachidonate 5-lipoxyg ..., and is the precursor for the productions of leukotriene B4 (LTB4) and leukotriene C4 (LTC4). Biosynthesis Following the biosynthesis of eicosanoid, triggered as a result of infection or inflammation, the resulting arachidonic acid substrate is released from the cell membrane phospholipid will enter the lipooxygenase pathway to produce leukotriene A4. In this pathway, arachidonic acid is converted into 5-hydroperoxyeicosatetraenoic acid (5-HPETE) as a result of a catalytic complex consisting of the enzyme 5-lipoxygenase (5-LO) and 5-lipoxygenase-activating protein (FLAP) in the presence of ATP and calcium ions. The resulting 5-HPETE yields the unstable allylic epoxide substrate LTA4 ...
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Inflammatory Response
Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', ''dolor'', ''rubor'', ''tumor'', and ''functio laesa''). Inflammation is a generic response, and therefore is considered a mechanism of innate immunity, whereas adaptive immunity is specific to each pathogen. Inflammation is a protective response involving immune cells, blood vessels, and molecular mediators. The function of inflammation is to eliminate the initial cause of cell injury, clear out damaged cells and tissues, and initiate tissue repair. Too little inflammation could lead to progressive tissue destruction by the harmful stimulus (e.g. bacteria) and compromise the survival of the organism. However inflammation can also have negative effects. Too much inflammation, in the form of chronic inflammation, is associated with various ...
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