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== Production == |
== Production == |
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| − | MaR1 was first defined as a product of DHA formed by cultures of human [[monocyte]]-derived macrophages.<ref name="pmid25359497"/> Studies implicate the following pathway in its formation: 12-lipoxygenase converts DHA to its 14-hydroxperoxy intermediate, 14(''S'')-hydroperoxy-4''Z'',7''Z'',10''Z'',12''E'',16''Z'',19''Z''-DHA (14-HpDHA); 14-HpDHA is converted enzymatically to its 13(''S''),14(''S'') [[epoxy]] derivative, termed 13(''S''),14(''S'')-epoxy-maresin which is then enzymatically hydrolyzed to Mar1. Byproducts of this metabolism include the reduction of 14-HpDHA to its hydroxyl counterpart, 14(''S'')-hydroxy-4''Z'',7''Z'',10''Z'',12''E'',16''Z'',19''Z''-DHA (14-HDPA); the [[5-lipoxygenase]]-dependent conversion of 14-HpDHA and/or 14-HDHA to 7(''S''),14(''S'')-dihydroxy-4''Z'',8''E'',10''Z'',12''E'',15''Z'',19''Z''-DHA; and the non-enzymatic hydrolysis of 14-HpDHA to 7(''S''/''R''),14(''S'')-DHA and 13(''S''/''R'')-DHA products.<ref> |
+ | MaR1 was first defined as a product of DHA formed by cultures of human [[monocyte]]-derived macrophages.<ref name="pmid25359497"/> Studies implicate the following pathway in its formation: 12-lipoxygenase converts DHA to its 14-hydroxperoxy intermediate, 14(''S'')-hydroperoxy-4''Z'',7''Z'',10''Z'',12''E'',16''Z'',19''Z''-DHA (14-HpDHA); 14-HpDHA is converted enzymatically to its 13(''S''),14(''S'') [[epoxy]] derivative, termed 13(''S''),14(''S'')-epoxy-maresin which is then enzymatically hydrolyzed to Mar1. Byproducts of this metabolism include the reduction of 14-HpDHA to its hydroxyl counterpart, 14(''S'')-hydroxy-4''Z'',7''Z'',10''Z'',12''E'',16''Z'',19''Z''-DHA (14-HDPA); the [[5-lipoxygenase]]-dependent conversion of 14-HpDHA and/or 14-HDHA to 7(''S''),14(''S'')-dihydroxy-4''Z'',8''E'',10''Z'',12''E'',15''Z'',19''Z''-DHA; and the non-enzymatic hydrolysis of 14-HpDHA to 7(''S''/''R''),14(''S'')-DHA and 13(''S''/''R'')-DHA products.<ref name="pmid25139562">{{cite journal | pmid = 25139562 | pmc = 4324013 | year = 2015 | author1 = Serhan | first1 = C. N. | title = Protectins and maresins: New pro-resolving families of mediators in acute inflammation and resolution bioactive metabolome | journal = Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids | volume = 1851 | issue = 4 | pages = 397–413 | last2 = Dalli | first2 = J | last3 = Colas | first3 = R. A. | last4 = Winkler | first4 = J. W. | last5 = Chiang | first5 = N | doi = 10.1016/j.bbalip.2014.08.006 }}</ref> Concurrently, the macrophages also convert DHA to 13(''R''),14(''S'')-dihydroxy-4''Z'',7''Z'',9''E'',11''E'',16''Z'',19''Z''-docosapentaenoic acid, i.e. maresin 2 (MaR2).<ref name="pmid25036362">{{cite journal | pmid = 25036362 | pmc = 4103848 | year = 2014 | author1 = Deng | first1 = B | title = Maresin biosynthesis and identification of maresin 2, a new anti-inflammatory and pro-resolving mediator from human macrophages | journal = PLoS ONE | volume = 9 | issue = 7 | pages = e102362 | last2 = Wang | first2 = C. W. | last3 = Arnardottir | first3 = H. H. | last4 = Li | first4 = Y | last5 = Cheng | first5 = C. Y. | last6 = Dalli | first6 = J | last7 = Serhan | first7 = C. N. | doi = 10.1371/journal.pone.0102362 }}</ref> The measurement of 17-HDHA in tissues is used as a marker for the level of activation of the maresin-producing pathway.<ref name="pmid26667839"/> |
== Sources == |
== Sources == |
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| − | The maresans have been detected primarily as products made by monocyte-macrophage cells types. MaR1 has been identified in the synovial fluid taken from the joins of patients with [[rheumatoid arthritis]].<ref> |
+ | The maresans have been detected primarily as products made by monocyte-macrophage cells types. MaR1 has been identified in the synovial fluid taken from the joins of patients with [[rheumatoid arthritis]].<ref name="pmid23747022">{{cite journal | pmid = 23747022 | pmc = 3732499 | year = 2013 | author1 = Serhan | first1 = C. N. | title = Resolution phase lipid mediators of inflammation: Agonists of resolution | journal = Current Opinion in Pharmacology | volume = 13 | issue = 4 | pages = 632–40 | last2 = Chiang | first2 = N | doi = 10.1016/j.coph.2013.05.012 }}</ref> In a murine model of [[acute respiratory distress syndrome]], MaR1 production was detected; its generation appeared to reflect an interaction between blood [[platelets]] and neutrophils wherein 12-lipoxygenase-rich platelets generated 13(''S''),14(''S'')-epoxy-maresin which was then passed to neutrophils which hydrolyzed the epoxy maresin to MaR1.<ref name="pmid25369934">{{cite journal | pmid = 25369934 | pmc = 4246348 | year = 2014 | author1 = Abdulnour | first1 = R. E. | title = Maresin 1 biosynthesis during platelet-neutrophil interactions is organ-protective | journal = Proceedings of the National Academy of Sciences | volume = 111 | issue = 46 | pages = 16526–31 | last2 = Dalli | first2 = J | last3 = Colby | first3 = J. K. | last4 = Krishnamoorthy | first4 = N | last5 = Timmons | first5 = J. Y. | last6 = Tan | first6 = S. H. | last7 = Colas | first7 = R. A. | last8 = Petasis | first8 = N. A. | last9 = Serhan | first9 = C. N. | last10 = Levy | first10 = B. D. | doi = 10.1073/pnas.1407123111 }}</ref> [[Planaria]] worms metabolize DHA to Mar1 during the healing phase of experimentally induced tissue injury.<ref name="pmid25539814">{{cite journal | pmid = 25539814 | pmc = 4297713 | year = 2015 | author1 = Krishnamoorthy | first1 = N | title = Cutting edge: Maresin-1 engages regulatory T cells to limit type 2 innate lymphoid cell activation and promote resolution of lung inflammation | journal = The Journal of Immunology | volume = 194 | issue = 3 | pages = 863–7 | last2 = Burkett | first2 = P. R. | last3 = Dalli | first3 = J | last4 = Abdulnour | first4 = R. E. | last5 = Colas | first5 = R | last6 = Ramon | first6 = S | last7 = Phipps | first7 = R. P. | last8 = Petasis | first8 = N. A. | last9 = Kuchroo | first9 = V. K. | last10 = Serhan | first10 = C. N. | last11 = Levy | first11 = B. D. | doi = 10.4049/jimmunol.1402534 }}</ref> |
== Activities == |
== Activities == |
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Studies suggest that Maresins are involved in resolving inflammatory and allergic reactions, in wound healing, and in abating neuropathic pain. |
Studies suggest that Maresins are involved in resolving inflammatory and allergic reactions, in wound healing, and in abating neuropathic pain. |
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| − | Mar1 enhances the uptake (i.e. stimulates the [[efferocytosis]]) of [[apoptotic]] human neutrophils by human macrophages, stimulates macrophage[[phagocytosis]], and limits the infiltration of neutrophils into the inflamed peritoneum of mice.<ref |
+ | Mar1 enhances the uptake (i.e. stimulates the [[efferocytosis]]) of [[apoptotic]] human neutrophils by human macrophages, stimulates macrophage[[phagocytosis]], and limits the infiltration of neutrophils into the inflamed peritoneum of mice.<ref name="pmid23747022"/><ref name="pmid25139562"/> In a murine model of [[acute respiratory distress syndrome]], MaR1 generation was detected in a temporally regulated manner with early MaR1 production was dependent on platelet-neutrophil interactions; intravascular MaR1 was organ-protective, leading to decreased lung neutrophils, edema, tissue hypoxia, and prophlogistic mediators.<ref name="pmid25369934"/> |
| − | In a murine model of a self-limiting pulmonary allergic reaction, MaR1 reduced lung inflammation. It appeared to act at least in part by augmenting the generation of [[regulatory T cells]] which interacted with Group 2 innate lymphoid cells (i.e. Helper T cell lymphocytes, see [[Innate lymphoid cell#GroupILC]]) to markedly suppress the production of two [[cytokines]], [[Interleukin-5]] and [[Interleukin-13]], implicated in mediating allergic reactions.<ref> |
+ | In a murine model of a self-limiting pulmonary allergic reaction, MaR1 reduced lung inflammation. It appeared to act at least in part by augmenting the generation of [[regulatory T cells]] which interacted with Group 2 innate lymphoid cells (i.e. Helper T cell lymphocytes, see [[Innate lymphoid cell#GroupILC]]) to markedly suppress the production of two [[cytokines]], [[Interleukin-5]] and [[Interleukin-13]], implicated in mediating allergic reactions.<ref name="pmid25539814"/><ref>{{cite journal | pmid = 26546247 | pmc = 4854800 | year = 2015 | author1 = Duvall | first1 = M. G. | title = DHA- and EPA-derived resolvins, protectins, and maresins in airway inflammation | journal = European Journal of Pharmacology | last2 = Levy | first2 = B. D. | doi = 10.1016/j.ejphar.2015.11.001 }}</ref> MaR1 accelerated tissue regeneration in experimentally injured [[planaria]] worms. In particular, it increasing the rate of head reappearance in beheaded worms.<ref>{{cite journal | pmid = 22253477 | pmc = 3316905 | year = 2012 | author1 = Serhan | first1 = C. N. | title = Macrophage proresolving mediator maresin 1 stimulates tissue regeneration and controls pain | journal = The FASEB Journal | volume = 26 | issue = 4 | pages = 1755–65 | last2 = Dalli | first2 = J | last3 = Karamnov | first3 = S | last4 = Choi | first4 = A | last5 = Park | first5 = C. K. | last6 = Xu | first6 = Z. Z. | last7 = Ji | first7 = R. R. | last8 = Zhu | first8 = M | last9 = Petasis | first9 = N. A. | doi = 10.1096/fj.11-201442 }}</ref> And, MaR1 reduced neuropathic pain in a mouse model by inhibiting a neuron [[ion channel]], [[TRPV1]], and thereby blocking capsaicin-induced inward currents and neuron excitation.<ref name="pmid23747022"/><ref name="pmid25139562"/> |
| − | Mar2 possess at least some of the activities ascribed to MaR1. It enhances human macrophage phagocytosis of particles and efferocytosis of apoptotic human neutrophils and reduces neutrophil infiltration into the inflamed peritoneum of mice.<ref |
+ | Mar2 possess at least some of the activities ascribed to MaR1. It enhances human macrophage phagocytosis of particles and efferocytosis of apoptotic human neutrophils and reduces neutrophil infiltration into the inflamed peritoneum of mice.<ref name="pmid25036362"/> Its potencies ins producing these responses are similar to those of MaR1. |
| − | 13(''S''),14(''S'')-epoxy-maresin inhibits the production of the [[arachidonic acid]] metabolite, [[Leukotriene B4]] (LTB<sub>4</sub>), by directly inactivating the enzyme, [[Leukotriene-A4 hydrolase]], which converts the LTB<sub>4</sub> precursor, [[Leukotriene A4]], to LTB<sub>4</sub>; this effect may contribute to the resolution of inflammatory responses by reducing the production of the proinflammatory mediator, LTB<sub>4</sub>.<ref |
+ | 13(''S''),14(''S'')-epoxy-maresin inhibits the production of the [[arachidonic acid]] metabolite, [[Leukotriene B4]] (LTB<sub>4</sub>), by directly inactivating the enzyme, [[Leukotriene-A4 hydrolase]], which converts the LTB<sub>4</sub> precursor, [[Leukotriene A4]], to LTB<sub>4</sub>; this effect may contribute to the resolution of inflammatory responses by reducing the production of the proinflammatory mediator, LTB<sub>4</sub>.<ref name="pmid25139562"/> |
== Clinical relevancy == |
== Clinical relevancy == |
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| − | Studies find that the maresins inhibit certain pro-inflammatory functions in human neutrophils and macrophages in vitro, that MaR1 and Mar2 reduce the entry of blood neutrophils into the inflamed peritoneum in a mouse model, and that Mar1 promotes the resolution of allergic pulmonary inflammation in a mouse model as well as wound healing in planaria worm model. These studies have not yet translated to human physiology or pathology. It is noted that MaR1 is detectable in the synovial fluid of patients with rheumatoid arthritis.<ref |
+ | Studies find that the maresins inhibit certain pro-inflammatory functions in human neutrophils and macrophages in vitro, that MaR1 and Mar2 reduce the entry of blood neutrophils into the inflamed peritoneum in a mouse model, and that Mar1 promotes the resolution of allergic pulmonary inflammation in a mouse model as well as wound healing in planaria worm model. These studies have not yet translated to human physiology or pathology. It is noted that MaR1 is detectable in the synovial fluid of patients with rheumatoid arthritis.<ref name="pmid23747022"/> It is also noted that macrophages derived by culturing the monocytes isolated from the blood of patients with [[Localized aggressive periodontitis]] have reduced levels of 12-lipoxygenase and MaR1 as well as reduced phagocytosis and killing of the periodontal pathogenic bacteria, [[Porphyromonas gingivalis]] and [[Aggregatibacter actinomycetemcomitans]]; the latter functional defects were improved by treating the cells with MaR1.<ref name="pmid26667839"/> |
Further studies are needed to determine if maresins play a functional role in resolving inflammation, promoting wound healing, or limiting neuropathic pain and/or if maresins or their metabolism-resisent analogs are clinically useful in treating the latter conditions. |
Further studies are needed to determine if maresins play a functional role in resolving inflammation, promoting wound healing, or limiting neuropathic pain and/or if maresins or their metabolism-resisent analogs are clinically useful in treating the latter conditions. |
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